Burn Enhances Toll-Like Receptor Induced Responses by Circulating Leukocytes

DTIC Science & Technology

2012-04-30

Introduction Major burn is associated with a local and sys- temic activation of the innate immune system resulting in a profound inflammatory...plications. Previous studies have shown that responses after burn differ between fixed-tissue immune cells and circulating immune cells [15]. In the current...Abstract: Burn and toll-like receptors (TLR) are associated with innate immune system activation, but the impact of burn on TLR-induced inflammation

Relationship between High Red Cell Distribution Width and Systemic Inflammatory Response Syndrome after Extracorporeal Circulation.

PubMed

Seth, Harsh Sateesh; Mishra, Prashant; Khandekar, Jayant V; Raut, Chaitanya; Mohapatra, Chandan Kumar Ray; Ammannaya, Ganesh Kumar K; Saini, Jaskaran Singh; Shah, Vaibhav

2017-01-01

Cardiac surgical operations involving extracorporeal circulation may develop severe inflammatory response. This severe inflammatory response syndrome (SIRS) is usually associated with poor outcome with no predictive marker. Red cell distribution width (RDW) is a routine hematological marker with a role in inflammation. We aim to determine the relationship between RDW and SIRS through our study. A total of 1250 patients who underwent cardiac surgery with extracorporeal circulation were retrospectively analyzed out of which 26 fell into the SIRS criteria and 26 consecutive control patients were taken. RDW, preoperative clinical data, operative time and postoperative data were compared between SIRS and control groups. The demographic profile of the patients was similar. RDW was significantly higher in the SIRS versus control group (15.5±2.0 vs. 13.03±1.90), respectively with P value <0.0001. There was significant mortality in the SIRS group, 20 (76.92%) as compared to 2 (7.6%) in control group with a P value of <0.005. Multiple logistic regression analysis revealed that there was significant association with high RDW and development of SIRS after extracorporeal circulation (OR for RDW levels exceeding 13.5%; 95% CI 1.0-1.2; P<0.05). Increased RDW was significantly associated with increased risk of SIRS after extracorporeal circulation. Thus, RDW can act as a useful tool to predict SIRS in patients undergoing cardiac surgery with extracorporeal circulation. Hence, more aggressive measures can be taken in patients with high RDW to prevent postoperative morbidity and mortality.

Description of human AAA by cytokine and immune cell aberrations compared to risk-factor matched controls.

PubMed

Wang, S Keisin; Green, Linden A; Gutwein, Ashley R; Drucker, Natalie A; Motaganahalli, Raghu L; Gupta, Alok K; Fajardo, Andres; Murphy, Michael P

2018-04-28

The pathogenesis driving the formation of abdominal aortic aneurysms continues to be poorly understood. Therefore, we systemically define the cytokine and circulating immune cell environment observed in human abdominal aortic aneurysm compared with risk-factor matched controls. From 2015 to 2017, a total of 274 patients donated blood to the Indiana University Center for Aortic Disease. Absolute concentrations of circulating cytokines were determined, using enzyme-linked immunosorbent assays while the expression of circulating immune cell phenotypes were assayed via flow cytometric analysis. Human abdominal aortic aneurysm is characterized by a significant depletion of the antigen-specific, CD4 + Tr1 regulatory lymphocyte that corresponds to an upregulation of the antigen-specific, inflammatory Th17 cell. We found no differences in the incidence of Treg, B10, and myeloid-derived suppressor regulatory cells. Similarly, no disparities were noted in the following inflammatory cytokines: IL-1β, C-reactive protein, tumor necrosis factor α, interferon γ, and IL-23. However, significant upregulation of the inflammatory cytokines osteopontin, IL-6, and IL-17 were noted. Additionally, no changes were observed in the regulatory cytokines IL-2, IL-4, IL-13, TNF-stimulated gene 6 protein, and prostaglandin E2, but we did observe a significant decrease in the essential regulatory cytokine IL-10. In this investigation, we systematically characterize the abdominal aortic aneurysm-immune environment and present preliminary evidence that faulty immune regulation may also contribute to aneurysm formation and growth. Copyright © 2018 Elsevier Inc. All rights reserved.

Cell-free fetal DNA and spontaneous preterm birth

PubMed Central

Davidson, Donald J; Norman, Jane E

2018-01-01

Inflammation is known to play a key role in preterm and term parturition. Cell-free fetal DNA (cff-DNA) is present in the maternal circulation and increases with gestational age and some pregnancy complications (e.g. preterm birth, preeclampsia). Microbial DNA and adult cell-free DNA can be pro-inflammatory through DNA-sensing mechanisms such as Toll-like receptor 9 and the Stimulator of Interferon Genes (STING) pathway. However, the pro-inflammatory properties of cff-DNA, and the possible effects of this on pregnancy and parturition are unknown. Clinical studies have quantified cff-DNA levels in the maternal circulation in women who deliver preterm and women who deliver at term and show an association between preterm labor and higher cff-DNA levels in the 2nd, 3rd trimester and at onset of preterm birth symptoms. Together with potential pro-inflammatory properties of cff-DNA, this rise suggests a potential mechanistic role in the pathogenesis of spontaneous preterm birth. In this review, we discuss the evidence linking cff-DNA to adverse pregnancy outcomes, including preterm birth, obtained from preclinical and clinical studies. PMID:29269517

Inflammatory response and extracorporeal circulation.

PubMed

Kraft, Florian; Schmidt, Christoph; Van Aken, Hugo; Zarbock, Alexander

2015-06-01

Patients undergoing cardiac surgery with extracorporeal circulation (EC) frequently develop a systemic inflammatory response syndrome. Surgical trauma, ischaemia-reperfusion injury, endotoxaemia and blood contact to nonendothelial circuit compounds promote the activation of coagulation pathways, complement factors and a cellular immune response. This review discusses the multiple pathways leading to endothelial cell activation, neutrophil recruitment and production of reactive oxygen species and nitric oxide. All these factors may induce cellular damage and subsequent organ injury. Multiple organ dysfunction after cardiac surgery with EC is associated with an increased morbidity and mortality. In addition to the pathogenesis of organ dysfunction after EC, this review deals with different therapeutic interventions aiming to alleviate the inflammatory response and consequently multiple organ dysfunction after cardiac surgery. Copyright © 2015 Elsevier Ltd. All rights reserved.

Interleukin 35 (IL-35) and IL-37: Intestinal and peripheral expression by T and B regulatory cells in patients with Inflammatory Bowel Disease.

PubMed

Fonseca-Camarillo, Gabriela; Furuzawa-Carballeda, Janette; Yamamoto-Furusho, Jesús K

2015-10-01

The aim of the study was to characterize and to quantify peripheral and tissue. IL-35- and IL-37-producing cells in Inflammatory Bowel Disease (IBD) patients. We studied a total of 38 active UC, 31 inactive UC, 17 active CD, and 13 inactive CD and 50 non-inflamed tissues as control group. Gene expression was measured by real time polymerase chain reaction (RT-PCR) and protein expression was evaluated in tissue by immunohistochemistry and in peripheral blood mononuclear cells by flow cytometry. Higher levels of IL-35 was produced by intestinal regulatory B cells and circulating regulatory CD4(+) and CD8(+) T cells in active vs. inactive disease or healthy donors (P<0.05). The IL-37 was conspicuously synthesized by circulating B cells, active natural killer cells and monocytes. These results suggest that down-regulation of inflammation in active IBD patients might be based on the increased expression of IL-35 and IL-37. Copyright © 2015 Elsevier Ltd. All rights reserved.

Effect of strenuous physical exercise on circulating cell-derived microparticles.

PubMed

Chaar, Vicky; Romana, Marc; Tripette, Julien; Broquere, Cédric; Huisse, Marie-Geneviève; Hue, Olivier; Hardy-Dessources, Marie-Dominique; Connes, Philippe

2011-01-01

Strenuous exercise is associated with an inflammatory response involving the activation of several types of blood cells. In order to document the specific activation of these cell types, we studied the effect of three maximal exercise tests conducted to exhaustion on the quantitative and qualitative pattern of circulating cell-derived microparticles and inflammatory molecules in healthy subjects. This study mainly indicated that the plasma concentration of microparticles from platelets and polymorphonuclear neutrophils (PMN) was increased immediately after the strenuous exercise. In addition, the increase in plasma concentration of microparticles from PMN and platelets was still observed after 2 hours of recovery. A similar pattern was observed for the IL-6 plasma level. In contrast, no change was observed for either soluble selectins or plasma concentration of microparticles from red blood cells, monocytes and endothelial cells. In agreement, sVCAM-1 and sICAM-1 levels were not changed by the exercise. We conclude that a strenuous exercise is accompanied by platelet- and PMN-derived microparticle production that probably reflects the activation of these two cell types.

New evidence for the therapeutic potential of curcumin to treat nonalcoholic fatty liver disease in humans.

PubMed

Inzaugarat, María Eugenia; De Matteo, Elena; Baz, Placida; Lucero, Diego; García, Cecilia Claudia; Gonzalez Ballerga, Esteban; Daruich, Jorge; Sorda, Juan Antonio; Wald, Miriam Ruth; Cherñavsky, Alejandra Claudia

2017-01-01

The immune system acts on different metabolic tissues that are implicated in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Leptin and linoleic acid have the ability to potentially affect immune cells, whereas curcumin is a known natural polyphenol with antioxidant and anti-inflammatory properties. This study was designed to evaluate the pro-inflammatory and pro-oxidant effects of leptin and linoleic acid on immune cells from patients with NAFLD and to corroborate the modulatory effects of curcumin and its preventive properties against the progression of NAFLD using a high-fat diet (HFD)-induced NAFLD/nonalcoholic steatohepatitis mouse model. The ex vivo experiments showed that linoleic acid increased the production of reactive oxygen species in monocytes and liver macrophages, whereas leptin enhanced tumor necrosis factor-α (TNF-α) production in monocytes and interferon-γ production in circulating CD4+ cells. Conversely, oral administration of curcumin prevented HFD-induced liver injury, metabolic alterations, intrahepatic CD4+ cell accumulation and the linoleic acid- and leptin- induced pro-inflammatory and pro-oxidant effects on mouse liver macrophages. Our findings provide new evidence for the therapeutic potential of curcumin to treat human NAFLD. However, the development of a preventive treatment targeting human circulating monocytes and liver macrophages as well as peripheral and hepatic CD4+ cells requires additional research.

Stressed lungs: unveiling the role of circulating stress ...

EPA Pesticide Factsheets

Ozone, a major component of smog generated through the interaction of light and anthropogenic emissions, induces adverse pulmonary, cardiovascular, and systemic health effects upon inhalation. It is generally accepted that ozone-induced lung injury is mediated by its interaction with lung lining components causing local oxidative changes, which then leads to cell damage and recruitment of inflammatory cells. It is postulated that the spillover of reactive intermediates and pro-inflammatory molecules from lung to systemic circulation mediates extra-pulmonary effects. However, recent work from our laboratory supports an alternative hypothesis that circulating stress hormones, such as epinephrine and corticosterone/cortisol, are involved in mediating ozone pulmonary effects. We have shown in rats and humans that ozone increases the levels of circulating stress hormones through activation of the hypothalamus- pituitary-adrenal (HPA) axis before any measurable effects are observed in the lung. The surgical removal of adrenals diminishes circulating stress hormones and at the same time, the pulmonary effects of ozone suggesting a significant contribution of these hormones in ozone-induced lung injury and inflammation. While ozone effects in the lung have been extensively studied, the contribution of central nervous system -mediated hormonal stress response has not been examined. In order to understand the signaling pathways that might be involved in ozone-induced lun

VLA-4 antagonists: potent inhibitors of lymphocyte migration.

PubMed

Yang, Ginger X; Hagmann, William K

2003-05-01

Circulating lymphocytes normally migrate through extravascular spaces in relatively low numbers as important members of the immunosurveillance process. That is until signals are received by endothelial cells that there is an underlying infection or inflammatory condition. These vascular surface cells in turn overexpress and present ligands to circulating lymphocyte adhesion molecules. Upon encountering this higher density of ligands, lymphocytes, which had been leisurely rolling along the vascular surface, now become more firmly attached, change shape, and migrate through tight junctions to the sites of infection or inflammation. If the initiating events are not resolved and the condition becomes chronic, there can be a sustained extravasation of lymphocytes that can exacerbate the inflammatory condition, which in turn will continue to recruit more inflammatory cells resulting in unwanted tissue destruction. It is for the attenuation of this cycle of sustained inflammatory cell recruitment that very late activating antigen-4 (VLA-4) antagonists are being developed. Most lymphocytes, except neutrophils, express VLA-4 on their surface and they interact with endothelial vascular cell adhesion molecule-1 (VCAM-1). It is this interaction that VLA-4 antagonists are intended to disrupt, thus, putting an end to the cycle of chronic inflammation, which is the hallmark of many diseases. This review will provide an update of VLA-4 antagonists that have appeared since early 2001 and will discuss some of the issues, both positive and negative, that may be encountered in their development. Copyright 2003 Wiley Periodicals, Inc.

Genetic diminution of circulating prothrombin ameliorates multiorgan pathologies in sickle cell disease mice.

PubMed

Arumugam, Paritha I; Mullins, Eric S; Shanmukhappa, Shiva Kumar; Monia, Brett P; Loberg, Anastacia; Shaw, Maureen A; Rizvi, Tilat; Wansapura, Janaka; Degen, Jay L; Malik, Punam

2015-10-08

Sickle cell disease (SCD) results in vascular occlusions, chronic hemolytic anemia, and cumulative organ damage. A conspicuous feature of SCD is chronic inflammation and coagulation system activation. Thrombin (factor IIa [FIIa]) is both a central protease in hemostasis and a key modifier of inflammatory processes. To explore the hypothesis that reduced prothrombin (factor II [FII]) levels in SCD will limit vaso-occlusion, vasculopathy, and inflammation, we used 2 strategies to suppress FII in SCD mice. Weekly administration of FII antisense oligonucleotide "gapmer" to Berkeley SCD mice to selectively reduce circulating FII levels to ∼10% of normal for 15 weeks significantly diminished early mortality. More comprehensive, long-term comparative studies were done using mice with genetic diminution of circulating FII. Here, cohorts of FII(lox/-) mice (constitutively carrying ∼10% normal FII) and FII(WT) mice were tracked in parallel for a year following the imposition of SCD via hematopoietic stem cell transplantation. This genetically imposed suppression of FII levels resulted in an impressive reduction in inflammation (reduction in leukocytosis, thrombocytosis, and circulating interleukin-6 levels), reduced endothelial cell dysfunction (reduced endothelial activation and circulating soluble vascular cell adhesion molecule), and a significant improvement in SCD-associated end-organ damage (nephropathy, pulmonary hypertension, pulmonary inflammation, liver function, inflammatory infiltration, and microinfarctions). Notably, all of these benefits were achieved with a relatively modest 1.25-fold increase in prothrombin times, and in the absence of hemorrhagic complications. Taken together, these data establish that prothrombin is a powerful modifier of SCD-induced end-organ damage, and present a novel therapeutic target to ameliorate SCD pathologies. © 2015 by The American Society of Hematology.

Sickle Cell Vaso-occlusive Crisis Induces the Release of Circulating Serum Heat Shock Protein-70

PubMed Central

Adewoye, Adeboye H.; Klings, Elizabeth S.; Farber, Harrison W.; Palaima, Elizabeth; Bausero, Maria A.; McMahon, Lillian; Odhiambo, Adam; Surinder, Safaya; Yoder, Mark; Steinberg, Martin H.; Asea, Alexzander

2006-01-01

Inflammation may play an important role in the pathophysiology of sickle cell disease (SCD), and recent studies have identified the 70-kDa heat shock protein (Hsp70) as an important mediator of inflammatory responses. Here we demonstrate a significant increase in circulating serum Hsp70 level in SCD during vaso-occlusive crisis (VOC) as compared with baseline steady-state levels (P < 0.05) and a significant increase in Hsp70 levels in SCD at baseline compared with normal controls (P < 0.05). Taken together, these results indicate that circulating serum Hsp70 might be a marker for VOC in SCD. PMID:15726596

Sickle cell vaso-occlusive crisis induces the release of circulating serum heat shock protein-70.

PubMed

Adewoye, Adeboye H; Klings, Elizabeth S; Farber, Harrison W; Palaima, Elizabeth; Bausero, Maria A; McMahon, Lillian; Odhiambo, Adam; Surinder, Safaya; Yoder, Mark; Steinberg, Martin H; Asea, Alexzander

2005-03-01

Inflammation may play an important role in the pathophysiology of sickle cell disease (SCD), and recent studies have identified the 70-kDa heat shock protein (Hsp70) as an important mediator of inflammatory responses. Here we demonstrate a significant increase in circulating serum Hsp70 level in SCD during vaso-occlusive crisis (VOC) as compared with baseline steady-state levels (P <0.05) and a significant increase in Hsp70 levels in SCD at baseline compared with normal controls (P <0.05). Taken together, these results indicate that circulating serum Hsp70 might be a marker for VOC in SCD.

Inflammatory Mediators Drive Adverse Right Ventricular Remodeling and Dysfunction and Serve as Potential Biomarkers.

PubMed

Sydykov, Akylbek; Mamazhakypov, Argen; Petrovic, Aleksandar; Kosanovic, Djuro; Sarybaev, Akpay S; Weissmann, Norbert; Ghofrani, Hossein A; Schermuly, Ralph T

2018-01-01

Adverse right ventricular (RV) remodeling leads to ventricular dysfunction and failure that represents an important determinant of outcome in patients with pulmonary hypertension (PH). Recent evidence indicates that inflammatory activation contributes to the pathogenesis of adverse RV remodeling and dysfunction. It has been shown that accumulation of inflammatory cells such as macrophages and mast cells in the right ventricle is associated with maladaptive RV remodeling. In addition, inhibition of inflammation in animal models of RV failure ameliorated RV structural and functional impairment. Furthermore, a number of circulating inflammatory mediators have been demonstrated to be associated with RV performance. This work reviews the role of inflammation in RV remodeling and dysfunction and discusses anti-inflammatory strategies that may attenuate adverse structural alterations while promoting improvement of RV function.

Inflammatory Mediators Drive Adverse Right Ventricular Remodeling and Dysfunction and Serve as Potential Biomarkers

PubMed Central

Sydykov, Akylbek; Mamazhakypov, Argen; Petrovic, Aleksandar; Kosanovic, Djuro; Sarybaev, Akpay S.; Weissmann, Norbert; Ghofrani, Hossein A.; Schermuly, Ralph T.

2018-01-01

Adverse right ventricular (RV) remodeling leads to ventricular dysfunction and failure that represents an important determinant of outcome in patients with pulmonary hypertension (PH). Recent evidence indicates that inflammatory activation contributes to the pathogenesis of adverse RV remodeling and dysfunction. It has been shown that accumulation of inflammatory cells such as macrophages and mast cells in the right ventricle is associated with maladaptive RV remodeling. In addition, inhibition of inflammation in animal models of RV failure ameliorated RV structural and functional impairment. Furthermore, a number of circulating inflammatory mediators have been demonstrated to be associated with RV performance. This work reviews the role of inflammation in RV remodeling and dysfunction and discusses anti-inflammatory strategies that may attenuate adverse structural alterations while promoting improvement of RV function. PMID:29875701

Circulating CD4+CXCR5+ T cells contribute to proinflammatory responses in multiple ways in coronary artery disease.

PubMed

Ding, Ru; Gao, Wenwu; He, Zhiqing; Wu, Feng; Chu, Yang; Wu, Jie; Ma, Lan; Liang, Chun

2017-11-01

Coronary artery disease (CAD) is a common subtype of cardiovascular disease. The major contributing event is atherosclerosis, which is a progressive inflammatory condition resulting in the thickening of the arterial wall and the formation of atheromatous plaques. Recent evidence suggests that circulating CD4 + CXCR5 + T cells can contribute to inflammatory reactions. In this study, the frequency, phenotype, and function of circulating CD4 + CXCR5 + T cells in CAD patients were examined. Data showed that circulating CD4 + CXCR5 + T cells in CAD patients were enriched with a PD-1 + CCR7 - subset, which was previously identified as the most potent in B cell help. The CD4 + CXCR5 + T cells in CAD patients also secreted significantly higher levels of IFN-γ, IL-17A, and IL-21 than those from healthy controls. Depleting the PD-1 + population significantly reduced the cytokine secretion. Interestingly, the CD4 + CXCR5 + PD-1 - T cells significantly upregulated PD-1 following anti-CD3/CD28 or SEB stimulation. CD4 + CXCR5 + T cells from CAD patients also demonstrated more potent capacity to stimulate B cell inflammation than those from healthy individuals. The phosphorylation of STAT1 and STAT3 were significantly higher in B cells incubated with CD4 + CXCR5 + T cells from CAD than controls. The IL-6 and IFN-γ expression were also significantly higher in B cells incubated with CD4 + CXCR5 + T cells from CAD. Together, this study demonstrated that CAD patients presented a highly activated CD4 + CXCR5 + T cell subset that could contribute to proinflammatory responses in multiple ways. The possibility of using CD4 + CXCR5 + T cells as a therapeutic target should therefore be examined in CAD patients. Copyright © 2017 Elsevier B.V. All rights reserved.

Anti-oxidative and anti-inflammatory vasoprotective effects of caloric restriction in aging: role of circulating factors and SIRT1

PubMed Central

Csiszar, Anna; Labinskyy, Nazar; Jimenez, Rosario; Pinto, John T.; Ballabh, Praveen; Losonczy, Gyorgy; Pearson, Kevin J.; de Cabo, Rafael; Ungvari, Zoltan

2009-01-01

Endothelial-dysfunction, oxidative stress and inflammation are associated with vascular aging and promote the development of cardiovascular-disease. Caloric restriction (CR) mitigates conditions associated with aging, but its effects on vascular dysfunction during aging remain poorly defined. To determine whether CR exerts vasoprotective effects in aging, aortas of ad libitum (AL) fed young and aged and CR-aged F344 rats were compared. Aging in AL-rats was associated with impaired acetylcholine-induced relaxation, vascular oxidative stress and increased NF-κB-activity. Lifelong CR significantly improved endothelial function, attenuated vascular ROS production, inhibited NF-κB activity and down-regulated inflammatory genes. To elucidate the role of circulating factors in mediation of the vasoprotective effects of CR, we determined whether sera obtained from CR-animals can confer anti-oxidant and anti-inflammatory effects in cultured coronary-arterial endothelial cells (CAECs), mimicking the effects of CR. In CAECs cultured in the presence of AL-serum TNFα elicited oxidative-stress, NF-κB-activation and inflammatory gene expression. By contrast, treatment of CAECs with CR-serum attenuated TNFα-induced ROS generation and prevented NF-κB-activation and induction of inflammatory genes. siRNA-knockdown of SIRT1 mitigated the anti-oxidant and anti-inflammatory effects of CR-serum. CR exerts anti-oxidant and anti-inflammatory vascular effects, which are likely mediated by circulating factors, in part, via a SIRT1-dependent pathway. PMID:19549533

Circulating innate lymphoid cells are unchanged in response to DAC HYP therapy.

PubMed

Gillard, Geoffrey O; Saenz, Steven A; Huss, David J; Fontenot, Jason D

2016-05-15

Innate lymphoid cells (ILCs) play an important role in immunity, inflammation, and tissue remodeling and their dysregulation is implicated in autoimmune and inflammatory disorders. We analyzed the impact of daclizumab, a humanized monoclonal anti-CD25 antibody, on circulating natural killer (NK) cells and ILCs in a cohort of multiple sclerosis patients. An increase in CD56(bright) NK cells and CD56(hi)CD16(intermediate) transitional NK cells was observed. No significant change in total ILCs or major ILC subpopulations was observed. These results refine our understanding of the impact of daclizumab on innate lymphoid cell populations. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Mesenchymal-Epithelial Transition and Circulating Tumor Cells in Small Cell Lung Cancer.

PubMed

Hamilton, Gerhard; Rath, Barbara

2017-01-01

Cancer patients die of metastatic disease but knowledge regarding individual steps of this complex process of intravasation, spread and extravasation leading to secondary lesions is incomplete. Subpopulations of tumor cells are supposed to undergo an epithelial-mesenchymal transition (EMT), to enter the bloodstream and eventually establish metastases in a reverse process termed mesenchymal-epithelial transition (MET). Small cell lung cancer (SCLC) represents a unique model to study metastatic spread due to early dissemination and relapse, as well as availability of a panel of circulating cancer cell (CTC) lines recently. Additionally, chemosensitive SCLC tumor cells switch to a completely resistant phenotype during cancer recurrence. In advanced disease, SCLC patients display extremely high blood counts of CTCs in contrast to other tumors, like breast, prostate and colon cancer. Local inflammatory conditions at the primary tumor site and recruitment of macrophages seem to increase the shedding of tumor cells into the circulation in processes which may proceed independently of EMT. Since millions of cells are released by tumors into the circulation per day, analysis of a limited number of CTCs at specific time points are difficult to be related to the development of metastatic lesions which may occur approximately one year later. We have obtained a panel of SCLC CTC cell line from patients with relapsing disease, which share characteristic markers of this malignancy and a primarily epithelial phenotype with unique formation of large tumorospheres, containing quiescent and hypoxic cells. Although smoking and inflammation promote EMT, partial expression of vimentin indicates a transitional state with partial EMT in these cell lines at most. The CTC lines exhibit high expression of EpCAM , absent phosphorylation of β-catenin and background levels of Snail. Provided that these tumor cells had ever undergone EMT, here in advanced disease MET seem to have occurred already in the peripheral circulation. Alternative explanations for the expression of mesenchymal markers of the CTC lines are the heterogeneity of SCLC cells, cooperative migration or altered gene expression in response to the inflammatory tumor microenvironment allowing for tumor spread without EMT/MET.

Peptidoglycan from the gut microbiota governs the lifespan of circulating phagocytes at homeostasis.

PubMed

Hergott, Christopher B; Roche, Aoife M; Tamashiro, Edwin; Clarke, Thomas B; Bailey, Aubrey G; Laughlin, Alice; Bushman, Frederic D; Weiser, Jeffrey N

2016-05-19

Maintenance of myeloid cell homeostasis requires continuous turnover of phagocytes from the bloodstream, yet whether environmental signals influence phagocyte longevity in the absence of inflammation remains unknown. Here, we show that the gut microbiota regulates the steady-state cellular lifespan of neutrophils and inflammatory monocytes, the 2 most abundant circulating myeloid cells and key contributors to inflammatory responses. Treatment of mice with broad-spectrum antibiotics, or with the gut-restricted aminoglycoside neomycin alone, accelerated phagocyte turnover and increased the rates of their spontaneous apoptosis. Metagenomic analyses revealed that neomycin altered the abundance of intestinal bacteria bearing γ-d-glutamyl-meso-diaminopimelic acid, a ligand for the intracellular peptidoglycan sensor Nod1. Accordingly, signaling through Nod1 was both necessary and sufficient to mediate the stimulatory influence of the flora on myeloid cell longevity. Stimulation of Nod1 signaling increased the frequency of lymphocytes in the murine intestine producing the proinflammatory cytokine interleukin 17A (IL-17A), and liberation of IL-17A was required for transmission of Nod1-dependent signals to circulating phagocytes. Together, these results define a mechanism through which intestinal microbes govern a central component of myeloid homeostasis and suggest perturbations of commensal communities can influence steady-state regulation of cell fate. © 2016 by The American Society of Hematology.

Peptidoglycan from the gut microbiota governs the lifespan of circulating phagocytes at homeostasis

PubMed Central

Hergott, Christopher B.; Roche, Aoife M.; Tamashiro, Edwin; Clarke, Thomas B.; Bailey, Aubrey G.; Laughlin, Alice; Bushman, Frederic D.

2016-01-01

Maintenance of myeloid cell homeostasis requires continuous turnover of phagocytes from the bloodstream, yet whether environmental signals influence phagocyte longevity in the absence of inflammation remains unknown. Here, we show that the gut microbiota regulates the steady-state cellular lifespan of neutrophils and inflammatory monocytes, the 2 most abundant circulating myeloid cells and key contributors to inflammatory responses. Treatment of mice with broad-spectrum antibiotics, or with the gut-restricted aminoglycoside neomycin alone, accelerated phagocyte turnover and increased the rates of their spontaneous apoptosis. Metagenomic analyses revealed that neomycin altered the abundance of intestinal bacteria bearing γ-d-glutamyl-meso-diaminopimelic acid, a ligand for the intracellular peptidoglycan sensor Nod1. Accordingly, signaling through Nod1 was both necessary and sufficient to mediate the stimulatory influence of the flora on myeloid cell longevity. Stimulation of Nod1 signaling increased the frequency of lymphocytes in the murine intestine producing the proinflammatory cytokine interleukin 17A (IL-17A), and liberation of IL-17A was required for transmission of Nod1-dependent signals to circulating phagocytes. Together, these results define a mechanism through which intestinal microbes govern a central component of myeloid homeostasis and suggest perturbations of commensal communities can influence steady-state regulation of cell fate. PMID:26989200

Investigating the Relationships Between Alcohol Consumption, Cannabis Use, and Circulating Cytokines: A Preliminary Analysis.

PubMed

Karoly, Hollis C; Bidwell, L Cinnamon; Mueller, Raeghan L; Hutchison, Kent E

2018-03-01

In recent years, human and animal studies have converged to support altered inflammatory signaling as a molecular mechanism underlying the pathophysiology of alcohol use disorders (AUDs). Alcohol binds to receptors on immune cells, triggering signaling pathways that produce pro-inflammatory cytokines. Chronic inflammation is associated with tissue damage, which may contribute to negative effects of AUD. Conversely, cannabis is associated with decreased inflammatory signaling, and animal studies suggest that cannabinoids may impact alcohol-induced inflammation. Thus, the impact of cannabis on inflammation in AUDs in humans warrants examination. We explored the relationship between self-reported alcohol and cannabis use and circulating levels of the pro-inflammatory cytokines interleukin 6 (IL-6), IL-8, and IL-1β in the blood. Among 66 regular drinkers (mean age = 30.08), we examined circulating cytokines and administered questionnaires assessing alcohol consumption and days of cannabis use over the past 90 days. We examined whether alcohol consumption, cannabis use, and gender were associated with changes in circulating cytokines, and whether there was a significant interaction between alcohol and cannabis use predicting blood levels of circulating cytokines. A positive association between alcohol and IL-6 emerged. We also observed a negative association between cannabis and IL-1β. Follow-up moderation analyses indicated a cannabis by alcohol interaction predicting circulating IL-6, such that cannabis nonusers showed a stronger relationship between alcohol and IL-6 compared to cannabis users. These preliminary findings suggest that cannabinoid compounds may serve to mitigate inflammation associated with alcohol use. In addition, the present results provide data to inform future investigations, with the goal of ultimately leveraging knowledge of the role of inflammation in AUDs to develop more effective treatments focused on novel immune targets. Copyright © 2017 by the Research Society on Alcoholism.

Nutritional effects on T-cell immunometabolism

PubMed Central

Cohen, Sivan; Danzaki, Keiko; MacIver, Nancie J.

2017-01-01

T cells are highly influenced by nutrient uptake from their environment, and changes in overall nutritional status, such as malnutrition or obesity, can result in altered T-cell metabolism and behavior. In states of severe malnutrition or starvation, T-cell survival, proliferation, and inflammatory cytokine production are all decreased, as is T-cell glucose uptake and metabolism. The altered T-cell function and metabolism seen in malnutrition is associated with altered adipokine levels, most particularly decreased leptin. Circulating leptin levels are low in malnutrition, and leptin has been shown to be a key link between nutrition and immunity. The current view is that leptin signaling is required to upregulate activated T-cell glucose metabolism and thereby fuel T-cell activation. In the setting of obesity, T cells have been found to have a key role in promoting the recruitment of inflammatory macrophages to adipose depots along with the production of inflammatory cytokines that promote the development of insulin resistance leading to diabetes. Deletion of T cells, key T-cell transcription factors, or pro-inflammatory T-cell cytokines prevents insulin resistance in obesity and underscores the importance of T cells in obesity-associated inflammation and metabolic disease. Altogether, T cells have a critical role in nutritional immunometabolism. PMID:28054344

Stearidonic and eicosapentaenoic acids inhibit interleukin-6 expression in ob/ob mouse adipose stem cells via toll-like receptor-2-mediated pathways

USDA-ARS?s Scientific Manuscript database

Increases in adipose tissue weight positively correlates with increased circulating inflammatory cytokines such as interleukin-6 (IL-6). We previously have shown that adipose stem cell produce significantly higher levels of IL-6 when compared to other cell types in the adipose tissue in genetically ...

Radiation therapy induces circulating serum Hsp72 in patients with prostate cancer.

PubMed

Hurwitz, Mark D; Kaur, Punit; Nagaraja, Ganachari M; Bausero, Maria A; Manola, Judith; Asea, Alexzander

2010-06-01

Hsp72 found in the extracellular milieu has been shown to play an important role in immune regulation. The impact of common cancer therapies on extracellular release of Hsp72 however, has been to date undefined. Serum from 13 patients undergoing radiation therapy (XRT) for prostate cancer with or without hormonal therapy (ADT) was measured for levels of circulating serum Hsp72 and pro-inflammatory cytokines (IL-6 and TNF-alpha) using the classical sandwich ELISA technique and the relative expression of CD8(+) T lymphocytes and natural killer (NK) cells was measured using flow cytometry. Mouse orthotopic xenograft of human prostate cancer tumors (DU-145 and PC-3) were used to validate and further characterize the response noted in the clinical setting. The biological significance of tumor released Hsp72 was studied in human dendritic cells (DC) in vitro. Circulating serum Hsp72 levels increased an average of 3.5-fold (median per patient 4.8-fold) with XRT but not with ADT (p=0.0002). Increases in IL-6 (3.3-fold), TNF-alpha (1.8-fold), CD8(+) CTL (2.1-fold) and NK cells (3.2-fold) also occurred. Using PC-3 and DU-145 human prostate cancer xenograft models in mice, we confirmed that XRT induces Hsp72 release primarily from implanted tumors. In vitro studies using supernatant recovered from irradiated human prostate cancer cells point to exosomes containing Hsp72 as a possible stimulator of pro-inflammatory cytokine production and costimulatory molecules expression in human DC. The current study confirms for the first time in an actual clinical setting elevation of circulating serum Hsp72 with XRT. The accompanying studies in mice and in vitro identify the released exosomes containing Hsp72 as playing a pivotal role in stimulating pro-inflammatory immune responses. These findings, if validated, may lead to new treatment paradigms for common human malignancies. Copyright 2010 Elsevier Ireland Ltd. All rights reserved.

Radiation therapy induces circulating serum Hsp72 in patients with prostate cancer

PubMed Central

Hurwitz, Mark D.; Kaur, Punit; Nagaraja, Ganachari M.; Bausero, Maria A.; Manola, Judith; Asea, Alexzander

2010-01-01

Background and purpose Hsp72 found in the extracellular milieu has been shown to play an important role in immune regulation. The impact of common cancer therapies on extracellular release of Hsp72 however, has been to date undefined. Materials and methods Serum from 13 patients undergoing radiation therapy (XRT) for prostate cancer with or without hormonal therapy (ADT) was measured for levels of circulating serum Hsp72 and pro-inflammatory cytokines (IL-6 and TNF-α) using the classical sandwich ELISA technique and the relative expression of CD8+ T lymphocytes and natural killer (NK) cells was measured using flow cytometry. Mouse orthotopic xenograft of human prostate cancer tumors (DU145 and PC3) were used to validate and further characterize the response noted in the clinical setting. The biological significance of tumor released Hsp72 was studied in human dendritic cells (DC) in vitro. Results Circulating serum Hsp72 levels increased an average of 3.5-fold (median per patient 4.8-fold) with XRT but not with ADT (p = 0.0002). Increases in IL-6 (3.3-fold), TNF-α (1.8-fold), CD8+ CTL (2.1-fold) and NK cells (3.2-fold) also occurred. Using PC3 and DU145 human prostate cancer xenograft models in mice, we confirmed that XRT induces Hsp72 release primarily from implanted tumors. In vitro studies using supernatant recovered from irradiated human prostate cancer cells point to exosomes containing Hsp72 as a possible stimulator of pro-inflammatory cytokine production and costimulatory molecules expression in human DC. Conclusions The current study confirms for the first time in an actual clinical setting elevation of circulating serum Hsp72 with XRT. The accompanying studies in mice and in vitro identify the released exosomes containing Hsp72 as playing a pivotal role in stimulating pro-inflammatory immune responses. These findings, if validated, may lead to new treatment paradigms for common human malignancies. PMID:20430459

New evidence for the therapeutic potential of curcumin to treat nonalcoholic fatty liver disease in humans

PubMed Central

Inzaugarat, María Eugenia; De Matteo, Elena; Baz, Placida; Lucero, Diego; García, Cecilia Claudia; Gonzalez Ballerga, Esteban; Daruich, Jorge; Sorda, Juan Antonio; Wald, Miriam Ruth

2017-01-01

Introduction The immune system acts on different metabolic tissues that are implicated in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Leptin and linoleic acid have the ability to potentially affect immune cells, whereas curcumin is a known natural polyphenol with antioxidant and anti-inflammatory properties. Aims This study was designed to evaluate the pro-inflammatory and pro-oxidant effects of leptin and linoleic acid on immune cells from patients with NAFLD and to corroborate the modulatory effects of curcumin and its preventive properties against the progression of NAFLD using a high-fat diet (HFD)-induced NAFLD/nonalcoholic steatohepatitis mouse model. Results The ex vivo experiments showed that linoleic acid increased the production of reactive oxygen species in monocytes and liver macrophages, whereas leptin enhanced tumor necrosis factor-α (TNF-α) production in monocytes and interferon-γ production in circulating CD4+ cells. Conversely, oral administration of curcumin prevented HFD-induced liver injury, metabolic alterations, intrahepatic CD4+ cell accumulation and the linoleic acid- and leptin- induced pro-inflammatory and pro-oxidant effects on mouse liver macrophages. Conclusion Our findings provide new evidence for the therapeutic potential of curcumin to treat human NAFLD. However, the development of a preventive treatment targeting human circulating monocytes and liver macrophages as well as peripheral and hepatic CD4+ cells requires additional research. PMID:28257515

In vitro Flow Adhesion Assay for Analyzing Shear-resistant Adhesion of Metastatic Cancer Cells to Endothelial Cells.

PubMed

Kang, Shin-Ae; Bajana, Sandra; Tanaka, Takemi

2016-02-20

Hematogenous metastasis is a primary cause of mortality from metastatic cancer. The shear-resistant adhesion of circulating tumor cells to the vascular endothelial cell surface under blood flow is an essential step in cell extravasation and further tissue invasion. This is similar to a process exploited by leukocytes for adhesion to inflamed blood vessels (leukocyte mimicry). The shear resistant adhesion is mediated by high affinity interactions between endothelial adhesion molecules and their counter receptor ligand expressed on circulating cells. Thus, weak interaction results in a rapid detachment of circulating cells from endothelium. Despite the critical role of vascular adhesion of cancer cells in hematogenous metastasis, our knowledge regarding this process has been limited due to the difficulty of mimicking dynamic flow conditions in vitro . In order to gain better insight into the shear-resistant adhesion of cancer cells to the endothelium, we developed a protocol for measuring the shear resistant adhesion of circulating tumor cells to endothelial cells under physiologic flow conditions by adapting a well established flow adhesion assay for inflammatory cells. This technique is useful to evaluate 1) the shear resistant adhesion competency of cancer cells and 2) the endothelial adhesion molecules necessary to support cancer cell adhesion (Kang et al. , 2015).

High concentration of branched-chain amino acids promotes oxidative stress, inflammation and migration of human peripheral blood mononuclear cells via mTORC1 activation.

PubMed

Zhenyukh, Olha; Civantos, Esther; Ruiz-Ortega, Marta; Sánchez, Maria Soledad; Vázquez, Clotilde; Peiró, Concepción; Egido, Jesús; Mas, Sebastián

2017-03-01

Leucine, isoleucine and valine are essential aminoacids termed branched-chain amino acids (BCAA) due to its aliphatic side-chain. In several pathological and physiological conditions increased BCAA plasma concentrations have been described. Elevated BCAA levels predict insulin resistance development. Moreover, BCAA levels higher than 2mmol/L are neurotoxic by inducing microglial activation in maple syrup urine disease. However, there are no studies about the direct effects of BCAA in circulating cells. We have explored whether BCAA could promote oxidative stress and pro-inflammatory status in peripheral blood mononuclear cells (PBMCs) obtained from healthy donors. In cultured PBMCs, 10mmol/L BCAA increased the production of reactive oxygen species (ROS) via both NADPH oxidase and the mitochondria, and activated Akt-mTOR signalling. By using several inhibitors and activators of these molecular pathways we have described that mTOR activation by BCAA is linked to ROS production and mitochondrial dysfunction. BCAA stimulated the activation of the redox-sensitive transcription factor NF-κB, which resulted in the release of pro-inflammatory molecules, such as interleukin-6, tumor necrosis factor-α, intracellular adhesion molecule-1 or CD40L, and the migration of PBMCs. In conclusion, elevated BCAA blood levels can promote the activation of circulating PBMCs, by a mechanism that involving ROS production and NF-κB pathway activation. These data suggest that high concentrations of BCAA could exert deleterious effects on circulating blood cells and therefore contribute to the pro-inflammatory and oxidative status observed in several pathophysiological conditions. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Role of inflammation in the aging bones.

PubMed

Abdelmagid, Samir M; Barbe, Mary F; Safadi, Fayez F

2015-02-15

Chronic inflammation in aging is characterized by increased inflammatory cytokines, bone loss, decreased adaptation, and defective tissue repair in response to injury. Aging leads to inherent changes in mesenchymal stem cell (MSC) differentiation, resulting in impaired osteoblastogenesis. Also, the pro-inflammatory cytokines increase with aging, leading to enhanced myelopoiesis and osteoclastogenesis. Bone marrow macrophages (BMMs) play pivotal roles in osteoblast differentiation, the maintenance of hematopoietic stem cells (HSCs), and subsequent bone repair. However, during aging, little is known about the role of macrophages in the differentiation and function of MSC and HSC. Aged mammals have higher circulating pro-inflammatory cytokines than young adults, supporting the hypothesis of increased inflammation with aging. This review will aid in the understanding of the potential role(s) of pro-inflammatory (M1) and anti-inflammatory (M2) macrophages in differentiation and function of osteoblasts and osteoclasts in relation to aging. Copyright © 2014 Elsevier Inc. All rights reserved.

Association between circulating ascorbic acid, α-tocopherol, 25-hydroxyvitamin D, and plasma cytokine concentrations in young adults: a cross-sectional study.

PubMed

García-Bailo, Bibiana; Roke, Kaitlin; Mutch, David M; El-Sohemy, Ahmed; Badawi, Alaa

2012-11-16

Inflammation and oxidative stress are associated with the development of numerous chronic diseases. Circulating ascorbic acid, α-tocopherol, and 25-hydroxyvitamin D (25(OH)D) may help reduce concentrations of pro-inflammatory cytokines through their antioxidant and anti-inflammatory properties. These micronutrients may act synergistically, and they may have different anti-inflammatory effects, but previous studies have assessed the link between each of these micronutrients and inflammation in isolation without controlling for the other micronutrients. Our objective was to examine the association between circulating concentrations of ascorbic acid, α-tocopherol, and 25(OH) D and a panel of pro-inflammatory cytokines in an ethnically diverse population of young adults. Participants (n = 1,007) from the Toronto Nutrigenomics and Health study provided fasting blood samples for biomarker measurements and were subsequently categorized into tertiles for each micronutrient based on their circulating concentrations. We conducted Pearson's correlation analyses across all micronutrients and cytokines. The associations between individual micronutrients and cytokines were examined using analysis of covariance with age, sex, waist circumference, ethnicity, physical activity, season of blood collection, total cholesterol, hormonal contraceptive use among women, and the other two micronutrients as covariates. We observed weak micronutrient-cytokine correlations, moderate correlations between certain cytokines, and strong correlations between specific cytokines, particularly interleukin 1- receptor antagonist (IL-1RA), interferon-γ (IFN-γ), and platelet-derived growth factor BB (PDGF-bb). After full covariate adjustment, circulating α-tocopherol was inversely associated with IFN-γ and regulated upon activation normal T-cell expressed and secreted (RANTES). We observed an unexpected positive association between ascorbic acid and IFN-γ. 25(OH)D was not associated with altered concentrations of any inflammatory biomarkers. These findings suggest that α-tocopherol, but not ascorbic acid or 25(OH)D, is inversely associated with inflammation in healthy young adults.

Post-Effect of Air Quality Improvement on Biomarkers for Systemic Inflammation and Microparticles in Asthma Patients After the 2008 Beijing Olympic Games: a Pilot Study.

PubMed

Gao, Jinming; Xu, Xiaohua; Ying, Zhekang; Jiang, Lei; Zhong, Mianhua; Wang, Aixia; Chen, Lung-Chi; Lu, Bo; Sun, Qinghua

2017-08-01

This study's aim was to investigate the post-effect of an air quality improvement on systemic inflammation and circulating microparticles in asthmatic patients during, and 2 months after, the Beijing Olympics 2008. We measured the levels of circulating inflammatory cytokines and microparticles in the peripheral blood from asthma patients and healthy controls during (phase 1), and 2 months after (phase 2) the Beijing 2008 Olympic Games. The concentrations of circulating cytokines (including TNFα, IL-6, IL-8, and IL-10) were still seen reduced in phase 2 when compared with those in phase 1. The number of circulating endothelial cell-derived microparticles was significantly lower during the phase 2 than that during phase 1 in asthma patients. The level of plasma lipopolysaccharide-binding protein (LBP) was significantly decreased in asthmatics in phase 2. The level of norepinephrine was significantly higher in phase 2 than that in phase 1 in plasma from both asthma patients and healthy subjects. There were no significant differences in the gene profile for the toll-like receptor (TLR) signaling from peripheral blood mononuclear cells. In vitro, microvesicles from patients with asthma impaired the relaxation to bradykinin and contraction to acetylcholine, whereas microparticles from healthy subjects did not. These data suggested that reduction in systemic pro-inflammatory responses and circulating LBP and increased level of norepinephrine in asthma patients persisted even after 2 months of the air pollution intervention. These changes were independent of the TLR signaling pathway. Circulating microparticles might be associated with airway smooth muscle dysfunction.

Interventional Vitamin C-A Strategy for Attenuation of Coagulopathy and Inflammation in Hemorrhagic Trauma and Shock

DTIC Science & Technology

2017-10-01

edema, protein leak and exuberant infiltration of inflammatory cells. Significant hemorrhage and cellular damage were also evident in liver and kidney ...Treatment with VitC also reduced the expression of pro-inflammatory mediators in lungs, liver and kidneys . Preliminary lipidomic analysis showed that VitC at...Histological changes to lung, liver and kidney f. Proteomic analysis of plasma for identification of novel circulating proteins, and g. Lipidomic

Identification of a novel proinflammatory human skin-homing Vγ9Vδ2 T cell subset with a potential role in psoriasis.

PubMed

Laggner, Ute; Di Meglio, Paola; Perera, Gayathri K; Hundhausen, Christian; Lacy, Katie E; Ali, Niwa; Smith, Catherine H; Hayday, Adrian C; Nickoloff, Brian J; Nestle, Frank O

2011-09-01

γδ T cells mediate rapid tissue responses in murine skin and participate in cutaneous immune regulation including protection against cancer. The role of human γδ cells in cutaneous homeostasis and pathology is characterized poorly. In this study, we show in vivo evidence that human blood contains a distinct subset of proinflammatory cutaneous lymphocyte Ag and CCR6-positive Vγ9Vδ2 T cells, which is rapidly recruited into perturbed human skin. Vγ9Vδ2 T cells produced an array of proinflammatory mediators including IL-17A and activated keratinocytes in a TNF-α- and IFN-γ-dependent manner. Examination of the common inflammatory skin disease psoriasis revealed a striking reduction of circulating Vγ9Vδ2 T cells in psoriasis patients compared with healthy controls and atopic dermatitis patients. Decreased numbers of circulating Vγ9Vδ2 T cells normalized after successful treatment with psoriasis-targeted therapy. Taken together with the increased presence of Vγ9Vδ2 T cells in psoriatic skin, these data indicate redistribution of Vγ9Vδ2 T cells from the blood to the skin compartment in psoriasis. In summary, we report a novel human proinflammatory γδ T cell involved in skin immune surveillance with immediate response characteristics and with potential clinical relevance in inflammatory skin disease.

Decreased Circulating mtDNA Levels in Professional Male Volleyball Players.

PubMed

Nasi, Milena; Cristani, Alessandro; Pinti, Marcello; Lamberti, Igor; Gibellini, Lara; De Biasi, Sara; Guazzaloca, Alessandro; Trenti, Tommaso; Cossarizza, Andrea

2016-01-01

Exercise exerts various effects on the immune system, and evidence is emerging on its anti-inflammatory effects; the mechanisms on the basis of these modifications are poorly understood. Mitochondrial DNA (mtDNA) released from damaged cells acts as a molecule containing the so-called damage-associated molecular patterns and can trigger sterile inflammation. Indeed, high plasma levels of mtDNA are associated to several inflammatory conditions and physiological aging and longevity. The authors evaluated plasma mtDNA in professional male volleyball players during seasonal training and the possible correlation between mtDNA levels and clinical parameters, body composition, and physical performance. Plasma mtDNA was quantified by real-time PCR every 2 mo in 12 professional volleyball players (PVPs) during 2 consecutive seasons. As comparison, 20 healthy nonathlete male volunteers (NAs) were analyzed. The authors found lower levels of mtDNA in plasma of PVPs than in NAs. However, PVPs showed a decrease of circulating mtDNA only in the first season, while no appreciable variations were observed during the second season. No correlation was observed among mtDNA, hematochemical, and anthropometric parameters. Regular physical activity appeared associated with lower levels of circulating mtDNA, further confirming the protective, anti-inflammatory effect of exercise.

Circulating DNA and its methylation level in inflammatory bowel disease and related colon cancer.

PubMed

Bai, Xuming; Zhu, Yaqun; Pu, Wangyang; Xiao, Li; Li, Kai; Xing, Chungen; Jin, Yong

2015-01-01

Both of chronic inflammation and abnormal immune in inflammatory bowel disease can induce colon cancer. Previous research showed that cell apoptosis and necrosis become the main source of circulating DNA in the peripheral blood during tumorigenesis that reduced along with methylation degree. However, its role in the process of colitis transforming to colon cancer is not clarified. Drinking 3% DSS was used to establish colitis model, while 3% dextran sodium sulfate (DSS) combined with azo oxidation methane (AOM) intraperitoneal injection was applied to establish colitis related colon cancer model. Circulating DNA and its methylation level in peripheral blood were tested. Morphology observation, HE staining, and p53 and β-catenin expression detection confirmed that drinking 3% DSS and 3% DSS combined with AOM intraperitoneal injection can successfully establish colitis and colitis associated colorectal cancer models. Circulating DNA level in colitis and colon cancer mice increased by gradient compared with control, while significant difference was observed between each other. Circulating DNA methylation level decreased obviously in colitis and colon cancer, and significant difference was observed between each other. Abnormal protein expression, circulating DNA and its methylation level in ulcerative colitis associated colorectal tissues change in gradient, suggesting that circulating DNA and its methylation level can be treated as new markers for colitis cancer transformation that has certain significance to explore the mechanism of human ulcerative colitis canceration.

Circulating microparticles in acute diabetic Charcot foot exhibit a high content of inflammatory cytokines, and support monocyte-to-osteoclast cell induction.

PubMed

Pasquier, Jennifer; Thomas, Binitha; Hoarau-Véchot, Jessica; Odeh, Tala; Robay, Amal; Chidiac, Omar; Dargham, Soha R; Turjoman, Rebal; Halama, Anna; Fakhro, Khalid; Menzies, Robert; Jayyousi, Amin; Zirie, Mahmoud; Al Suwaidi, Jassim; Rafii, Arash; Malik, Rayaz A; Talal, Talal; Abi Khalil, Charbel

2017-11-27

Circulating microparticles (MPs) are major mediators in cardiovascular complications of type 2 diabetes (T2D); however, their contribution to Charcot foot (CF) disease is not known. Here, we purified and assessed the origin, concentration and content of circulating MPs from 33 individuals: 11 with T2D and acute CF, 11 T2D patients with equivalent neuropathy and 11 non-diabetic controls. First, we demonstrated that there were no differences in the distribution of MPs of endothelial, platelet origin among the 3 groups. However, MPs from leukocytes and monocytes origin were increased in CF patients. Moreover, we demonstrated that monocytes-derived MPs originated more frequently from intermediate and non-classical monocytes in CF patients. Five cytokines (G-CSF, GM-CSF, IL-1-ra, IL-2 and IL-16) were significantly increased in MPs from acute CF patients. Applying ingenuity pathways analysis, we found that those cytokines interacted well and induced the activation of pathways that are involved in osteoclast formation. Further, we treated THP-1 monocytes and monocytes sorted from healthy patients with CF-derived MPs during their differentiation into osteoclasts, which increased their differentiation into multinucleated osteoclast-like cells. Altogether, our study suggests that circulating MPs in CF disease have a high content of inflammatory cytokines and could increase osteoclast differentiation in vitro.

Chronic alcohol consumption is associated with changes in the distribution, immunophenotype, and the inflammatory cytokine secretion profile of circulating dendritic cells.

PubMed

Laso, Francisco Javier; Vaquero, José Miguel; Almeida, Julia; Marcos, Miguel; Orfao, Alberto

2007-05-01

Alcoholism is frequently associated with altered immune responses, limited information being available on its effects on dendritic cells (DC). In the present study we analyze the effects of chronic alcoholism on circulating DC. For the first time we studied the numerical distribution of DC in peripheral blood (PB), their immunophenotype, and their ex vivo pattern of spontaneous cytokine secretion, in chronic alcoholic patients without liver disease (AWLD group; n=17) and active ethanol (EtOH) intake, as well as in subjects with alcohol liver cirrhosis (ALC group; n=21). A significantly decreased HLADR expression and an increased reactivity for CD123 was observed on PB DC from AWLD patients; additionally, increased secretion of interleukin (IL) 1beta, IL6, IL12, and tumor necrosis factor-alpha (TNFalpha) by DC was also noted in this group. Conversely, patients with ALC and at least 1 year of alcohol withdrawal (ALCAW group) showed a decreased number of total circulating DC, whereas ALC patients with active EtOH intake (ALCET group) had an abnormally low production of IL1beta and TNFalpha by PB DC. Chronic alcoholism in the absence of liver disease is associated with an increased secretion of inflammatory cytokines by PB DC, whereas ALCAW and ALCET patients show decreased numbers of circulating DC and reduced secretion of these cytokines, respectively.

Upregulation of circulating components of the alternative renin-angiotensin system in inflammatory bowel disease: A pilot study.

PubMed

Garg, Mayur; Burrell, Louise M; Velkoska, Elena; Griggs, Karen; Angus, Peter W; Gibson, Peter R; Lubel, John S

2015-09-01

The relationship between intestinal inflammation and circulating components of the renin-angiotensin system (RAS) is poorly understood. Demographic and clinical data were obtained from healthy controls and patients with inflammatory bowel disease (IBD). Plasma concentrations of the classical RAS components (angiotensin-converting enzyme (ACE) and angiotensin II (Ang II)) and alternative RAS components (ACE2 and angiotensin (1-7) (Ang (1-7))) were analysed by radioimmuno- and enzymatic assays. Systemic inflammation was assessed using serum C-reactive protein (CRP), white cell count, platelet count and albumin, and intestinal inflammation by faecal calprotectin. Nineteen healthy controls (11 female; mean age 38 years, range 23-68), 19 patients with Crohn's disease (11 female; aged 45 years, range 23-76) and 15 patients with ulcerative colitis (6 female; aged 42 years, 26-64) were studied. Circulating classical RAS component levels were similar across the three groups, whereas ACE2 activity and Ang (1-7) concentrations were higher in patients with IBD compared to controls (ACE2: 21.5 vs 13.3 pmol/ml/min, p<0.05; Ang (1-7): 22.8 vs 14.1 pg/ml, p<0.001). Ang (1-7) correlated weakly with platelet and white cell counts, but not calprotectin or CRP, in patients with IBD. Circulating components of the alternative RAS are increased in patients with IBD. © The Author(s) 2014.

Cell–specific Variation in E-selectin Ligand Expression Among Human Peripheral Blood Mononuclear Cells: Implications for Immunosurveillance and Pathobiology

PubMed Central

Silva, Mariana; Fung, Ronald Kam Fai; Donnelly, Conor Brian; Videira, Paula Alexandra; Sackstein, Robert

2017-01-01

Both host defense and immunopathology are shaped by the ordered recruitment of circulating leukocytes to affected sites, a process initiated by binding of blood-borne cells to E-selectin displayed at target endothelial beds. Accordingly, knowledge of the expression and function of leukocyte E-selectin ligands is key to understanding the tempo and specificity of immunoreactivity. Here, we performed E-selectin adherence assays under hemodynamic flow conditions coupled with flow cytometry and western blot analysis to elucidate the function and structural biology of glycoprotein E-selectin ligands expressed on human peripheral blood mononuclear cells (PBMCs). Circulating monocytes uniformly express high levels of the canonical E-selectin binding determinant sLeX and display markedly greater adhesive interactions with E-selectin than do circulating lymphocytes, which exhibit variable E-selectin binding among CD4+ and CD8+ T-cells but no binding by B-cells. Monocytes prominently present sLeX decorations on an array of protein scaffolds including PSGL-1, CD43, and CD44 (rendering the E-selectin ligands CLA, CD43E, and HCELL, respectively), and B-cells altogether lack E-selectin ligands. Quantitative PCR gene expression studies of glycosyltransferases that regulate display of sLeX reveal high transcript levels among circulating monocytes and low levels among circulating B-cells, and, commensurately, cell surface α(1,3)-fucosylation reveals that acceptor sialyllactosaminyl glycans convertible into sLeX are abundantly expressed on human monocytes yet are relatively deficient on B-cells. Collectively, these findings unveil distinct cell-specific patterns of E-selectin ligand expression among human PBMCs, indicating that circulating monocytes are specialized to engage E-selectin and providing key insights into the molecular effectors mediating recruitment of these cells at inflammatory sites. PMID:28330896

Injury, inflammation and the emergence of human specific genes

DTIC Science & Technology

2016-07-12

genes in circulating and resident human immune cells can be studied in mice after the transplantation and engraft- ment of human hemato- lymphoid immune...Martinek J, Strowig T, Gearty SV, Teichmann LL, et al. Development and function of human innate immune cells in a humanized mouse model. Nat Bio...normal wound repair and regeneration, we hypothesize that the preponderance of human-specific genes expressed in human inflammatory cells is commensurate

Increased Levels of Pro-Inflammatory and Anti-Inflammatory Cellular Responses in Parkinson's Disease Patients: Search for a Disease Indicator.

PubMed

Yang, Likun; Guo, Changfeng; Zhu, Jie; Feng, Yi; Chen, Weiliang; Feng, Zhizhong; Wang, Dan; Sun, Shibai; Lin, Wei; Wang, Yuhai

2017-06-18

BACKGROUND Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder and it arises when most of the dopaminergic neurons of substantia nigra region die. Several mechanisms have been postulated as the causative event in PD pathology, and neuroinflammation is most crucial among them. MATERIAL AND METHODS We analyzed T-helper 17 (Th17) cells and myeloid-derived suppressor cells (MDSCs) from 80 PD patients to assess inflammatory processes and to find a cost-effective means to evaluate PD prognosis. RESULTS We found significantly increased numbers of Th17 cells and MDSCs count in peripheral circulation in PD patients compared with controls (p<0.001). A positive correlation was found between Th17 cells and MDSCs in PD patients (r=0.421, p<0.05). CONCLUSIONS Our results show the effector role of Th17 cells and MDSCs in PD pathology and shows their utility as effective biomarkers for PD diagnosis.

Role of Platelet-Derived Microvesicles As Crosstalk Mediators in Atherothrombosis and Future Pharmacology Targets: A Link between Inflammation, Atherosclerosis, and Thrombosis

PubMed Central

Badimon, Lina; Suades, Rosa; Fuentes, Eduardo; Palomo, Iván; Padró, Teresa

2016-01-01

Reports in the last decade have suggested that the role of platelets in atherosclerosis and its thrombotic complications may be mediated, in part, by local secretion of platelet-derived microvesicles (pMVs), small cell blebs released during the platelet activation process. MVs are the most abundant cell-derived microvesicle subtype in the circulation. High concentrations of circulating MVs have been reported in patients with atherosclerosis, acute vascular syndromes, and/or diabetes mellitus, suggesting a potential correlation between the quantity of microvesicles and the clinical severity of the atherosclerotic disease. pMVs are considered to be biomarkers of disease but new information indicates that pMVs are also involved in signaling functions. pMVs evoke or promote haemostatic and inflammatory responses, neovascularization, cell survival, and apoptosis, processes involved in the pathophysiology of cardiovascular disease. This review is focused on the complex cross-talk between platelet-derived microvesicles, inflammatory cells and vascular elements and their relevance in the development of the atherosclerotic disease and its clinical outcomes, providing an updated state-of-the art of pMV involvement in atherothrombosis and pMV potential use as therapeutic agent influencing cardiovascular biomedicine in the future. PMID:27630570

TNF-alpha and IL-6 inhibit apolipoprotein A-IV production induced by linoleic acid in human intestinal Caco2 cells.

PubMed

Li, Xiaoming; Xu, Min; Liu, Min; Ji, Yong; Li, Zongfang

2015-01-01

Apolipoprotein A-IV (apoA-IV) is a protein mainly synthesized by enterocytes in the intestine. Its gene expression is suppressed during fasting and stimulated during active fat absorption. Chronic feeding of a high-fat (HF) diet abolishes the differential expression between fasting and fat-feeding and therefore may contribute to diet-induced obesity since apoA-IV is a potent satiety factor. It is well established that the circulating pro-inflammatory cytokines TNF-α and IL-6 are increased by HF feeding. To determine whether pro-inflammatory cytokines are involved in the diminished response of apoA-IV gene expression to fat-feeding, different concentrations of linoleic acid (LA), an important dietary fatty acid, was used to stimulate apoA-IV expression in human intestinal Caco2 cells. Cells were pre-treated with or without human recombinant TNF-α, IL-6 or their combination before the addition of LA. Real-time PCR and ELISA were used to detect and quantify RNA transcripts and proteins of apoA-IV and the cytokines. LA stimulated gene and protein expression of apoA-IV in a dose and time dependent manner. Pre-treatment with the cytokines for 72 h significantly inhibited the increased expression of apoA-IV gene and protein induced by LA. Furthermore, the cytokines, especially TNF-α, also positively up-regulate the cytokine themselves in Caco2 cells. Our data indicate that the pro-inflammatory cytokines may be responsible for the reduced apoA-IV production in response to fat feeding. Because of apoA-IV's role in satiety, we propose the inhibitory effect of circulating pro-inflammatory cytokines on apoA-IV production contributes to diet-induced obesity.

Characterization of innate lymphoid cells in human skin and blood demonstrates increase of NKp44+ ILC3 in psoriasis.

PubMed

Villanova, Federica; Flutter, Barry; Tosi, Isabella; Grys, Katarzyna; Sreeneebus, Hemawtee; Perera, Gayathri K; Chapman, Anna; Smith, Catherine H; Di Meglio, Paola; Nestle, Frank O

2014-04-01

Innate lymphoid cells (ILCs) are increasingly appreciated as key regulators of tissue immunity. However, their role in human tissue homeostasis and disease remains to be fully elucidated. Here we characterize the ILCs in human skin from healthy individuals and from the inflammatory skin disease psoriasis. We show that a substantial proportion of IL-17A and IL-22 producing cells in the skin and blood of normal individuals and psoriasis patients are CD3-negative innate lymphocytes. Deep immunophenotyping of human ILC subsets showed a statistically significant increase in the frequency of circulating NKp44+ ILC3 in the blood of psoriasis patients compared with healthy individuals or atopic dermatitis patients. More than 50% of circulating NKp44+ ILC3 expressed cutaneous lymphocyte-associated antigen, indicating their potential for skin homing. Analysis of skin tissue revealed a significantly increased frequency of total ILCs in the skin compared with blood. Moreover, the frequency of NKp44+ ILC3 was significantly increased in non-lesional psoriatic skin compared with normal skin. A detailed time course of a psoriasis patient treated with anti-tumor necrosis factor showed a close association between therapeutic response, decrease in inflammatory skin lesions, and decrease of circulating NKp44+ ILC3. Overall, data from this initial observational study suggest a potential role for NKp44+ ILC3 in psoriasis pathogenesis.

Characterization of innate lymphoid cells (ILC) in human skin and blood demonstrates increase of NKp44+ ILC3 in psoriasis

PubMed Central

Tosi, Isabella; Grys, Katarzyna; Sreeneebus, Hemawtee; Perera, Gayathri K; Chapman, Anna; Smith, Catherine H; Di Meglio, Paola; Nestle, Frank O

2013-01-01

Innate lymphoid cells (ILC) are increasingly appreciated as key regulators of tissue immunity. However, their role in human tissue homeostasis and disease remains to be fully elucidated. Here we characterise the ILC in human skin from healthy individuals and from the inflammatory skin disease psoriasis. We show that a substantial proportion of IL-17A and IL-22 producing cells in skin and blood of normal individuals and psoriasis patients are CD3 negative innate lymphocytes. Deep immunophenotyping of human ILC subsets showed a statistically significant increase in the frequency of circulating NKp44+ ILC3 in blood of psoriasis patients compared to healthy individuals or atopic dermatitis patients. More than 50% of circulating NKp44+ ILC3 expressed cutaneous lymphocyte-associated antigen indicating their potential for skin homing. Analysis of skin tissue revealed a significantly increased frequency of total ILC in skin compared to blood. Moreover the frequency of NKp44+ ILC3 was significantly increased in non-lesional psoriatic skin compared to normal skin. A detailed time course of a psoriasis patient treated with anti-TNF showed a close association between therapeutic response, decrease in inflammatory skin lesions, and decrease of circulating NKp44+ ILC3. Overall, data from this initial observational study suggest a potential role for NKp44+ ILC3 in psoriasis pathogenesis. PMID:24352038

Inhibition of COX-2 reduces the age-dependent increase of hippocampal inflammatory markers, corticosterone secretion, and behavioral impairments in the rat.

PubMed

Casolini, Paola; Catalani, Assia; Zuena, Anna R; Angelucci, Luciano

2002-05-01

Brain aging as well as brain degenerative processes with accompanying cognitive impairments are generally associated with hyperactivity of the hypothalamus-pituitary-adrenal axis, the end product of which, the glucocorticoid hormone, has been warranted the role of cell damage primum movens ("cascade hypothesis"). However, chronic inflammatory activity occurs in the hippocampus of aged rats as well as in the brain of Alzheimer's disease patients. The concomitant increase in the secretion of the glucocorticoid hormone, the endogenous anti-inflammatory and pro-inflammatory markers, has prompted us to investigate the two phenomena in the aging rat, and to work out its meaning. This study shows that: (I) interleukin-1beta (IL-1beta), tumor necrosis factor alpha (TNFalpha), and prostaglandin E(2) (PGE(2)) increase with age in the rats hippocampus, and (II) chronic oral treatment with celecoxib, a selective cycloxygenase-2 (COX-2) inhibitor, is able to contrast the age-dependent increase in hippocampal levels of pro-inflammatory markers and circulating anti-inflammatory corticosterone, provided that it is started at an early stage of aging. Under these conditions, age-related impairments in cognitive ability may be ameliorated. Taken together, these results indicate that there is a natural tendency to offset the age-dependent increase in brain inflammatory processes via the homeostatic increase of the circulating glucocorticoid hormone. Copyright 2002 Wiley-Liss, Inc.

CD39 is incorporated into plasma microparticles where it maintains functional properties and impacts endothelial activation.

PubMed

Banz, Yara; Beldi, Guido; Wu, Yan; Atkinson, Ben; Usheva, Anny; Robson, Simon C

2008-08-01

Plasma microparticles (MPs, <1.5 mum) originate from platelet and cell membrane lipid rafts and possibly regulate inflammatory responses and thrombogenesis. These actions are mediated through their phospholipid-rich surfaces and associated cell-derived surface molecules. The ectonucleotidase CD39/ecto-nucleoside triphosphate diphosphohydrolase1 (E-NTPDase1) modulates purinergic signalling through pericellular ATP and ADP phosphohydrolysis and is localized within lipid rafts in the membranes of endothelial- and immune cells. This study aimed to determine whether CD39 associates with circulating MPs and might further impact phenotype and function. Plasma MPs were found to express CD39 and exhibited classic E-NTPDase ecto-enzymatic activity. Entpd1 (Cd39) deletion in mice produced a pro-inflammatory phenotype associated with quantitative and qualitative differences in the MP populations, as determined by two dimensional-gel electrophoresis, western blot and flow cytometry. Entpd1-null MPs were also more abundant, had significantly higher proportions of platelet- and endothelial-derived elements and decreased levels of interleukin-10, tumour necrosis factor receptor 1 and matrix metalloproteinase 2. Consequently, Cd39-null MP augment endothelial activation, as determined by inflammatory cytokine release and upregulation of adhesion molecules in vitro. In conclusion, CD39 associates with circulating MP and may directly or indirectly confer functional properties. Our data also suggest a modulatory role for CD39 within MP in the exchange of regulatory signals between leucocytes and vascular cells.

Immunology in the liver--from homeostasis to disease.

PubMed

Heymann, Felix; Tacke, Frank

2016-02-01

The liver is a central immunological organ with a high exposure to circulating antigens and endotoxins from the gut microbiota, particularly enriched for innate immune cells (macrophages, innate lymphoid cells, mucosal-associated invariant T (MAIT) cells). In homeostasis, many mechanisms ensure suppression of immune responses, resulting in tolerance. Tolerance is also relevant for chronic persistence of hepatotropic viruses or allograft acceptance after liver transplantation. The liver can rapidly activate immunity in response to infections or tissue damage. Depending on the underlying liver disease, such as viral hepatitis, cholestasis or NASH, different triggers mediate immune-cell activation. Conserved mechanisms such as molecular danger patterns (alarmins), Toll-like receptor signalling or inflammasome activation initiate inflammatory responses in the liver. The inflammatory activation of hepatic stellate and Kupffer cells results in the chemokine-mediated infiltration of neutrophils, monocytes, natural killer (NK) and natural killer T (NKT) cells. The ultimate outcome of the intrahepatic immune response (for example, fibrosis or resolution) depends on the functional diversity of macrophages and dendritic cells, but also on the balance between pro-inflammatory and anti-inflammatory T-cell populations. As reviewed here, tremendous progress has helped to understand the fine-tuning of immune responses in the liver from homeostasis to disease, indicating promising targets for future therapies in acute and chronic liver diseases.

Intermittent fasting during Ramadan attenuates proinflammatory cytokines and immune cells in healthy subjects.

PubMed

Faris, Mo'ez Al-Islam E; Kacimi, Safia; Al-Kurd, Ref'at A; Fararjeh, Mohammad A; Bustanji, Yasser K; Mohammad, Mohammad K; Salem, Mohammad L

2012-12-01

Intermittent fasting and caloric restriction have been shown to extend life expectancy and reduce inflammation and cancer promotion in animal models. It was hypothesized that intermittent prolonged fasting practiced during the month of Ramadan (RIF) could positively affect the inflammatory state. To investigate this hypothesis, a cross-sectional study was designed to investigate the impact of RIF on selected inflammatory cytokines and immune biomarkers in healthy subjects. Fifty (21 men and 29 women) healthy volunteers who practiced Ramadan fasting were recruited for the investigation of circulating proinflammatory cytokines (interleukin [IL]-1β, IL-6, and tumor necrosis factor α), immune cells (total leukocytes, monocytes, granulocytes, and lymphocytes), and anthropometric and dietary assessments. The investigations were conducted 1 week before Ramadan fasting, at the end of the third week of Ramadan, and 1 month after the cessation of Ramadan month. The proinflammatory cytokines IL-1β, IL-6, and tumor necrosis factor α; systolic and diastolic blood pressures; body weight; and body fat percentage were significantly lower (P < .05) during Ramadan as compared with before Ramadan or after the cessation of Ramadan fasting. Immune cells significantly decreased during Ramadan but still remained within the reference ranges. These results indicate that RIF attenuates inflammatory status of the body by suppressing proinflammatory cytokine expression and decreasing body fat and circulating levels of leukocytes. Copyright © 2012 Elsevier Inc. All rights reserved.

The effects of grounding (earthing) on inflammation, the immune response, wound healing, and prevention and treatment of chronic inflammatory and autoimmune diseases

PubMed Central

Oschman, James L; Chevalier, Gaétan; Brown, Richard

2015-01-01

Multi-disciplinary research has revealed that electrically conductive contact of the human body with the surface of the Earth (grounding or earthing) produces intriguing effects on physiology and health. Such effects relate to inflammation, immune responses, wound healing, and prevention and treatment of chronic inflammatory and autoimmune diseases. The purpose of this report is two-fold: to 1) inform researchers about what appears to be a new perspective to the study of inflammation, and 2) alert researchers that the length of time and degree (resistance to ground) of grounding of experimental animals is an important but usually overlooked factor that can influence outcomes of studies of inflammation, wound healing, and tumorigenesis. Specifically, grounding an organism produces measurable differences in the concentrations of white blood cells, cytokines, and other molecules involved in the inflammatory response. We present several hypotheses to explain observed effects, based on current research results and our understanding of the electronic aspects of cell and tissue physiology, cell biology, biophysics, and biochemistry. An experimental injury to muscles, known as delayed onset muscle soreness, has been used to monitor the immune response under grounded versus ungrounded conditions. Grounding reduces pain and alters the numbers of circulating neutrophils and lymphocytes, and also affects various circulating chemical factors related to inflammation. PMID:25848315

Adipose-derived mesenchymal stem cell-derived exosomes alleviate overwhelming systemic inflammatory reaction and organ damage and improve outcome in rat sepsis syndrome

PubMed Central

Chang, Chia-Lo; Sung, Pei-Hsun; Chen, Kuan-Hung; Shao, Pei-Lin; Yang, Chih-Chao; Cheng, Ben-Chung; Lin, Kun-Chen; Chen, Chih-Hung; Chai, Han-Tan; Chang, Hsueh-Wen; Yip, Hon-Kan; Chen, Hong-Hwa

2018-01-01

This study tested the hypothesis that healthy adipose-derived mesenchymal stem cell (ADMSC)-derived exosomes (HMSCEXO) and apoptotic (A) (induced by 12 h hypoxia/12 h starvation)-ADMSC-derived exosomes (AMSCEXO) were comparably effective at alleviating sepsis syndrome [SS; induced by cecal-ligation and puncture (CLP)]-induced systemic inflammation and reduced organ damage and unfavorable outcomes in rats. SD rats were divided into sham control (SC), SS only, SS + HMSCEXO (100 µg intravenous administration 3 h after CLP), and AMSCEXO. By day 5 after CLP procedure, the mortality rate was significantly higher in SS than in SC and HMSCEXO (all P < 0.01), but it showed no significant different between SC and HMSCEXO, between AMSCEXO and HMSCEXO or between SS and AMSCEXO (P > 0.05). The levels of inflammatory mediators in circulation (CD11b/c/Ly6G/MIF), bronchioalveolar lavage (CD11b/c/Ly6G) and abdominal ascites (CD11b/c/CD14/Ly6G/MIF) were highest in SS, lowest in SC and significantly higher in AMSCEXO than in HMSCEXO (all P < 0.001). The circulating/splenic levels of immune cells (CD34+/CD4+/CD3+/CD8+) were expressed in an identical pattern whereas the T-reg+ cells exhibited an opposite pattern of inflammation among the groups (all P < 0.001). The protein expressions of inflammation (MMP-9/MIF/TNF-α/NF-κB/IL-1β) and oxidative stress (NOX-1/NOX-2/oxidized protein), and cellular expressions (CD14+/CD68+) in lung/kidney parenchyma exhibited an identical pattern of inflammatory mediators (all P < 0.001). The kidney/lung injury scores displayed an identical pattern of inflammatory mediators among the groups (all P < 0.001). In conclusion, HMSCEXO might be superior to AMSCEXO for improving survival and suppressing the inflammatory reactions in rats after SS. PMID:29736200

Acute Immunomodulatory Effects of Binge Alcohol Ingestion

PubMed Central

Afshar, Majid; Richards, Stephanie; Mann, Dean; Cross, Alan; Smith, Gordon B.; Netzer, Giora; Kovacs, Elizabeth; Hasday, Jeffrey

2014-01-01

BACKGROUND Blood alcohol is present in a third of trauma patients and has been associated with organ dysfunction. In both human studies and in animal models, it is clear that alcohol intoxication exerts immunomodulatory effects several hours to days after exposure, when blood alcohol is no longer detectable. The early immunomodulatory effects of alcohol while blood alcohol is still elevated are not well understood. METHODS Human volunteers achieved binge alcohol intoxication after high-dose alcohol consumption. Blood was collected for analysis prior to alcohol ingestion, and 20 min, 2 h, and 5 h after alcohol ingestion. Flow cytometry was performed on isolated peripheral blood mononuclear cells, and cytokine generation in whole blood was measured by enzyme-linked immunosorbent assay (ELISA) after 24-h stimulation with lipopolysaccharide (LPS) and phytohemagglutinin-M (PHA) stimulation. RESULTS An early pro-inflammatory state was evident at 20 min when blood alcohol levels were ~130 mg/dL, which was characterized by an increase in total circulating leukocytes, monocytes, and natural killer cells. During this time, a transient increase in LPS-induced tumor necrosis factor (TNF)-α levels and enhanced LPS sensitivity occurred. At 2 and 5 h post-alcohol binge, an anti-inflammatory state was shown with reduced numbers of circulating monocytes and natural killer cells, attenuated LPS-induced interleukin (IL)-1β levels, and a trend toward increased interleukin (IL)-10 levels. CONCLUSIONS A single episode of binge alcohol intoxication exerted effects on the immune system that caused an early and transient pro-inflammatory state followed by an anti-inflammatory state. PMID:25572859

HETEROTYPIC INTERACTIONS ENABLED BY POLARIZED NEUTROPHIL MICRODOMAINS MEDIATE THROMBO-INFLAMMATORY INJURY

PubMed Central

Hidalgo, Andrés; Chang, Jungshan; Jang, Jung-Eun; Peired, Anna J.; Chiang, Elaine Y.; Frenette, Paul S.

2009-01-01

Selectins and their ligands mediate leukocyte rolling allowing interactions with chemokines that lead to integrin activation and arrest. Here, we demonstrate that E-selectin is critical to induce a secondary wave of activating signals transduced specifically by E-selectin ligand-1, that induces polarized, activated αMβ2 integrin clusters at the leading edge of crawling neutrophils, allowing the capture of circulating erythrocytes or platelets. In a humanized model of sickle cell disease (SCD), the capture of erythrocytes by αMβ2 microdomains leads to acute lethal vascular occlusions. In a model of transfusion-related acute lung injury, polarized neutrophils capture circulating platelets, resulting in the generation of oxidative species that produces vascular damage and lung injury. Inactivation of E-selectin or αMβ2 prevented tissue injury in both inflammatory models, suggesting broad implications of this paradigm in thrombo-inflammatory diseases. These results indicate that endothelial selectins can influence neutrophil behavior beyond its canonical rolling step through delayed, organ-damaging, polarized activation. PMID:19305412

Circulating osteogentic precursor cells in non-hereditary heterotopic ossification.

PubMed

Egan, Kevin P; Duque, Gustavo; Keenan, Mary Ann; Pignolo, Robert J

2018-04-01

Non-hereditary heterotopic ossification (NHHO) may occur after musculoskeletal trauma, central nervous system (CNS) injury, or surgery. We previously described circulating osteogenic precursor (COP) cells as a bone marrow-derived type 1 collagen + CD45 + subpopulation of mononuclear adherent cells that are able of producing extraskeletal ossification in a murine in vivo implantation assay. In the current study, we performed a tissue analysis of COP cells in NHHO secondary to defined conditions, including traumatic brain injury, spinal cord injury, cerebrovascular accident, trauma without neurologic injury, and joint arthroplasty. All bone specimens revealed the presence of COP cells at 2-14 cells per high power field. COP cells were localized to early fibroproliferative and neovascular lesions of NHHO with evidence for their circulatory status supported by their presence near blood vessels in examined lesions. This study provides the first systematic evaluation of COP cells as a contributory histopathological finding associated with multiple forms of NHHO. These data support that circulating, hematopoietic-derived cells with osteogenic potential can seed inflammatory sites, such as those subject to soft tissue injury, and due to their migratory nature, may likely be involved in seeding sites distant to CNS injury. Copyright © 2018 Elsevier Inc. All rights reserved.

Effects of exercise training on chronic inflammation in obesity : current evidence and potential mechanisms.

PubMed

You, Tongjian; Arsenis, Nicole C; Disanzo, Beth L; Lamonte, Michael J

2013-04-01

Chronic, systemic inflammation is an independent risk factor for several major clinical diseases. In obesity, circulating levels of inflammatory markers are elevated, possibly due to increased production of pro-inflammatory cytokines from several tissues/cells, including macrophages within adipose tissue, vascular endothelial cells and peripheral blood mononuclear cells. Recent evidence supports that adipose tissue hypoxia may be an important mechanism through which enlarged adipose tissue elicits local tissue inflammation and further contributes to systemic inflammation. Current evidence supports that exercise training, such as aerobic and resistance exercise, reduces chronic inflammation, especially in obese individuals with high levels of inflammatory biomarkers undergoing a longer-term intervention. Several studies have reported that this effect is independent of the exercise-induced weight loss. There are several mechanisms through which exercise training reduces chronic inflammation, including its effect on muscle tissue to generate muscle-derived, anti-inflammatory 'myokine', its effect on adipose tissue to improve hypoxia and reduce local adipose tissue inflammation, its effect on endothelial cells to reduce leukocyte adhesion and cytokine production systemically, and its effect on the immune system to lower the number of pro-inflammatory cells and reduce pro-inflammatory cytokine production per cell. Of these potential mechanisms, the effect of exercise training on adipose tissue oxygenation is worth further investigation, as it is very likely that exercise training stimulates adipose tissue angiogenesis and increases blood flow, thereby reducing hypoxia and the associated chronic inflammation in adipose tissue of obese individuals.

Mucosal-Associated Invariant T Cell Deficiency in Chronic Obstructive Pulmonary Disease.

PubMed

Kwon, Yong Soo; Jin, Hye-Mi; Cho, Young-Nan; Kim, Moon-Ju; Kang, Jeong-Hwa; Jung, Hyun-Ju; Park, Ki-Jeong; Kee, Hae Jin; Kee, Seung-Jung; Park, Yong-Wook

2016-01-01

Mucosal-associated invariant T (MAIT) cells have been reported to play an important role in mucosal immunity. However, little is known about the roles of MAIT cells in chronic obstructive pulmonary disease (COPD). The aims of this study were to examine the levels of circulating MAIT cells and their subsets in COPD patients and to investigate the potential relationship between clinical parameters and MAIT cell levels. Forty-five COPD patients and 57 healthy control subjects were enrolled in the study. Circulating MAIT cells and their subset levels in the peripheral blood were measured by flow cytometry. Disease grades were classified according to the GOLD criteria for the assessment of severity of COPD. Circulating MAIT cell levels were found to be significantly reduced in COPD patients. In particular, this MAIT cell deficiency was more prominent in CD8+ and double-negative T cell subsets. Interestingly, elevated serum C-reactive protein level and reduced FEV1/FVC ratio were associated with MAIT cell deficiency in COPD patients. Furthermore, the circulating MAIT levels were found to be significantly lower in patients with moderate to severe COPD than in patients with mild COPD. Our data shows that MAIT cells are numerically deficient in the peripheral blood of patients with COPD. In addition, this MAIT cell deficiency was found to reflect inflammatory activity and disease severity. These findings provide important information for monitoring the changes in MAIT cell levels and for predicting the prognosis during the disease course.

T-cell homeostasis in breast cancer survivors with persistent fatigue.

PubMed

Bower, Julienne E; Ganz, Patricia A; Aziz, Najib; Fahey, John L; Cole, Steve W

2003-08-06

Approximately 30% of women successfully treated for breast cancer suffer persistent fatigue of unknown origin. Recent studies linking inflammatory processes to central nervous system-mediated fatigue led us to examine cellular immune system status in 20 fatigued breast cancer survivors and 19 matched non-fatigued breast cancer survivors. Fatigued survivors, compared with non-fatigued survivors, had statistically significantly increased numbers of circulating T lymphocytes (mean 31% increase, 95% confidence interval [CI] = 6% to 56%; P =.015 by two-sided analysis of variance [ANOVA]), with pronounced elevation in the numbers of CD4+ T lymphocytes (mean 41% increase, 95% CI = 15% to 68%; P =.003 by two-sided ANOVA) and CD56+ effector T lymphocytes (mean 52% increase, 95% CI = 4% to 99%; P =.027 by two-sided ANOVA). These changes were independent of patient demographic and treatment characteristics. Absolute numbers of B cells, natural killer cells, granulocytes, and monocytes were not altered. The increased numbers of circulating T cells correlated with elevations in the level of serum interleukin 1 receptor antagonist (for CD3+ cells, r =.56 and P =.001; for CD3+/CD4+ cells, r =.68 and P<.001, by Spearman rank correlation). Results of this study suggest that persistent fatigue in breast cancer survivors might be associated with a chronic inflammatory process involving the T-cell compartment. These results require confirmation in a larger study that is specifically designed to address this hypothesis.

Circulating tumor cells promote the metastatic colonization of disseminated carcinoma cells by inducing systemic inflammation

PubMed Central

Luo, Chao; Shu, Yu; Luo, Jing; Qin, Jian; Wang, Yu; Li, Dong; Wang, Shan-Shan; Chi, Gang; Guo, Fang; Zhang, Gui-Mei; Feng, Zuo-Hua

2017-01-01

Circulating tumor cells (CTCs) have been studied well in the prognosis for malignant diseases as liquid biopsy, but their contribution to tumor metastasis is not clearly defined. Here we report that CTCs could promote the metastatic colonization of disseminated carcinoma cells by inducing systemic inflammation and neutrophil recruitment to pre-metastatic organs. Depletion of neutrophils in vivo could effectively abrogate the promoting effect of CTCs on tumor cell metastasis. In the presence of CTCs, the pro-tumor function of neutrophils was augmented, whereas the antitumor function of neutrophils was suppressed. Mechanically, CTC-derived ligands for TLR2 and TLR4 (TLR2/4) induced the systemic inflammation, thus increasing the production of proinflammatory cytokines such as G-CSF and IL-6 that could induce the conversion of neutrophil function from tumor-suppressing to tumor-promoting. Moreover, CTCs induced the production of endogenous TLR2/4 ligands such as S100A8, S100A9, and SAA3, which may amplify the stimulating effect that induces the expression of proinflammatory cytokines. The promoting effect of CTCs on tumor cell metastasis could be abrogated by suppressing inflammatory response with IL-37, an anti-inflammatory cytokine, or blocking CTC-derived ligands for TLR2/4. Identification of the metastatic axis of CTCs/systemic inflammation/neutrophils may provide potential targets for preventing tumor cell metastasis. PMID:28415700

Shed-blood-separation and cell-saver: an integral Part of MiECC? Shed-blood-separation and its influence on the perioperative inflammatory response during coronary revascularization with minimal invasive extracorporeal circulation systems - a randomized controlled trial.

PubMed

Bauer, Adrian; Hausmann, Harald; Schaarschmidt, Jan; Scharpenberg, Martin; Troitzsch, Dirk; Johansen, Peter; Nygaard, Hans; Eberle, Thomas; Hasenkam, J Michael

2018-03-01

The postoperative systemic inflammatory response after cardiopulmonary bypass (CPB) is still an undesirable side-effect after cardiac surgery. It is most likely caused by blood contact with foreign surfaces and by the surgical trauma itself. However, the recirculation of activated shed mediastinal blood is another main cause of blood cell activation and cytokine release. Minimal invasive extracorporeal circulation (MiECC) comprises a completely closed circuit, coated surfaces and the separation of suction blood. We hypothesized that MiECC, with separated cell saved blood, would induce less of a systemic inflammatory response than MiECC with no cell-saver. The aim of this study was, therefore, to investigate the impact of cell washing shed blood from the operating field versus direct return to the ECC on the biomarkers for systemic inflammation. In the study, patients with MiECC and cell-saver were compared with the control group, patients with MiECC and direct re-transfusion of the drawn blood shed from the surgical field. High amounts of TNF-α (+ 120% compared to serum blood) were found in the shed blood itself, but a significant reduction was demonstrated with the use of a cell-saver (TNF-α ng/l post-ECC 10 min: 9.5±3.5 vs. 19.7±14.5, p<0.0001). The values for procalcitonin were not significantly increased in the control group (6h: 1.07±3.4 vs. 2.15±9.55, p=0.19) and lower for C-reactive protein (CRP) (24h: 147.1±64.0 vs.134.4±52.4 p=0.28). The use of a cell-saver and the processing of shed blood as an integral part of MiECC significantly reduces the systemic cytokine load. We, therefore, recommend the integration of cell-saving devices in MiECC to reduce the perioperative inflammatory response.

Exendin-4 and GLP-1 decreases induced expression of ICAM-1, VCAM-1 and RAGE in human retinal pigment epithelial cells.

PubMed

Dorecka, Mariola; Siemianowicz, Krzysztof; Francuz, Tomasz; Garczorz, Wojciech; Chyra, Agnieszka; Klych, Agnieszka; Romaniuk, Wanda

2013-01-01

Advanced glycation end products (AGEs) take part in the development of diabetic retinopathy. Hyperglycemia triggers an inflammatory response in the retina. These mechanisms may lead to an enhanced expression of adhesion molecules (ICAM-1 and VCAM-1) in human retinal pigment epithelium (HRPE). Glucagon-like peptide 1 (GLP-1) functions as an incretin hormone with antidiabetogenic properties. GLP-1 also possesses vasoprotective properties. The aim of our study was to evaluate the influence of glycated albumin (GlyAlb; 100; 500 and 1000 mg/l) and pro-inflammatory cytokine, TNF-α (2.5 and 10 ng/ml), on expression of RAGE, ICAM-1 and VCAM-1 and to evaluate the influence of GLP-1 (100 nM) and its analogue, exendin-4 (10 nM), on the expression of RAGE, ICAM-1 and VCAM-1 in stimulated HRPE. TNF-α increased RAGE expression in HRPE cells. The addition of GlyAlb (500 and 1000 mg/l) resulted in a decrease of RAGE expression. Both TNF-α and GlyAlb increased the secretion of both adhesion molecules. In cells co-treated with GLP-1 or exendin-4 both incretins decreased RAGE expression in TNF-α treated cells, and in GlyAlb group. The ICAM-1 expression was lowered by exendin-4 and GLP-1 in cells stimulated by TNF-α and GlyAlb. The similar results were obtained for VCAM-1. All observed alterations were statistically significant. The obtained results indicate that both GLP-1 and exendin-4 by decreasing the expression of RAGE in HRPE can make these cells more resistant to circulating AGEs, and decreased expression of circulating VCAM-1 and ICAM-1, can be the result of anti-inflammatory properties of incretins and decreased expression of RAGE.

Effects of transplanted circulating endothelial progenitor cells and platelet microparticles in atherosclerosis development.

PubMed

Georgescu, Adriana; Alexandru, Nicoleta; Andrei, Eugen; Dragan, Emanuel; Cochior, Daniel; Dias, Sérgio

2016-08-01

Atherosclerosis is an inflammatory disease, in which risk factors such as hyperlipidemia and hypertension affect the arterial endothelium, resulting in dysfunction, cell damage or both. The number of circulating endothelial progenitor cells and microparticles provides invaluable outcome prediction for atherosclerosis disease. However, evidence for the therapeutic potential of endothelial progenitor cells and microparticles in atherosclerosis development is limited. Our study was designed to investigate the possible protective role of a cell therapy-based approach, using endothelial progenitor cells and the dual behaviour of circulating platelet microparticles, on atherosclerosis development in hypertensive-hypercholesterolemic hamster model. Consequently, control hamsters received four intravenous inoculations of: (1) 1×10(5) endothelial progenitor cells of healthy origins in one dose per month, during four months of diet-induced atherosclerosis, and after hypertensive-hypercholesterolemic diet for further four months; (2) in a second set of experiments, 1×10(5) endothelial progenitor cells of healthy origins or/and 1×10(5) platelet microparticles of atherosclerotic origins were inoculated every other month during hypertensive-hypercholesterolemic diet. Endothelial progenitor cell treatment had the following effects: (1) re-established plasmatic parameters: cholesterol and triglyceride concentrations, blood pressure, heart rate, cytokine and chemokine profiles, platelet microparticle pro-thrombotic activity and endothelial progenitor cell paracrine activity reflected by cytokine/chemokine detection; (2) reduced lipid, macrophage and microparticle accumulation in liver; (3) reduced atherosclerosis development, revealed by decreased lipid, macrophage and microparticle content of arterial wall; (4) induced the recruitment and incorporation of endothelial progenitor cells into liver and arterial wall; (5) improved arterial dysfunction by increasing contraction and relaxation; (6) reduced the protein expression of specific pro-inflammatory molecules in liver and arterial wall. Platelet microparticle transplantation aggravated the above-mentioned biomarkers and atherosclerosis process, which were partially reverted with co-inoculation of platelet microparticles and endothelial progenitor cells. With this study, we demonstrate in a hypertensive-hypercholesterolemic hamster model, that the endothelial progenitor cell-based therapy suppresses the development of atherosclerosis and reduces hepatic lipid and macrophage accumulation with the consequent alleviation of dyslipidaemia and hypertension. Our results support the notion that increasing the number of circulating endothelial progenitor cells by different ways could be a promising therapeutic tool for atherosclerosis. © 2016 Société Française des Microscopies and Société de Biologie Cellulaire de France. Published by John Wiley & Sons Ltd.

Gamma Delta T-Cells Regulate Wound Myeloid Cell Activity After Burn

DTIC Science & Technology

2014-03-01

With regard to trauma , recent studies have shown the presence of activated +% T cells in the circulation of patients with severe inflammatory response...14). No analgesics were used postburn because they can impact the immune response to burn injury and other forms of trauma (15). The mice were then...burn, trauma , and sepsis (17, 19, 24Y26). Gr-1, CD11b, and F4/80 antigens have been shown to be expressed on the surface of immature myeloid cells

Impact of brief exercise on circulating monocyte gene and microRNA expression: implications for atherosclerotic vascular disease

PubMed Central

Radom-Aizik, Shlomit; Zaldivar, Frank P.; Haddad, Fadia; Cooper, Dan M.

2014-01-01

Physical activity can prevent and/or attenuate atherosclerosis, a disease clearly linked to inflammation. Paradoxically, even brief exercise induces a stress response and increases inflammatory cells like monocytes in the circulation. We hypothesized that exercise would regulate the expression of genes, gene pathways, and microRNAs in monocytes in a way that could limit pro-inflammatory function and drive monocytes to prevent, rather than contribute to, atherosclerosis. Twelve healthy men (22-30 yr old) performed ten 2-min bouts of cycle ergometer exercise at a constant work equivalent to an average of 82% of maximum O2 consumption interspersed with 1-min rest. Blood was drawn before and immediately after the exercise. Monocytes were isolated from peripheral blood mononuclear cells. Flow cytometry was used to identify monocyte subtypes. We used Affymetrix U133+2.0 arrays for gene expression and Agilent Human miRNA V2 Microarray for miRNAs. A stringent statistical approach (FDR < 0.05) was used to determine that exercise significantly altered the expression of 894 annotated genes and 19 miRNAs. We found distinct gene alterations that were likely to direct monocytes in an anti-inflammatory, anti-atherogenic pathway, including the downregulation of monocyte TNF, TLR4, and CD36 genes and the upregulation of EREG and CXCR4. Exercise significantly altered a number of microRNAs that likely influence monocytes involvement in vascular health. Exercise leads to a novel genomic profile of circulating monocytes, which appears to promote cardiovascular health despite the overall stress response. PMID:24423463

Increase of endothelial progenitor cells in acute graft-versus-host disease after allogeneic haematopoietic stem cell transplantation for acute myeloid leukaemia.

PubMed

Medinger, Michael; Heim, Dominik; Gerull, Sabine; Halter, Jörg; Krenger, Werner; Buser, Andreas; Lengerke, Claudia; Bucher, Christoph; Passweg, Jakob

2016-08-01

Circulating endothelial progenitor cells (EPCs; CD31+ CD34(bright)CD133+ CD45(dim) cells) are novel markers of endothelial dysfunction and related to inflammatory processes such as acute graft-versus-host disease (aGvHD). 47 patients with acute myeloid leukaemia (AML) who were in complete remission as they underwent allogeneic hematopoietic stem cell transplantation with myeloablative conditioning with PBSC as stem cell source were enrolled in the study. Blood samples for the quantitative analysis of circulating EPC levels were drawn at different time points in patients with and without aGvHD. CD34+ VEGFR2/KDR+ CD133+ triple-positive cells identified among CD34+ cells by FACS. EPC were quantified and data are presented as cells/ml whole blood. Circulating EPC levels were not significantly different in patients with and without aGvHD prior to conditioning (baseline) and at the time of engraftment. However, at diagnosis of aGvHD≥grade 2, EPC levels increased whereas in patients without aGvHD the EPC levels remained significantly lower (3021±278 versus 2322±195 cells/ml; p<0.001). Patients with steroid-refractory aGvHD had high levels of EPC throughout. EPC levels fell in responding patients. Our results demonstrate that the number of circulating EPCs is increased in patients with aGvHD compared to patients without aGvHD. Copyright © 2016 Elsevier Ltd. All rights reserved.

Reverse transendothelial cell migration in inflammation: to help or to hinder?

PubMed

Burn, Thomas; Alvarez, Jorge Ivan

2017-05-01

The endothelium provides a strong barrier separating circulating blood from tissue. It also provides a significant challenge for immune cells in the bloodstream to access potential sites of infection. To mount an effective immune response, leukocytes traverse the endothelial layer in a process known as transendothelial migration. Decades of work have allowed dissection of the mechanisms through which immune cells gain access into peripheral tissues, and subsequently to inflammatory foci. However, an often under-appreciated or potentially ignored question is whether transmigrated leukocytes can leave these inflammatory sites, and perhaps even return across the endothelium and re-enter circulation. Although evidence has existed to support "reverse" transendothelial migration for a number of years, it is only recently that mechanisms associated with this process have been described. Here we review the evidence that supports both reverse transendothelial migration and reverse interstitial migration within tissues, with particular emphasis on some of the more recent studies that finally hint at potential mechanisms. Additionally, we postulate the biological significance of retrograde migration, and whether it serves as an additional mechanism to limit pathology, or provides a basis for the dissemination of systemic inflammation.

Neutrophil ageing is regulated by the microbiome

PubMed Central

Zhang, Dachuan; Chen, Grace; Manwani, Deepa; Mortha, Arthur; Xu, Chunliang; Faith, Jeremiah J.; Burk, Robert D.; Kunisaki, Yuya; Jang, Jung-Eun; Scheiermann, Christoph; Merad, Miriam; Frenette, Paul S.

2015-01-01

Blood polymorphonuclear neutrophils provide immune protection against pathogens but also may promote tissue injury in inflammatory diseases1,2. Although neutrophils are generally considered as a relatively homogeneous population, evidence for heterogeneity is emerging3,4. Under steady-state conditions, neutrophil heterogeneity may arise from ageing and the replenishment by newly released neutrophils from the bone marrow5. Aged neutrophils up-regulate CXCR4, a receptor allowing their clearance in the bone marrow6,7, with feedback inhibition of neutrophil production via the IL17/G-CSF axis8, and rhythmic modulation of the haematopoietic stem cell niche5. The aged subset also expresses low levels of L-selectin (CD62L)5,9. Previous studies have suggested that in vitro-aged neutrophils exhibit impaired migration and reduced pro-inflammatory properties6,10. Here, we show using in vivo ageing analyses that the neutrophil pro-inflammatory activity correlates positively with their ageing in the circulation. Aged neutrophils represent an overly active subset exhibiting enhanced αMβ2 integrin (Mac-1) activation and neutrophil extracellular trap (NET) formation under inflammatory conditions. Neutrophil ageing is driven by the microbiota via Toll-like receptors (TLRs)- and myeloid differentiation factor 88 (Myd88)-mediated signalling pathways. Depletion of the microbiota significantly reduces the number of circulating aged neutrophils and dramatically improves the pathogenesis and inflammation-related organ damage in models of sickle cell disease or endotoxin-induced septic shock. These results thus identify an unprecedented role for the microbiota in regulating a disease-promoting neutrophil subset. PMID:26374999

Interleukin-35 administration counteracts established murine type 1 diabetes--possible involvement of regulatory T cells.

PubMed

Singh, Kailash; Kadesjö, Erik; Lindroos, Julia; Hjort, Marcus; Lundberg, Marcus; Espes, Daniel; Carlsson, Per-Ola; Sandler, Stellan; Thorvaldson, Lina

2015-07-30

The anti-inflammatory cytokine IL-35 is produced by regulatory T (Treg) cells to suppress autoimmune and inflammatory responses. The role of IL-35 in type 1 diabetes (T1D) remains to be answered. To elucidate this, we investigated the kinetics of Treg cell response in the multiple low dose streptozotocin induced (MLDSTZ) T1D model and measured the levels of IL-35 in human T1D patients. We found that Treg cells were increased in MLDSTZ mice. However, the Treg cells showed a decreased production of anti-inflammatory (IL-10, IL-35, TGF-β) and increased pro-inflammatory (IFN-γ, IL-2, IL-17) cytokines, indicating a phenotypic shift of Treg cells under T1D condition. IL-35 administration effectively both prevented development of, and counteracted established MLDSTZ T1D, seemingly by induction of Eos expression and IL-35 production in Treg cells, thus reversing the phenotypic shift of the Treg cells. IL-35 administration reversed established hyperglycemia in NOD mouse model of T1D. Moreover, circulating IL-35 levels were decreased in human T1D patients compared to healthy controls. These findings suggest that insufficient IL-35 levels play a pivotal role in the development of T1D and that treatment with IL-35 should be investigated in treatment of T1D and other autoimmune diseases.

Targeting B cells in immune-mediated inflammatory disease: a comprehensive review of mechanisms of action and identification of biomarkers.

PubMed

Dörner, Thomas; Kinnman, Nils; Tak, Paul P

2010-03-01

B cell-depletion therapy, particularly using anti-CD20 treatment, has provided proof of concept that targeting B cells and the humoral response may result in clinical improvements in immune-mediated inflammatory disease. In this review, the mechanisms of action of B cell-targeting drugs are investigated, and potential biomarkers associated with response to treatment in patients with autoimmune diseases are identified. Most available data relate to B cell depletion using anti-CD20 therapy (rituximab) in patients with rheumatoid arthritis (RA). Treatment leads to significant clinical benefit, but apparently fails to deplete long-lived plasma cells, and discontinuation is associated with relapse. Biomarkers commonly used in studies of B cell-targeted therapies include rheumatoid factor, anti-citrullinated peptide antibodies, and immunoglobulin (Ig) levels. More recently, there has been interest in markers such as B cell phenotype analysis, and B lymphocyte stimulator (BLyS)/a proliferation-inducing ligand (APRIL), the latter particularly in studies of the IgG Fc-transmembrane activator and CAML interactor (TACI) fusion protein (atacicept) and anti-BLyS therapy (belimumab). Data from clinical trials of B cell-depleting agents in RA suggest that specific autoantibodies, BLyS, APRIL, and circulating and synovial B lineage cell levels may have potential as biomarkers predictive of response to treatment. Further trials validating these markers against clinical outcomes in RA are required. In patients with systemic lupus erythematosus, Fc receptors and levels of circulating immune cells (including B cells and natural killer cells) may be relevant markers. 2010 Elsevier Inc. All rights reserved.

Tenascin-C Deficiency in Apo E−/− Mouse Increases Eotaxin Levels: Implications for Atherosclerosis

PubMed Central

Wang, Lai; Shah, Prediman K.; Wang, Wei; Song, Lei; Yang, Mingjie; Sharifi, Behrooz G.

2013-01-01

Aim To investigate the potential role of inflammatory cytokines in apo E−/− mouse in response to deletion of Tenascin-C (TNC) gene. Methods and results We used antibody array and ELISA to compare the profile of circulating inflammatory cytokines in apo E−/− mice and apo E−/− TNC−/− double knockout mice. In addition, tissue culture studies were performed to investigate the activity of cells from each mouse genotype in vitro. Cytokine array analysis and subsequent ELISA showed that circulating eotaxin levels were selectively and markedly increased in response to TNC gene deletion in apo E−/− mice. In addition, considerable variation was noted in the circulating level of eotaxin among the control apo E−/− mouse group. Inbreeding of apo E−/− mice with high or low levels of plasma eotaxin showed that the level of eotaxin per se determines the extent of atherosclerosis in this mouse genotype. While endothelial cells from apo E−/− mice had low level of eotaxin expression, cells derived from apo E−/−TNC−/− mice expressed a high level of eotaxin. Transient transfection of eotaxin promoter-reporter constructs revealed that eotaxin expression is regulated at the transcriptional level by TNC. Histochemical analysis of aortic sections revealed the massive accumulation of mast cells in the adventitia of double KO mice lesions whereas no such accumulation was detected in the control group. Plasma from the apo E−/−TNC−/− mice markedly stimulated mast cell migration whereas plasma from the apo E−/− mice had no such effect. Conclusion These observations support the emerging hypothesis that TNC expression controls eotaxin level in apo E−/− mice and that this chemokine plays a key role in the development of atherosclerosis. PMID:23433402

Accumulation and therapeutic modulation of 6-sulfo LacNAc(+) dendritic cells in multiple sclerosis.

PubMed

Thomas, Katja; Dietze, Kristin; Wehner, Rebekka; Metz, Imke; Tumani, Hayrettin; Schultheiß, Thorsten; Günther, Claudia; Schäkel, Knut; Reichmann, Heinz; Brück, Wolfgang; Schmitz, Marc; Ziemssen, Tjalf

2014-10-01

To examine the potential role of 6-sulfo LacNAc(+) (slan) dendritic cells (DCs) displaying pronounced proinflammatory properties in the pathogenesis of multiple sclerosis (MS). We determined the presence of slanDCs in demyelinated brain lesions and CSF samples of patients with MS. In addition, we explored the impact of methylprednisolone, interferon-β, glatiramer acetate, or natalizumab on the frequency of blood-circulating slanDCs in patients with MS. We also evaluated whether interferon-β modulates important proinflammatory capabilities of slanDCs. SlanDCs accumulate in highly inflammatory brain lesions and are present in the majority of CSF samples of patients with MS. Short-term methylprednisolone administration reduces the percentage of slanDCs in blood of patients with MS and the proportion of tumor necrosis factor-α- or CD150-expressing slanDCs. Long-term interferon-β treatment decreases the percentage of blood-circulating slanDCs in contrast to glatiramer acetate or natalizumab. Furthermore, interferon-β inhibits the secretion of proinflammatory cytokines by slanDCs and their capacity to promote proliferation and differentiation of T cells. Accumulation of slanDCs in highly inflammatory brain lesions and their presence in CSF indicate that slanDCs may play an important role in the immunopathogenesis of MS. The reduction of blood-circulating slanDCs and the inhibition of their proinflammatory properties by methylprednisolone and interferon-β may contribute to the therapeutic efficiency of these drugs in patients with MS.

Accumulation and therapeutic modulation of 6-sulfo LacNAc+ dendritic cells in multiple sclerosis

PubMed Central

Thomas, Katja; Dietze, Kristin; Wehner, Rebekka; Metz, Imke; Tumani, Hayrettin; Schultheiß, Thorsten; Günther, Claudia; Schäkel, Knut; Reichmann, Heinz; Brück, Wolfgang; Schmitz, Marc

2014-01-01

Objective: To examine the potential role of 6-sulfo LacNAc+ (slan) dendritic cells (DCs) displaying pronounced proinflammatory properties in the pathogenesis of multiple sclerosis (MS). Methods: We determined the presence of slanDCs in demyelinated brain lesions and CSF samples of patients with MS. In addition, we explored the impact of methylprednisolone, interferon-β, glatiramer acetate, or natalizumab on the frequency of blood-circulating slanDCs in patients with MS. We also evaluated whether interferon-β modulates important proinflammatory capabilities of slanDCs. Results: SlanDCs accumulate in highly inflammatory brain lesions and are present in the majority of CSF samples of patients with MS. Short-term methylprednisolone administration reduces the percentage of slanDCs in blood of patients with MS and the proportion of tumor necrosis factor-α– or CD150-expressing slanDCs. Long-term interferon-β treatment decreases the percentage of blood-circulating slanDCs in contrast to glatiramer acetate or natalizumab. Furthermore, interferon-β inhibits the secretion of proinflammatory cytokines by slanDCs and their capacity to promote proliferation and differentiation of T cells. Conclusion: Accumulation of slanDCs in highly inflammatory brain lesions and their presence in CSF indicate that slanDCs may play an important role in the immunopathogenesis of MS. The reduction of blood-circulating slanDCs and the inhibition of their proinflammatory properties by methylprednisolone and interferon-β may contribute to the therapeutic efficiency of these drugs in patients with MS. PMID:25340085

Short-term exercise training reduces anti-inflammatory action of interleukin-10 in adults with obesity.

PubMed

Barry, Julianne C; Simtchouk, Svetlana; Durrer, Cody; Jung, Mary E; Mui, Alice L; Little, Jonathan P

2018-06-06

A key pathological component of obesity is chronic low-grade inflammation, which is propagated by infiltration of immune cells into tissues and overproduction of pro-inflammatory cytokines. Cytokines that possess anti-inflammatory properties, such as interleukin (IL)-10 and IL6, may also play an important role. This study was designed to determine the impact of short-term exercise on the anti-inflammatory action of IL10 and IL6. Thirty-three inactive obese adults were randomized to two weeks of high-intensity interval training (HIIT) or moderate-intensity continuous training (MICT). Fasting blood samples were collected before and after training. Lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)-α production was measured in whole blood cultures in the presence or absence of IL10 or IL6. IL10 and IL6 receptor expression were measured on circulating monocytes, neutrophils, and T cells. HIIT and MICT reduced the ability of IL10 to inhibit LPS-induced TNFα production, with a greater effect with HIIT (Group × Time and IL10 × Time interactions, p's < 0.05). This reduction in IL10 function was not explained by altered IL10R1 expression, which was unchanged after training (p > 0.05). HIIT and MICT differentially affected IL6 function (Group × Time and IL6 × Time interactions, p's < 0.05) with evidence of reductions in the anti-inflammatory ability of IL6 with HIIT. Neither HIIT nor MICT altered levels of circulating IL10, IL6, or TNFα. The impact of short-term HIIT and MICT resulted in differential effects on anti-inflammatory cytokine function. The clinical implications remain to be determined but these novel findings indicate that measuring anti-inflammatory cytokine action could reveal important immunomodulatory effects of exercise. Copyright © 2018. Published by Elsevier Ltd.

Non-extracorporeal circulation for coronary artery bypass graft surgery is more beneficial than extracorporeal circulation.

PubMed

Yang, F-Y; Bao, Y-Z; Liu, F-S; Zhu, Y-C; Zheng, J; Zhang, J-H; Zheng, X-F; Wei, G-C

2015-04-01

The objective of this study was to compare coronary artery bypass graft (CABG) surgery with non-extracorporeal vs. extracorporeal circulation. The study outcomes included operative time, number of graft vessels, pulmonary infection rates, and systemic inflammatory markers. 96 patients received selective CABG, either with non-extracorporeal (study group; n = 48) or extracorporeal circulation (control group; n = 48). Operative time, pulmonary infection rates, and blood levels of inflammatory markers TNF-α, IL-6, and IL-8 before and 4, 24, and 48 hours after the surgery were quantified. Graft vessels were quantified using computed tomography. Operative time was significantly shorter in study group (4.58 ± 0.91 vs. 5.36 ± 1.12 hours in control group; p < 0.05). The number of graft vessels and pulmonary infection rates were comparable between both techniques. However, systemic inflammatory markers were significantly (p < 0.05) lower in study group at 4 and, partly, 24 hours after the surgery. Extracorporeal circulation prolongs operation and can aggravate systemic inflammatory response. Therefore, CABG with non-extracorporeal circulation offers more beneficial outcomes.

Myocardial pressure overload induces systemic inflammation through endothelial cell IL-33

PubMed Central

Chen, Wei-Yu; Hong, Jaewoo; Gannon, Joseph; Kakkar, Rahul; Lee, Richard T.

2015-01-01

Hypertension increases the pressure load on the heart and is associated with a poorly understood chronic systemic inflammatory state. Interleukin 33 (IL-33) binds to membrane-bound ST2 (ST2L) and has antihypertrophic and antifibrotic effects in the myocardium. In contrast, soluble ST2 appears to act as a decoy receptor for IL-33, blocking myocardial and vascular benefits, and is a prognostic biomarker in patients with cardiovascular diseases. Here we report that a highly local intramyocardial IL-33/ST2 conversation regulates the heart’s response to pressure overload. Either endothelial-specific deletion of IL33 or cardiomyocyte-specific deletion of ST2 exacerbated cardiac hypertrophy with pressure overload. Furthermore, pressure overload induced systemic circulating IL-33 as well as systemic circulating IL-13 and TGF-beta1; this was abolished by endothelial-specific deletion of IL33 but not by cardiomyocyte-specific deletion of IL33. Our study reveals that endothelial cell secretion of IL-33 is crucial for translating myocardial pressure overload into a selective systemic inflammatory response. PMID:25941360

Postpartum Circulating Markers of Inflammation and the Systemic Acute-Phase Response After Early-Onset Preeclampsia.

PubMed

van Rijn, Bas B; Bruinse, Hein W; Veerbeek, Jan H; Post Uiterweer, Emiel D; Koenen, Steven V; van der Bom, Johanna G; Rijkers, Ger T; Roest, Mark; Franx, Arie

2016-02-01

Preeclampsia is an inflammatory-mediated hypertensive disorder of pregnancy and seems to be an early indicator of increased cardiovascular risk, but mechanisms underlying this association are unclear. In this study, we identified levels of circulating inflammatory markers and dynamic changes in the systemic acute-phase response in 44 women with a history of severe early-onset preeclampsia, compared with 29 controls with only uneventful pregnancies at 1.5 to 3.5 years postpartum. Models used were in vivo seasonal influenza vaccination and in vitro whole-blood culture with T-cell stimulants and the toll-like receptor-4 ligand lipopolysaccharide. Outcome measures were C-reactive protein, interleukin-6 (IL-6), IL-18, fibrinogen, myeloperoxidase, and a panel of 13 cytokines representative of the innate and adaptive inflammatory response, in addition to established cardiovascular markers. The in vivo acute-phase response was higher for women with previous preeclampsia than that for controls without such a history, although only significant for C-reactive protein (P=0.04). Preeclampsia was associated with higher IL-1β (P<0.05) and IL-8 (P<0.01) responses to T-cell activation. Hierarchical clustering revealed 2 distinct inflammatory clusters associated with previous preeclampsia: an adaptive response cluster associated with increased C-reactive protein and IL-6 before and after vaccination, increased weight, and low high-density lipoprotein cholesterol; and a toll-like receptor-4 mediated the cluster associated with increased IL-18 before and after vaccination but not associated with other cardiovascular markers. Furthermore, we found interactions between previous preeclampsia, common TLR4 gene variants, and the IL-18 response to vaccination. In conclusion, preeclampsia is associated with alterations in the inflammatory response postpartum mostly independent of other established cardiovascular risk markers. © 2015 American Heart Association, Inc.

Effects of TiO2 and Co3O4 Nanoparticles on Circulating Angiogenic Cells

PubMed Central

Spigoni, Valentina; Cito, Monia; Alinovi, Rossella; Pinelli, Silvana; Passeri, Giovanni; Zavaroni, Ivana; Goldoni, Matteo; Campanini, Marco; Aliatis, Irene; Mutti, Antonio

2015-01-01

Background and Aim Sparse evidence suggests a possible link between exposure to airborne nanoparticles (NPs) and cardiovascular (CV) risk, perhaps through mechanisms involving oxidative stress and inflammation. We assessed the effects of TiO2 and Co3O4 NPs in human circulating angiogenic cells (CACs), which take part in vascular endothelium repair/replacement. Methods CACs were isolated from healthy donors’ buffy coats after culturing lymphomonocytes on fibronectin-coated dishes in endothelial medium for 7 days. CACs were pre-incubated with increasing concentration of TiO2 and Co3O4 (from 1 to 100 μg/ml) to test the effects of NP – characterized by Transmission Electron Microscopy – on CAC viability, apoptosis (caspase 3/7 activation), function (fibronectin adhesion assay), oxidative stress and inflammatory cytokine gene expression. Results Neither oxidative stress nor cell death were associated with exposure to TiO2 NP (except at the highest concentration tested), which, however, induced a higher pro-inflammatory effect compared to Co3O4 NPs (p<0.01). Exposure to Co3O4 NPs significantly reduced cell viability (p<0.01) and increased caspase activity (p<0.01), lipid peroxidation end-products (p<0.05) and pro-inflammatory cytokine gene expression (p<0.05 or lower). Notably, CAC functional activity was impaired after exposure to both TiO2 (p<0.05 or lower) and Co3O4 (p<0.01) NPs. Conclusions In vitro exposure to TiO2 and Co3O4 NPs exerts detrimental effects on CAC viability and function, possibly mediated by accelerated apoptosis, increased oxidant stress (Co3O4 NPs only) and enhancement of inflammatory pathways (both TiO2 and Co3O4 NPs). Such adverse effects may be relevant for a potential role of exposure to TiO2 and Co3O4 NPs in enhancing CV risk in humans. PMID:25803285

Protease-activated receptor (PAR)2, but not PAR1, is involved in collateral formation and anti-inflammatory monocyte polarization in a mouse hind limb ischemia model.

PubMed

van den Hengel, Lisa G; Hellingman, Alwine A; Nossent, Anne Yael; van Oeveren-Rietdijk, Annemarie M; de Vries, Margreet R; Spek, C Arnold; van Zonneveld, Anton Jan; Reitsma, Pieter H; Hamming, Jaap F; de Boer, Hetty C; Versteeg, Henri H; Quax, Paul H A

2013-01-01

In collateral development (i.e. arteriogenesis), mononuclear cells are important and exist as a heterogeneous population consisting of pro-inflammatory and anti-inflammatory/repair-associated cells. Protease-activated receptor (PAR)1 and PAR2 are G-protein-coupled receptors that are both expressed by mononuclear cells and are involved in pro-inflammatory reactions, while PAR2 also plays a role in repair-associated responses. Here, we investigated the physiological role of PAR1 and PAR2 in arteriogenesis in a murine hind limb ischemia model. PAR1-deficient (PAR1-/-), PAR2-deficient (PAR2-/-) and wild-type (WT) mice underwent femoral artery ligation. Laser Doppler measurements revealed reduced post-ischemic blood flow recovery in PAR2-/- hind limbs when compared to WT, while PAR1-/- mice were not affected. Upon ischemia, reduced numbers of smooth muscle actin (SMA)-positive collaterals and CD31-positive capillaries were found in PAR2-/- mice when compared to WT mice, whereas these parameters in PAR1-/- mice did not differ from WT mice. The pool of circulating repair-associated (Ly6C-low) monocytes and the number of repair-associated (CD206-positive) macrophages surrounding collaterals in the hind limbs were increased in WT and PAR1-/- mice, but unaffected in PAR2-/- mice. The number of repair-associated macrophages in PAR2-/- hind limbs correlated with CD11b- and CD115-expression on the circulating monocytes in these animals, suggesting that monocyte extravasation and M-CSF-dependent differentiation into repair-associated cells are hampered. PAR2, but not PAR1, is involved in arteriogenesis and promotes the repair-associated response in ischemic tissues. Therefore, PAR2 potentially forms a new pro-arteriogenic target in coronary artery disease (CAD) patients.

Seminal Plasma Enhances Cervical Adenocarcinoma Cell Proliferation and Tumour Growth In Vivo

PubMed Central

Sutherland, Jason R.; Sales, Kurt J.; Jabbour, Henry N.; Katz, Arieh A.

2012-01-01

Cervical cancer is one of the leading causes of cancer-related death in women in sub-Saharan Africa. Extensive evidence has shown that cervical cancer and its precursor lesions are caused by Human papillomavirus (HPV) infection. Although the vast majority of HPV infections are naturally resolved, failure to eradicate infected cells has been shown to promote viral persistence and tumorigenesis. Furthermore, following neoplastic transformation, exposure of cervical epithelial cells to inflammatory mediators either directly or via the systemic circulation may enhance progression of the disease. It is well recognised that seminal plasma contains an abundance of inflammatory mediators, which are identified as regulators of tumour growth. Here we investigated the role of seminal plasma in regulating neoplastic cervical epithelial cell growth and tumorigenesis. Using HeLa cervical adenocarcinoma cells, we found that seminal plasma (SP) induced the expression of the inflammatory enzymes, prostaglandin endoperoxide synthase (PTGS1 and PTGS2), cytokines interleukin (IL) -6, and -11 and vascular endothelial growth factor-A(VEGF-A). To investigate the role of SP on tumour cell growth in vivo, we xenografted HeLa cells subcutaneously into the dorsal flank of nude mice. Intra-peritoneal administration of SP rapidly and significantly enhanced the tumour growth rate and size of HeLa cell xenografts in nude mice. As observed in vitro, we found that SP induced expression of inflammatory PTGS enzymes, cytokines and VEGF-A in vivo. Furthermore we found that SP enhances blood vessel size in HeLa cell xenografts. Finally we show that SP-induced cytokine production, VEGF-A expression and cell proliferation are mediated via the induction of the inflammatory PTGS pathway. PMID:22442729

Seminal plasma enhances cervical adenocarcinoma cell proliferation and tumour growth in vivo.

PubMed

Sutherland, Jason R; Sales, Kurt J; Jabbour, Henry N; Katz, Arieh A

2012-01-01

Cervical cancer is one of the leading causes of cancer-related death in women in sub-Saharan Africa. Extensive evidence has shown that cervical cancer and its precursor lesions are caused by Human papillomavirus (HPV) infection. Although the vast majority of HPV infections are naturally resolved, failure to eradicate infected cells has been shown to promote viral persistence and tumorigenesis. Furthermore, following neoplastic transformation, exposure of cervical epithelial cells to inflammatory mediators either directly or via the systemic circulation may enhance progression of the disease. It is well recognised that seminal plasma contains an abundance of inflammatory mediators, which are identified as regulators of tumour growth. Here we investigated the role of seminal plasma in regulating neoplastic cervical epithelial cell growth and tumorigenesis. Using HeLa cervical adenocarcinoma cells, we found that seminal plasma (SP) induced the expression of the inflammatory enzymes, prostaglandin endoperoxide synthase (PTGS1 and PTGS2), cytokines interleukin (IL) -6, and -11 and vascular endothelial growth factor-A (VEGF-A). To investigate the role of SP on tumour cell growth in vivo, we xenografted HeLa cells subcutaneously into the dorsal flank of nude mice. Intra-peritoneal administration of SP rapidly and significantly enhanced the tumour growth rate and size of HeLa cell xenografts in nude mice. As observed in vitro, we found that SP induced expression of inflammatory PTGS enzymes, cytokines and VEGF-A in vivo. Furthermore we found that SP enhances blood vessel size in HeLa cell xenografts. Finally we show that SP-induced cytokine production, VEGF-A expression and cell proliferation are mediated via the induction of the inflammatory PTGS pathway.

Role of Hemichannels in CNS Inflammation and the Inflammasome Pathway.

PubMed

Kim, Yeri; Davidson, Joanne O; Gunn, Katherine C; Phillips, Anthony R; Green, Colin R; Gunn, Alistair J

2016-01-01

Neurodegenerative, cardiovascular, and metabolic disorders, once triggered, share a number of common features, including sustained inflammatory cell activation and vascular disruption. These shared pathways are induced independently of any genetic predisposition to the disease or the precise external stimulus. Glial cells respond to injury with an innate immune response that includes release of proinflammatory cytokines and chemokines. Vascular endothelial cells may also be affected, leading to opening of the blood-brain barrier that facilitates invasion by circulating inflammatory cells. Inflammation can trigger acute neural injury followed by chronic inflammation that plays a key role in neurodegenerative conditions. Gap junction channels normally allow direct cell-to-cell communication. They are formed by the docking of two hemichannels, one contributed by each of the neighboring cells. While the opening probability of these channels is tightly controlled under resting conditions, hemichannels can open in response to injury or inflammatory factors, forming a large, relatively nonselective membrane pore. In this review, we consider the CNS immune system from the perspective that modulating connexin hemichannel opening can prevent tissue damage arising from excessive and uncontrolled inflammation. We discuss connexin channel roles in microglia, astrocytes, and endothelial cells in both acute and chronic inflammatory conditions, and in particular describe the role of connexin hemichannels in the inflammasome pathway where they contribute to both its activation and its spread to neighboring cells. Finally, we describe the benefits of hemichannel block in animal models of brain injury. © 2016 Elsevier Inc. All rights reserved.

Dysregulation of Innate Lymphoid Cells in Common Variable Immunodeficiency.

PubMed

Maglione, Paul J; Cols, Montserrat; Cunningham-Rundles, Charlotte

2017-10-05

Common variable immunodeficiency (CVID) is the most prevalent symptomatic primary immune deficiency. With widespread use of immunoglobulin replacement therapy, non-infectious complications, such as autoimmunity, chronic intestinal inflammation, and lung disease, have replaced infections as the major cause of morbidity and mortality in this immune deficiency. The pathogenic mechanisms that underlie the development of these complications in CVID are not known; however, there have been numerous associated laboratory findings. Among the most intriguing of these associations is elevation of interferon signature genes in CVID patients with inflammatory/autoimmune complications, as a similar gene expression profile is found in systemic lupus erythematosus and other chronic inflammatory diseases. Linked with this heightened interferon signature in CVID is an expansion of circulating IFN-γ-producing innate lymphoid cells. Innate lymphoid cells are key regulators of both protective and pathogenic immune responses that have been extensively studied in recent years. Further exploration of innate lymphoid cell biology in CVID may uncover key mechanisms underlying the development of inflammatory complications in these patients and may inspire much needed novel therapeutic approaches.

Dysregulation of Innate Lymphoid Cells in Common Variable Immunodeficiency

PubMed Central

Maglione, Paul J.; Cols, Montserrat

2018-01-01

Common variable immunodeficiency (CVID) is the most prevalent symptomatic primary immune deficiency. With widespread use of immunoglobulin replacement therapy, non-infectious complications, such as autoimmunity, chronic intestinal inflammation, and lung disease, have replaced infections as the major cause of morbidity and mortality in this immune deficiency. The pathogenic mechanisms that underlie the development of these complications in CVID are not known; however, there have been numerous associated laboratory findings. Among the most intriguing of these associations is elevation of interferon signature genes in CVID patients with inflammatory/autoimmune complications, as a similar gene expression profile is found in systemic lupus erythematosus and other chronic inflammatory diseases. Linked with this heightened interferon signature in CVID is an expansion of circulating IFN-γ-producing innate lymphoid cells. Innate lymphoid cells are key regulators of both protective and pathogenic immune responses that have been extensively studied in recent years. Further exploration of innate lymphoid cell biology in CVID may uncover key mechanisms underlying the development of inflammatory complications in these patients and may inspire much needed novel therapeutic approaches. PMID:28983810

DOE Office of Scientific and Technical Information (OSTI.GOV)

Paquette, Stéphane G.; Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, Ontario; Banner, David

Pandemic H1N1 influenza A (H1N1pdm) elicits stronger pulmonary inflammation than previously circulating seasonal H1N1 influenza A (sH1N1), yet mechanisms of inflammatory activation in respiratory epithelial cells during H1N1pdm infection are unclear. We investigated host responses to H1N1pdm/sH1N1 infection and virus entry mechanisms in primary human bronchial epithelial cells in vitro. H1N1pdm infection rapidly initiated a robust inflammatory gene signature (3 h post-infection) not elicited by sH1N1 infection. Protein secretion inhibition had no effect on gene induction. Infection with membrane fusion deficient H1N1pdm failed to induce robust inflammatory gene expression which was rescued with restoration of fusion ability, suggesting H1N1pdm directlymore » triggered the inflammatory signature downstream of membrane fusion. Investigation of intra-virion components revealed H1N1pdm viral RNA (vRNA) triggered a stronger inflammatory phenotype than sH1N1 vRNA. Thus, our study is first to report H1N1pdm induces greater inflammatory gene expression than sH1N1 in vitro due to direct virus–epithelial cell interaction. - Highlights: • We investigated H1N1pdm/sH1N1 infection in primary epithelial cells. • H1N1pdm directly initiated a robust inflammatory gene signature, sH1N1 did not. • H1N1pdm viral RNA triggered a stronger response than sH1N1. • H1N1pdm induces greater response due to direct virus–cell interaction. • These results have potential to impact vaccine and therapeutic development.« less

Regular exercise during haemodialysis promotes an anti-inflammatory leucocyte profile

PubMed Central

Dungey, Maurice; Young, Hannah M L; Churchward, Darren R; Burton, James O; Smith, Alice C

2017-01-01

Abstract Background Cardiovascular disease is the most common cause of mortality in haemodialysis (HD) patients and is highly predicted by markers of chronic inflammation. Regular exercise may have beneficial anti-inflammatory effects, but this is unclear in HD patients. This study assessed the effect of regular intradialytic exercise on soluble inflammatory factors and inflammatory leucocyte phenotypes. Methods Twenty-two HD patients from a centre where intradialytic cycling was offered thrice weekly and 16 HD patients receiving usual care volunteered. Exercising patients aimed to cycle for 30 min at rating of perceived exertion of ‘somewhat hard’. Baseline characteristics were compared with 16 healthy age-matched individuals. Physical function, soluble inflammatory markers and leucocyte phenotypes were assessed again after 6 months of regular exercise. Results Patients were less active than their healthy counterparts and had significant elevations in measures of inflammation [interleukin-6 (IL-6), C-reactive protein (CRP), tumour necrosis factor-α (TNF-α), intermediate and non-classical monocytes; all P < 0.001]. Six months of regular intradialytic exercise improved physical function (sit-to-stand 60). After 6 months, the proportion of intermediate monocytes in the exercising patients reduced compared with non-exercisers (7.58 ± 1.68% to 6.38 ± 1.81% versus 6.86 ± 1.45% to 7.88 ± 1.66%; P < 0.01). Numbers (but not proportion) of regulatory T cells decreased in the non-exercising patients only (P < 0.05). Training had no significant effect on circulating IL-6, CRP or TNF-α concentrations. Conclusions These findings suggest that regular intradialytic exercise is associated with an anti-inflammatory effect at a circulating cellular level but not in circulating cytokines. This may be protective against the increased risk of cardiovascular disease and mortality that is associated with chronic inflammation and elevated numbers of intermediate monocytes. PMID:29225811

How do immune cells support and shape the brain in health, disease, and aging?

PubMed

Schwartz, Michal; Kipnis, Jonathan; Rivest, Serge; Prat, Alexandre

2013-11-06

For decades, several axioms have prevailed with respect to the relationships between the CNS and circulating immune cells. Specifically, immune cell entry was largely considered to be pathological or to mark the beginning of pathology within the brain. Moreover, local inflammation associated with neurodegenerative diseases such Alzheimer's disease or amyotrophic lateral sclerosis, were considered similar in their etiology to inflammatory diseases, such as remitting relapsing-multiple sclerosis. The ensuing confusion reflected a lack of awareness that the etiology of the disease as well as the origin of the immune cells determines the nature of the inflammatory response, and that inflammation resolution is an active cellular process. The last two decades have seen a revolution in these prevailing dogmas, with a significant contribution made by the authors. Microglia and infiltrating monocyte-derived macrophages are now known to be functionally distinct and of separate origin. Innate and adaptive immune cells are now known to have protective/healing properties in the CNS, as long as their activity is regulated, and their recruitment is well controlled; their role is appreciated in maintenance of brain plasticity in health, aging, and chronic neurodevelopmental and neurodegenerative diseases. Moreover, it is now understood that the barriers of the brain are not uniform in their interactions with the circulating immune cells. The implications of these new findings to the basic understanding of CNS repair processes, brain aging, and a wide spectrum of CNS disorders, including acute injuries, Rett syndrome, Alzheimer's disease, and multiple sclerosis, will be discussed.

Circulating inflammatory monocytes contribute to impaired influenza vaccine responses in HIV-infected participants.

PubMed

George, Varghese K; Pallikkuth, Suresh; Pahwa, Rajendra; de Armas, Lesley R; Rinaldi, Stefano; Pan, Li; Pahwa, Savita

2018-06-19

Antibody responses are often impaired in old age and in HIV-positive (HIV+) infection despite virologic control with antiretroviral therapy but innate immunologic determinants are not well understood. Monocytes and natural killer cells were examined for relationships to age, HIV infection and influenza vaccine responses. Virologically suppressed HIV+ (n = 139) and HIV-negative (HIV-) (n = 137) participants classified by age as young (18-39 years), middle-aged (40-59 years) and old (≥60 years) were evaluated preinfluenza and postinfluenza vaccination. Prevaccination frequencies of inflammatory monocytes were highest in old HIV+ and HIV-, with old HIV+ exhibiting higher frequency of integrin CD11b on inflammatory monocytes that was correlated with age, expression of C-C chemokine receptor-2 (CCR2) and plasma soluble tumor necrosis factor receptor-1 (sTNFR1), with inverse correlation with postvaccination influenza H1N1 antibody titers. Higher frequencies of CD11b inflammatory monocytes (CD11b, >48.4%) compared with low frequencies of CD11b inflammatory monocytes (<15.8%) was associated with higher prevaccination frequencies of total and inflammatory monocytes and higher CCR2 MFI, higher plasma sTNFR1 and CXCL-10 with higher lipopolysaccharide stimulated expression of TNFα and IL-6, concomitant with lower postvaccination influenza antibody titers. In HIV+ CD11b expressers, the depletion of inflammatory monocytes from peripheral blood mononuclear cells resulted in enhanced antigen-specific CD4 T-cell proliferation. Immature CD56 natural killer cells were lower in young HIV+ compared with young HIV- participants. Perturbations of innate immunity and inflammation signified by high CD11b on inflammatory monocytes are exacerbated with aging in HIV+ and negatively impact immune function involved in Ab response to influenza vaccination.

The drug efflux pump Pgp1 in pro-inflammatory lymphocytes is a target for novel treatment strategies in COPD.

PubMed

Hodge, Greg; Holmes, Mark; Jersmann, Hubertus; Reynolds, Paul N; Hodge, Sandra

2013-06-03

Pro-inflammatory/cytotoxic T cells (IFNγ, TNFα, granzyme B+) are increased in the peripheral circulation in COPD. NKT-like and NK cells are effector lymphocytes that we have also shown to be major sources of pro-inflammatory cytokines and granzymes. P-glycoprotein 1 (Pgp1) is a transmembrane efflux pump well characterised in drug resistant cancer cells. We hypothesized that Pgp1 would be increased in peripheral blood T, NKT-like and NK cells in patients with COPD, and that this would be accompanied by increased expression of IFNγ, TNFα and granzyme B. We further hypothesized that treatment with cyclosporine A, a Pgp1 inhibitor, would render cells more sensitive to treatment with corticosteroids. Pgp1, granzyme B, IFNγ and TNFα expression were measured in peripheral blood T, NK and NKT-like cells from COPD patients and control subjects (± cyclosporine A and prednisolone) following in vitro stimulation and results correlated with uptake of efflux dye Calcein-AM using flow cytometry. There was increased Pgp1 expression by peripheral blood T, NKT-like and NK cells co-expressing IFNγ, TNFα and granzyme B in COPD patients compared with controls (e.g. %IFNγ/Pgp1 T, NKT-like, NK for COPD (Control): 25(6), 54(27), 39(23)). There was an inverse correlation between Pgp1 expression and Calcein-AM uptake. Treatment with 2.5 ng/ml cylosporin A and10-6 M prednisolone resulted in synergistic inhibition of pro-inflammatory cytokines in Pgp1 + cells (p < 0.05 for all). Treatment strategies that target Pgp1 in T, NKT-like and NK cells may reduce systemic inflammatory mediators in COPD and improve patient morbidity.

Sulforaphane pretreatment prevents systemic inflammation and renal injury in response to cardiopulmonary bypass.

PubMed

Nguyen, Bao; Luong, Le; Naase, Hatam; Vives, Marc; Jakaj, Gentjan; Finch, Jonathan; Boyle, Joseph; Mulholland, John W; Kwak, Jong-hwan; Pyo, Suhkneung; de Luca, Amalia; Athanasiou, Thanos; Angelini, Gianni; Anderson, Jon; Haskard, Dorian O; Evans, Paul C

2014-08-01

Systemic inflammatory responses are a major cause of morbidity and mortality in patients undergoing cardiac surgery with cardiopulmonary bypass. However, the underlying molecular mechanisms for systemic inflammation in response to cardiopulmonary bypass are poorly understood. A porcine model was established to study the signaling pathways that promote systemic inflammation in response to cardiac surgery with cardiopulmonary bypass under well-controlled experimental conditions. The influence of sulforaphane, an anti-inflammatory compound derived from green vegetables, on inflammation and injury in response to cardiopulmonary bypass was also studied. Intracellular staining and flow cytometry were performed to measure phosphorylation of p38 mitogen-activated protein kinase and the transcription factor nuclear factor-κB in granulocytes and mononuclear cells. Surgery with cardiopulmonary bypass for 1 to 2 hours enhanced phosphorylation of p38 (2.5-fold) and nuclear factor-κB (1.6-fold) in circulating mononuclear cells. Cardiopulmonary bypass also modified granulocytes by activating nuclear factor-κB (1.6-fold), whereas p38 was not altered. Histologic analyses revealed that cardiopulmonary bypass promoted acute tubular necrosis. Pretreatment of animals with sulforaphane reduced p38 (90% reduction) and nuclear factor-κB (50% reduction) phosphorylation in leukocytes and protected kidneys from injury. Systemic inflammatory responses after cardiopulmonary bypass were associated with activation of p38 and nuclear factor-κB pathways in circulating leukocytes. Inflammatory responses to cardiopulmonary bypass can be reduced by sulforaphane, which reduced leukocyte activation and protected against renal injury. Copyright © 2014 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.

A novel hypothesis for an alkaline phosphatase 'rescue' mechanism in the hepatic acute phase immune response.

PubMed

Pike, Adrianne F; Kramer, Nynke I; Blaauboer, Bas J; Seinen, Willem; Brands, Ruud

2013-12-01

The liver isoform of the enzyme alkaline phosphatase (AP) has been used classically as a serum biomarker for hepatic disease states such as hepatitis, steatosis, cirrhosis, drug-induced liver injury, and hepatocellular carcinoma. Recent studies have demonstrated a more general anti-inflammatory role for AP, as it is capable of dephosphorylating potentially deleterious molecules such as nucleotide phosphates, the pathogenic endotoxin lipopolysaccharide (LPS), and the contact clotting pathway activator polyphosphate (polyP), thereby reducing inflammation and coagulopathy systemically. Yet the mechanism underlying the observed increase in liver AP levels in circulation during inflammatory insults is largely unknown. This paper hypothesizes an immunological role for AP in the liver and the potential of this system for damping generalized inflammation along with a wide range of ancillary pathologies. Based on the provided framework, a mechanism is proposed in which AP undergoes transcytosis in hepatocytes from the canalicular membrane to the sinusoidal membrane during inflammation and the enzyme's expression is upregulated as a result. Through a tightly controlled, nucleotide-stimulated negative feedback process, AP is transported in this model as an immune complex with immunoglobulin G by the asialoglycoprotein receptor through the cell and secreted into the serum, likely using the receptor's State 1 pathway. The subsequent dephosphorylation of inflammatory stimuli by AP and uptake of the circulating immune complex by endothelial cells and macrophages may lead to decreased inflammation and coagulopathy while providing an early upstream signal for the induction of a number of anti-inflammatory gene products, including AP itself. © 2013.

High fat diet alters gut microbiota and the expression of Paneth cell-antimicrobial peptides preceding changes of circulating inflammatory cytokines

USDA-ARS?s Scientific Manuscript database

Obesity is established as a critical risk factor for many diseases including intestinal cancer. One of the responsible mechanisms for this relationship is the chronic inflammation driven by obesity. However, it remains to be defined whether high fat diet-induced obesity first exacerbates the intesti...

Oxidative Burst of Circulating Neutrophils Following Traumatic Brain Injury in Human

PubMed Central

Liao, Yiliu; Liu, Peng; Guo, Fangyuan; Zhang, Zhi-Yuan; Zhang, Zhiren

2013-01-01

Besides secondary injury at the lesional site, Traumatic brain injury (TBI) can cause a systemic inflammatory response, which may cause damage to initially unaffected organs and potentially further exacerbate the original injury. Here we investigated plasma levels of important inflammatory mediators, oxidative activity of circulating leukocytes, particularly focusing on neutrophils, from TBI subjects and control subjects with general trauma from 6 hours to 2 weeks following injury, comparing with values from uninjured subjects. We observed increased plasma level of inflammatory cytokines/molecules TNF-α, IL-6 and CRP, dramatically increased circulating leukocyte counts and elevated expression of TNF-α and iNOS in circulating leukocytes from TBI patients, which suggests a systemic inflammatory response following TBI. Our data further showed increased free radical production in leukocyte homogenates and elevated expression of key oxidative enzymes iNOS, COX-2 and NADPH oxidase (gp91phox) in circulating leukocytes, indicating an intense induction of oxidative burst following TBI, which is significantly greater than that in control subjects with general trauma. Furthermore, flow cytometry assay proved neutrophils as the largest population in circulation after TBI and showed significantly up-regulated oxidative activity and suppressed phagocytosis rate for circulating neutrophils following brain trauma. It suggests that the highly activated neutrophils might play an important role in the secondary damage, even outside the injured brain. Taken together, the potent systemic inflammatory response induced by TBI, especially the intensively increase oxidative activity of circulating leukocytes, mainly neutrophils, may lead to a systemic damage, dysfunction/damage of bystander tissues/organs and even further exacerbate secondary local damage. Controlling these pathophysiological processes may be a promising therapeutic strategy and will protect unaffected organs and the injured brain from the secondary damage. PMID:23894384

Role of the Retinal Vascular Endothelial Cell in Ocular Disease

PubMed Central

Bharadwaj, Arpita S.; Appukuttan, Binoy; Wilmarth, Phillip A.; Pan, Yuzhen; Stempel, Andrew J.; Chipps, Timothy J.; Benedetti, Eric E.; Zamora, David O.; Choi, Dongseok; David, Larry L.; Smith, Justine R.

2012-01-01

Retinal endothelial cells line the arborizing microvasculature that supplies and drains the neural retina. The anatomical and physiological characteristics of these endothelial cells are consistent with nutritional requirements and protection of a tissue critical to vision. On the one hand, the endothelium must ensure the supply of oxygen and other nutrients to the metabolically active retina, and allow access to circulating cells that maintain the vasculature or survey the retina for the presence of potential pathogens. On the other hand, the endothelium contributes to the blood-retinal barrier that protects the retina by excluding circulating molecular toxins, microorganisms, and pro-inflammatory leukocytes. Features required to fulfill these functions may also predispose to disease processes, such as retinal vascular leakage and neovascularization, and trafficking of microbes and inflammatory cells. Thus, the retinal endothelial cell is a key participant in retinal ischemic vasculopathies that include diabetic retinopathy and retinopathy of prematurity, and retinal inflammation or infection, as occurs in posterior uveitis. Using gene expression and proteomic profiling, it has been possible to explore the molecular phenotype of the human retinal endothelial cell and contribute to understanding of the pathogenesis of these diseases. In addition to providing support for the involvement of well-characterized endothelial molecules, profiling has the power to identify new players in retinal pathologies. Findings may have implications for the design of new biological therapies. Additional progress in this field is anticipated as other technologies, including epigenetic profiling methods, whole transcriptome shotgun sequencing, and metabolomics, are used to study the human retinal endothelial cell. PMID:22982179

Measuring T cell cytokines in allergic upper and lower airway inflammation: can we move to the clinic?

PubMed

Bullens, Dominique M A

2007-06-01

Recent insights regarding the development of allergic diseases such as allergic rhinitis, asthma and atopic eczema are based on the functional diversity of T helper (Th)1 and Th2 lymphocytes. Th2 cells (secreting Interleukin (IL)-4, IL-5, IL-9 and IL-13) are considered to be responsible for the induction and for many of the manifestations of atopic diseases. Local overproduction of Th2 cytokines at the site of allergic inflammation, and an intrinsic defect in the production of IFN-gamma by Th1 cells in atopic individuals, have now been reported by several authors. Both IFN-gamma and IL-10 have been suggested to play a modulatory role in the induction and maintenance of allergen-specific tolerance in healthy individuals. However, recent studies indicate that Th1 cells, secreting IFN-gamma might cause severe airway inflammation. On the other hand, 'inflammatory T cells' or Th17 cells, producing IL-17, could represent a link between T cell inflammation and granulocytic influx as observed in allergic airway inflammation. We focus in this review on local (at the side of inflammation) T cell cytokine production and cytokine production by circulating T cells (after in vitro restimulation) from individuals with allergic airway disease, rhinitis and/or asthma. We furthermore review the changes in local T cell cytokine production and/or cytokine production by circulating T cells (after restimulation in vitro) from allergic/asthmatic individuals after treatment with anti-inflammatory agents or immunotherapy. Finally, we discuss whether measuring these T cell cytokines in the airways might be of diagnostic importance or could help to follow-up patients with allergy/asthma.

Extracellular vesicles from mice with alcoholic liver disease carry a distinct protein cargo and induce macrophage activation through heat shock protein 90.

PubMed

Saha, Banishree; Momen-Heravi, Fatemeh; Furi, Istvan; Kodys, Karen; Catalano, Donna; Gangopadhyay, Anwesha; Haraszti, Reka; Satishchandran, Abhishek; Iracheta-Vellve, Arvin; Adejumo, Adeyinka; Shaffer, Scott A; Szabo, Gyongyi

2018-05-01

A salient feature of alcoholic liver disease (ALD) is Kupffer cell (KC) activation and recruitment of inflammatory monocytes and macrophages (MØs). These key cellular events of ALD pathogenesis may be mediated by extracellular vesicles (EVs). EVs transfer biomaterials, including proteins and microRNAs, and have recently emerged as important effectors of intercellular communication. We hypothesized that circulating EVs from mice with ALD have a protein cargo characteristic of the disease and mediate biological effects by activating immune cells. The total number of circulating EVs was increased in mice with ALD compared to pair-fed controls. Mass spectrometric analysis of circulating EVs revealed a distinct signature for proteins involved in inflammatory responses, cellular development, and cellular movement between ALD EVs and control EVs. We also identified uniquely important proteins in ALD EVs that were not present in control EVs. When ALD EVs were injected intravenously into alcohol-naive mice, we found evidence of uptake of ALD EVs in recipient livers in hepatocytes and MØs. Hepatocytes isolated from mice after transfer of ALD EVs, but not control EVs, showed increased monocyte chemoattractant protein 1 mRNA and protein expression, suggesting a biological effect of ALD EVs. Compared to control EV recipient mice, ALD EV recipient mice had increased numbers of F4/80 hi cluster of differentiation 11b (CD11b) lo KCs and increased percentages of tumor necrosis factor alpha-positive/interleukin 12/23-positive (inflammatory/M1) KCs and infiltrating monocytes (F4/80 int CD11b hi ), while the percentage of CD206 + CD163 + (anti-inflammatory/M2) KCs was decreased. In vitro, ALD EVs increased tumor necrosis factor alpha and interleukin-1β production in MØs and reduced CD163 and CD206 expression. We identified heat shock protein 90 in ALD EVs as the mediator of ALD-EV-induced MØ activation. Our study indicates a specific protein signature of ALD EVs and demonstrates a functional role of circulating EVs containing heat shock protein 90 in mediating KC/MØ activation in the liver. (Hepatology 2018;67:1986-2000). © 2017 by the American Association for the Study of Liver Diseases.

Advancing drug delivery systems for the treatment of multiple sclerosis.

PubMed

Tabansky, Inna; Messina, Mark D; Bangeranye, Catherine; Goldstein, Jeffrey; Blitz-Shabbir, Karen M; Machado, Suly; Jeganathan, Venkatesh; Wright, Paul; Najjar, Souhel; Cao, Yonghao; Sands, Warren; Keskin, Derin B; Stern, Joel N H

2015-12-01

Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease of the central nervous system. It is characterized by demyelination of neurons and loss of neuronal axons and oligodendrocytes. In MS, auto-reactive T cells and B cells cross the blood-brain barrier (BBB), causing perivenous demyelinating lesions that form multiple discrete inflammatory demyelinated plaques located primarily in the white matter. In chronic MS, cortical demyelination and progressive axonal transections develop. Treatment for MS can be stratified into disease-modifying therapies (DMTs) and symptomatic therapy. DMTs aim to decrease circulating immune cells or to prevent these cells from crossing the BBB and reduce the inflammatory response. There are currently 10 DMTs approved for the relapsing forms of MS; these vary with regard to their efficacy, route and frequency of administration, adverse effects, and toxicity profile. Better drug delivery systems are being developed in order to decrease adverse effects, increase drug efficacy, and increase patient compliance through the direct targeting of pathologic cells. Here, we address the uses and benefits of advanced drug delivery systems, including nanoparticles, microparticles, fusion antibodies, and liposomal formulations. By altering the properties of therapeutic particles and enhancing targeting, breakthrough drug delivery technologies potentially applicable to multiple disease treatments may rapidly emerge.

Microparticles Mediate Hepatic Ischemia-Reperfusion Injury and Are the Targets of Diannexin (ASP8597)

PubMed Central

Wong, Heng Jian; Croft, Kevin; Mori, Trevor; Farrell, Geoffrey C.

2014-01-01

Background & Aims Ischemia–reperfusion injury (IRI) can cause hepatic failure after liver surgery or transplantation. IRI causes oxidative stress, which injures sinusoidal endothelial cells (SECs), leading to recruitment and activation of Kupffer cells, platelets and microcirculatory impairment. We investigated whether injured SECs and other cell types release microparticles during post-ischemic reperfusion, and whether such microparticles have pro-inflammatory, platelet-activating and pro-injurious effects that could contribute to IRI pathogenesis. Methods C57BL6 mice underwent 60 min of partial hepatic ischemia followed by 15 min–24 hrs of reperfusion. We collected blood and liver samples, isolated circulating microparticles, and determined protein and lipid content. To establish mechanism for microparticle production, we subjected murine primary hepatocytes to hypoxia-reoxygenation. Because microparticles express everted phosphatidylserine residues that are the target of annexin V, we analyzed the effects of an annexin V-homodimer (Diannexin or ASP8597) on post-ischemia microparticle production and function. Results Microparticles were detected in the circulation 15–30 min after post-ischemic reperfusion, and contained markers of SECs, platelets, natural killer T cells, and CD8+ cells; 4 hrs later, they contained markers of macrophages. Microparticles contained F2-isoprostanes, indicating oxidative damage to membrane lipids. Injection of mice with TNF-α increased microparticle formation, whereas Diannexin substantially reduced microparticle release and prevented IRI. Hypoxia-re-oxygenation generated microparticles from primary hepatocytes by processes that involved oxidative stress. Exposing cultured hepatocytes to preparations of microparticles isolated from the circulation during IRI caused injury involving mitochondrial membrane permeability transition. Microparticles also activated platelets and induced neutrophil migration in vitro. The inflammatory properties of microparticles involved activation of NF-κB and JNK, increased expression of E-selectin, P-selectin, ICAM-1 and VCAM-1. All these processes were blocked by coating microparticles with Diannexin. Conclusions Following hepatic IRI, microparticles circulate and can be taken up by hepatocytes, where they activate signaling pathways that mediate inflammation and hepatocyte injury. Diannexin prevents microparticle formation and subsequent inflammation. PMID:25222287

Circulating and Tissue-Resident CD4+ T Cells With Reactivity to Intestinal Microbiota Are Abundant in Healthy Individuals and Function Is Altered During Inflammation.

PubMed

Hegazy, Ahmed N; West, Nathaniel R; Stubbington, Michael J T; Wendt, Emily; Suijker, Kim I M; Datsi, Angeliki; This, Sebastien; Danne, Camille; Campion, Suzanne; Duncan, Sylvia H; Owens, Benjamin M J; Uhlig, Holm H; McMichael, Andrew; Bergthaler, Andreas; Teichmann, Sarah A; Keshav, Satish; Powrie, Fiona

2017-11-01

Interactions between commensal microbes and the immune system are tightly regulated and maintain intestinal homeostasis, but little is known about these interactions in humans. We investigated responses of human CD4 + T cells to the intestinal microbiota. We measured the abundance of T cells in circulation and intestinal tissues that respond to intestinal microbes and determined their clonal diversity. We also assessed their functional phenotypes and effects on intestinal resident cell populations, and studied alterations in microbe-reactive T cells in patients with chronic intestinal inflammation. We collected samples of peripheral blood mononuclear cells and intestinal tissues from healthy individuals (controls, n = 13-30) and patients with inflammatory bowel diseases (n = 119; 59 with ulcerative colitis and 60 with Crohn's disease). We used 2 independent assays (CD154 detection and carboxy-fluorescein succinimidyl ester dilution assays) and 9 intestinal bacterial species (Escherichia coli, Lactobacillus acidophilus, Bifidobacterium animalis subsp lactis, Faecalibacterium prausnitzii, Bacteroides vulgatus, Roseburia intestinalis, Ruminococcus obeum, Salmonella typhimurium, and Clostridium difficile) to quantify, expand, and characterize microbe-reactive CD4 + T cells. We sequenced T-cell receptor Vβ genes in expanded microbe-reactive T-cell lines to determine their clonal diversity. We examined the effects of microbe-reactive CD4 + T cells on intestinal stromal and epithelial cell lines. Cytokines, chemokines, and gene expression patterns were measured by flow cytometry and quantitative polymerase chain reaction. Circulating and gut-resident CD4 + T cells from controls responded to bacteria at frequencies of 40-4000 per million for each bacterial species tested. Microbiota-reactive CD4 + T cells were mainly of a memory phenotype, present in peripheral blood mononuclear cells and intestinal tissue, and had a diverse T-cell receptor Vβ repertoire. These cells were functionally heterogeneous, produced barrier-protective cytokines, and stimulated intestinal stromal and epithelial cells via interleukin 17A, interferon gamma, and tumor necrosis factor. In patients with inflammatory bowel diseases, microbiota-reactive CD4 + T cells were reduced in the blood compared with intestine; T-cell responses that we detected had an increased frequency of interleukin 17A production compared with responses of T cells from blood or intestinal tissues of controls. In an analysis of peripheral blood mononuclear cells and intestinal tissues from patients with inflammatory bowel diseases vs controls, we found that reactivity to intestinal bacteria is a normal property of the human CD4 + T-cell repertoire, and does not necessarily indicate disrupted interactions between immune cells and the commensal microbiota. T-cell responses to commensals might support intestinal homeostasis, by producing barrier-protective cytokines and providing a large pool of T cells that react to pathogens. Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.

Innate immunity and the sensing of infection, damage and danger in the female genital tract.

PubMed

Sheldon, Iain Martin; Owens, Siân-Eleri; Turner, Matthew Lloyd

2017-02-01

Tissue homeostasis in the female genital tract is challenged by infection, damage, and even physiological events during reproductive cycles. We propose that the evolutionarily ancient system of innate immunity is sufficient to sense and respond to danger in the non-pregnant female genital tract. Innate immunity produces a rapidly inducible, non-specific response when cells sense danger. Here we provide a primer on innate immunity and discuss what is known about how danger signals are sensed in the endometrium and ovary, the impact of inflammatory responses on reproduction, and how endocrinology and innate immunity are integrated. Endometrial epithelial and stromal cells, and ovarian granulosa cells express pattern recognition receptors, similar to cells of the innate immune system. These pattern recognition receptors, such as the Toll-like receptors, bind pathogen-associated or damage-associated molecular patterns. Activation of pattern recognition receptors leads to inflammation, recruitment of immune cells from the peripheral circulation, and phagocytosis. Although the inflammatory response helps maintain or restore endometrial health, there may also be negative consequences for fertility, including perturbation of oocyte competence. The intensity of the inflammatory response reflects the balance between the level of danger and the systems that regulate innate immunity, including the endocrine environment. Understanding innate immunity is important because disease and inappropriate inflammatory responses in the endometrium or ovary cause infertility. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Exacerbation of Acute Traumatic Brain Injury by Circulating Extracellular Vesicles.

PubMed

Hazelton, Isla; Yates, Abi; Dale, Ashley; Roodselaar, Jay; Akbar, Naveed; Ruitenberg, Marc J; Anthony, Daniel C; Couch, Yvonne

2018-02-15

Inflammatory lesions in the brain activate a systemic acute-phase response (APR), which is dependent on the release of extracellular vesicles (EVs) into the circulation. The resulting APR is responsible for regulating leukocyte mobilization and subsequent recruitment to the brain. Factors that either exacerbate or inhibit the APR will also exacerbate or inhibit central nervous system (CNS) inflammation as a consequence and have the potential to influence ongoing secondary damage. Here, we were interested to discover how the circulating EV population changes after traumatic brain injury (TBI) and how manipulation of the circulating EV pool impacts on the outcome of TBI. We found the number of circulating EVs increased rapidly post-TBI, and this was accompanied by an increase in CNS and hepatic leukocyte recruitment. In an adoptive transfer study, we then evaluated the outcomes of TBI after administering EVs derived from either in vitro macrophage or endothelial cell lines stimulated with lipopolysaccharide (LPS), or from murine plasma from an LPS challenge using the air-pouch model. By manipulating the circulating EV population, we were able to demonstrate that each population of transferred EVs increased the APR. However, the characteristics of the response were dependent on the nature of the EVs; specifically, it was significantly increased when animals were challenged with macrophage-derived EVs, suggesting that the cellular origins of EVs may determine their function. Selectively targeting EVs from macrophage/monocyte populations is likely to be of value in reducing the impact of the systemic inflammatory response on the outcome of traumatic CNS injury.

Is There a Role for Bioactive Lipids in the Pathobiology of Diabetes Mellitus?

PubMed Central

Das, Undurti N.

2017-01-01

Inflammation, decreased levels of circulating endothelial nitric oxide (eNO) and brain-derived neurotrophic factor (BDNF), altered activity of hypothalamic neurotransmitters (including serotonin and vagal tone) and gut hormones, increased concentrations of free radicals, and imbalance in the levels of bioactive lipids and their pro- and anti-inflammatory metabolites have been suggested to play a role in diabetes mellitus (DM). Type 1 diabetes mellitus (type 1 DM) is due to autoimmune destruction of pancreatic β cells because of enhanced production of IL-6 and tumor necrosis factor-α (TNF-α) and other pro-inflammatory cytokines released by immunocytes infiltrating the pancreas in response to unknown exogenous and endogenous toxin(s). On the other hand, type 2 DM is due to increased peripheral insulin resistance secondary to enhanced production of IL-6 and TNF-α in response to high-fat and/or calorie-rich diet (rich in saturated and trans fats). Type 2 DM is also associated with significant alterations in the production and action of hypothalamic neurotransmitters, eNO, BDNF, free radicals, gut hormones, and vagus nerve activity. Thus, type 1 DM is because of excess production of pro-inflammatory cytokines close to β cells, whereas type 2 DM is due to excess of pro-inflammatory cytokines in the systemic circulation. Hence, methods designed to suppress excess production of pro-inflammatory cytokines may form a new approach to prevent both type 1 and type 2 DM. Roux-en-Y gastric bypass and similar surgeries ameliorate type 2 DM, partly by restoring to normal: gut hormones, hypothalamic neurotransmitters, eNO, vagal activity, gut microbiota, bioactive lipids, BDNF production in the gut and hypothalamus, concentrations of cytokines and free radicals that results in resetting glucose-stimulated insulin production by pancreatic β cells. Our recent studies suggested that bioactive lipids, such as arachidonic acid, eicosapentaneoic acid, and docosahexaenoic acid (which are unsaturated fatty acids) and their anti-inflammatory metabolites: lipoxin A4, resolvins, protectins, and maresins, may have antidiabetic actions. These bioactive lipids have anti-inflammatory actions, enhance eNO, BDNF production, restore hypothalamic dysfunction, enhance vagal tone, modulate production and action of ghrelin, leptin and adiponectin, and influence gut microbiota that may explain their antidiabetic action. These pieces of evidence suggest that methods designed to selectively deliver bioactive lipids to pancreatic β cells, gut, liver, and muscle may prevent type 1 and type 2 DM. PMID:28824543

Redox signaling in acute pancreatitis

PubMed Central

Pérez, Salvador; Pereda, Javier; Sabater, Luis; Sastre, Juan

2015-01-01

Acute pancreatitis is an inflammatory process of the pancreatic gland that eventually may lead to a severe systemic inflammatory response. A key event in pancreatic damage is the intracellular activation of NF-κB and zymogens, involving also calcium, cathepsins, pH disorders, autophagy, and cell death, particularly necrosis. This review focuses on the new role of redox signaling in acute pancreatitis. Oxidative stress and redox status are involved in the onset of acute pancreatitis and also in the development of the systemic inflammatory response, being glutathione depletion, xanthine oxidase activation, and thiol oxidation in proteins critical features of the disease in the pancreas. On the other hand, the release of extracellular hemoglobin into the circulation from the ascitic fluid in severe necrotizing pancreatitis enhances lipid peroxidation in plasma and the inflammatory infiltrate into the lung and up-regulates the HIF–VEGF pathway, contributing to the systemic inflammatory response. Therefore, redox signaling and oxidative stress contribute to the local and systemic inflammatory response during acute pancreatitis. PMID:25778551

Systemic inflammatory response following acute myocardial infarction

PubMed Central

Fang, Lu; Moore, Xiao-Lei; Dart, Anthony M; Wang, Le-Min

2015-01-01

Acute cardiomyocyte necrosis in the infarcted heart generates damage-associated molecular patterns, activating complement and toll-like receptor/interleukin-1 signaling, and triggering an intense inflammatory response. Inflammasomes also recognize danger signals and mediate sterile inflammatory response following acute myocardial infarction (AMI). Inflammatory response serves to repair the heart, but excessive inflammation leads to adverse left ventricular remodeling and heart failure. In addition to local inflammation, profound systemic inflammation response has been documented in patients with AMI, which includes elevation of circulating inflammatory cytokines, chemokines and cell adhesion molecules, and activation of peripheral leukocytes and platelets. The excessive inflammatory response could be caused by a deregulated immune system. AMI is also associated with bone marrow activation and spleen monocytopoiesis, which sustains a continuous supply of monocytes at the site of inflammation. Accumulating evidence has shown that systemic inflammation aggravates atherosclerosis and markers for systemic inflammation are predictors of adverse clinical outcomes (such as death, recurrent myocardial infarction, and heart failure) in patients with AMI. PMID:26089856

Monocytes and Macrophages in Pregnancy and Pre-Eclampsia

PubMed Central

Faas, Marijke M.; Spaans, Floor; De Vos, Paul

2014-01-01

Preeclampsia is an important complication in pregnancy, characterized by hypertension and proteinuria in the second half of pregnancy. Generalized activation of the inflammatory response is thought to play a role in the pathogenesis of pre-eclampsia. Monocytes may play a central role in this inflammatory response. Monocytes are short lived cells that mature in the circulation and invade into tissues upon an inflammatory stimulus and develop into macrophages. Macrophages are abundantly present in the endometrium and play a role in implantation and placentation in normal pregnancy. In pre-eclampsia, these macrophages appear to be present in larger numbers and are also activated. In the present review, we focused on the role of monocytes and macrophages in the pathophysiology of pre-eclampsia. PMID:25071761

Links demystified: Periodontitis and cancer

PubMed Central

Pendyala, Gowri; Joshi, Saurabh; Chaudhari, Shantanu; Gandhage, Dhananjay

2013-01-01

Cancer is marked by the uncontrolled growth of cells, tissue invasion and metastasis to various organs via the circulatory and lymphatic systems. Recent data have expanded the concept that inflammation is a critical component of tumor progression. Many cancers arise from sites of infection, chronic irritation, and inflammation. The tumor microenvironment, which is largely orchestrated by inflammatory cells, is an indispensable participant in the neoplastic process, fostering proliferation, survival, and migration. Periodontal disease, a chronic inflammatory condition is characterized by an oral bacterial infection leading to inflammation within the supporting tissues of the teeth, which often leads to the destruction of the periodontal tissues and alveolar bone that support the teeth. This oral inflammation often has systemic effects leading to an increased concentration of circulating inflammatory markers with the severity of disease being correlated directly with levels of serum inflammatory markers. Periodontal infection has been linked to organ and systemic diseases. There is documented evidence of significant associations between cancer of the lung, kidney, pancreas, hematological and oral cancers, and periodontal disease. This articles reviews and summarizes the possible biological mechanisms involved between periodontal infection and cancer. PMID:24379856

Links demystified: Periodontitis and cancer.

PubMed

Pendyala, Gowri; Joshi, Saurabh; Chaudhari, Shantanu; Gandhage, Dhananjay

2013-11-01

Cancer is marked by the uncontrolled growth of cells, tissue invasion and metastasis to various organs via the circulatory and lymphatic systems. Recent data have expanded the concept that inflammation is a critical component of tumor progression. Many cancers arise from sites of infection, chronic irritation, and inflammation. The tumor microenvironment, which is largely orchestrated by inflammatory cells, is an indispensable participant in the neoplastic process, fostering proliferation, survival, and migration. Periodontal disease, a chronic inflammatory condition is characterized by an oral bacterial infection leading to inflammation within the supporting tissues of the teeth, which often leads to the destruction of the periodontal tissues and alveolar bone that support the teeth. This oral inflammation often has systemic effects leading to an increased concentration of circulating inflammatory markers with the severity of disease being correlated directly with levels of serum inflammatory markers. Periodontal infection has been linked to organ and systemic diseases. There is documented evidence of significant associations between cancer of the lung, kidney, pancreas, hematological and oral cancers, and periodontal disease. This articles reviews and summarizes the possible biological mechanisms involved between periodontal infection and cancer.

Circulating dendritic cells of multiple sclerosis patients are proinflammatory and their frequency is correlated with MS-associated genetic risk factors.

PubMed

Thewissen, Kristof; Nuyts, Amber H; Deckx, Nathalie; Van Wijmeersch, Bart; Nagels, Guy; D'hooghe, Marie; Willekens, Barbara; Cras, Patrick; Eijnde, Bert O; Goossens, Herman; Van Tendeloo, Viggo F I; Stinissen, Piet; Berneman, Zwi N; Hellings, Niels; Cools, Nathalie

2014-04-01

The role of the adaptive immune system and more specifically T cells in the pathogenesis of multiple sclerosis (MS) has been studied extensively. Emerging evidence suggests that dendritic cells (DCs), which are innate immune cells, also contribute to MS. This study aimed to characterize circulating DC populations in MS and to investigate the contribution of MS-associated genetic risk factors to DCs. Ex vivo analysis of conventional (cDCs) and plasmacytoid DCs (pDCs) was carried out on peripheral blood of MS patients (n = 110) and age- and gender-matched healthy controls (n = 112). Circulating pDCs were significantly decreased in patients with chronic progressive MS compared to relapsing-remitting MS and healthy controls. While no differences in cDCs frequency were found between the different study groups, HLA-DRB1*1501(+) MS patients and patients not carrying the protective IL-7Rα haplotype 2 have reduced frequencies of circulating cDCs and pDCs, respectively. MS-derived DCs showed enhanced IL-12p70 production upon TLR ligation and had an increased expression of the migratory molecules CCR5 and CCR7 as well as an enhanced in vitro chemotaxis. DCs in MS are in a pro-inflammatory state, have a migratory phenotype and are affected by genetic risk factors, thereby contributing to pathogenic responses.

Circulating gluten-specific FOXP3+CD39+ regulatory T cells have impaired suppressive function in patients with celiac disease.

PubMed

Cook, Laura; Munier, C Mee Ling; Seddiki, Nabila; van Bockel, David; Ontiveros, Noé; Hardy, Melinda Y; Gillies, Jana K; Levings, Megan K; Reid, Hugh H; Petersen, Jan; Rossjohn, Jamie; Anderson, Robert P; Zaunders, John J; Tye-Din, Jason A; Kelleher, Anthony D

2017-12-01

Celiac disease is a chronic immune-mediated inflammatory disorder of the gut triggered by dietary gluten. Although the effector T-cell response in patients with celiac disease has been well characterized, the role of regulatory T (Treg) cells in the loss of tolerance to gluten remains poorly understood. We sought to define whether patients with celiac disease have a dysfunction or lack of gluten-specific forkhead box protein 3 (FOXP3) + Treg cells. Treated patients with celiac disease underwent oral wheat challenge to stimulate recirculation of gluten-specific T cells. Peripheral blood was collected before and after challenge. To comprehensively measure the gluten-specific CD4 + T-cell response, we paired traditional IFN-γ ELISpot with an assay to detect antigen-specific CD4 + T cells that does not rely on tetramers, antigen-stimulated cytokine production, or proliferation but rather on antigen-induced coexpression of CD25 and OX40 (CD134). Numbers of circulating gluten-specific Treg cells and effector T cells both increased significantly after oral wheat challenge, peaking at day 6. Surprisingly, we found that approximately 80% of the ex vivo circulating gluten-specific CD4 + T cells were FOXP3 + CD39 + Treg cells, which reside within the pool of memory CD4 + CD25 + CD127 low CD45RO + Treg cells. Although we observed normal suppressive function in peripheral polyclonal Treg cells from patients with celiac disease, after a short in vitro expansion, the gluten-specific FOXP3 + CD39 + Treg cells exhibited significantly reduced suppressive function compared with polyclonal Treg cells. This study provides the first estimation of FOXP3 + CD39 + Treg cell frequency within circulating gluten-specific CD4 + T cells after oral gluten challenge of patients with celiac disease. FOXP3 + CD39 + Treg cells comprised a major proportion of all circulating gluten-specific CD4 + T cells but had impaired suppressive function, indicating that Treg cell dysfunction might be a key contributor to disease pathogenesis. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

JAK-STAT Pathway Activation in Malignant and Non-Malignant Cells Contributes to MPN Pathogenesis and Therapeutic Response

PubMed Central

Kleppe, Maria; Kwak, Minsuk; Koppikar, Priya; Riester, Markus; Keller, Matthew; Bastian, Lennart; Hricik, Todd; Bhagwat, Neha; McKenney, Anna Sophia; Papalexi, Efthymia; Abdel-Wahab, Omar; Rampal, Raajit; Marubayashi, Sachie; Chen, Jonathan J.; Romanet, Vincent; Fridman, Jordan S.; Bromberg, Jacqueline; Teruya-Feldstein, Julie; Murakami, Masato; Radimerski, Thomas; Michor, Franziska; Fan, Rong; Levine, Ross L.

2015-01-01

The identification of JAK2/MPL mutations in patients with myeloproliferative neoplasms (MPN) led to the clinical development of JAK kinase inhibitors, including ruxolitinib. Ruxolitinib reduces splenomegaly and systemic symptoms in myelofibrosis (MF) and improves overall survival; however the mechanism by which JAK inhibitors achieve efficacy has not been delineated. MPN patients present with increased levels of circulating pro-inflammatory cytokines, which are mitigated by JAK inhibitor therapy. We sought to elucidate mechanisms by which JAK inhibitors attenuate cytokine-mediated pathophysiology. Single cell profiling demonstrated that hematopoietic cells from MF models and patient samples aberrantly secrete inflammatory cytokines. Pan-hematopoietic Stat3 deletion reduced disease severity and attenuated cytokine secretion, with similar efficacy as observed with ruxolitinib therapy. By contrast, Stat3 deletion restricted to MPN cells did not reduce disease severity or cytokine production. Consistent with these observations, we found that malignant and non-malignant cells aberrantly secrete cytokines and JAK inhibition reduces cytokine production from both populations. PMID:25572172

Developmental changes in circulating IL-8/CXCL8 isoforms in neonates.

PubMed

Maheshwari, Akhil; Voitenok, Nikolai N; Akalovich, Svetlana; Shaik, Sadiq S; Randolph, David A; Sims, Brian; Patel, Rakesh P; Killingsworth, Cheryl R; Fallon, Michael B; Ohls, Robin K

2009-04-01

Interleukin-8 (IL-8/CXCL8) is widely expressed in fetal tissues although inflammatory changes are not seen. Circulating IL-8 is comprised of an endothelial-derived [ala-IL-8](77) isoform and another, more potent [ser-IL-8](72) secreted by most other cells; [ala-IL-8](77) can be converted into [ser-IL-8](72) by proteolytic removal of an N-terminal pentapeptide from [ala-IL-8](77). In this study, we show [ala-IL-8](77) is the predominant circulating isoform of IL-8 in premature neonates but not in term neonates/adults, who have [ser-IL-8](72) as the major isoform. This isoform switch from the less potent [ala-IL-8](77) to [ser-IL-8](72) correlates with a maturational increase in the neutrophil chemotactic potency of plasma IL-8. The emergence of [ser-IL-8](72) as the major isoform is likely due to increased plasma [ala-IL-8](77)-convertase activity and/or changes in the cellular sources of IL-8. Developmental changes in IL-8 isoforms may serve to minimize its inflammatory effects in the fetus and also provide a mechanism to restore its full activity after birth.

The metabolites in peripheral blood mononuclear cells showed greater differences between patients with impaired fasting glucose or type 2 diabetes and healthy controls than those in plasma.

PubMed

Kim, Minjoo; Kim, Minkyung; Han, Ji Yun; Lee, Sang-Hyun; Jee, Sun Ha; Lee, Jong Ho

2017-03-01

To determine differences between peripheral blood mononuclear cells and the plasma metabolites in patients with impaired fasting glucose or type 2 diabetes and healthy controls. In all, 65 nononobese patients (aged 30-70 years) with impaired fasting glucose or type 2 diabetes and 65 nonobese sex-matched healthy controls were included, and fasting peripheral blood mononuclear cell and plasma metabolomes were profiled. The diabetic or impaired fasting glucose patients showed higher circulating and peripheral blood mononuclear cell lipoprotein phospholipase A 2 activities, high-sensitivity C-reactive protein and tumour necrosis factor-α than controls. Compared with controls, impaired fasting glucose or diabetic subjects showed increases in 11 peripheral blood mononuclear cell metabolites: six amino acids (valine, leucine, methionine, phenylalanine, tyrosine and tryptophan), l-pyroglutamic acid, two fatty acid amides containing palmitic amide and oleamide and two lysophosphatidylcholines. In impaired fasting glucose or diabetic patients, peripheral blood mononuclear cell lipoprotein phospholipase A 2 positively associated with peripheral blood mononuclear cell lysophosphatidylcholines and circulating inflammatory markers, including tumour necrosis factor-α, high-sensitivity C-reactive protein and lipoprotein phospholipase A 2 activities. In plasma metabolites between patients and healthy controls, we observed significant increases in only three amino acids (proline, valine and leucine) and decreases in only five lysophosphatidylcholines. This study demonstrates significant differences in the peripheral blood mononuclear cell metabolome in patients with impaired fasting glucose or diabetes compared with healthy controls. These differences were greater than those observed in the plasma metabolome. These data suggest peripheral blood mononuclear cells as a useful tool to better understand the inflammatory pathophysiology of diabetes.

Circulating platelet aggregates damage endothelial cells in culture.

PubMed

Aluganti Narasimhulu, Chandrakala; Nandave, Mukesh; Bonilla, Diana; Singaravelu, Janani; Sai-Sudhakar, Chittoor B; Parthasarathy, Sampath

2017-06-01

Presence of circulating endothelial cells (CECs) in systemic circulation may be an indicator of endothelial damage and/or denudation, and the body's response to repair and revascularization. Thus, we hypothesized that aggregated platelets (AgPlts) can disrupt/denude the endothelium and contribute to the presence of CEC and EC-derived particles (ECDP). Endothelial cells were grown in glass tubes and tagged with/without 0.5 μm fluorescent beads. These glass tubes were connected to a mini-pump variable-flow system to study the effect of circulating AgPlts on the endothelium. ECs in glass tube were exposed to medium alone, nonaggregated platelets (NAgPlts), AgPlts, and 90 micron polystyrene beads at a flow rate of 20 mL/min for various intervals. Collected effluents were cultured for 72 h to analyze the growth potential of dislodged but intact ECs. Endothelial damage was assessed by real time polymerase chain reaction (RT-PCR) for inflammatory genes and Western blot analysis for von Willebrand factor. No ECs and ECDP were observed in effluents collected after injecting medium alone and NAgPlts, whereas AgPlts and Polybeads drastically dislodged ECs, releasing ECs and ECDP in effluents as the time increased. Effluents collected when endothelial cell damage was seen showed increased presence of von Willebrand factor as compared to control effluents. Furthermore, we analyzed the presence of ECs and ECDPs in heart failure subjects, as well as animal plasma samples. Our study demonstrates that circulating AgPlts denude the endothelium and release ECs and ECDP. Direct mechanical disruption and shear stress caused by circulating AgPlts could be the underlying mechanism of the observed endothelium damage. Copyright © 2017 Elsevier Inc. All rights reserved.

Local and Systemic Inflammatory Biomarkers of Diabetic Retinopathy: An Integrative Approach.

PubMed

Vujosevic, Stela; Simó, Rafael

2017-05-01

To review the usefulness of local and systemic inflammatory biomarkers of diabetic retinopathy (DR) to implement a more personalized treatment. An integrated research (from ophthalmologist and diabetologist point of view) of most significant literature on serum, vitreous, and aqueous humor (AH) biochemical biomarkers related to inflammation at early and advanced stages of DR (including diabetic macular edema [DME] and proliferative DR) was performed. Moreover, novel imaging retinal biomarkers of local "inflammatory condition" were described. Multiple inflammatory cytokines and chemokines are increased in DR in both serum as well as in the eye (vitreous and AH). Nevertheless, local rather than systemic production of proinflammatory cytokines seems more relevant in the pathogenesis of both DR and DME. In the eye, retinal glia cells (macroglia and microglia) together with RPE are major sources of proinflammatory and angiogenic modulators. Retinal imaging allows for noninvasive clinical evaluation of retinal inflammatory response induced by diabetes mellitus. Proinflammatory cytokines/chemokines play an essential role in the pathogenesis of DR. Therefore, circulating biomarkers and retinal imaging aimed at assessing inflammation have emerged as useful tools for monitoring the onset and progression of DR. In addition, "liquid biopsy" of AH seems a good option in patients with advanced stages of DR requiring intravitreous injections. This strategy may permit us to implement a more personalized treatment with better visual function outcome. Further evaluation and validation of circulating and local biomarkers, as well as multimodal imaging is needed to gain new insights into this issue.

Sphingosine 1-phosphate receptor 3 regulates recruitment of anti-inflammatory monocytes to microvessels during implant arteriogenesis

PubMed Central

Awojoodu, Anthony O.; Ogle, Molly E.; Sefcik, Lauren S.; Bowers, Daniel T.; Martin, Kyle; Brayman, Kenneth L.; Lynch, Kevin R.; Peirce-Cottler, Shayn M.; Botchwey, Edward

2013-01-01

Endothelial cells play significant roles in conditioning tissues after injury by the production and secretion of angiocrine factors. At least two distinct subsets of monocytes, CD45+CD11b+Gr1+Ly6C+ inflammatory and CD45+CD11b+Gr1−Ly6C− anti-inflammatory monocytes, respond differentially to these angiocrine factors and promote pathogen/debris clearance and arteriogenesis/tissue regeneration, respectively. We demonstrate here that local sphingosine 1-phosphate receptor 3 (S1P3) agonism recruits anti-inflammatory monocytes to remodeling vessels. Poly(lactic-co-glycolic acid) thin films were used to deliver FTY720, an S1P1/3 agonist, to inflamed and ischemic tissues, which resulted in a reduction in proinflammatory cytokine secretion and an increase in regenerative cytokine secretion. The altered balance of cytokine secretion results in preferential recruitment of anti-inflammatory monocytes from circulation. The chemotaxis of these cells, which express more S1P3 than inflammatory monocytes, toward SDF-1α was also enhanced with FTY720 treatment, but not in S1P3 knockout cells. FTY720 delivery enhanced arteriolar diameter expansion and increased length density of the local vasculature. This work establishes a role for S1P receptor signaling in the local conditioning of tissues by angiocrine factors that preferentially recruit regenerative monocytes that can enhance healing outcomes, tissue regeneration, and biomaterial implant functionality. PMID:23918395

Increasing Maternal Body Mass Index Is Associated with Systemic Inflammation in the Mother and the Activation of Distinct Placental Inflammatory Pathways1

PubMed Central

Aye, Irving L.M.H.; Lager, Susanne; Ramirez, Vanessa I.; Gaccioli, Francesca; Dudley, Donald J.; Jansson, Thomas; Powell, Theresa L.

2014-01-01

ABSTRACT Obese pregnant women have increased levels of proinflammatory cytokines in maternal circulation and placental tissues. However, the pathways contributing to placental inflammation in obesity are largely unknown. We tested the hypothesis that maternal body mass index (BMI) was associated with elevated proinflammatory cytokines in maternal and fetal circulations and increased activation of placental inflammatory pathways. A total of 60 women of varying pre-/early pregnancy BMI, undergoing delivery by Cesarean section at term, were studied. Maternal and fetal (cord) plasma were collected for analysis of insulin, leptin, IL-1beta, IL-6, IL-8, monocyte chemoattractant protein (MCP) 1, and TNFalpha by multiplex ELISA. Activation of the inflammatory pathways in the placenta was investigated by measuring the phosphorylated and total protein expression of p38-mitogen-activated protein kinase (MAPK), c-Jun-N-terminal kinase (JNK)-MAPK, signal transducer-activated transcription factor (STAT) 3, caspase-1, IL-1beta, IkappaB-alpha protein, and p65 DNA-binding activity. To determine the link between activated placental inflammatory pathways and elevated maternal cytokines, cultured primary human trophoblast (PHT) cells were treated with physiological concentrations of insulin, MCP-1, and TNFalpha, and inflammatory signaling analyzed by Western blot. Maternal BMI was positively correlated with maternal insulin, leptin, MCP-1, and TNFalpha, whereas only fetal leptin was increased with BMI. Placental phosphorylation of p38-MAPK and STAT3, and the expression of IL-1beta protein, were increased with maternal BMI; phosphorylation of p38-MAPK was also correlated with birth weight. In contrast, placental NFkappaB, JNK and caspase-1 signaling, and fetal cytokine levels were unaffected by maternal BMI. In PHT cells, p38-MAPK was activated by MCP-1 and TNFalpha, whereas STAT3 phosphorylation was increased following TNFalpha treatment. Maternal BMI is associated with elevated maternal cytokines and activation of placental p38-MAPK and STAT3 inflammatory pathways, without changes in fetal systemic inflammatory profile. Activation of p38-MAPK by MCP-1 and TNFalpha, and STAT3 by TNFalpha, suggests a link between elevated proinflammatory cytokines in maternal plasma and activation of placental inflammatory pathways. We suggest that inflammatory processes associated with elevated maternal BMI may influence fetal growth by altering placental function. PMID:24759787

Increasing maternal body mass index is associated with systemic inflammation in the mother and the activation of distinct placental inflammatory pathways.

PubMed

Aye, Irving L M H; Lager, Susanne; Ramirez, Vanessa I; Gaccioli, Francesca; Dudley, Donald J; Jansson, Thomas; Powell, Theresa L

2014-06-01

Obese pregnant women have increased levels of proinflammatory cytokines in maternal circulation and placental tissues. However, the pathways contributing to placental inflammation in obesity are largely unknown. We tested the hypothesis that maternal body mass index (BMI) was associated with elevated proinflammatory cytokines in maternal and fetal circulations and increased activation of placental inflammatory pathways. A total of 60 women of varying pre-/early pregnancy BMI, undergoing delivery by Cesarean section at term, were studied. Maternal and fetal (cord) plasma were collected for analysis of insulin, leptin, IL-1beta, IL-6, IL-8, monocyte chemoattractant protein (MCP) 1, and TNFalpha by multiplex ELISA. Activation of the inflammatory pathways in the placenta was investigated by measuring the phosphorylated and total protein expression of p38-mitogen-activated protein kinase (MAPK), c-Jun-N-terminal kinase (JNK)-MAPK, signal transducer-activated transcription factor (STAT) 3, caspase-1, IL-1beta, IkappaB-alpha protein, and p65 DNA-binding activity. To determine the link between activated placental inflammatory pathways and elevated maternal cytokines, cultured primary human trophoblast (PHT) cells were treated with physiological concentrations of insulin, MCP-1, and TNFalpha, and inflammatory signaling analyzed by Western blot. Maternal BMI was positively correlated with maternal insulin, leptin, MCP-1, and TNFalpha, whereas only fetal leptin was increased with BMI. Placental phosphorylation of p38-MAPK and STAT3, and the expression of IL-1beta protein, were increased with maternal BMI; phosphorylation of p38-MAPK was also correlated with birth weight. In contrast, placental NFkappaB, JNK and caspase-1 signaling, and fetal cytokine levels were unaffected by maternal BMI. In PHT cells, p38-MAPK was activated by MCP-1 and TNFalpha, whereas STAT3 phosphorylation was increased following TNFalpha treatment. Maternal BMI is associated with elevated maternal cytokines and activation of placental p38-MAPK and STAT3 inflammatory pathways, without changes in fetal systemic inflammatory profile. Activation of p38-MAPK by MCP-1 and TNFalpha, and STAT3 by TNFalpha, suggests a link between elevated proinflammatory cytokines in maternal plasma and activation of placental inflammatory pathways. We suggest that inflammatory processes associated with elevated maternal BMI may influence fetal growth by altering placental function. © 2014 by the Society for the Study of Reproduction, Inc.

The CD14+CD16+ Inflammatory Monocyte Subset Displays Increased Mitochondrial Activity and Effector Function During Acute Plasmodium vivax Malaria

PubMed Central

Antonelli, Lis R. V.; Leoratti, Fabiana M. S.; Costa, Pedro A. C.; Rocha, Bruno C.; Diniz, Suelen Q.; Tada, Mauro S.; Pereira, Dhelio B.; Teixeira-Carvalho, Andrea; Golenbock, Douglas T.; Gonçalves, Ricardo; Gazzinelli, Ricardo T.

2014-01-01

Infection with Plasmodium vivax results in strong activation of monocytes, which are important components of both the systemic inflammatory response and parasite control. The overall goal of this study was to define the role of monocytes during P. vivax malaria. Here, we demonstrate that P. vivax–infected patients display significant increase in circulating monocytes, which were defined as CD14+CD16− (classical), CD14+CD16+ (inflammatory), and CD14loCD16+ (patrolling) cells. While the classical and inflammatory monocytes were found to be the primary source of pro-inflammatory cytokines, the CD16+ cells, in particular the CD14+CD16+ monocytes, expressed the highest levels of activation markers, which included chemokine receptors and adhesion molecules. Morphologically, CD14+ were distinguished from CD14lo monocytes by displaying larger and more active mitochondria. CD14+CD16+ monocytes were more efficient in phagocytizing P. vivax-infected reticulocytes, which induced them to produce high levels of intracellular TNF-α and reactive oxygen species. Importantly, antibodies specific for ICAM-1, PECAM-1 or LFA-1 efficiently blocked the phagocytosis of infected reticulocytes by monocytes. Hence, our results provide key information on the mechanism by which CD14+CD16+ cells control parasite burden, supporting the hypothesis that they play a role in resistance to P. vivax infection. PMID:25233271

Inflammatory cytokines and chemokines, skeletal muscle and polycystic ovary syndrome: effects of pioglitazone and metformin treatment.

PubMed

Ciaraldi, Theodore P; Aroda, Vanita; Mudaliar, Sunder R; Henry, Robert R

2013-11-01

Chronic low-grade inflammation is a common feature of insulin resistant states, including obesity and type 2 diabetes. Less is known about inflammation in Polycystic Ovary Syndrome (PCOS). Thus we evaluated the impact of PCOS on circulating cytokine levels and the effects of anti-diabetic therapies on insulin action, cytokine and chemokine levels and inflammatory signaling in skeletal muscle. Twenty subjects with PCOS and 12 healthy normal cycling (NC) subjects of similar body mass index were studied. PCOS subjects received oral placebo or pioglitazone, 45 mg/d, for 6 months. All PCOS subjects then had metformin, 2 g/day, added to their treatment. Circulating levels of cytokines, chemokines, and adiponectin, skeletal muscle markers of inflammation and phosphorylation of signaling proteins, insulin action evaluated by the hyperinsulinemic/euglycemic clamp procedure and Homeostasis Model Assessment of Insulin Resistance were measured. Circulating levels of a number of cytokines and chemokines were generally similar between PCOS and NC subjects. Levels in PCOS subjects were not altered by pioglitazone or metformin treatment, even though whole body insulin action and adiponectin levels increased with pioglitazone. In spite of the lack of change in levels of cytokines and chemokines, several markers of inflammation in skeletal muscle were improved with Pio treatment. PCOS may represent a state of elevated sensitivity of inflammatory cells in skeletal muscle to cytokines and chemokines, a property that could be reversed by pioglitazone treatment together with improved insulin action. © 2013.

Chronic hyperinsulinemia promotes meta-inflammation and extracellular matrix deposition in adipose tissue: Implications of nitric oxide.

PubMed

Kumar, Durgesh; Shankar, Kripa; Patel, Saraswati; Gupta, Abhishek; Varshney, Salil; Gupta, Sanchita; Rajan, Sujith; Srivastava, Ankita; Vishwakarma, Achchhe Lal; Gaikwad, Anil N

2018-05-10

Various imperative studies support the notion that hyperinsulinemia (HI) itself serves as the common link between adipose tissue inflammation (ATI) and metabolic syndrome. However, the contribution of HI mediated ATI and its metabolic consequences are yet to be explored. We induced chronic HI per se in mice by administration of exogenous insulin for 8 weeks through mini-osmotic pumps. For the reduction of circulating insulin in response to excess calorie intake, we have partially ablated β-cells by using streptozotocin (STZ) in the diet-induced obesity (DIO) and genetic mice models (db/db). Flow cytometry analysis was performed for the quantification of immune cells in stromal vascular fraction (SVF) isolated from epididymal white adipose tissue (eWAT). Our studies demonstrated that chronic HI augmented ATI in terms of elevated pro-inflammatory cells (M1 macrophages and NK-cells) and suppressed anti-inflammatory cells (M2 macrophages, eosinophils and regulatory T-cells). These results were correlated with altered obesity-associated metabolic phenotype. Partial reduction of circulating insulin level attenuated excess calorie-induced ATI and improved insulin sensitivity. Mechanistically, an imbalance in M1 and M2 macrophage proportions in eWAT promoted iNOS (inducible nitric oxide synthase): arginase-1 imbalance that resulted into extracellular matrix (ECM) deposition and insulin resistance (IR) development. However, iNOS -/- mice were protected from HI-induced M1:M2 macrophage imbalance, ECM deposition and IR in adipose tissue. Overall, we conclude that chronic HI per se contributed in ATI and iNOS corroborated ECM deposition. Copyright © 2018. Published by Elsevier B.V.

Endotoxin-induced lung alveolar cell injury causes brain cell damage.

PubMed

Rodríguez-González, Raquel; Ramos-Nuez, Ángela; Martín-Barrasa, José Luis; López-Aguilar, Josefina; Baluja, Aurora; Álvarez, Julián; Rocco, Patricia R M; Pelosi, Paolo; Villar, Jesús

2015-01-01

Sepsis is the most common cause of acute respiratory distress syndrome, a severe lung inflammatory disorder with an elevated morbidity and mortality. Sepsis and acute respiratory distress syndrome involve the release of inflammatory mediators to the systemic circulation, propagating the cellular and molecular response and affecting distal organs, including the brain. Since it has been reported that sepsis and acute respiratory distress syndrome contribute to brain dysfunction, we investigated the brain-lung crosstalk using a combined experimental in vitro airway epithelial and brain cell injury model. Conditioned medium collected from an in vitro lipopolysaccharide-induced airway epithelial cell injury model using human A549 alveolar cells was subsequently added at increasing concentrations (no conditioned, 2%, 5%, 10%, 15%, 25%, and 50%) to a rat mixed brain cell culture containing both astrocytes and neurons. Samples from culture media and cells from mixed brain cultures were collected before treatment, and at 6 and 24 h for analysis. Conditioned medium at 15% significantly increased apoptosis in brain cell cultures 24 h after treatment, whereas 25% and 50% significantly increased both necrosis and apoptosis. Levels of brain damage markers S100 calcium binding protein B and neuron-specific enolase, interleukin-6, macrophage inflammatory protein-2, as well as matrix metalloproteinase-9 increased significantly after treating brain cells with ≥2% conditioned medium. Our findings demonstrated that human epithelial pulmonary cells stimulated with bacterial lipopolysaccharide release inflammatory mediators that are able to induce a translational clinically relevant and harmful response in brain cells. These results support a brain-lung crosstalk during sepsis and sepsis-induced acute respiratory distress syndrome. © 2014 by the Society for Experimental Biology and Medicine.

The Potential Role of Aerobic Exercise-Induced Pentraxin 3 on Obesity-Related Inflammation and Metabolic Dysregulation.

PubMed

Slusher, Aaron L; Huang, Chun-Jung; Acevedo, Edmund O

2017-01-01

Obesity is defined as the excess accumulation of intra-abdominal body fat, resulting in a state of chronic, low-grade proinflammation that can directly contribute to the development of insulin resistance. Pentraxin 3 (PTX3) is an acute-phase protein that is expressed by a variety of tissue and cell sources and provides an anti-inflammatory property to downregulate the production of proinflammatory cytokines, in particular interleukin-1 beta and tumor necrosis factor alpha. Although PTX3 may therapeutically aid in altering the proinflammatory milieu in obese individuals, and despite elevated expression of PTX3 mRNA observed in adipose tissue, the circulating level of PTX3 is reduced with obesity. Interestingly, aerobic activity has been demonstrated to elevate PTX3 levels. Therefore, the purpose of this review is to discuss the therapeutic potential of PTX3 to positively regulate obesity-related inflammation and discuss the proposition for utilizing aerobic exercise as a nonpharmacological anti-inflammatory treatment strategy to enhance circulating PTX3 concentrations in obese individuals.

Tumors Alter Inflammation and Impair Dermal Wound Healing in Female Mice

PubMed Central

Pyter, Leah M.; Husain, Yasmin; Calero, Humberto; McKim, Daniel B.; Lin, Hsin-Yun; Godbout, Jonathan P.; Sheridan, John F.; Engeland, Christopher G.; Marucha, Phillip T.

2016-01-01

Tissue repair is an integral component of cancer treatment (e.g., due to surgery, chemotherapy, radiation). Previous work has emphasized the immunosuppressive effects of tumors on adaptive immunity and has shown that surgery incites cancer metastases. However, the extent to which and how tumors may alter the clinically-relevant innate immune process of wound healing remains an untapped potential area of improvement for treatment, quality of life, and ultimately, mortality of cancer patients. In this study, 3.5 mm full-thickness dermal excisional wounds were placed on the dorsum of immunocompetent female mice with and without non-malignant flank AT-84 murine oral squamous cell carcinomas. Wound closure rate, inflammatory cell number and inflammatory signaling in wounds, and circulating myeloid cell concentrations were compared between tumor-bearing and tumor-free mice. Tumors delayed wound closure, suppressed inflammatory signaling, and altered myeloid cell trafficking in wounds. An in vitro scratch “wounding” assay of adult dermal fibroblasts treated with tumor cell-conditioned media supported the in vivo findings. This study demonstrates that tumors are sufficient to disrupt fundamental and clinically-relevant innate immune functions. The understanding of these underlying mechanisms provides potential for therapeutic interventions capable of improving the treatment of cancer while reducing morbidities and mortality. PMID:27548621

DOE Office of Scientific and Technical Information (OSTI.GOV)

Choi, Hong Seo; Lee, Hyun Min; Kim, Won-Tae

Highlights: • This study generates a monoclonal antibody CA27 against the mycoplasmal p37 protein. • CA27 isolates circulating tumor cells (CTCs) from the blood of liver cancer patients. • Results show the first evidence for mycoplasma infected-CTCs in cancer patients. - Abstract: Many studies have shown that persistent infections of bacteria promote carcinogenesis and metastasis. Infectious agents and their products can modulate cancer progression through the induction of host inflammatory and immune responses. The presence of circulating tumor cells (CTCs) is considered as an important indicator in the metastatic cascade. We unintentionally produced a monoclonal antibody (MAb) CA27 against themore » mycoplasmal p37 protein in mycoplasma-infected cancer cells during the searching process of novel surface markers of CTCs. Mycoplasma-infected cells were enriched by CA27-conjugated magnetic beads in the peripheral blood mononuclear cells in patients with hepatocellular carcinoma (HCC) and analyzed by confocal microscopy with anti-CD45 and CA27 antibodies. CD45-negative and CA27-positive cells were readily detected in three out of seven patients (range 12–30/8.5 ml blood), indicating that they are mycoplasma-infected circulating epithelial cells. CA27-positive cells had larger size than CD45-positive hematological lineage cells, high nuclear to cytoplasmic ratios and irregular nuclear morphology, which identified them as CTCs. The results show for the first time the existence of mycoplasma-infected CTCs in patients with HCC and suggest a possible correlation between mycoplasma infection and the development of cancer metastasis.« less

Inflammatory Monocytes Mediate Early and Organ-Specific Innate Defense During Systemic Candidiasis

PubMed Central

Ngo, Lisa Y.; Kasahara, Shinji; Kumasaka, Debra K.; Knoblaugh, Sue E.; Jhingran, Anupam; Hohl, Tobias M.

2014-01-01

Candida albicans is a commensal fungus that can cause systemic disease in patients with breaches in mucosal integrity, indwelling catheters, and defects in phagocyte function. Although circulating human and murine monocytes bind C. albicans and promote inflammation, it remains unclear whether C-C chemokine receptor 2 (CCR2)– and Ly6C-expressing inflammatory monocytes exert a protective or a deleterious function during systemic infection. During murine systemic candidiasis, interruption of CCR2-dependent inflammatory monocyte trafficking into infected kidneys impaired fungal clearance and decreased murine survival. Depletion of CCR2-expressing cells led to uncontrolled fungal growth in the kidneys and brain and demonstrated an essential antifungal role for inflammatory monocytes and their tissue-resident derivatives in the first 48 hours postinfection. Adoptive transfer of purified inflammatory monocytes in depleted hosts reversed the defect in fungal clearance to a substantial extent, indicating a compartmentally and temporally restricted protective function that can be transferred to enhance systemic innate antifungal immunity. PMID:23922372

Xenogeneic human umbilical cord-derived mesenchymal stem cells reduce mortality in rats with acute respiratory distress syndrome complicated by sepsis

PubMed Central

Wallace, Christopher Glenn; Sung, Pei-Hsun; Sheu, Jiunn-Jye; Chung, Sheng-Ying; Chen, Yung-Lung; Lu, Hung-I; Ko, Sheung-Fat; Sun, Cheuk-Kwan; Chiang, Hsin-Ju; Chang, Hsueh-Wen; Lee, Mel S.; Yip, Hon-Kan

2017-01-01

This study tested the hypothesis that xenogeneic human umbilical cord-derived mesenchymal stem cell (HUCDMSC) therapy would improve survival rates in rats with acute respiratory distress-syndrome (ARDS, induction by 48 h inhalation of 100% oxygen) and sepsis-syndrome (SS, induction by cecal-ligation and puncture) (ARDS-SS). Adult-male Sprague-Dawley rats were categorized into group 1 (sham-controls), group 2 (ARDS-SS), group 3 [ARDS-SS+HUCDMSC (1.2 ×106 cells administered 1 h after SS-induction)], and group 4 [ARDS-SS+HUCDMSC (1.2 ×106 cells administered 24 h after SS-induction)]. The mortality rate was higher in groups 2 and 4 than in groups 1 and 3 (all p<0.0001). The blood pressure after 28 h was lower in groups 2, 3 and 4 (p<0.0001) than in group 1. Albumin levels and percentages of inflammatory cells in broncho-alveolar lavage fluid, and the percentages of inflammatory and immune cells in circulation, were lowest in group 1, highest in group 2, and higher in group 3 than group 4 (all p<0.0001). The percentages of inflammatory cells in ascites and kidney parenchyma showed identical patterns, as did kidney injury scores (all p<0.0001). EarlyHUCDMSC therapy reduced rodent mortality after induced ARDS-SS. PMID:28484089

Xenogeneic human umbilical cord-derived mesenchymal stem cells reduce mortality in rats with acute respiratory distress syndrome complicated by sepsis.

PubMed

Lee, Fan-Yen; Chen, Kuan-Hung; Wallace, Christopher Glenn; Sung, Pei-Hsun; Sheu, Jiunn-Jye; Chung, Sheng-Ying; Chen, Yung-Lung; Lu, Hung-I; Ko, Sheung-Fat; Sun, Cheuk-Kwan; Chiang, Hsin-Ju; Chang, Hsueh-Wen; Lee, Mel S; Yip, Hon-Kan

2017-07-11

This study tested the hypothesis that xenogeneic human umbilical cord-derived mesenchymal stem cell (HUCDMSC) therapy would improve survival rates in rats with acute respiratory distress-syndrome (ARDS, induction by 48 h inhalation of 100% oxygen) and sepsis-syndrome (SS, induction by cecal-ligation and puncture) (ARDS-SS). Adult-male Sprague-Dawley rats were categorized into group 1 (sham-controls), group 2 (ARDS-SS), group 3 [ARDS-SS+HUCDMSC (1.2 ×106 cells administered 1 h after SS-induction)], and group 4 [ARDS-SS+HUCDMSC (1.2 ×106 cells administered 24 h after SS-induction)]. The mortality rate was higher in groups 2 and 4 than in groups 1 and 3 (all p<0.0001). The blood pressure after 28 h was lower in groups 2, 3 and 4 (p<0.0001) than in group 1. Albumin levels and percentages of inflammatory cells in broncho-alveolar lavage fluid, and the percentages of inflammatory and immune cells in circulation, were lowest in group 1, highest in group 2, and higher in group 3 than group 4 (all p<0.0001). The percentages of inflammatory cells in ascites and kidney parenchyma showed identical patterns, as did kidney injury scores (all p<0.0001). EarlyHUCDMSC therapy reduced rodent mortality after induced ARDS-SS.

Hypercholesterolemia induces T cell expansion in humanized immune mice.

PubMed

Proto, Jonathan D; Doran, Amanda C; Subramanian, Manikandan; Wang, Hui; Zhang, Mingyou; Sozen, Erdi; Rymond, Christina C; Kuriakose, George; D'Agati, Vivette; Winchester, Robert; Sykes, Megan; Yang, Yong-Guang; Tabas, Ira

2018-06-01

Emerging data suggest that hypercholesterolemia has stimulatory effects on adaptive immunity and that these effects can promote atherosclerosis and perhaps other inflammatory diseases. However, research in this area has relied primarily on inbred strains of mice whose adaptive immune system can differ substantially from that of humans. Moreover, the genetically induced hypercholesterolemia in these models typically results in plasma cholesterol levels that are much higher than those in most humans. To overcome these obstacles, we studied human immune system-reconstituted mice (hu-mice) rendered hypercholesterolemic by treatment with adeno-associated virus 8-proprotein convertase subtilisin/kexin type 9 (AAV8-PCSK9) and a high-fat/high-cholesterol Western-type diet (WD). These mice had a high percentage of human T cells and moderate hypercholesterolemia. Compared with hu-mice that had lower plasma cholesterol, the PCSK9-WD mice developed a T cell-mediated inflammatory response in the lung and liver. Human CD4+ and CD8+ T cells bearing an effector memory phenotype were significantly elevated in the blood, spleen, and lungs of PCSK9-WD hu-mice, whereas splenic and circulating regulatory T cells were reduced. These data show that moderately high plasma cholesterol can disrupt human T cell homeostasis in vivo. This process may not only exacerbate atherosclerosis, but also contribute to T cell-mediated inflammatory diseases in the hypercholesterolemia setting.

Quantification of mast cells in different stages of periodontal disease.

PubMed

Marjanović, Dragan; Andjelković, Zlatibor; Brkić, Zlata; Videnović, Goran; Šehalić, Meliha; Matvjenko, Vladimir; Leštarević, Snežana; Djordjević, Nadica

2016-05-01

Mast cells are mononuclear cells originating from bone marrow. They produce various biologically active substances, which allow them to actively participate in immune and inflammatory processes associated with periodontal disease. The study focused on distribution and density of mast cells in healthy gingiva as well as in different stages of periodontal disease. The material used for this purpose was gingival biopsies taken from 96 patients classified into 4 groups: healthy gingiva, gingivitis, initial and severe periodontal disease. Toluidine blue staining according to Spicer was utilized for identifying mast cells. Basing on our study, the density of mast cells in the gingival tissue increases with the progression of the infection, which means they are more numerous in gingivitis compared to healthy gingiva, as well as in periodontal disease compared to gingivitis. Increase in the number of mast cells in the infected gingiva can be correlated with an increased influx of inflammatory cells from blood circulation into the gingival stroma, as well as with the collagen lysis, since these cells produce substances with collagenolytic potential. Based on the distribution of mast cells, it could be concluded that in the evolution of periodontal disease there are significant dynamic alterations in migration and localization of these cells.

Human colonic myocytes are involved in postischemic inflammation through ADAM17-dependent TNFα production

PubMed Central

Jarry, Anne; Bach-Ngohou, Kalyane; Masson, Damien; Dejoie, Thomas; Lehur, Paul-Antoine; Mosnier, Jean-François; Denis, Marc G; Laboisse, Christian L

2005-01-01

The aim of this study was to identify human colonic resident cells able to initiate an inflammatory response in postischemic injury. Postischemic colonic injury, a condition relevant to various clinical settings, involves an inflammatory cascade in intestinal tissues through the recruitment of circulating inflammatory cells. However, there is no information on the nature of resident cells of the different intestinal layers able to initiate a postischemic inflammatory response. It is however an important issue in the context of a pharmacological approach of the early phase of intestinal ischemia. We reasoned that maintaining the different colonic layers as explant cultures in an oxygenated medium immediately after colonic resection, that is, after an ischemic period, would allow one to identify the resident cells able to initiate an inflammatory cascade, without interference of recruited inflammatory/immune cells. To this end, we designed an explant culture system that operationally defines three compartments in surgical specimens of the human colon, based on the microdissected layers, that is, mucosa, submucosa (containing muscularis mucosae) and muscularis propria. To validate the results obtained in explant cultures in the clinical setting of ischemic colitis, eight cases of sigmoid volvulus were examined. Only the myocytes-containing explants produced tumor necrosis factor alpha (TNFα), via an ADAM17 (a disintegrin and metalloproteinase-17)-dependent pathway, as shown by the abrogation of TNFα production by the inhibitor Tapi-2. Immunofluorescence studies identified nonvascular and vascular myocytes as resident cells coexpressing TNFα and ADAM17, both in our postischemic explant system and in surgical specimens from ischemic colitis patients. Finally, time-course experiments on explanted tissues showed that TNFα production by myocytes was an early event triggered by a postischemic oxidative stress involving nuclear factor kappa B (NF-κB). In conclusion, this study identifies human intestinal myocytes as resident cells able to initiate an inflammatory reaction through TNFα production in postischemic conditions, and delineates two points of control in TNFα production, NF-κB and ADAM17, which can be targeted by pharmacological manipulation. PMID:16273118

Homeostatic regulation of T cell trafficking by a B cell-derived peptide is impaired in autoimmune and chronic inflammatory disease.

PubMed

Chimen, Myriam; McGettrick, Helen M; Apta, Bonita; Kuravi, Sahithi J; Yates, Clara M; Kennedy, Amy; Odedra, Arjun; Alassiri, Mohammed; Harrison, Matthew; Martin, Ashley; Barone, Francesca; Nayar, Saba; Hitchcock, Jessica R; Cunningham, Adam F; Raza, Karim; Filer, Andrew; Copland, David A; Dick, Andrew D; Robinson, Joseph; Kalia, Neena; Walker, Lucy S K; Buckley, Christopher D; Nash, Gerard B; Narendran, Parth; Rainger, G Ed

2015-05-01

During an inflammatory response, lymphocyte recruitment into tissue must be tightly controlled because dysregulated trafficking contributes to the pathogenesis of chronic disease. Here we show that during inflammation and in response to adiponectin, B cells tonically inhibit T cell trafficking by secreting a peptide (PEPITEM) proteolytically derived from 14.3.3 zeta delta (14.3.3.ζδ) protein. PEPITEM binds cadherin-15 on endothelial cells, promoting synthesis and release of sphingosine-1 phosphate, which inhibits trafficking of T cells without affecting recruitment of other leukocytes. Expression of adiponectin receptors on B cells and adiponectin-induced PEPITEM secretion wanes with age, implying immune senescence of the pathway. Additionally, these changes are evident in individuals with type 1 diabetes or rheumatoid arthritis, and circulating PEPITEM in patient serum is reduced compared to that of healthy age-matched donors. In both diseases, tonic inhibition of T cell trafficking across inflamed endothelium is lost. Control of patient T cell trafficking is re-established by treatment with exogenous PEPITEM. Moreover, in animal models of peritonitis, hepatic ischemia-reperfusion injury, Salmonella infection, uveitis and Sjögren's syndrome, PEPITEM reduced T cell recruitment into inflamed tissues.

Homeostatic regulation of T cell trafficking by a B cell derived peptide is impaired in autoimmune and chronic inflammatory disease

PubMed Central

Apta, Bonita; Kuravi, Sahithi J.; Yates, Clara M.; Kennedy, Amy; Odedra, Arjun; Alassiri, Mohammed; Harrison, Matthew; Martin, Ashley; Barone, Francesca; Nayar, Saba; Hitchcock, Jessica R.; Cunningham, Adam F.; Raza, Karim; Filer, Andrew; Copland, David A.; Dick, Andrew D.; Robinson, Joseph; Kalia, Neena; Walker, Lucy S. K.; Buckley, Christopher D.; Nash, Gerard B.; Narendran, Parth; Rainger, G. Ed.

2015-01-01

During an inflammatory response, lymphocyte recruitment into tissue must be tightly controlled because dysregulated trafficking contributes to the pathogenesis of chronic disease. Here we show that during inflammation and in response to adiponectin, B cells tonically inhibit T cell trafficking by secreting a peptide (PEPITEM) proteolytically derived from 14.3.3.ζδ protein. PEPITEM binds cadherin-15 on endothelial cells, promoting synthesis and release of sphingosine-1 phosphate, which inhibits trafficking of T cells without affecting recruitment of other leukocytes. Expression of adiponectin receptors on B cells and adiponectin induced PEPITEM secretion wanes with age, implying immune senescence of the pathway. Additionally, these changes are evident in individuals with type-1-diabetes or rheumatoid arthritis, and circulating PEPITEM in patient serum is reduced compared to healthy age matched donors. In both diseases, tonic inhibition of T cell trafficking across inflamed endothelium is lost. Importantly, control of patient T cell trafficking is re-established by exogenous PEPITEM. Moreover, in animal models of peritonitis, hepatic I/R injury, Salmonella infection, Uveitis and Sjögren’s Syndrome, PEPITEM could reduce T cell recruitment into inflamed tissues. PMID:25894827

An exploratory study of inflammatory cytokines as prognostic biomarkers in patients with ductal pancreatic adenocarcinoma.

PubMed

Dima, Simona O; Tanase, Cristiana; Albulescu, Radu; Herlea, Vlad; Chivu-Economescu, Mihaela; Purnichescu-Purtan, Raluca; Dumitrascu, Traian; Duda, Dan G; Popescu, Irinel

2012-10-01

We measured the serum concentration of a panel of inflammatory cytokines and evaluated their association with circulating proangiogenic biomarkers and with outcome in patients with pancreatic ductal adenocarcinoma (PDAC). We collected serum samples from 36 patients with PDAC, 9 patients with chronic pancreatitis, and 22 healthy volunteers as a control. Inflammatory cytokines and proangiogenic biomarkers were measured using the multianalyte xMAP array and carcinoembryonic antigen (CEA) and carbohydrate 19-9 by immunoassay. Patients with PDAC had higher circulating levels of interleukin 6 (IL-6) than those of patients with pancreatitis or healthy individuals and higher levels of IL-10 and tumor necrosis factor α (TNF-α) compared with those of healthy individuals. In patients with PDAC, circulating IL-6, TNF-α, IL-1β, and IL-10 correlated with serum concentrations of vascular endothelial growth factor and basic fibroblast growth factor; circulating IL-6, IL-1β, and TNF-α correlated with carbohydrate 19-9; and IL-8, IL-10, and TNF-α correlated with CEA levels. Circulating IL-8, TNF-α, and CEA; tumor stage; and lymph node metastases were associated with a poor outcome. The results of this exploratory study indicate that inflammatory cytokines should be pursued as potential prognostic biomarkers as well as targets for therapy in larger studies in PDAC.

Altered Methylation Profile of Lymphocytes Is Concordant with Perturbation of Lipids Metabolism and Inflammatory Response in Obesity

PubMed Central

Jacobsen, Mette J.; Mentzel, Caroline M. Junker; Olesen, Ann Sofie; Huby, Thierry; Jørgensen, Claus B.; Barrès, Romain; Fredholm, Merete

2016-01-01

Obesity is associated with immunological perturbations that contribute to insulin resistance. Epigenetic mechanisms can control immune functions and have been linked to metabolic complications, although their contribution to insulin resistance still remains unclear. In this study, we investigated the link between metabolic dysfunction and immune alterations with the epigenetic signature in leukocytes in a porcine model of obesity. Global DNA methylation of circulating leukocytes, adipose tissue leukocyte trafficking, and macrophage polarisation were established by flow cytometry. Adipose tissue inflammation and metabolic function were further characterised by quantification of metabolites and expression levels of genes associated with obesity and inflammation. Here we show that obese pigs showed bigger visceral fat pads, higher levels of circulating LDL cholesterol, and impaired glucose tolerance. These changes coincided with impaired metabolism, sustained macrophages infiltration, and increased inflammation in the adipose tissue. Those immune alterations were linked to global DNA hypermethylation in both B-cells and T-cells. Our results provide novel insight into the possible contribution of immune cell epigenetics into the immunological disturbances observed in obesity. The dramatic changes in the transcriptomic and epigenetic signature of circulating lymphocytes reinforce the concept that epigenetic processes participate in the increased immune cell activation and impaired metabolic functions in obesity. PMID:26798656

Sterile Inflammation of Brain, due to Activation of Innate Immunity, as a Culprit in Psychiatric Disorders

PubMed Central

Ratajczak, Mariusz Z.; Pedziwiatr, Daniel; Cymer, Monika; Kucia, Magda; Kucharska-Mazur, Jolanta; Samochowiec, Jerzy

2018-01-01

Evidence has accumulated that the occurrence of psychiatric disorders is related to chronic inflammation. In support of this linkage, changes in the levels of circulating pro-inflammatory cytokines and chemokines in the peripheral blood (PB) of psychiatric patients as well as correlations between chronic inflammatory processes and psychiatric disorders have been described. Furthermore, an inflammatory process known as “sterile inflammation” when initiated directly in brain tissue may trigger the onset of psychoses. In this review, we will present the hypothesis that prolonged or chronic activation of the complement cascade (ComC) directly triggers inflammation in the brain and affects the proper function of this organ. Based on the current literature and our own work on mechanisms activating the ComC we hypothesize that inflammation in the brain is initiated by the mannan-binding lectin pathway of ComC activation. This activation is triggered by an increase in brain tissue of danger-associated molecular pattern (DAMP) mediators, including extracellular ATP and high-mobility group box 1 (HMGB1) protein, which are recognized by circulating pattern-recognition receptors, including mannan-binding lectin (MBL), that activate the ComC. On the other hand, this process is controlled by the anti-inflammatory action of heme oxygenase 1 (HO-1). In this review, we will try to connect changes in the release of DAMPs in the brain with inflammatory processes triggered by the innate immunity involving activation of the ComC as well as the inflammation-limiting effects of the anti-inflammatory HO-1 pathway. We will also discuss parallel observations that during ComC activation subsets of stem cells are mobilized into PB from bone marrow that are potentially involved in repair mechanisms. PMID:29541038

Sterile Inflammation of Brain, due to Activation of Innate Immunity, as a Culprit in Psychiatric Disorders.

PubMed

Ratajczak, Mariusz Z; Pedziwiatr, Daniel; Cymer, Monika; Kucia, Magda; Kucharska-Mazur, Jolanta; Samochowiec, Jerzy

2018-01-01

Evidence has accumulated that the occurrence of psychiatric disorders is related to chronic inflammation. In support of this linkage, changes in the levels of circulating pro-inflammatory cytokines and chemokines in the peripheral blood (PB) of psychiatric patients as well as correlations between chronic inflammatory processes and psychiatric disorders have been described. Furthermore, an inflammatory process known as "sterile inflammation" when initiated directly in brain tissue may trigger the onset of psychoses. In this review, we will present the hypothesis that prolonged or chronic activation of the complement cascade (ComC) directly triggers inflammation in the brain and affects the proper function of this organ. Based on the current literature and our own work on mechanisms activating the ComC we hypothesize that inflammation in the brain is initiated by the mannan-binding lectin pathway of ComC activation. This activation is triggered by an increase in brain tissue of danger-associated molecular pattern (DAMP) mediators, including extracellular ATP and high-mobility group box 1 (HMGB1) protein, which are recognized by circulating pattern-recognition receptors, including mannan-binding lectin (MBL), that activate the ComC. On the other hand, this process is controlled by the anti-inflammatory action of heme oxygenase 1 (HO-1). In this review, we will try to connect changes in the release of DAMPs in the brain with inflammatory processes triggered by the innate immunity involving activation of the ComC as well as the inflammation-limiting effects of the anti-inflammatory HO-1 pathway. We will also discuss parallel observations that during ComC activation subsets of stem cells are mobilized into PB from bone marrow that are potentially involved in repair mechanisms.

Participation of blood vessel cells in human adaptive immune responses.

PubMed

Pober, Jordan S; Tellides, George

2012-01-01

Circulating T cells contact blood vessels either when they extravasate across the walls of microvessels into inflamed tissues or when they enter into the walls of larger vessels in inflammatory diseases such as atherosclerosis. The blood vessel wall is largely composed of three cell types: endothelial cells lining the entire vascular tree; pericytes supporting the endothelium of microvessels; and smooth muscle cells forming the bulk of large vessel walls. Each of these cell types interacts with and alters the behavior of infiltrating T cells in different ways, making these cells active participants in the processes of immune-mediated inflammation. In this review, we compare and contrast what is known about the nature of these interactions in humans. Copyright © 2011 Elsevier Ltd. All rights reserved.

Protein S is protective in pulmonary fibrosis.

PubMed

Urawa, M; Kobayashi, T; D'Alessandro-Gabazza, C N; Fujimoto, H; Toda, M; Roeen, Z; Hinneh, J A; Yasuma, T; Takei, Y; Taguchi, O; Gabazza, E C

2016-08-01

Essentials Epithelial cell apoptosis is critical in the pathogenesis of idiopathic pulmonary fibrosis. Protein S, a circulating anticoagulant, inhibited apoptosis of lung epithelial cells. Overexpression of protein S in lung cells reduced bleomycin-induced pulmonary fibrosis. Intranasal therapy with exogenous protein S ameliorated bleomycin-induced pulmonary fibrosis. Background Pulmonary fibrosis is the terminal stage of interstitial lung diseases, some of them being incurable and of unknown etiology. Apoptosis plays a critical role in lung fibrogenesis. Protein S is a plasma anticoagulant with potent antiapoptotic activity. The role of protein S in pulmonary fibrosis is unknown. Objectives To evaluate the clinical relevance of protein S and its protective role in pulmonary fibrosis. Methods and Results The circulating level of protein S was measured in patients with pulmonary fibrosis and controls by the use of enzyme immunoassays. Pulmonary fibrosis was induced with bleomycin in transgenic mice overexpressing human protein S and wild-type mice, and exogenous protein S or vehicle was administered to wild-type mice; fibrosis was then compared in both models. Patients with pulmonary fibrosis had reduced circulating levels of protein S as compared with controls. Inflammatory changes, the levels of profibrotic cytokines, fibrosis score, hydroxyproline content in the lungs and oxygen desaturation were significantly reduced in protein S-transgenic mice as compared with wild-type mice. Wild-type mice treated with exogenous protein S showed significant decreases in the levels of inflammatory and profibrotic markers and fibrosis in the lungs as compared with untreated control mice. After bleomycin infusion, mice overexpressing human protein S showed significantly low caspase-3 activity, enhanced expression of antiapoptotic molecules and enhanced Akt and Axl kinase phosphorylation as compared with wild-type counterparts. Protein S also inhibited apoptosis of alveolar epithelial cells in vitro. Conclusions These observations suggest clinical relevance and a protective role of protein S in pulmonary fibrosis. © 2016 International Society on Thrombosis and Haemostasis.

T helper type 2-polarized invariant natural killer T cells reduce disease severity in acute intra-abdominal sepsis

PubMed Central

Anantha, R V; Mazzuca, D M; Xu, S X; Porcelli, S A; Fraser, D D; Martin, C M; Welch, I; Mele, T; Haeryfar, S M M; McCormick, J K

2014-01-01

Sepsis is characterized by a severe systemic inflammatory response to infection that is associated with high morbidity and mortality despite optimal care. Invariant natural killer T (iNK T) cells are potent regulatory lymphocytes that can produce pro- and/or anti-inflammatory cytokines, thus shaping the course and nature of immune responses; however, little is known about their role in sepsis. We demonstrate here that patients with sepsis/severe sepsis have significantly elevated proportions of iNK T cells in their peripheral blood (as a percentage of their circulating T cells) compared to non-septic patients. We therefore investigated the role of iNK T cells in a mouse model of intra-abdominal sepsis (IAS). Our data show that iNK T cells are pathogenic in IAS, and that T helper type 2 (Th2) polarization of iNK T cells using the synthetic glycolipid OCH significantly reduces mortality from IAS. This reduction in mortality is associated with the systemic elevation of the anti-inflammatory cytokine interleukin (IL)-13 and reduction of several proinflammatory cytokines within the spleen, notably interleukin (IL)-17. Finally, we show that treatment of sepsis with OCH in mice is accompanied by significantly reduced apoptosis of splenic T and B lymphocytes and macrophages, but not natural killer cells. We propose that modulation of iNK T cell responses towards a Th2 phenotype may be an effective therapeutic strategy in early sepsis. PMID:24965554

Drag reducing polymers decrease hepatic injury and metastases after liver ischemia-reperfusion

PubMed Central

Yazdani, Hamza O.; Sud, Vikas; Goswami, Julie; Loughran, Patricia; Huang, Hai; Simmons, Richard L.; Tsung, Allan

2017-01-01

Introduction Surgery, a crucial therapeutic modality in the treatment of solid tumors, can induce sterile inflammatory processes which can result in metastatic progression. Liver ischemia and reperfusion (I/R) injury, an inevitable consequence of hepatic resection of metastases, has been shown to foster hepatic capture of circulating cancer cells and accelerate metastatic growth. Efforts to reduce these negative consequences have not been thoroughly investigated. Drag reducing polymers (DRPs) are blood-soluble macromolecules that can, in nanomolar concentrations, increase tissue perfusion, decrease vascular resistance and decrease near-wall microvascular concentration of neutrophils and platelets thereby possibly reducing the inflammatory microenvironment. We hypothesize that DRP can potentially be used to ameliorate metastatic capture of tumor cells and tumor growth within the I/R liver. Methods Experiments were performed utilizing a segmental ischemia model of mice livers. Five days prior or immediately prior to ischemia, murine colon adenocarcinoma cells (MC38) were injected into the spleen. DRP (polyethylene oxide) or a control of low-molecular-weight polyethylene glycol without drag reducing properties were administered intraperitoneally at the onset of reperfusion. Results After three weeks from I/R, we observed that liver I/R resulted in an increased ability to capture and foster growth of circulating tumor cells; in addition, the growth of pre-existing micrometastases was accelerated three weeks later. These effects were significantly curtailed when mice were treated with DRPs at the time of I/R. Mechanistic investigations in vivo indicated that DRPs protected the livers from I/R injury as evidenced by significant decreases in hepatocellular damage, neutrophil recruitment into the liver, formation of neutrophil extracellular traps, deposition of platelets, formation of microthrombi within the liver sinusoids and release of inflammatory cytokines. Conclusions DRPs significantly attenuated metastatic tumor development and growth. DRPs warrant further investigation as a potential treatment for liver I/R injury in the clinical setting to improve cancer-specific outcomes. PMID:28938688

Anti-angiogenic and anti-inflammatory effects of long-circulating liposomes co-encapsulating curcumin and doxorubicin on C26 murine colon cancer cells.

PubMed

Sesarman, Alina; Tefas, Lucia; Sylvester, Bianca; Licarete, Emilia; Rauca, Valentin; Luput, Lavinia; Patras, Laura; Banciu, Manuela; Porfire, Alina

2018-04-01

Emerging treatment options for colon cancer are needed to overcome the limitations regarding the side effects of current chemotherapeutics and drug resistance. The goal of this study was to assess the antitumor actions of PEGylated long-circulating liposomes (LCL) co-delivering curcumin (CURC) and doxorubicin (DOX) on murine colon carcinoma cells (C26). The cytotoxicity of CURC and DOX, administered alone or in combination, either in free or LCL form, was evaluated with regard to antiproliferative effects on C26 cells and to protumor processes that might be affected. Our results indicated that PEGylated LCL-CURC-DOX exerted strong antiproliferative effects on C26 cells, slightly exceeding those induced by free CURC-DOX, but higher than either agent administered alone in their free form. These effects of LCL-CURC-DOX were due to the inhibition of the production of angiogenic/inflammatory proteins in a NF-κB-dependent manner, but were independent of ROS production or AP-1 c-Jun activation. Notable, the anti-angiogenic actions of LCL-CURC-DOX appeared to be much stronger than those induced by the co-administration of CURC and DOX in their free form, on C26 colon cancer cells. LCL-CURC-DOX demonstrated enhanced cytotoxicity on C26 murine colon cancer cells by inhibiting the production of the majority of factors involved in tumor-associated angiogenesis and inflammation and is now being evaluated in vivo regarding its efficacy towards tumor growth in colon cancer. Copyright © 2017 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier B.V. All rights reserved.

Is there an optimal vitamin D status for immunity in athletes and military personnel?

PubMed

He, Cheng-Shiun; Aw Yong, Xin Hui; Walsh, Neil P; Gleeson, Michael

2016-01-01

Vitamin D is mainly obtained through sunlight ultraviolet-B (UVB) exposure of the skin, with a small amount typically coming from the diet.It is now clear that vitamin D has important roles beyond its well-known effects on calcium and bone homeostasis. Immune cells express the vitamin D receptor, including antigen presenting cells, T cells and B cells, and these cells are all capable of synthesizing the biologically active vitamin D metabolite, 1, 25 hydroxy vitamin D.There has been growing interest in the benefits of supplementing vitamin D as studies report vitamin D insufficiency (circulating 25(OH)D < 50 nmol/L) in more than half of all athletes and military personnel tested during the winter, when skin sunlight UVB is negligible. The overwhelming evidence supports avoiding vitamin D deficiency (25(OH)D< 30 nmol/L)to maintain immunity and prevent upper respiratory illness (URI) in athletes and military personnel.Recent evidence supports an optimal circulating 25(OH)D of 75 nmol/L to prevent URI and enhance innate immunity and mucosal immunity and bring about anti-inflammatory actions through the induction of regulatory T cells and the inhibition of pro-inflammatory cytokine production. We provide practical recommendations for how vitamin D sufficiency can be achieved in most individuals by safe sunlight exposure in the summer and daily 1, 000 IU vitamin D3 supplementation in the winter. Studies are required in athletes and military personnel to determine the impact of these recommendations on immunity and URI; and,to demonstrate the purported benefit of achieving 25(OH)D>75 nmol/L. Copyright © 2015 International Society of Exercise and Immunology. All rights reserved.

Prevention of vascular inflammation by nanoparticle targeting of adherent neutrophils

NASA Astrophysics Data System (ADS)

Wang, Zhenjia; Li, Jing; Cho, Jaehyung; Malik, Asrar B.

2014-03-01

Inflammatory diseases such as acute lung injury and ischaemic tissue injury are caused by the adhesion of a type of white blood cell--polymorphonuclear neutrophils--to the lining of the circulatory system or vascular endothelium and unchecked neutrophil transmigration. Nanoparticle-mediated targeting of activated neutrophils on vascular endothelial cells at the site of injury may be a useful means of directly inactivating neutrophil transmigration and hence mitigating vascular inflammation. Here, we report a method employing drug-loaded albumin nanoparticles, which efficiently deliver drugs into neutrophils adherent to the surface of the inflamed endothelium. Using intravital microscopy of tumour necrosis factor-α-challenged mouse cremaster post-capillary venules, we demonstrate that fluorescently tagged albumin nanoparticles are largely internalized by neutrophils adherent to the activated endothelium via cell surface Fcɣ receptors. Administration of albumin nanoparticles loaded with the spleen tyrosine kinase inhibitor, piceatannol, which blocks `outside-in' β2 integrin signalling in leukocytes, detached the adherent neutrophils and elicited their release into the circulation. Thus, internalization of drug-loaded albumin nanoparticles into neutrophils inactivates the pro-inflammatory function of activated neutrophils, thereby offering a promising approach for treating inflammatory diseases resulting from inappropriate neutrophil sequestration and activation.

Dysregulated Homeostasis of Acetylcholine Levels in Immune Cells of RR-Multiple Sclerosis Patients.

PubMed

Di Bari, Maria; Reale, Marcella; Di Nicola, Marta; Orlando, Viviana; Galizia, Sabrina; Porfilio, Italo; Costantini, Erica; D'Angelo, Chiara; Ruggieri, Serena; Biagioni, Stefano; Gasperini, Claudio; Tata, Ada Maria

2016-11-30

Multiple sclerosis (MS) is characterized by pro-inflammatory cytokine production. Acetylcholine (ACh) contributes to the modulation of central and peripheral inflammation. We studied the homeostasis of the cholinergic system in relation to cytokine levels in immune cells and sera of relapsing remitting-MS (RR-MS) patients. We demonstrated that lower ACh levels in serum of RR-MS patients were inversely correlated with the increased activity of the hydrolyzing enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Interestingly, the expression of the ACh biosynthetic enzyme and the protein carriers involved in non-vesicular ACh release were found overexpressed in peripheral blood mononuclear cells of MS patients. The inflammatory state of the MS patients was confirmed by increased levels of TNFα, IL-12/IL-23p40, IL-18. The lower circulating ACh levels in sera of MS patients are dependent on the higher activity of cholinergic hydrolyzing enzymes. The smaller ratio of ACh to TNFα, IL-12/IL-23p40 and IL-18 in MS patients, with respect to healthy donors (HD), is indicative of an inflammatory environment probably related to the alteration of cholinergic system homeostasis.

Dysregulated Homeostasis of Acetylcholine Levels in Immune Cells of RR-Multiple Sclerosis Patients

PubMed Central

Di Bari, Maria; Reale, Marcella; Di Nicola, Marta; Orlando, Viviana; Galizia, Sabrina; Porfilio, Italo; Costantini, Erica; D’Angelo, Chiara; Ruggieri, Serena; Biagioni, Stefano; Gasperini, Claudio; Tata, Ada Maria

2016-01-01

Multiple sclerosis (MS) is characterized by pro-inflammatory cytokine production. Acetylcholine (ACh) contributes to the modulation of central and peripheral inflammation. We studied the homeostasis of the cholinergic system in relation to cytokine levels in immune cells and sera of relapsing remitting-MS (RR-MS) patients. We demonstrated that lower ACh levels in serum of RR-MS patients were inversely correlated with the increased activity of the hydrolyzing enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Interestingly, the expression of the ACh biosynthetic enzyme and the protein carriers involved in non-vesicular ACh release were found overexpressed in peripheral blood mononuclear cells of MS patients. The inflammatory state of the MS patients was confirmed by increased levels of TNFα, IL-12/IL-23p40, IL-18. The lower circulating ACh levels in sera of MS patients are dependent on the higher activity of cholinergic hydrolyzing enzymes. The smaller ratio of ACh to TNFα, IL-12/IL-23p40 and IL-18 in MS patients, with respect to healthy donors (HD), is indicative of an inflammatory environment probably related to the alteration of cholinergic system homeostasis. PMID:27916909

Systemic metabolic signaling in acute and chronic gastrointestinal inflammation of inflammatory bowel diseases.

PubMed

Karrasch, T; Obermeier, F; Straub, R H

2014-06-01

Acute and chronic intestinal inflammation stimulates innate and adaptive immune systems, thereby increasing energy demand of activated immune cells. Energy regulation by systemically released mediators is of critical importance for homeostasis. We wanted to find out how systemic metabolic mediators are affected during intestinal inflammation. A total of 123 patients suffering from Crohn's disease (CD), 76 patients with ulcerative colitis (UC), and 21 healthy controls were recruited. Patients receiving systemic steroids or therapy regimens including biologicals (anti-TNF) were excluded from the study. Serum levels of IL-6, CRP, insulin, glucose, free fatty acid, and RBP-4 were measured by ELISA and RIA. Intestinal inflammation was accompanied by elevated systemic inflammatory para-meters such as IL-6 and CRP in UC and CD and, concomitantly, with elevated insulin levels and increased insulin/glucose ratio in patients with UC. This indicates insulin resistance in liver, muscle, and fat. In addition, intestinal inflammation was associated with elevated levels of circulating free fatty acids in UC and CD, indicating an activation of the organism's appeal for energy-rich substrates (energy appeal reaction). RBP-4 serum levels were also high in acute and chronic intestinal inflammation in UC and CD, which can support insulin resistance. The organism's "energy appeal reaction" in response to acute and chronic inflammation provides free energy in the circulation, which is needed by inflammatory cells. A major mechanism of the redirection program is insulin resistance. New therapeutic strategies might be developed in the future, directly impacting on the storage and utilization of energy-rich fuels. © Georg Thieme Verlag KG Stuttgart · New York.

Parkinson disease-associated LRRK2 G2019S transgene disrupts marrow myelopoiesis and peripheral Th17 response.

PubMed

Park, Jeongho; Lee, Jang-Won; Cooper, Scott C; Broxmeyer, Hal E; Cannon, Jason R; Kim, Chang H

2017-10-01

Parkinson's disease (PD) is a neurodegenerative disease, whereas Crohn's disease is an inflammatory bowel disease. Interestingly, polymorphisms in the LRRK2 gene have been identified as risk factors for both diseases. LRRK2 G2019S is the most prevalent mutation found in PD. To gain insights into the role of the LRRK2 G2019S gene on the development and activation of the immune system in the brain-gut axis, we investigated the effect of LRRK2 G2019S on bone marrow myeloid progenitors and myeloid cell function in the periphery. We used bacterial artificial chromosome transgenic rats harboring the human LRRK2 G2019S gene. LRRK2 G2019S transgene decreased the numbers of monocytic and granulocytic progenitors in the bone marrow. However, the numbers of peripheral, immature myeloid cells with suppressive activity were increased in the gut and blood circulation of LRRK2 G2019S compared with control rats in various acute and chronic inflammatory responses. In inflammatory conditions, Th17 cell activity was suppressed, but tissue-associated phylum Bacteroidetes was abnormally increased in the intestine of LRRK2 G2019S rats. The abnormally expanded myeloid cells because of the LRRK2 G2019S gene were highly suppressive on Th17 cell differentiation. Moreover, we found that inhibition of LRRK2 kinase affects myeloid progenitors and myeloid cell differentiation. Taken together, the results indicate that abnormal LRRK2 activity can alter bone marrow myelopoiesis, peripheral myeloid cell differentiation, and intestinal immune homeostasis. These findings may have ramifications in immune and inflammatory responses in patients with LRRK2 abnormalities. © Society for Leukocyte Biology.

Leptin does not induce an inflammatory response in the murine placenta.

PubMed

Appel, S; Turnwald, E-M; Alejandre-Alcazar, M A; Ankerne, J; Rother, E; Janoschek, R; Wohlfarth, M; Vohlen, C; Schnare, M; Meißner, U; Dötsch, J

2014-06-01

Leptin is described as a pro-inflammatory signal in fat tissue, which is released from adipocytes and in turn activates immune cells. Also, leptin levels are known to be increased in pregnancies complicated with enhanced inflammatory processes in the placenta. Hence, we assumed that increased leptin amounts might contribute to inducing an inflammatory response in the placenta. To test this hypothesis, pregnant mice were continuously infused with recombinant murine leptin s. c. from day g13 to g16, resulting in a 3-fold increase of maternal circulating serum leptin levels. Dissected placentas were examined for the expression of pro-inflammatory cytokines IL-6 and TNF-alpha and the anti-inflammatory cytokine IL-10 using qPCR analysis. No changes were found except for TNF-alpha, which was slightly elevated upon leptin stimulation. However, TNF-alpha protein levels were not significantly higher in placentas from leptin treated mice. Also, leukocyte infiltration in the labyrinth section of placentas was not increased. In summary, our data demonstrate for the first time that elevated leptin levels alone do not induce an inflammatory response in the placenta. © Georg Thieme Verlag KG Stuttgart · New York.

Microparticles Engineered to Highly Express Peroxisome Proliferator-Activated Receptor-γ Decreased Inflammatory Mediator Production and Increased Adhesion of Recipient Monocytes

PubMed Central

Sahler, Julie; Woeller, Collynn F.; Phipps, Richard P.

2014-01-01

Circulating blood microparticles are submicron vesicles released primarily by megakaryocytes and platelets that act as transcellular communicators. Inflammatory conditions exhibit elevated blood microparticle numbers compared to healthy conditions. Direct functional consequences of microparticle composition, especially internal composition, on recipient cells are poorly understood. Our objective was to evaluate if microparticle composition could impact the function of recipient cells, particularly during inflammatory provocation. We therefore engineered the composition of megakaryocyte culture-derived microparticles to generate distinct microparticle populations that were given to human monocytes to assay for influences recipient cell function. Herein, we tested the responses of monocytes exposed to either control microparticles or microparticles that contain the anti-inflammatory transcription factor, peroxisome proliferator-activated receptor-γ (PPARγ). In order to normalize relative microparticle abundance from two microparticle populations, we implemented a novel approach that utilizes a Nanodrop Spectrophotometer to assay for microparticle density rather than concentration. We found that when given to peripheral blood mononuclear cells, microparticles were preferentially internalized by CD11b+ cells, and furthermore, microparticle composition had a profound functional impact on recipient monocytes. Specifically, microparticles containing PPARγ reduced activated monocyte production of the proinflammatory cytokines interleukin-8 and monocyte chemotactic protein-1 compared to activated monocytes exposed to control microparticles. Additionally, treatment with PPARγ microparticles greatly increased monocyte cell adherence. This change in morphology occurred simultaneously with increased production of the key extracellular matrix protein, fibronectin and increased expression of the fibronectin-binding integrin, ITGA5. PPARγ microparticles also changed monocyte mRNA levels of several genes including those under PPARγ control. Overall, the delivery of PPARγ from microparticles to human monocytes influenced gene expression, decreased inflammatory mediator production and increased monocyte adherence. These results support the concept that the composition of blood microparticles has a profound impact on the function of cells with which they interact, and likely plays a role in vascular inflammation. PMID:25426628

Microparticles engineered to highly express peroxisome proliferator-activated receptor-γ decreased inflammatory mediator production and increased adhesion of recipient monocytes.

PubMed

Sahler, Julie; Woeller, Collynn F; Phipps, Richard P

2014-01-01

Circulating blood microparticles are submicron vesicles released primarily by megakaryocytes and platelets that act as transcellular communicators. Inflammatory conditions exhibit elevated blood microparticle numbers compared to healthy conditions. Direct functional consequences of microparticle composition, especially internal composition, on recipient cells are poorly understood. Our objective was to evaluate if microparticle composition could impact the function of recipient cells, particularly during inflammatory provocation. We therefore engineered the composition of megakaryocyte culture-derived microparticles to generate distinct microparticle populations that were given to human monocytes to assay for influences recipient cell function. Herein, we tested the responses of monocytes exposed to either control microparticles or microparticles that contain the anti-inflammatory transcription factor, peroxisome proliferator-activated receptor-γ (PPARγ). In order to normalize relative microparticle abundance from two microparticle populations, we implemented a novel approach that utilizes a Nanodrop Spectrophotometer to assay for microparticle density rather than concentration. We found that when given to peripheral blood mononuclear cells, microparticles were preferentially internalized by CD11b+ cells, and furthermore, microparticle composition had a profound functional impact on recipient monocytes. Specifically, microparticles containing PPARγ reduced activated monocyte production of the proinflammatory cytokines interleukin-8 and monocyte chemotactic protein-1 compared to activated monocytes exposed to control microparticles. Additionally, treatment with PPARγ microparticles greatly increased monocyte cell adherence. This change in morphology occurred simultaneously with increased production of the key extracellular matrix protein, fibronectin and increased expression of the fibronectin-binding integrin, ITGA5. PPARγ microparticles also changed monocyte mRNA levels of several genes including those under PPARγ control. Overall, the delivery of PPARγ from microparticles to human monocytes influenced gene expression, decreased inflammatory mediator production and increased monocyte adherence. These results support the concept that the composition of blood microparticles has a profound impact on the function of cells with which they interact, and likely plays a role in vascular inflammation.

Time-course study of different innate immune mediators produced by UV-irradiated skin: comparative effects of short and daily versus a single harmful UV exposure.

PubMed

Cela, Eliana M; Friedrich, Adrian; Paz, Mariela L; Vanzulli, Silvia I; Leoni, Juliana; González Maglio, Daniel H

2015-05-01

The modulatory effects of solar UV radiation on the immune system have been widely studied. As the skin is the main target of UV radiation, our purpose was to compare the impact on skin innate immunity of two contrasting ways to be exposed to sunlight. Hairless mice were UV irradiated with a single high UV dose simulating a harmful exposure, or with repetitive low UV doses simulating short occasional daily exposures. Skin samples were taken at different times after UV irradiation to evaluate skin histology, inflammatory cell recruitment, epidermal T-cell population and the mitochondrial function of epidermal cells. The transcriptional profiles of pro-inflammatory cytokines, chemokines, antimicrobial peptides and Toll-like receptors were evaluated by RT-PCR and ELISA in tissue homogenates. Finally, a lymphangiography was performed to assess modification in the lymphatic vessel system. A single high UV dose produces a deep inflammatory state characterized by the production of pro-inflammatory cytokines and chemokines that, in turn, induces the recruitment of neutrophils and macrophages into the irradiated area. On the other hand, repetitive low UV doses drive the skin to a photo-induced alert state in which there is no sign of inflammation, but the epithelium undergoes changes in thickness, the lymphatic circulation increases, and the transcription of antimicrobial peptides is induced. © 2014 John Wiley & Sons Ltd.

Resistant Starch Regulates Gut Microbiota: Structure, Biochemistry and Cell Signalling.

PubMed

Yang, Xiaoping; Darko, Kwame Oteng; Huang, Yanjun; He, Caimei; Yang, Huansheng; He, Shanping; Li, Jianzhong; Li, Jian; Hocher, Berthold; Yin, Yulong

2017-01-01

Starch is one of the most popular nutritional sources for both human and animals. Due to the variation of its nutritional traits and biochemical specificities, starch has been classified into rapidly digestible, slowly digestible and resistant starch. Resistant starch has its own unique chemical structure, and various forms of resistant starch are commercially available. It has been found being a multiple-functional regulator for treating metabolic dysfunction. Different functions of resistant starch such as modulation of the gut microbiota, gut peptides, circulating growth factors, circulating inflammatory mediators have been characterized by animal studies and clinical trials. In this mini-review, recent remarkable progress in resistant starch on gut microbiota, particularly the effect of structure, biochemistry and cell signaling on nutrition has been summarized, with highlights on its regulatory effect on gut microbiota. © 2017 The Author(s). Published by S. Karger AG, Basel.

Chronic systemic IL-1β exacerbates central neuroinflammation independently of the blood-brain barrier integrity.

PubMed

Murta, Verónica; Farías, María Isabel; Pitossi, Fernando Juan; Ferrari, Carina Cintia

2015-01-15

Peripheral circulating cytokines are involved in immune to brain communication and systemic inflammation is considered a risk factor for flaring up the symptoms in most neurodegenerative diseases. We induced both central inflammatory demyelinating lesion, and systemic inflammation with an interleukin-1β expressing adenovector. The peripheral pro-inflammatory stimulus aggravated the ongoing central lesion independently of the blood-brain barrier (BBB) integrity. This model allows studying the role of specific molecules and cells (neutrophils) from the innate immune system, in the relationship between central and peripheral communication, and on relapsing episodes of demyelinating lesions, along with the role of BBB integrity. Copyright © 2014 Elsevier B.V. All rights reserved.

Resolution of inflammation by interleukin-9-producing type 2 innate lymphoid cells

PubMed Central

Rauber, Simon; Luber, Markus; Weber, Stefanie; Maul, Lisa; Soare, Alina; Wohlfahrt, Thomas; Lin, Neng-Yu; Dietel, Katharina; Bozec, Aline; Herrmann, Martin; Kaplan, Mark H.; Weigmann, Benno; Zaiss, Mario M.; Fearon, Ursula; Veale, Douglas J.; Canete, Juan D.; Distler, Oliver; Rivellese, Felice; Pitzalis, Costantino; Neurath, Markus F.; McKenzie, Andrew N.J.; Wirtz, Stefan; Schett, Georg; Distler, Jörg H.W.; Ramming, Andreas

2017-01-01

Inflammatory diseases such as arthritis are chronic conditions that fail to resolve spontaneously. While the cytokine and cellular pathways triggering arthritis are well defined, those responsible for the resolution of inflammation are incompletely characterized. Here we identified IL-9-producing type 2 innate lymphoid cells (ILC2s) as a molecular and cellular pathway that orchestrates the resolution of chronic inflammation. In mice, the absence of IL-9 impaired ILC2 proliferation, activation of regulatory T cells (Treg) and resulted in chronic arthritis with excessive cartilage destruction and bone loss. In contrast, treatment with IL-9 promoted ILC2-dependent Treg activation and effectively induced resolution of inflammation and protection of bone. Rheumatoid arthritis patients in remission demonstrated high numbers of IL-9+ ILC2s in the joints and in the circulation. Hence, fostering IL-9-mediated ILC2 activation may offer a novel therapeutic approach inducing resolution of inflammation rather than suppression of inflammatory responses. PMID:28714991

Pharmacological inhibition of myostatin suppresses systemic inflammation and muscle atrophy in mice with chronic kidney disease.

PubMed

Zhang, Liping; Rajan, Vik; Lin, Eugene; Hu, Zhaoyong; Han, H Q; Zhou, Xiaolan; Song, Yanping; Min, Hosung; Wang, Xiaonan; Du, Jie; Mitch, William E

2011-05-01

Chronic kidney disease (CKD) and several other catabolic conditions are characterized by increased circulating inflammatory cytokines, defects in IGF-1 signaling, abnormal muscle protein metabolism, and progressive muscle atrophy. In these conditions, no reliable treatments successfully block the development of muscle atrophy. In mice with CKD, we found a 2- to 3-fold increase in myostatin expression in muscle. Its pharmacological inhibition by subcutaneous injections of an anti-myostatin peptibody into CKD mice (IC(50) ∼1.2 nM) reversed the loss of body weight (≈5-7% increase in body mass) and muscle mass (∼10% increase in muscle mass) and suppressed circulating inflammatory cytokines vs. results from CKD mice injected with PBS. Pharmacological myostatin inhibition also decreased the rate of protein degradation (16.38 ± 1.29%; P<0.05), increased protein synthesis in extensor digitorum longus muscles (13.21 ± 1.09%; P<0.05), markedly enhanced satellite cell function, and improved IGF-1 intracellular signaling. In cultured muscle cells, TNF-α increased myostatin expression via a NF-κB-dependent pathway, whereas muscle cells exposed to myostatin stimulated IL-6 production via p38 MAPK and MEK1 pathways. Because IL-6 stimulates muscle protein breakdown, we conclude that CKD increases myostatin through cytokine-activated pathways, leading to muscle atrophy. Myostatin antagonism might become a therapeutic strategy for improving muscle growth in CKD and other conditions with similar characteristics.

Selective induction of phospholipase D1 in pathogen-activated human monocytes.

PubMed

Locati, M; Riboldi, E; Bonecchi, R; Transidico, P; Bernasconi, S; Haribabu, B; Morris, A J; Mantovani, A; Sozzani, S

2001-08-15

Phospholipase D (PLD) activation is part of the complex signalling cascade induced during phagocyte activation. Two PLD isoforms have been cloned, but their role in phagocyte functions is still poorly defined. We report that resting fresh circulating human monocytes expressed PLD1. PLD1 protein expression was rapidly down-regulated during cell culture. Lipopolysaccharide and pathogen-derived agonists (Candida albicans, arabinoside-terminated lipoarabinomannan and Gram-positive bacteria, but not mannose-capped lipoarabinomannan or double-stranded RNA) strongly induced PLD1 expression at both the mRNA and protein levels. Pro-inflammatory cytokines [interleukin (IL)-1beta and tumour necrosis factor alpha] had only a weak effect, whereas immune cytokines (IL-6 and interferon gamma), anti-inflammatory cytokines (IL-13 and IL-10) and chemoattractants (fMet-Leu-Phe and macrophage chemoattractant protein 1) were inactive. None of the agonists tested induced significant changes in the basal expression of PLD2 mRNA. Consistent with PLD1 up-regulation was the observation that PLD enzymic activity was higher in monocytes treated with active-pathogen-derived agonists than in control cells, when stimulated with PMA or with chemotactic agonists (fMet-Leu-Phe and C5a). Thus PLD2 seems to be a constitutive enzyme in circulating monocytes. Conversely, PLD1 is an inducible protein, rapidly regulated during culture conditions and selectively induced during cell activation. Therefore PLD1 might have a relevant role in immune responses against pathogens and in chronic inflammation.

Circulating microparticles: square the circle

PubMed Central

2013-01-01

Background The present review summarizes current knowledge about microparticles (MPs) and provides a systematic overview of last 20 years of research on circulating MPs, with particular focus on their clinical relevance. Results MPs are a heterogeneous population of cell-derived vesicles, with sizes ranging between 50 and 1000 nm. MPs are capable of transferring peptides, proteins, lipid components, microRNA, mRNA, and DNA from one cell to another without direct cell-to-cell contact. Growing evidence suggests that MPs present in peripheral blood and body fluids contribute to the development and progression of cancer, and are of pathophysiological relevance for autoimmune, inflammatory, infectious, cardiovascular, hematological, and other diseases. MPs have large diagnostic potential as biomarkers; however, due to current technological limitations in purification of MPs and an absence of standardized methods of MP detection, challenges remain in validating the potential of MPs as a non-invasive and early diagnostic platform. Conclusions Improvements in the effective deciphering of MP molecular signatures will be critical not only for diagnostics, but also for the evaluation of treatment regimens and predicting disease outcomes. PMID:23607880

Preferential silent survival of intracellular bacteria in hemoglobin-primed macrophages.

PubMed

Subramanian, Karthik; Winarsih, Imelda; Keerthani, Chandrakumaran; Ho, Bow; Ding, Jeak Ling

2014-01-01

Hemolysis releases hemoglobin (Hb), a prooxidant, into circulation. While the heme iron is a nutrient for the invading pathogens, it releases ROS, which is both microbicidal and cytotoxic, making it a double-edged sword. Previously, we found a two-pass detoxification mechanism involving the endocytosis of Hb into monocytes in collaboration with vascular endothelial cells to overcome oxidative damage. This prompted us to examine the effect of Hb priming on host cell viability and intracellular bacterial clearance during a hemolytic infection. Here, we demonstrate that Hb-primed macrophages harbor a higher intracellular bacterial load but with suppressed apoptosis. p-ERK and p-p38 MAPK were significantly downregulated, with concomitant impairment of Bax and downstream caspases. The Hb-primed cells harboring intracellular bacteria upregulated anti-inflammatory IL-10 and downregulated proinflammatory TNF-α, which further enhanced the infectivity of the neighboring cells. Our findings suggest that opportunistic intracellular pathogens exploit the Hb-scavenging machinery of the host to silently persist within the circulating phagocytes by suppressing apoptosis while escaping immune surveillance. © 2014 S. Karger AG, Basel.

Mice lacking Tbk1 activity exhibit immune cell infiltrates in multiple tissues and increased susceptibility to LPS-induced lethality.

PubMed

Marchlik, Erica; Thakker, Paresh; Carlson, Thaddeus; Jiang, Zhaozhao; Ryan, Mark; Marusic, Suzana; Goutagny, Nadege; Kuang, Wen; Askew, G Roger; Roberts, Victoria; Benoit, Stephen; Zhou, Tianhui; Ling, Vincent; Pfeifer, Richard; Stedman, Nancy; Fitzgerald, Katherine A; Lin, Lih-Ling; Hall, J Perry

2010-12-01

TBK1 is critical for immunity against microbial pathogens that activate TLR4- and TLR3-dependent signaling pathways. To address the role of TBK1 in inflammation, mice were generated that harbor two copies of a mutant Tbk1 allele. This Tbk1(Δ) allele encodes a truncated Tbk1(Δ) protein that is catalytically inactive and expressed at very low levels. Upon LPS stimulation, macrophages from Tbk1(Δ/Δ) mice produce normal levels of proinflammatory cytokines (e.g., TNF-α), but IFN-β and RANTES expression and IRF3 DNA-binding activity are ablated. Three-month-old Tbk1(Δ/Δ) mice exhibit mononuclear and granulomatous cell infiltrates in multiple organs and inflammatory cell infiltrates in their skin, and they harbor a 2-fold greater amount of circulating monocytes than their Tbk1(+/+) and Tbk1(+/Δ) littermates. Skin from 2-week-old Tbk1(Δ/Δ) mice is characterized by reactive changes, including hyperkeratosis, hyperplasia, necrosis, inflammatory cell infiltrates, and edema. In response to LPS challenge, 3-month-old Tbk1(Δ/Δ) mice die more quickly and in greater numbers than their Tbk1(+/+) and Tbk1(+/Δ) counterparts. This lethality is accompanied by an overproduction of several proinflammatory cytokines in the serum of Tbk1(Δ/Δ) mice, including TNF-α, GM-CSF, IL-6, and KC. This overproduction of serum cytokines in Tbk1(Δ/Δ) mice following LPS challenge and their increased susceptibility to LPS-induced lethality may result from the reactions of their larger circulating monocyte compartment and their greater numbers of extravasated immune cells.

Intravenous Glutamine Administration Modulates TNF-α/IL-10 Ratio and Attenuates NFkB Phosphorylation in a Protein Malnutrition Model.

PubMed

Santos, Andressa Cristina Antunes; Correia, Carolina Argondizo; de Oliveira, Dalila Cunha; Nogueira-Pedro, Amanda; Borelli, Primavera; Fock, Ricardo Ambrosio

2016-12-01

Protein malnutrition (PM) is a major public health problem in developing countries, affecting the inflammatory response and increasing susceptibility to opportunistic infections. For this reason, an adequate nutritional intervention can improve the quality of life of patients. Glutamine (GLN) is a nonessential amino acid, but can be considered "conditionally essential" for macrophage function in stress situations, in which it plays a role in the improvement of the inflammatory response. Concerning this issue, in the current study, it was of interest to evaluate some biological aspects of peritoneal cells from a protein malnutrition (PM) mouse model challenged with lipopolysaccharide (LPS) and treated intravenously with GLN. Two-month-old male Balb/c mice were subjected to a low-protein diet (2 % protein) and stimulated intravenously with LPS 1 h prior to the injection of 0.75 mg/kg GLN. Malnourished animals showed a reduced number of total peritoneal cells. Malnourished animals stimulated with LPS or LPS plus GLN did not show differences in peritoneal cell counts; however, the control group showed increased cellularity after LPS stimulus, which was reversed after GLN injection. Further, in the animals from both groups stimulated with LPS, GLN decreased the circulating levels of TNF-α and the levels of TNF-α produced by peritoneal cells; additionally, GLN decreased the IL-10 circulating levels in the malnourished animals stimulated with LPS. In addition, peritoneal cells of the control and malnourished groups stimulated with LPS showed a negative modulation of the NFkB signaling pathway after GLN injection. In conclusion, this study shows that GLN has the capacity to reduce TNF-α synthesis as well as to act as a negative regulator of NFkB phosphorylation, leading to a positive outcome in the control of TNF-α production.

NASH is an Inflammatory Disorder: Pathogenic, Prognostic and Therapeutic Implications

PubMed Central

van Rooyen, Derrick; Gan, Lay; Chitturi, Shivrakumar

2012-01-01

While non-alcoholic fatty liver disease (NAFLD) is highly prevalent (15% to 45%) in modern societies, only 10% to 25% of cases develop hepatic fibrosis leading to cirrhosis, end-stage liver disease or hepatocellular carcinoma. Apart from pre-existing fibrosis, the strongest predictor of fibrotic progression in NAFLD is steatohepatitis or non-alcoholic steatohepatitis (NASH). The critical features other than steatosis are hepatocellular degeneration (ballooning, Mallory hyaline) and mixed inflammatory cell infiltration. While much is understood about the relationship of steatosis to metabolic factors (over-nutrition, insulin resistance, hyperglycemia, metabolic syndrome, hypoadiponectinemia), less is known about inflammatory recruitment, despite its importance for the perpetuation of liver injury and fibrogenesis. In this review, we present evidence that liver inflammation has prognostic significance in NAFLD. We then consider the origins and components of liver inflammation in NASH. Hepatocytes injured by toxic lipid molecules (lipotoxicity) play a central role in the recruitment of innate immunity involving Toll-like receptors (TLRs), Kupffer cells (KCs), lymphocytes and neutrophils and possibly inflammasome. The key pro-inflammatory signaling pathways in NASH are nuclear factor-kappa B (NF-κB) and c-Jun N-terminal kinase (JNK). The downstream effectors include adhesion molecules, chemokines, cytokines and the activation of cell death pathways leading to apoptosis. The upstream activators of NF-κB and JNK are more contentious and may depend on the experimental model used. TLRs are strong contenders. It remains possible that inflammation in NASH originates outside the liver and in the gut microbiota that prime KC/TLR responses, inflamed adipose tissue and circulating inflammatory cells. We briefly review these mechanistic considerations and project their implications for the effective treatment of NASH. PMID:22570745

The Potential Role of Aerobic Exercise-Induced Pentraxin 3 on Obesity-Related Inflammation and Metabolic Dysregulation

PubMed Central

Acevedo, Edmund O.

2017-01-01

Obesity is defined as the excess accumulation of intra-abdominal body fat, resulting in a state of chronic, low-grade proinflammation that can directly contribute to the development of insulin resistance. Pentraxin 3 (PTX3) is an acute-phase protein that is expressed by a variety of tissue and cell sources and provides an anti-inflammatory property to downregulate the production of proinflammatory cytokines, in particular interleukin-1 beta and tumor necrosis factor alpha. Although PTX3 may therapeutically aid in altering the proinflammatory milieu in obese individuals, and despite elevated expression of PTX3 mRNA observed in adipose tissue, the circulating level of PTX3 is reduced with obesity. Interestingly, aerobic activity has been demonstrated to elevate PTX3 levels. Therefore, the purpose of this review is to discuss the therapeutic potential of PTX3 to positively regulate obesity-related inflammation and discuss the proposition for utilizing aerobic exercise as a nonpharmacological anti-inflammatory treatment strategy to enhance circulating PTX3 concentrations in obese individuals. PMID:28400677

Comprehensive intestinal T helper cell profiling reveals specific accumulation of IFN-γ+IL-17+coproducing CD4+ T cells in active inflammatory bowel disease.

PubMed

Globig, Anna-Maria; Hennecke, Nadine; Martin, Bianca; Seidl, Maximilian; Ruf, Günther; Hasselblatt, Peter; Thimme, Robert; Bengsch, Bertram

2014-12-01

Skewed T helper (TH) cell responses and specific functions of TH1, TH2, TH17, and Treg cells have been implicated in the pathogenesis of inflammatory bowel disease (IBD) that led to the establishment of the pathogenic TH1/TH2 and TH17/Treg cell imbalance paradigms. However, the relevant TH cell population driving mucosal inflammation is still unknown. We performed a comprehensive TH cell profiling of circulating and intestinal lymphocytes isolated from patients with Crohn's disease (CD; n = 69) and ulcerative colitis (UC; n = 41) undergoing endoscopy or surgical resection and compared them with healthy controls (n = 45). Mucosal inflammation was assessed endoscopically and histologically. TH cells were analyzed by flow cytometric evaluation of cytokine production and differentiation marker expression. Specialized TH cell populations were enriched in the intestinal mucosa compared with peripheral blood. Specifically, we observed a concomitant upregulation of TH17 cells and Tregs in active inflammatory lesions in patients with both CD and UC compared with quiescent/mildly inflamed lesions and healthy tissue. Of note, interferon γ+ interleukin (IL)-17+coproducing CD4+ T cells with high expression of T-bet, CD26, and IL-22 resembling recently described pathogenic TH17 cells were specifically enriched in the inflamed mucosal tissue. Our results argue against the controversial TH1/TH2 or TH17/Treg paradigms. In contrast, they suggest that a subpopulation of TH17 cells sharing a TH1 signature may be specifically involved in intestinal inflammation in CD and UC. These findings provide a better understanding of IBD pathogenesis and may help explain the efficacy of anti-IL-12p40/IL-23 and failure of anti-IL-17A therapies despite the enrichment of TH17 cells.

Substance P ameliorates collagen II-induced arthritis in mice via suppression of the inflammatory response

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hong, Hyun Sook; Son, Youngsook, E-mail: ysson@khu.ac.kr

Highlights: • SP can increase IL-10 levels and reduce TNF-α and IL-17 levels in RA. • SP causes the increase in T{sub reg}, M2 macrophage, and MSCs in RA. • SP-induced immune suppression leads to the blockade of RA progression. • SP can be used as the therapeutics for autoimmune-related inflammatory diseases. - Abstract: Current rheumatoid arthritis (RA) therapies such as biologics inhibiting pathogenic cytokines substantially delay RA progression. However, patient responses to these agents are not always complete and long lasting. This study explored whether substance P (SP), an 11 amino acids long endogenous neuropeptide with the novel abilitymore » to mobilize mesenchymal stem cells (MSC) and modulate injury-mediated inflammation, can inhibit RA progression. SP efficacy was evaluated by paw swelling, clinical arthritis scoring, radiological analysis, histological analysis of cartilage destruction, and blood levels of tumor necrosis factor-alpha (TNF-α) interleukin (IL)-10, and IL-17 in vivo. SP treatment significantly reduced local inflammatory signs, mean arthritis scores, degradation of joint cartilage, and invasion of inflammatory cells into the synovial tissues. Moreover, the SP treatment markedly reduced the size of spleens enlarged by excessive inflammation in CIA, increased IL-10 levels, and decreased TNF-α and IL-17 levels. Mobilization of stem cells and induction of T{sub reg} and M2 type macrophages in the circulation were also increased by the SP treatment. These effect of SP might be associated with the suppression of inflammatory responses in RA and, furthermore, blockade of RA progression. Our results propose SP as a potential therapeutic for autoimmune-related inflammatory diseases.« less

Effect of Dietary Fatty Acids on Inflammatory Gene Expression in Healthy Humans*

PubMed Central

Weaver, Kelly L.; Ivester, Priscilla; Seeds, Michael; Case, L. Douglas; Arm, Jonathan P.; Chilton, Floyd H.

2009-01-01

Over the past 100 years, changes in the food supply in Western nations have resulted in alterations in dietary fatty acid consumption, leading to a dramatic increase in the ratio of omega-6 (ω6) to ω3 polyunsaturated fatty acids (PUFA) in circulation and in tissues. Increased ω6/ω3 ratios are hypothesized to increase inflammatory mediator production, leading to higher incidence of inflammatory diseases, and may impact inflammatory gene expression. To determine the effect of reducing the ω6/ω3 ratio on expression of inflammatory pathway genes in mononuclear cells, healthy humans were placed on a controlled diet for 1 week, then given fish oil and borage oil for an additional 4 weeks. Serum and neutrophil fatty acid composition and ex vivo leukotriene B4 production from stimulated neutrophils were measured at the start and end of the supplementation period and after a 2-week washout. RNA was isolated from mononuclear cells and expression of PI3K, Akt, NFκB, and inflammatory cytokines was measured by real-time PCR. A marked increase was seen in serum and neutrophil levels of long-chain ω3 PUFA concomitant with a reduction in the ω6/ω3 PUFA ratio (40%). The ex vivo capacity of stimulated neutrophils to produce leukotriene B4 was decreased by 31%. Expression of PI3Kα and PI3Kγ and the quantity of PI3Kα protein in mononuclear cells was reduced after supplementation, as was the expression of several proinflammatory cytokines. These data reveal that PUFA may exert their clinical effects via their capacity to regulate the expression of signal transduction genes and genes for proinflammatory cytokines. PMID:19359242

Effect of Inflammatory and Noninflammatory Stress on Beta-Hydroxybutyrate and Free Fatty Acids in Rat Blood.

DTIC Science & Technology

fasting plus screen-restraint and fasting plus femoral fracture. Inflammatory stresses caused a marked inhibition of the normal fasting-induced ketosis ...and a reduction in the level of circulating free fatty acids. Noninflammatory stresses caused no inhibition of the normal fasting-induced ketosis but did cause a reduction in the level of circulating free fatty acids. (Author)

Relationship between inflammation, insulin resistance and type 2 diabetes: 'cause or effect'?

PubMed

Greenfield, Jerry R; Campbell, Lesley V

2006-05-01

Inflammation has been implicated as an important aetiological factor in the development of both insulin resistance and type 2 diabetes mellitus. This conclusion is predominantly drawn from studies demonstrating associations between elevated (but 'normal range') levels of circulating acute phase inflammatory markers, typified by C-reactive protein (CRP), and indices of insulin resistance and the development of type 2 diabetes. There is debate as to whether these associations are independent of body fatness or, rather, an epiphenomenon of obesity, particularly central obesity, a strong predictor of insulin resistance and type 2 diabetes and an important source of inflammatory cytokines, such as interleukin-6. Some of this controversy and the inability to draw definitive conclusions from these studies relate to the fact that most studies measure body fat and its distribution indirectly using anthropometric estimates, such as Body Mass Index and waist circumference, rather than directly by dual-energy X-ray absorptiometry, computed tomography or magnetic resonance imaging. Furthermore, use of the term inflammation may be inappropriate when describing mild elevations of CRP in the 'normal range' in the absence of the other changes that characterise classical inflammatory diseases, such as a reduction in levels (or evidence of consumption) of complement proteins. Debate as to whether obesity mediates the association between circulating levels of inflammatory markers and insulin resistance can be resolved by well-designed studies using body fat measured by gold-standard methods. In this review, we present evidence to support the suggestion that body fat is the primary determinant of circulating inflammatory marker levels in the basal state and that marginally elevated levels of circulating interleukin-6 and CRP in obesity are a consequence rather than a cause of insulin resistance. The importance of genetic influences in determining both body fatness and circulating CRP levels will also be discussed. The review will conclude with a discussion of possible mechanisms linking body fat and insulin resistance to elevated circulating levels of inflammatory markers, including the possible role of the toll-like family of immune receptors.

Association between gait characteristics and endothelial oxidative stress and inflammation in patients with symptomatic peripheral artery disease.

PubMed

Gardner, Andrew W; Montgomery, Polly S; Casanegra, Ana I; Silva-Palacios, Federico; Ungvari, Zoltan; Csiszar, Anna

2016-06-01

The aim of the study was to determine whether gait characteristics were associated with endothelial cell inflammation, oxidative stress, and apoptosis and with circulating biomarkers of inflammation and antioxidant capacity in older patients with symptomatic peripheral artery disease (PAD). Gait measurements of 231 symptomatic men and women with PAD were assessed during a 4-m walk test. Patients were further characterized on endothelial effects of circulating factors present in the sera using a cell culture-based bioassay on primary human arterial endothelial cells and on circulating inflammatory and vascular biomarkers. In a multivariate regression model for gait speed, the significant independent variables were age (p < 0.001), intercellular cell adhesion molecule-1 (ICAM-1) (p < 0.001), diabetes (p = 0.003), sex (p = 0.003), and history of cerebrovascular accidents (p = 0.021). In multivariate analyses for gait cadence, the significant independent predictors included high-sensitivity C-reactive protein (HsCRP) (p < 0.001), diabetes (p = 0.001), and hypertension (p = 0.001). In a multivariate regression model for gait stride length, the significant independent variables were HsCRP (p < 0.001), age (p < 0.001), ICAM-1 (p < 0.001), hypertension (p = 0.002), cellular reactive oxygen species production (p = 0.007), and sex (p = 0.008). Higher levels of circulating biomarkers of inflammation and endothelial cell oxidative stress were associated with slower gait speed, slower cadence, and shorter stride length in older symptomatic patients with PAD. Additionally, this profile of impaired gait was more evident in older patients, in women, and in those with diabetes, hypertension, and history of cerebrovascular accidents.

Suppression of LPS-induced transcription and cytokine secretion by the dietary isothiocyanate sulforaphane.

PubMed

Folkard, Danielle L; Melchini, Antonietta; Traka, Maria H; Al-Bakheit, Ala'a; Saha, Shikha; Mulholland, Francis; Watson, Andrew; Mithen, Richard F

2014-12-01

Diets rich in cruciferous vegetables are associated with lower levels of pro-inflammatory cytokines, which may contribute to potential health-promoting properties of these vegetables. We investigate whether sulforaphane (SF), an isothiocyanate (ITC) obtained from broccoli, could suppress LPS-induced transcription and subsequent pro-inflammatory cytokine secretion at a physiologically relevant concentration using in vitro models of chronic inflammation. We find that exposure of the LPS receptor Toll-like receptor-4 (TLR4) to physiologically appropriate concentrations of SF under non-reducing conditions results in covalent modification of cysteine residues 246 and 609. We further demonstrate that the changes in expression of 1210 genes (p ≤ 0.01) in THP-1 monocytes and the secretion of pro-inflammatory cytokines in both human peripheral blood mononuclear cells (PBMCs) and THP-1 monocytes induced by LPS exposure can be completely suppressed through exposure with physiologically appropriate concentrations of SF. Finally, we show that in vivo exposure of human PBMCs to ITCs within human circulation reduces secretion of pro-inflammatory cytokines following subsequent ex vivo LPS challenge (p < 0.001). Covalent modification of TLR4 by ITCs and resultant suppression of LPS-induced cell signalling could lead to reductions in levels of pro-inflammatory cytokines in people with chronic diseases who consume diets rich in cruciferous vegetables. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Promises and paradoxes of regulatory T cells in inflammatory bowel disease.

PubMed

Lord, James D

2015-10-28

Since their discovery two decades ago, CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) have become the subject of intense investigation by immunologists. Unlike other T cells, which promote an immune response, Tregs actively inhibit inflammation when activated by their cognate antigen, thus raising hope that these cells could be engineered into a highly targeted, antigen-specific, immunosuppressant therapy. Although Tregs represent less than 10% of circulating CD4(+)T cells, they have been shown to play an essential role in preventing or limiting inflammation in a variety of animal models and human diseases. In particular, spontaneous intestinal inflammation has been shown to occur in the absence of Tregs, suggesting that there may be a Treg defect central to the pathogenesis of human inflammatory bowel disease (IBD). However, over the past decade, multiple groups have reported no qualitative or quantitative deficits in Tregs from the intestines and blood of IBD patients to explain why these cells fail to regulate inflammation in Crohn's disease and ulcerative colitis. In this review, we will discuss the history of Tregs, what is known about them in IBD, and what progress and obstacles have been seen with efforts to employ them for therapeutic benefit.

Transient expansion of activated CD8+ T cells characterizes tuberculosis-associated immune reconstitution inflammatory syndrome in patients with HIV: a case control study

PubMed Central

2013-01-01

Background CD4+ T cell activation indicators have been reported to be a common phenomenon underlying diverse manifestations of immune reconstitution inflammatory syndrome (IRIS). However, we have found that a high frequency of circulating CD8+ T cells is a specific risk factor for mycobacterial IRIS. Therefore, we investigated whether CD8+ T cells from patients who develop TB IRIS were specifically activated. Methods We obtained PBMCs from HIV+ patients prior to and 4, 8, 12, 24, 52 and 104 weeks after initiating antiretroviral therapy. CD38 and HLADR expression on naive, central memory and effector memory CD8+ and CD4+ T cells were determined by flow cytometry. Absolute counts and frequencies of CD8+ T cell subsets were compared between patients who developed TB IRIS, who developed other IRIS forms and who remained IRIS-free. Results TB IRIS patients showed significantly higher counts of naive CD8+ T cells than the other groups at most time points, with a contraction of the effector memory subpopulation occurring later in the follow-up period. Activated (CD38+ HLADR+) CD8+ T cells from all groups decreased with treatment but transiently peaked in TB IRIS patients. This increase was due to an increase in activated naive CD8+ T cell counts during IRIS. Additionally, the CD8+ T cell subpopulations of TB IRIS patients expressed HLADR without CD38 more frequently and expressed CD38 without HLADR less frequently than cells from other groups. Conclusions CD8+ T cell activation is specifically relevant to TB IRIS. Different IRIS forms may involve different alterations in T cell subsets, suggesting different underlying inflammatory processes. PMID:23688318

Th17 Cells Induce Dopaminergic Neuronal Death via LFA-1/ICAM-1 Interaction in a Mouse Model of Parkinson's Disease.

PubMed

Liu, Zhan; Huang, Yan; Cao, Bei-Bei; Qiu, Yi-Hua; Peng, Yu-Ping

2017-12-01

T helper (Th)17 cells, a subset of CD4 + T lymphocytes, have strong pro-inflammatory property and appear to be essential in the pathogenesis of many inflammatory diseases. However, the involvement of Th17 cells in Parkinson's disease (PD) that is characterized by a progressive degeneration of dopaminergic (DAergic) neurons in the nigrostriatal system is unclear. Here, we aimed to demonstrate that Th17 cells infiltrate into the brain parenchyma and induce neuroinflammation and DAergic neuronal death in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)- or 1-methyl-4-phenylpyridinium (MPP + )-induced PD models. Blood-brain barrier (BBB) disruption in the substantia nigra (SN) was assessed by the signal of FITC-labeled albumin that was injected into blood circulation via the ascending aorta. Live cell imaging system was used to observe a direct contact of Th17 cells with neurons by staining these cells using the two adhesion molecules, leukocyte function-associated antigen (LFA)-1 and intercellular adhesion molecule (ICAM)-1, respectively. Th17 cells invaded into the SN where BBB was disrupted in MPTP-induced PD mice. Th17 cells exacerbated DAergic neuronal loss and pro-inflammatory/neurotrophic factor disorders in MPP + -treated ventral mesencephalic (VM) cell cultures. A direct contact of LFA-1-stained Th17 cells with ICAM-1-stained VM neurons was dynamically captured. Either blocking LFA-1 in Th17 cells or blocking ICAM-1 in VM neurons with neutralizing antibodies abolished Th17-induced DAergic neuronal death. These results establish that Th17 cells infiltrate into the brain parenchyma of PD mice through lesioned BBB and exert neurotoxic property by promoting glial activation and importantly by a direct damage to neurons depending on LFA-1/ICAM-1 interaction.

Associations of aldosterone and renin concentrations with inflammation-the Study of Health in Pomerania and the German Conn's Registry.

PubMed

Grotevendt, A; Wallaschofski, H; Reincke, M; Adolf, C; Quinkler, M; Nauck, M; Hoffmann, W; Rettig, R; Hannemann, A

2017-08-01

Chronic inflammation is an age-independent and body mass index-independent contributor to the development of multi-morbidity. Alterations of the renin-angiotensin-aldosterone system are observed within the context of proinflammatory states. We assessed circulating aldosterone, renin, and inflammatory biomarker concentrations in healthy, normotensive subjects and patients with primary aldosteronism. We included 1177 normotensive individuals from the population-based Study of Health in Pomerania (first follow-up, Study of Health in Pomerania-1) and 103 primary aldosteronism patients from the German Conn's Registry. A 1:1 matching for sex, age, body mass index, smoking status, diabetes mellitus, and the estimated glomerular filtration rate was performed to determine whether primary aldosteronism patients exhibit higher inflammatory biomarker concentrations than normotensive controls. The associations of plasma aldosterone concentration or plasma renin concentration with circulating fibrinogen concentrations, white blood cell count, and high sensitive C-reactive protein concentrations in the normotensive sample were determined with multivariable linear and logistic regression analyses. 1:1 matched primary aldosteronism patients demonstrated significantly (p < 0.01) higher plasma aldosterone concentration (198 vs. 47 ng/l), lower plasma renin concentration (3.1 vs. 7.7 ng/l) and higher high sensitive C-reactive protein concentrations (1.5 vs. 1.0 mg/l) than normotensive controls. Within the normotensive cohort, plasma renin concentration but not plasma aldosterone concentration was positively associated with fibrinogen concentrations and white blood cell count. Further, a J-shaped association between plasma renin concentration and high sensitive C-reactive protein concentrations was detected. High plasma aldosterone concentration in a primary aldosteronism cohort and high plasma renin concentration in normotensive subjects are associated with increased concentrations of inflammatory biomarkers. This suggests a link between the renin-angiotensin-aldosterone system and inflammatory processes in patients with primary aldosteronism and even in normotensive subjects.

Lipopolysaccharide Clearance, Bacterial Clearance, and Systemic Inflammatory Responses Are Regulated by Cell Type–Specific Functions of TLR4 during Sepsis

PubMed Central

Deng, Meihong; Loughran, Patricia; Gibson, Gregory; Sodhi, Chhinder; Watkins, Simon; Hackam, David

2013-01-01

The morbidity associated with bacterial sepsis is the result of host immune responses to pathogens, which are dependent on pathogen recognition by pattern recognition receptors, such as TLR4. TLR4 is expressed on a range of cell types, yet the mechanisms by which cell-specific functions of TLR4 lead to an integrated sepsis response are poorly understood. To address this, we generated mice in which TLR4 was specifically deleted from myeloid cells (LysMTLR4KO) or hepatocytes (HCTLR4KO) and then determined survival, bacterial counts, host inflammatory responses, and organ injury in a model of cecal ligation and puncture (CLP), with or without antibiotics. LysM-TLR4 was required for phagocytosis and efficient bacterial clearance in the absence of antibiotics. Survival, the magnitude of the systemic and local inflammatory responses, and liver damage were associated with bacterial levels. HCTLR4 was required for efficient LPS clearance from the circulation, and deletion of HCTLR4 was associated with enhanced macrophage phagocytosis, lower bacterial levels, and improved survival in CLP without antibiotics. Antibiotic administration during CLP revealed an important role for hepatocyte LPS clearance in limiting sepsis-induced inflammation and organ injury. Our work defines cell type–selective roles for TLR4 in coordinating complex immune responses to bacterial sepsis and suggests that future strategies for modulating microbial molecule recognition should account for varying roles of pattern recognition receptors in multiple cell populations. PMID:23562812

Circulating CD21low B cells in common variable immunodeficiency resemble tissue homing, innate-like B cells

PubMed Central

Rakhmanov, Mirzokhid; Keller, Baerbel; Gutenberger, Sylvia; Foerster, Christian; Hoenig, Manfred; Driessen, Gertjan; van der Burg, Mirjam; van Dongen, Jacques J.; Wiech, Elisabeth; Visentini, Marcella; Quinti, Isabella; Prasse, Antje; Voelxen, Nadine; Salzer, Ulrich; Goldacker, Sigune; Fisch, Paul; Eibel, Hermann; Schwarz, Klaus; Peter, Hans-Hartmut; Warnatz, Klaus

2009-01-01

The homeostasis of circulating B cell subsets in the peripheral blood of healthy adults is well regulated, but in disease it can be severely disturbed. Thus, a subgroup of patients with common variable immunodeficiency (CVID) presents with an extraordinary expansion of an unusual B cell population characterized by the low expression of CD21. CD21low B cells are polyclonal, unmutated IgM+IgD+ B cells but carry a highly distinct gene expression profile which differs from conventional naïve B cells. Interestingly, while clearly not representing a memory population, they do share several features with the recently defined memory-like tissue, Fc receptor-like 4 positive B cell population in the tonsils of healthy donors. CD21low B cells show signs of previous activation and proliferation in vivo, while exhibiting defective calcium signaling and poor proliferation in response to B cell receptor stimulation. CD21low B cells express decreased amounts of homeostatic but increased levels of inflammatory chemokine receptors. This might explain their preferential homing to peripheral tissues like the bronchoalveolar space of CVID or the synovium of rheumatoid arthritis patients. Therefore, as a result of the close resemblance to the gene expression profile, phenotype, function and preferential tissue homing of murine B1 B cells, we suggest that CD21low B cells represent a human innate-like B cell population. PMID:19666505

Overexpression of porcine lipoprotein-associated phospholipase A2 in swine.

PubMed

Tang, Xiaochun; Wang, Gangqi; Liu, Xingxing; Han, Xiaolei; Li, Zhuang; Ran, Guangyao; Li, Zhanjun; Song, Qi; Ji, Yuan; Wang, Haijun; Wang, Yuhui; Ouyang, Hongsheng; Pang, Daxin

2015-09-25

Lipoprotein-associated phospholipase A 2 (Lp-PLA2) is associated with the risk of vascular disease. It circulates in human blood predominantly in association with low-density lipoprotein cholesterol (LDL-C) and hydrolyses oxidized phospholipids into pro-inflammatory products. However, in the mouse circulation, it predominantly binds to high-density lipoprotein cholesterol (HDL-C) and exhibits anti-inflammatory properties. To further investigate the effects of Lp-PLA2 in the circulation, we generated over-expressed Lp-PLA2 transgenic swine. The eukaryotic expression plasmid of porcine Lp-PLA2 which driven by EF1α promoter was constructed and generate transgenic swine via SCNT. The expression and activity of Lp-PLA2 in transgenic swine were evaluated, and the total cholesterol (TC), HDL-C, LDL-C and triglyceride (TG) levels in the fasting and fed states were also assessed. Compared with wild-type swine controls, the transgenic swine exhibited elevated Lp-PLA2 mRNA levels and activities, and the activity did not depend on the feeding state. The TC, HDL-C and LDL-C levels were not significantly increased. There was no change in the TG levels in the fasting state between transgenic and control pigs. However, in the fed state, the TG levels of transgenic swine were slightly increased compared with the control pigs and were significantly elevated compared with the fasting state. In addition, inflammatory gene (interleukin [IL]-6, monocyte chemotactic protein [MCP]-1 and tumor necrosis factor [TNF]-α) mRNA levels in peripheral blood mononuclear cells (PBMCs) were significantly increased. The results demonstrated that Lp-PLA2 is associated with triglycerides which may be helpful for understanding the relationship of this protein with cardiovascular disease. Copyright © 2015 Elsevier Inc. All rights reserved.

Curcumin longa extract-loaded nanoemulsion improves the survival of endotoxemic mice by inhibiting nitric oxide-dependent HMGB1 release.

PubMed

Ahn, Min Young; Hwang, Jung Seok; Lee, Su Bi; Ham, Sun Ah; Hur, Jinwoo; Kim, Jun Tae; Seo, Han Geuk

2017-01-01

High mobility group box 1 (HMGB1) is a well-known damage-related alarmin that participates in cellular inflammatory responses. However, the mechanisms leading to HMGB1 release in inflammatory conditions and the therapeutic agents that could prevent it remain poorly understood. This study attempted to examine whether the Curcumin longa herb, which is known to have anti-inflammatory property, can modulate cellular inflammatory responses by regulating HMGB1 release. The murine macrophage RAW264.7 cells were treated with lipopolysaccharide (LPS) and/or a C. longa extract-loaded nanoemulsion (CLEN). The levels of released HMGB1, nitric oxide (NO) production, inducible NO synthase (iNOS) expression, and phosphorylation of mitogen-activated protein kinases were analyzed in RAW264.7 macrophages. The effects of CLEN on survival of endotoxemic model mice, circulating HMGB1 levels, and tissue iNOS expression were also evaluated. We have shown that a nanoemulsion loaded with an extract from the C. longa rhizome regulates cellular inflammatory responses and LPS-induced systemic inflammation by suppressing the release of HMGB1 by macrophages. First, treatment of RAW264.7 macrophages with the nanoemulsion significantly attenuated their LPS-induced release of HMGB1: this effect was mediated by inhibiting c-Jun N-terminal kinase activation, which in turn suppressed the NO production and iNOS expression of the cells. The nanoemulsion did not affect LPS-induced p38 or extracellular signal-regulated kinase activation. Second, intraperitoneal administration of the nanoemulsion improved the survival rate of LPS-injected endotoxemic mice. This associated with marked reductions in circulating HMGB1 levels and tissue iNOS expression. The present study shows for the first time the mechanism by which C. longa ameliorates sepsis, namely, by suppressing NO signaling and thereby inhibiting the release of the proinflammatory cytokine HMGB1. These observations suggest that identification of agents, including those in the herb C. longa , that can inhibit HMGB1 production and/or activity may aid the treatment of endotoxemia.

Nrf2-driven CD36 and HO-1 gene expression in circulating monocytes correlates with favourable clinical outcome in pregnancy-associated malaria.

PubMed

Aubouy, Agnès; Olagnier, David; Bertin, Gwladys; Ezinmegnon, Sem; Majorel, Clarisse; Mimar, Saliha; Massougbodji, Achille; Deloron, Philippe; Pipy, Bernard; Coste, Agnès

2015-09-18

Pregnancy-associated malaria (PAM) constitutes one of the most severe forms of malaria infection leading to fetal growth restriction and high risk of infant death. The severity of the pathology is largely attributed to the recruitment of monocytes and macrophages in the placenta which is evidenced by dysregulated inflammation found in placental blood. Importantly, CD36(+) monocytes/macrophages are also thought to participate in the tight control of the pro- and anti-inflammatory responses following Plasmodium detection through elimination of apoptotic cells and malaria-infected erythrocytes, internalization and recycling of oxidized forms of low-density lipoprotein and collaboration with TLR2 in pro-inflammatory response. Interestingly, previous work demonstrated that CD36 expression was upregulated on inflammatory macrophages following stimulation of the Nrf2 transcription factor, whilst the PPARγ pathway was inhibited and non-functional in the same inflammatory conditions. This current study examined the possible role of Nrf2-driven gene expression, CD36 and Haem-Oxygenase-1 (HO-1), in PAM clinical outcomes. Clinical data and biological samples including peripheral blood mononuclear cells were collected from 27 women presenting PAM. Polychromatic flow cytometry was used to characterize innate immune cell subpopulations and quantify CD36 protein expression level on monocytes. mRNA levels of CD36, PPARγ, Nrf2 and HO-1 were determined by qPCR and related to clinical outcomes. Finally, the capacity of monocytes to modulate CD36 expression upon rosiglitazone or sulforaphane treatment, two respective PPARγ or Nrf2 activators, was also investigated. The CD36 receptor, mostly expressed by CD14(+) circulating monocytes, statistically correlated with increased infant birth weights. Interestingly, mRNA levels of the transcription factor Nrf2 and the enzyme HO-1 also correlated with lower parasitaemia and increased infant birth weight, while PPARγ mRNA levels did not. Finally, monocytes isolated from low infant birth weight pregnant women were capable of up-regulating CD36 via the Nrf2 pathway ex vivo. Altogether these results suggest that Nrf2-driven CD36 and HO-1 expression on innate immune cells could contribute to a protective and detoxifying mechanism during PAM. More powered and mechanistical studies are however needed to strengthen the conclusions of this study.

Fever of unknown origin in the elderly.

PubMed

Wakefield, K M; Henderson, S T; Streit, J G

1989-06-01

Fever is a prominent sign of an acute-phase response induced by microbial invasion, tissue injury, immunologic reactions, or inflammatory processes. This generalized host response is produced by a multiplicity of localized or systemic diseases and characterized by acute, subacute, or chronic changes in metabolic, endocrinologic, neurologic, and immunologic functions. The fundamental event is an initiation of the acute-phase response by the production of a mediated molecule called IL-1. This polypeptide is produced primarily from phagocytic cells such as blood monocytes, phagocytic lining cells of the liver and spleen, and other tissue macrophages. IL-1 produces a local reaction but also enters the circulation, acting as a hormone to mediate distant organ system responses to infection, immunologic reaction, and inflammatory processes. Fever is the result when IL-1 initiates the synthesis of prostaglandins, notably prostaglandin E2 in the thermoregulatory center located in the anterior hypothalamus. The thermostatic set point is then raised and mechanisms to conserve heat (vasoconstriction) and to produce heat (shivering) are initiated. The result is a sudden rise in body temperature. The same basic mechanisms are involved in FUO. Many of the biologic and biochemical changes that are seen in FUO are also evidence of an acute-phase response. The elevated erythrocyte sedimentation rate is partly due to increased synthesis of hepatic proteins, including compliment components, ceruloplasmin, fibrinogen, and C-reactive protein. IL-1 acts directly on the bone marrow to increase absolute numbers and immaturity of circulating neutrophils. Anemia is produced by many mechanisms, including the reduction of circulating serum iron. Although fever production in the elderly maybe delayed or of less intensity, it is still a marker of significant disease.(ABSTRACT TRUNCATED AT 400 WORDS)

Bioavailable Citrus sinensis Extract: Polyphenolic Composition and Biological Activity.

PubMed

Pepe, Giacomo; Pagano, Francesco; Adesso, Simona; Sommella, Eduardo; Ostacolo, Carmine; Manfra, Michele; Chieppa, Marcello; Sala, Marina; Russo, Mariateresa; Marzocco, Stefania; Campiglia, Pietro

2017-04-15

Citrus plants contain large amounts of flavonoids with beneficial effects on human health. In the present study, the antioxidant and anti-inflammatory potential of bioavailable polyphenols from Citrus sinensis was evaluated in vitro and ex vivo, using the murine macrophages cell line J774A.1 and primary peritoneal macrophages. Following simulated gastro-intestinal digestion, the in vitro bioavailability of Citrus sinensis polyphenolic extract was assessed using the human cell line Caco-2 grown as monolayers on a transwell membrane. Data demonstrated a relative permeation of its compounds (8.3%). Thus, the antioxidant and anti-inflammatory effect of polyphenolic Citrus sinensis fraction (Cs) was compared to the bioavailable one (CsB). Results revealed that Citrus extract were able to reduce macrophages pro-inflammatory mediators, including nitric oxide, iNOS, COX-2 and different cytokines. Moreover, the effect of Citrus sinensis polyphenols was associated with antioxidant effects, such as a reduction of reactive oxygen species (ROS) and heme-oxygenase-1 (HO-1) increased expression. Our results provide evidence that the bioavailable polyphenolic constituents of the Citrus sinensis extract accumulate prevalently at intestinal level and could reach systemic circulation exerting their effect. The bioavailable fraction showed a higher anti-inflammatory and antioxidant potential compared to the initial extract, thus highlighting its potential nutraceutical value.

The expression of inflammatory cytokines, TAM tyrosine kinase receptors and their ligands is upregulated in venous leg ulcer patients: a novel insight into chronic wound immunity.

PubMed

Filkor, Kata; Németh, Tibor; Nagy, István; Kondorosi, Éva; Urbán, Edit; Kemény, Lajos; Szolnoky, Győző

2016-08-01

The systemic host defence mechanisms, especially innate immunity, in venous leg ulcer patients are poorly investigated. The aim of the current study was to measure Candida albicans killing activity and gene expressions of pro- and anti-inflammatory cytokines and innate immune response regulators, TAM receptors and ligands of peripheral blood mononuclear cells separated from 69 venous leg ulcer patients and 42 control probands. Leg ulcer patients were stratified into responder and non-responder groups on the basis of wound healing properties. No statistical differences were found in Candida killing among controls, responders and non-responders. Circulating blood mononuclear cells of patients overexpress pro-inflammatory (IL-1α, TNFα, CXCL-8) and anti-inflammatory (IL-10) cytokines as well as TAM receptors (Tyro, Axl, MerTK) and their ligands Gas6 and Protein S compared with those of control individuals. IL-1α is notably overexpressed in venous leg ulcer treatment non-responders; in contrast, Axl gene expression is robustly stronger among responders. These markers may be considered as candidates for the prediction of treatment response among venous leg ulcer patients. © 2015 Medicalhelplines.com Inc and John Wiley & Sons Ltd.

Effects of Olive Oil Phenolic Compounds on Inflammation in the Prevention and Treatment of Coronary Artery Disease

PubMed Central

de Souza, Priscilla Azambuja Lopes; Marcadenti, Aline; Portal, Vera Lúcia

2017-01-01

Coronary artery disease (CAD) is responsible for more than 7 million deaths worldwide. In the early stages of the development of atherosclerotic plaques, cardiovascular risk factors stimulate vascular endothelial cells, initiating an inflammatory process, fundamental in the pathogenesis of CAD. The inclusion of potentially cardioprotective foods, such as olive oil, to the diet, may aid in the control of these risk factors, and in the reduction of cytokines and inflammatory markers. The present review aims to address the interaction between phenolic compounds present in olive oil, and inflammation, in the prevention and treatment of CAD. In vitro and in vivo studies suggest that phenolic compounds, such as hydroxytyrosol, tyrosol, and their secoiridoid derivatives, may reduce the expression of adhesion molecules and consequent migration of immune cells, modify the signaling cascade and the transcription network (blocking the signal and expression of the nuclear factor kappa B), inhibit the action of enzymes responsible for the production of eicosanoids, and consequently, decrease circulating levels of inflammatory markers. Daily consumption of olive oil seems to modulate cytokines and inflammatory markers related to CAD in individuals at risk for cardiovascular diseases. However, clinical studies that have evaluated the effects of olive oil and its phenolic compounds on individuals with CAD are still scarce. PMID:28973999

Inhaled concentrated ambient particles are associated with hematologic and bronchoalveolar lavage changes in canines.

PubMed Central

Clarke, R W; Coull, B; Reinisch, U; Catalano, P; Killingsworth, C R; Koutrakis, P; Kavouras, I; Murthy, G G; Lawrence, J; Lovett, E; Wolfson, J M; Verrier, R L; Godleski, J J

2000-01-01

Pulmonary inflammatory and hematologic responses of canines were studied after exposure to concentrated ambient particles (CAPs) using the Harvard ambient particle concentrator (HAPC). For pulmonary inflammatory studies, normal dogs were exposed in pairs to either CAPs or filtered air (paired studies) for 6 hr/day on 3 consecutive days. For hematologic studies, dogs were exposed for 6 hr/day for 3 consecutive days with one receiving CAPs while the other was simultaneously exposed to filtered air; crossover of exposure took place the following week (crossover studies). Physicochemical characterization of CAPs exposure samples included measurements of particle mass, size distribution, and composition. No statistical differences in biologic responses were found when all CAPs and all sham exposures were compared. However, the variability in biologic response was considerably higher with CAPs exposure. Subsequent exploratory graphical analyses and mixed linear regression analyses suggested associations between CAPs constituents and biologic responses. Factor analysis was applied to the compositional data from paired and crossover experiments to determine elements consistently associated with each other in CAPs samples. In paired experiments, four factors were identified; in crossover studies, a total of six factors were observed. Bronchoalveolar lavage (BAL) and hematologic data were regressed on the factor scores. Increased BAL neutrophil percentage, total peripheral white blood cell (WBC) counts, circulating neutrophils, and circulating lymphocytes were associated with increases in the aluminum/silicon factor. Increased circulating neutrophils and increased BAL macrophages were associated with the vanadium/nickel factor. Increased BAL neutrophils were associated with the bromine/lead factor when only the compositional data from the third day of CAPs exposure were used. Significant decreases in red blood cell counts and hemoglobin levels were correlated with the sulfur factor. BAL or hematologic parameters were not associated with increases in total CAPs mass concentration. These data suggest that CAPs inhalation is associated with subtle alterations in pulmonary and systemic cell profiles, and specific components of CAPs may be responsible for these biologic responses. PMID:11133399

Innate immunity, insulin resistance and type 2 diabetes.

PubMed

Fernández-Real, José Manuel; Pickup, John C

2008-01-01

Recent evidence has disclosed previously unrecognized links among insulin resistance, obesity, circulating immune markers, immunogenetic susceptibility, macrophage function and chronic infection. Genetic variations leading to altered production or function of circulating innate immune proteins, cellular pattern-recognition receptors and inflammatory cytokines have been linked with insulin resistance, type 2 diabetes, obesity and atherosclerosis. Cellular innate immune associations with obesity and insulin resistance include increased white blood cell count and adipose tissue macrophage numbers. The innate immune response is modulated possibly by both predisposition (genetic or fetal programming), perhaps owing to evolutionary pressures caused by acute infections at the population level (pandemics), and chronic low exposure to environmental products or infectious agents. The common characteristics shared among innate immunity activation, obesity and insulin resistance are summarized.

Impairment of Circulating CD4⁺CD25⁺GARP⁺ regulatory T cells in patients with acute coronary syndrome.

PubMed

Meng, Kai; Zhang, Wei; Zhong, Yucheng; Mao, Xiaobo; Lin, Yingzhong; Huang, Ying; Lang, Mingjian; Peng, Yudong; Zhu, Zhengfeng; Liu, Yuzhou; Zhao, Xiaoqi; Yu, Kunwu; Wu, Bangwei; Ji, Qingwei; Zeng, Qiutang

2014-01-01

Atherosclerosis (AS) is an inflammatory and immune disease. Regulatory T cells (Tregs) suppress the activation of T cells and have been shown to play a protective role during the pathogenesis of AS. However, specific markers for Tregs are lacking. Recently, glycoprotein A repetitions predominant (GARP) was discovered as a specific marker of activated Tregs, and we therefore utilized GARP as a specific surface marker for Tregs in the current study. To assess whether GARP(+) Tregs are downregulated in patients with acute coronary syndrome (ACS), we examined CD4(+)CD25(+)GARP(+) T cell frequencies as well as their associated cytokines and suppressive function. Additionally, we compared GARP expression to that of FOXP3, which may be more sensitive as a marker of activated Tregs in patients with ACS. Patients with ACS demonstrated a significant decrease in circulating CD4(+)CD25(+)GARP(+) Tregs. Moreover, the suppressive function of Tregs and levels of related cytokines were also impaired in ACS patients compared to those with stable angina (SA) or normal coronary artery (NCA). Additionally, after TCR stimulation, peripheral blood mononuclear cells (PBMCs) from patients with ACS exhibited a decrease in CD4(+)CD25(+)GARP(+) Tregs. These fnding indicate that circulating CD4(+)CD25(+)GARP(+) Tregs are impaired in patients withACS. Thus, targeting GARP may promote the protective function of Tregs in ACS. © 2014 S. Karger AG, Basel.

Liver failure induces a systemic inflammatory response. Prevention by recombinant N-terminal bactericidal/permeability-increasing protein.

PubMed Central

Boermeester, M. A.; Houdijk, A. P.; Meyer, S.; Cuesta, M. A.; Appelmelk, B. J.; Wesdorp, R. I.; Hack, C. E.; Van Leeuwen, P. A.

1995-01-01

The observed increased susceptibility of patients with fulminant hepatic failure for local and systemic infections has been hypothesized to be due to a failure for the hepatic clearance function and subsequent leaking of endogenous endotoxins into the systemic circulation. However, experimental evidence for such a systemic inflammation during liver failure due to endogenous endotoxemia is lacking. Therefore, we designed a study to clarify whether circulating endotoxins due to liver failure could lead to the development of systemic inflammations. In a rat model for liver failure induced by a two-thirds partial hepatectomy, we evaluated the course of circulating tumor necrosis factor and interleukin-6, changes in blood chemistry and hemodynamics, and histopathological changes in the lungs. Partially hepatectomized animals, but not sham-operated animals, demonstrated cardiac failure, increased levels of creatinin and urea, metabolic acidosis, high plasma levels of tumor necrosis factor and interleukin-6, and an influx of PMNs in the lungs-together indicating the development of a systemic inflammatory response. Continuous infusion of recombinant N-terminal bactericidal/permeability-increasing protein (rBPI23), a well described endotoxin-neutralizing protein, prevented these inflammatory reactions. Ex vivo experiments with rat plasma samples confirmed the presence of circulating endotoxins in partially hepatectomized rats as opposed to those treated with rBPI23. Thus, our results indicate that the early phase of liver failure induces a systemic inflammatory response triggered by circulating endotoxins, which can be prevented by perioperative infusion of rBPI23. Images Figure 2 PMID:7485405

SMC1A recruits tumor-associated-fibroblasts (TAFs) and promotes colorectal cancer metastasis.

PubMed

Zhou, Pengyang; Xiao, Nan; Wang, Jian; Wang, Zhanhuai; Zheng, Shuchun; Shan, Siyang; Wang, Jianping; Du, Jinlin; Wang, Jianwei

2017-01-28

Tumor-associated-fibroblasts (TAFs) are the most important host cells in the stroma and take part in extracellular matrix construction and cancer colony development. During cancer colonization, seed cells from primary tumor can reconstruct the microenvironment by recruiting circulating cancer cells and TAFs to the metastasis site. Previous studies have established that SMC1A, a subunit of cohesin, is an important trigger signal for liver metastasis in colorectal cancer. We investigated the particular effects as well as the underlying mechanism of SMC1A on TAFs recruitment during liver metastasis of colorectal cancer. Here, We found that: first, the high expression of SMC1A in colorectal cancer cells promotes the invasiveness and the viability of these cells by recruiting circulating TAFs, facilitating early tumor construction and tumorigenesis; second, different expression levels of SMC1A influenced the reformation of fibroblasts, which assisted tumorigenesis, and third, expression of SMC1A stimulated the secretion of the inflammatory mediators of TNF-α and IL-1β, and up-regulated the transcriptional expression of MMP2 and VEGF-β, both of which were involved in the tumor-related gene pathway. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Update on the pathogenesis of Scleroderma: focus on circulating progenitor cells.

PubMed

Brunasso, Alexandra Maria Giovanna; Massone, Cesare

2016-01-01

In systemic sclerosis (SSc), the development of fibrosis seems to be a consequence of the initial ischemic process related to an endothelial injury. The initial trigger event in SSc is still unknown, but circulating progenitor cells (CPCs) might play a key role. Such cells have the ability to traffic into injury sites, exhibiting inflammatory features of macrophages, tissue remodeling properties of fibroblasts, and vasculogenesis functions of endothelial cells. The different subsets of CPCs described thus far in SSc arise from a pool of circulating monocyte precursors (CD14 (+) cells) and probably correspond to a different degree of differentiation of a single cell of origin. Several subsets of CPCs have been described in patients with SSc, all have a monocytic origin but may or may not express CD14, and all of these cells have the ability to give origin to endothelial cells, or collagen (Col)-producing cells, or both. We were able to identify six subsets of CPCs: pluripotent stem cells (CD14 (+), CD45 (+), and CD34 (+)), monocyte-derived multipotential cells (MOMCs) or monocyte-derived mesenchymal progenitors (CD14 (+), CD45 (+), CD34 (+), Col I (+), CD11b (+), CD68 (+), CD105 (+), and VEGFR1 (+)), early endothelial progenitor cells (EPCs) or monocytic pro-angiogenic hematopoietic cells or circulating hematopoietic cells (CD14 (+), CD45 (+), CD34 (low/-), VEGFR2 (+/-), CXCR4 (+), c-kit (+), and DC117 (+)), late EPCs (CD14 (-), CD133 (+), VEGFR2 (+), CD144 (+) [VE-cadherin (+)], and CD146 (+)), fibroblast-like cells (FLCs)/circulating Col-producing monocytes (CD14 (+), CD45 (+), CD34 (+/-), and Col I (+)), and fibrocytes (CD14 (-), CD45 (+), CD34 (+), Col I (+), and CXCR4 (+)). It has been demonstrated that circulating CD14 (+) monocytes with an activated phenotype are increased in patients with SSc when compared with normal subjects. CD14 (+), CD34 (+), and Col I (+) spindle-shaped cells have been found in increased numbers in lungs of SSc patients with interstitial lung disease. Elevated blood amounts of early EPCs have been found in patients with SSc by different groups of researchers and such levels correlate directly with the interstitial lung involvement. The prevalence of hematopoietic markers expressed by CPCs that migrate from blood into injury sites in SSc differs and changes according to the degree of differentiation. CXCR4 is the most commonly expressed marker, followed by CD34 and CD45 at an end stage of differentiation. Such difference also indicates a continuous process of cell differentiation that might relate to the SSc clinical phenotype (degree of fibrosis and vascular involvement). A deeper understanding of the role of each subtype of CPCs in the development of the disease will help us to better classify patients in order to offer them targeted approaches in the future.

Oxidative stress and inflammatory markers in relation to circulating levels of adiponectin.

PubMed

Gustafsson, Stefan; Lind, Lars; Söderberg, Stefan; Zilmer, Mihkel; Hulthe, Johannes; Ingelsson, Erik

2013-07-01

Previous epidemiological studies together with animal studies have suggested an association between adiponectin and oxidative stress and inflammation, but community-based studies are lacking. Our objective was to investigate the relative importance of oxidative stress and inflammatory markers, representing different pathways in relation to adiponectin. In a cross-sectional sample of 929 70-year-old individuals (50% women) of the Prospective Investigation of the Vasculature in Uppsala Seniors study, relations between serum adiponectin and oxidative stress [conjugated dienes (CD), homocysteine, total antioxidant capacity, oxidized low-density lipoprotein (OxLDL), OxLDL antibodies, baseline CD of LDL, glutathione (GSH), total glutathione (TGSH), glutathione disulfide], circulation interleukins (IL-6, IL-8), other cytokines [tumor necrosis factor α, monocyte chemotactic protein-1 (MCP-1), epidermal growth factor (EGF), vascular endothelial growth factor], cell adhesion molecules (vascular cell adhesion molecule-1, intercellular adhesion molecule-1, E-selectin, P-selectin, L-selectin), and systemic inflammatory markers [C-reactive protein (CRP), leukocyte count] in separate models were investigated. In age- and sex-adjusted, as well as multivariable-adjusted models, adiponectin was significantly and positively associated with GSH, log TGSH, whereas an inverse association was observed for CD and log EGF. An inverse association between adiponectin and MCP-1, log E-selectin, and log CRP was significant in age- and sex-adjusted models, but not in multivariable-adjusted models. Our results imply that higher levels of adiponectin are associated with a more beneficial oxidative stress profile, with higher levels of principal anti-oxidative GSH and total GSH together with lower levels of lipid peroxidation, possibly through shared pathways. Further studies are needed to investigate whether changes in the oxidative stress profile may be a mechanism linking adiponectin with type 2 diabetes and/or cardiovascular disease. Copyright © 2012 The Obesity Society.

Pathogenic role of inflammatory response during Shiga toxin-associated hemolytic uremic syndrome (HUS).

PubMed

Exeni, Ramon Alfonso; Fernandez-Brando, Romina Jimena; Santiago, Adriana Patricia; Fiorentino, Gabriela Alejandra; Exeni, Andrea Mariana; Ramos, Maria Victoria; Palermo, Marina Sandra

2018-01-25

Hemolytic uremic syndrome (HUS) is defined as a triad of noninmune microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. The most frequent presentation is secondary to Shiga toxin (Stx)-producing Escherichia coli (STEC) infections, which is termed postdiarrheal, epidemiologic or Stx-HUS, considering that Stx is the necessary etiological factor. After ingestion, STEC colonize the intestine and produce Stx, which translocates across the intestinal epithelium. Once Stx enters the bloodstream, it interacts with renal endothelial and epithelial cells, and leukocytes. This review summarizes the current evidence about the involvement of inflammatory components as central pathogenic factors that could determine outcome of STEC infections. Intestinal inflammation may favor epithelial leakage and subsequent passage of Stx to the systemic circulation. Vascular damage triggered by Stx promotes not only release of thrombin and increased fibrin concentration but also production of cytokines and chemokines by endothelial cells. Recent evidence from animal models and patients strongly indicate that several immune cells types may participate in HUS physiopathology: neutrophils, through release of proteases and reactive oxygen species (ROS); monocytes/macrophages through secretion of cytokines and chemokines. In addition, high levels of Bb factor and soluble C5b-9 (sC5b-9) in plasma as well as complement factors adhered to platelet-leukocyte complexes, microparticles and microvesicles, suggest activation of the alternative pathway of complement. Thus, acute immune response secondary to STEC infection, the Stx stimulatory effect on different immune cells, and inflammatory stimulus secondary to endothelial damage all together converge to define a strong inflammatory status that worsens Stx toxicity and disease.

Quantitative intravital two-photon excitation microscopy reveals absence of pulmonary vaso-occlusion in unchallenged Sickle Cell Disease mice

PubMed Central

Bennewitz, Margaret F; Watkins, Simon C; Sundd, Prithu

2014-01-01

Sickle cell disease (SCD) is a genetic disorder that leads to red blood cell (RBC) sickling, hemolysis and the upregulation of adhesion molecules on sickle RBCs. Chronic hemolysis in SCD results in a hyper-inflammatory state characterized by activation of circulating leukocytes, platelets and endothelial cells even in the absence of a crisis. A crisis in SCD is often triggered by an inflammatory stimulus and can lead to the acute chest syndrome (ACS), which is a type of lung injury and a leading cause of mortality among SCD patients. Although it is believed that pulmonary vaso-occlusion could be the phenomenon contributing to the development of ACS, the role of vaso-occlusion in ACS remains elusive. Intravital imaging of the cremaster microcirculation in SCD mice has been instrumental in establishing the role of neutrophil-RBC-endothelium interactions in systemic vaso-occlusion; however, such studies, although warranted, have never been done in the pulmonary microcirculation of SCD mice. Here, we show that two-photon excitation fluorescence microscopy can be used to perform quantitative analysis of neutrophil and RBC trafficking in the pulmonary microcirculation of SCD mice. We provide the experimental approach that enables microscopic observations under physiological conditions and use it to show that RBC and neutrophil trafficking is comparable in SCD and control mice in the absence of an inflammatory stimulus. The intravital imaging scheme proposed in this study can be useful in elucidating the cellular and molecular mechanism of pulmonary vaso-occlusion in SCD mice following an inflammatory stimulus. PMID:25995970

Coxiella burnetii Induces Inflammatory Interferon-Like Signature in Plasmacytoid Dendritic Cells: A New Feature of Immune Response in Q Fever

PubMed Central

Ka, Mignane B.; Mezouar, Soraya; Ben Amara, Amira; Raoult, Didier; Ghigo, Eric; Olive, Daniel; Mege, Jean-Louis

2016-01-01

Plasmacytoid dendritic cells (pDCs) play a major role in antiviral immunity via the production of type I interferons (IFNs). There is some evidence that pDCs interact with bacteria but it is not yet clear whether they are protective or contribute to bacterial pathogenicity. We wished to investigate whether Coxiella burnetii, the agent of Q fever, interacts with pDCs. The stimulation of pDCs with C. burnetii increased the expression of activation and migratory markers (CD86 and CCR7) as determined by flow cytometry and modulated gene expression program as revealed by a microarray approach. Indeed, genes encoding for pro-inflammatory cytokines, chemokines, and type I INF were up-regulated. The up-regulation of type I IFN was correlated with an increase in IFN-α release by C. burnetii-stimulated pDCs. We also investigated pDCs in patients with Q fever endocarditis. Using flow cytometry and a specific gating strategy, we found that the number of circulating pDCs was significantly lower in patients with Q fever endocarditis as compared to healthy donors. In addition, the remaining circulating pDCs expressed activation and migratory markers. As a whole, our study identified non-previously reported activation of pDCs by C. burnetii and their modulation during Q fever. PMID:27446817

Myocardial revascularization with miniaturized extracorporeal circulation versus off pump: Evaluation of systemic and myocardial inflammatory response in a prospective randomized study.

PubMed

Formica, Francesco; Broccolo, Francesco; Martino, Antonello; Sciucchetti, Jennifer; Giordano, Vincenzo; Avalli, Leonello; Radaelli, Gianluigi; Ferro, Orazio; Corti, Fabrizio; Cocuzza, Clementina; Paolini, Giovanni

2009-05-01

This prospective randomized study sought to verify the systemic inflammatory response, inflammatory myocardial damage, and early clinical outcome in coronary surgery with the miniaturized extracorporeal circulation system or on the beating heart. Sixty consecutive patients were randomized to miniaturized extracorporeal circulation (n = 30) or off-pump coronary revascularization (off-pump coronary artery bypass grafting, n = 30). Intraoperative and postoperative data were recorded. Plasma levels of interleukin-6 and tumor necrosis factor-alpha were measured from systemic blood intraoperatively, at the end of operation, and 24 and 48 hours thereafter. Levels of the same markers and blood lactate were measured from coronary sinus blood intraoperatively to evaluate myocardial inflammation. Markers of myocardial damage were also analyzed. One patient died in the off-pump coronary artery bypass grafting group. There was no statistical difference in early clinical outcome in both groups. Release of interleukin-6 was higher in the off-pump coronary artery bypass grafting group 24 hours after the operation (P = .03), whereas levels of tumor necrosis factor-alpha were not different in both groups. Cardiac release of interleukin-6, tumor necrosis factor-alpha, and blood lactate were not different in both groups. Release of troponin T was not significantly different in both groups. Levels of creatine kinase mass were statistically higher in the miniaturized extracorporeal circulation group than in the off-pump coronary artery bypass grafting group, but only at the end of the operation (P < .0001). Hemoglobin levels were significantly higher in the miniaturized extracorporeal circulation group than in the off-pump coronary artery bypass grafting group after 24 hours (P = .01). Miniaturized extracorporeal circulation can be considered similar to off-pump surgery in terms of systemic inflammatory response, myocardial inflammation and damage, and early outcome.

Responsiveness of blood and sputum inflammatory cells in Japanese COPD patients, non-COPD smoking controls, and non-COPD nonsmoking controls

PubMed Central

Kawayama, Tomotaka; Kinoshita, Takashi; Matsunaga, Kazuko; Kobayashi, Akihiro; Hayamizu, Tomoyuki; Johnson, Malcolm; Hoshino, Tomoaki

2016-01-01

Purpose To compare pulmonary and systemic inflammatory mediator release, pre- and poststimulation, ex vivo, in cells from Japanese patients with chronic obstructive pulmonary disease (COPD), non-COPD smoking controls, and non-COPD nonsmoking controls (NSC). Patients and methods This was a nontreatment study with ten subjects per group. Inflammatory biomarker release, including interleukin (IL)-6 and -8, matrix metalloproteinase-9, and tumor necrosis factor (TNF)-α, was measured in peripheral blood mononuclear cells (PBMC) and sputum cells with and without lipopolysaccharide or TNF-α stimulation. Results In PBMC, basal TNF-α release (mean ± standard deviation) was significantly different between COPD (81.6±111.4 pg/mL) and nonsmoking controls (9.5±5.2 pg/mL) (P<0.05). No other significant differences were observed. Poststimulation biomarker release tended to increase, with the greatest changes in the COPD group. The greatest mean increases were seen in the lipopolysaccharide-induced release of matrix metalloproteinase-9, TNF-α, and IL-6 from PBMC. Pre- and poststimulation data from sputum samples were more variable and less conclusive than from PBMC. In the COPD group, induced sputum neutrophil levels were higher and macrophage levels were lower than in either control group. Significant correlations were seen between the number of sputum cells (macrophages and neutrophils) and biomarker levels (IL-8, IL-6, and TNF-α). Conclusion This was the first study to compare cellular inflammatory mediator release before and after stimulation among Japanese COPD, smoking controls, and nonsmoking controls populations. Poststimulation levels tended to be higher in patients with COPD. The results suggest that PBMC are already preactivated in the circulation in COPD patients. This provides further evidence that COPD is a multicomponent disease, involving both airway and systemic inflammation. PMID:26929615

Anti-inflammatory effects of tobramycin and a copper–tobramycin complex with superoxide dismutase-like activity

PubMed Central

Gziut, M; MacGregor, HJ; Nevell, TG; Mason, T; Laight, D; Shute, JK

2013-01-01

Background and Purpose Airway inflammation in cystic fibrosis (CF) patients is characterized by accumulations of neutrophils in the airway and T cells in bronchial tissue, with activation of platelets in the circulation. CF patients are routinely treated with systemic or inhaled tobramycin for airway infection with Pseudomonas aeruginosa. Clinical trials have indicated an anti-inflammatory effect of tobramycin beyond its bactericidal activity. Here, we investigate the anti-inflammatory properties of tobramycin in vitro and consider if these relate to the ability of tobramycin to bind copper, which is elevated in blood and sputum in CF. Experimental Approach A copper–tobramycin complex was synthesized. The effect of tobramycin and copper–tobramycin on neutrophil activation and migration of T cells and neutrophils across human lung microvascular endothelial cells in response to thrombin-activated platelets were investigated in vitro. Tobramycin uptake was detected by immunocytochemistry. Intracellular reactive oxygen species were detected using the fluorescent indicator, 2′,7′-dichlorofluorescein diacetate (DCFDA). Neutrophil superoxide, hydrogen peroxide and neutrophil elastase activity were measured using specific substrates. Copper was measured using atomic absorption spectroscopy. Key Results Tobramycin and copper–tobramycin were taken up by endothelial cells via a heparan sulphate-dependent mechanism and significantly inhibited T-cell and neutrophil transendothelial migration respectively. Copper–tobramycin has intracellular and extracellular superoxide dismutase-like activity. Neutrophil elastase inhibition by α1-antitrypsin is enhanced in the presence of copper–tobramycin. Tobramycin and copper–tobramycin are equally effective anti-pseudomonal antibiotics. Conclusions and Implications Anti-inflammatory effects of tobramycin in vivo may relate to the spontaneous formation of a copper–tobramycin complex, implying that copper–tobramycin may be more effective therapy. PMID:23072509

Responsiveness of blood and sputum inflammatory cells in Japanese COPD patients, non-COPD smoking controls, and non-COPD nonsmoking controls.

PubMed

Kawayama, Tomotaka; Kinoshita, Takashi; Matsunaga, Kazuko; Kobayashi, Akihiro; Hayamizu, Tomoyuki; Johnson, Malcolm; Hoshino, Tomoaki

2016-01-01

To compare pulmonary and systemic inflammatory mediator release, pre- and poststimulation, ex vivo, in cells from Japanese patients with chronic obstructive pulmonary disease (COPD), non-COPD smoking controls, and non-COPD nonsmoking controls (NSC). This was a nontreatment study with ten subjects per group. Inflammatory biomarker release, including interleukin (IL)-6 and -8, matrix metalloproteinase-9, and tumor necrosis factor (TNF)-α, was measured in peripheral blood mononuclear cells (PBMC) and sputum cells with and without lipopolysaccharide or TNF-α stimulation. In PBMC, basal TNF-α release (mean ± standard deviation) was significantly different between COPD (81.6±111.4 pg/mL) and nonsmoking controls (9.5±5.2 pg/mL) (P<0.05). No other significant differences were observed. Poststimulation biomarker release tended to increase, with the greatest changes in the COPD group. The greatest mean increases were seen in the lipopolysaccharide-induced release of matrix metalloproteinase-9, TNF-α, and IL-6 from PBMC. Pre- and poststimulation data from sputum samples were more variable and less conclusive than from PBMC. In the COPD group, induced sputum neutrophil levels were higher and macrophage levels were lower than in either control group. Significant correlations were seen between the number of sputum cells (macrophages and neutrophils) and biomarker levels (IL-8, IL-6, and TNF-α). This was the first study to compare cellular inflammatory mediator release before and after stimulation among Japanese COPD, smoking controls, and nonsmoking controls populations. Poststimulation levels tended to be higher in patients with COPD. The results suggest that PBMC are already preactivated in the circulation in COPD patients. This provides further evidence that COPD is a multicomponent disease, involving both airway and systemic inflammation.

Angiogenic T cell expansion correlates with severity of peripheral vascular damage in systemic sclerosis.

PubMed

Manetti, Mirko; Pratesi, Sara; Romano, Eloisa; Bellando-Randone, Silvia; Rosa, Irene; Guiducci, Serena; Fioretto, Bianca Saveria; Ibba-Manneschi, Lidia; Maggi, Enrico; Matucci-Cerinic, Marco

2017-01-01

The mechanisms underlying endothelial cell injury and defective vascular repair in systemic sclerosis (SSc) remain unclear. Since the recently discovered angiogenic T cells (Tang) may have an important role in the repair of damaged endothelium, this study aimed to analyze the Tang population in relation to disease-related peripheral vascular features in SSc patients. Tang (CD3+CD31+CXCR4+) were quantified by flow cytometry in peripheral blood samples from 39 SSc patients and 18 healthy controls (HC). Circulating levels of the CXCR4 ligand stromal cell-derived factor (SDF)-1α and proangiogenic factors were assessed in paired serum samples by immunoassay. Serial skin sections from SSc patients and HC were subjected to CD3/CD31 and CD3/CXCR4 double immunofluorescence. Circulating Tang were significantly increased in SSc patients with digital ulcers (DU) compared either with SSc patients without DU or with HC. Tang levels were significantly higher in SSc patients with late nailfold videocapillaroscopy (NVC) pattern than in those with early/active NVC patterns and in HC. No difference in circulating Tang was found when comparing either SSc patients without DU or patients with early/active NVC patterns and HC. In SSc peripheral blood, Tang percentage was inversely correlated to levels of SDF-1α and CD34+CD133+VEGFR-2+ endothelial progenitor cells (EPC), and positively correlated to levels of vascular endothelial growth factor and matrix metalloproteinase-9. Tang were frequently detected in SSc dermal perivascular inflammatory infiltrates. In summary, our findings demonstrate for the first time that Tang cells are selectively expanded in the circulation of SSc patients displaying severe peripheral vascular complications like DU. In SSc, Tang may represent a potentially useful biomarker reflecting peripheral vascular damage severity. Tang expansion may be an ineffective attempt to compensate the need for increased angiogenesis and EPC function. Further studies are required to clarify the function of Tang cells and investigate the mechanisms responsible for their change in SSc.

The role of JAM-A in inflammatory bowel disease: unrevealing the ties that bind.

PubMed

Vetrano, Stefania; Danese, Silvio

2009-05-01

Tight junctions (TJ) are junctional proteins whose function is to maintain an intact intestinal epithelial barrier and regulate the paracellular movement of water and solutes. Altered TJ structure and epithelial permeability are observed in inflammatory bowel disease and seem to have an important role in the pathogenesis of these diseases. Junctional adhesion molecule-A (JAM-A) is a protein expressed at tight junctions of epithelial and endothelial cells, as well as on circulating leukocytes. Its function at tight junctions appears to be crucial as an extracellular adhesive molecule in the direct regulation of intestinal barrier function. This review focuses on the role of JAM-A in controlling mucosal homeostasis by regulating the integrity and permeability of epithelial barrier function.

A Double-Blinded Randomized Study Investigating a Possible Anti-Inflammatory Effect of Saxagliptin versus Placebo as Add-On Therapy in Patients with Both Type 2 Diabetes And Stable Coronary Artery Disease.

PubMed

Njerve, Ida Unhammer; Åkra, Sissel; Weiss, Thomas W; Solheim, Svein; Øvstebø, Reidun; Aass, Hans Christian D; Byrkjeland, Rune; Arnesen, Harald; Seljeflot, Ingebjørg

2017-01-01

Promising results regarding potential anti-inflammatory and antiatherosclerotic effects of gliptins have been reported. Our aim was to investigate whether saxagliptin treatment modifies expression of inflammatory markers, primarily in peripheral blood mononuclear cells (PBMCs) and in circulating leukocytes in patients with stable coronary artery disease (CAD) and T2DM. Patients ( n = 12) were randomized to saxagliptin 5 mg daily or placebo for 3 months. Samples were taken at baseline and end of study in fasting state prior to intake of medications. PBMCs were isolated and cryopreserved at -150°C until ex vivo exposed to 1 ng/mL of lipopolysaccharide (LPS) for 4 hours. Gene expression was performed with custom-designed TaqMan® Arrays and relative quantification by real-time PCR (RT-qPCR). HbA1c was reduced in the saxagliptin-treated group compared to that in the change with placebo ( p = 0.042). In unstimulated PBMCs and in circulating leukocytes, we observed a significant increase in IL-10 expression in the saxagliptin group ( p = 0.043, both), significantly different from that in the placebo ( p = 0.009 and p = 0.032, resp.). No between group differences in changes were observed in any of the selected proinflammatory markers. In our small cohort of patients with combined T2DM and CAD, a possible anti-inflammatory effect of saxagliptin, observed in the present study by upregulation of IL-10 in leukocytes, needs to be confirmed in larger studies.

[Low-grade systemic inflammation and the development of metabolic diseases: from the molecular evidence to the clinical practice].

PubMed

León-Pedroza, José Israel; González-Tapia, Luis Alonso; del Olmo-Gil, Esteban; Castellanos-Rodríguez, Diana; Escobedo, Galileo; González-Chávez, Antonio

2015-01-01

Systemic inflammation is characterised by high circulating levels of inflammatory cytokines and increased macrophage infiltration in peripheral tissues. Most importantly, this inflammatory state does not involve damage or loss of function of the infiltrated tissue, which is a distinctive feature of the low-grade systemic inflammation. The term "meta-inflammation" has also been used to refer to the low-grade systemic inflammation due to its strong relationship with the development of cardio-metabolic diseases in obesity. A review is presented on the recent clinical and experimental evidence concerning the role of adipose tissue inflammation as a key mediator of low-grade systemic inflammation. Furthermore, the main molecular mechanisms involved in the inflammatory polarization of macrophages with the ability to infiltrate both the adipose tissue and the vascular endothelium via activation of toll-like receptors by metabolic damage-associated molecular patterns, such as advanced glycation-end products and oxidized lipoproteins, is discussed. Finally, a review is made of the pathogenic mechanisms through which the low-grade systemic inflammation contributes to develop insulin resistance, dyslipidaemia, atherogenesis, type 2 diabetes, and hypertension in obese individuals. A better understanding of the molecular mechanisms of low-grade systemic inflammation in promoting cardio-metabolic diseases is necessary, in order to further design novel anti-inflammatory therapies that take into consideration clinical data, as well as the circulating levels of cytokines, immune cells, and metabolic damage-associated molecular patterns in each patient. Copyright © 2015 Academia Mexicana de Cirugía A.C. Published by Masson Doyma México S.A. All rights reserved.

Relationship of Advanced Glycation End Products With Cardiovascular Disease in Menopausal Women

PubMed Central

Pertynska-Marczewska, Magdalena

2015-01-01

Cardiovascular disease (CVD) represents the most significant cause of death in postmenopausal women. Advanced glycation end products (AGEs) are formed by nonenzymatic modification of proteins, lipids, and nucleic acids by glucose. This review focuses on the contribution of AGEs and their receptors to the development of CVD in menopause. Advanced glycation end products circulate and activate the proinflammatory endothelial cell surface receptor called RAGE, bind to the extracellular matrix of the cardiovascular system, or bind to the circulating anti-inflammatory soluble form of RAGE (sRAGE). Data emerging from human and animal studies suggest that AGEs and both receptors (RAGE and sRAGE) are implicated in the pathophysiology of CVD. Particular emphasis has been given to the role of AGE–RAGE axis in oxidative stress, inflammation, endothelial cell toxicity, and progression of atherosclerosis in menopause. Data accruing from human and animal studies suggest that RAGE expression level and circulating sRAGE level are associated with estradiol and are correlated with CVD risk factors, such as adiposity, dyslipidemia, insulin resistance, diabetes, and metabolic syndrome. By recognizing the impact of AGEs on atherosclerosis, pharmacological strategies targeting the AGE–RAGE pathway hold therapeutic potential for CVD in menopausal women. PMID:25228634

Relationship of Advanced Glycation End Products With Cardiovascular Disease in Menopausal Women.

PubMed

Pertynska-Marczewska, Magdalena; Merhi, Zaher

2015-07-01

Cardiovascular disease (CVD) represents the most significant cause of death in postmenopausal women. Advanced glycation end products (AGEs) are formed by nonenzymatic modification of proteins, lipids, and nucleic acids by glucose. This review focuses on the contribution of AGEs and their receptors to the development of CVD in menopause. Advanced glycation end products circulate and activate the proinflammatory endothelial cell surface receptor called RAGE, bind to the extracellular matrix of the cardiovascular system, or bind to the circulating anti-inflammatory soluble form of RAGE (sRAGE). Data emerging from human and animal studies suggest that AGEs and both receptors (RAGE and sRAGE) are implicated in the pathophysiology of CVD. Particular emphasis has been given to the role of AGE-RAGE axis in oxidative stress, inflammation, endothelial cell toxicity, and progression of atherosclerosis in menopause. Data accruing from human and animal studies suggest that RAGE expression level and circulating sRAGE level are associated with estradiol and are correlated with CVD risk factors, such as adiposity, dyslipidemia, insulin resistance, diabetes, and metabolic syndrome. By recognizing the impact of AGEs on atherosclerosis, pharmacological strategies targeting the AGE-RAGE pathway hold therapeutic potential for CVD in menopausal women. © The Author(s) 2014.

Fate of Neutrophils during the Recovery Phase of Ischemia/Reperfusion Induced Acute Kidney Injury

PubMed Central

2017-01-01

Effective clearance of inflammatory cells is required for resolution of inflammation. Here, we show in vivo evidence that apoptosis and reverse transendothelial migration (rTEM) are important mechanisms in eliminating neutrophils and facilitating recovery following ischemia/reperfusion injury (IRI) of the kidney. The clearance of neutrophils was delayed in the Bax knockout (KO)BM → wild-type (WT) chimera in which bone marrow derived cells are partially resistant to apoptosis, compared to WTBM → WT mice. These mice also showed delayed functional, histological recovery, increased tissue cytokines, and accelerated fibrosis. The circulating intercellular adhesion molecule-1 (ICAM-1)+ Gr-1+ neutrophils displaying rTEM phenotype increased during the recovery phase and blockade of junctional adhesion molecule-C (JAM-C), a negative regulator of rTEM, resulted in an increase in circulating ICAM-1+ neutrophils, faster resolution of inflammation and recovery. The presence of Tamm-Horsfall protein (THP) in circulating ICAM-1+ neutrophils could suggest that they are derived from injured kidneys. In conclusion, we suggest that apoptosis and rTEM are critically involved in the clearance mechanisms of neutrophils during the recovery phase of IRI. PMID:28875605

Inflammatory biomarkers for persistent fatigue in breast cancer survivors.

PubMed

Collado-Hidalgo, Alicia; Bower, Julienne E; Ganz, Patricia A; Cole, Steve W; Irwin, Michael R

2006-05-01

This study seeks to define immunologic and inflammatory variables associated with persistent post-treatment fatigue in breast cancer survivors. Leukocyte subsets, plasma inflammatory markers, and ex vivo proinflammatory cytokine production were assessed in 50 fatigued and nonfatigued breast cancer survivors recruited > or = 2 years after successful primary therapy. Multivariate statistical analyses were used to define a composite immunologic biomarker of fatigue risk. Fatigued breast cancer survivors were distinguished from nonfatigued survivors by increased ex vivo monocyte production of interleukin (IL)-6 and tumor necrosis factor-alpha following lipopolysaccharide stimulation, elevated plasma IL-1ra and soluble IL-6 receptor (sIL-6R/CD126), decreased monocyte cell-surface IL-6R, and decreased frequencies of activated T lymphocytes and myeloid dendritic cells in peripheral blood (all P < 0.05). An inverse correlation between sIL-6R and cell-surface IL-6R was consistent with inflammation-mediated shedding of IL-6R, and in vitro studies confirmed that proinflammatory cytokines induced such shedding. Multivariate linear discriminant function analysis identified two immunologic markers, the ratio of sIL-6R to monocyte-associated IL-6R and decreased circulating CD69+ T lymphocytes, as highly diagnostic of fatigue (P = 0.0005), with cross-validation estimates indicating 87% classification accuracy (sensitivity = 0.83; specificity = 0.83). These results extend links between fatigue and inflammatory markers to show a functional alteration in proinflammatory cytokine response to lipopolysaccharide and define a prognostic biomarker of behavioral fatigue.

Targeting inflammation in diabetes: Newer therapeutic options

PubMed Central

Agrawal, Neeraj Kumar; Kant, Saket

2014-01-01

Inflammation has been recognised to both decrease beta cell insulin secretion and increase insulin resistance. Circulating cytokines can affect beta cell function directly leading to secretory dysfunction and increased apoptosis. These cytokines can also indirectly affect beta cell function by increasing adipocyte inflammation.The resulting glucotoxicity and lipotoxicity further enhance the inflammatory process resulting in a vicious cycle. Weight reduction and drugs such as metformin have been shown to decrease the levels of C-Reactive Protein by 31% and 13%, respectively. Pioglitazone, insulin and statins have anti-inflammatory effects. Interleukin 1 and tumor necrosis factor-α antagonists are in trials and NSAIDs such as salsalate have shown an improvement in insulin sensitivity. Inhibition of 12-lipo-oxygenase, histone de-acetylases, and activation of sirtuin-1 are upcoming molecular targets to reduce inflammation. These therapies have also been shown to decrease the conversion of pre-diabetes state to diabetes. Drugs like glicazide, troglitazone, N-acetylcysteine and selective COX-2 inhibitors have shown benefit in diabetic neuropathy by decreasing inflammatory markers. Retinopathy drugs are used to target vascular endothelial growth factor, angiopoietin-2, various proteinases and chemokines. Drugs targeting the proteinases and various chemokines are pentoxifylline, inhibitors of nuclear factor-kappa B and mammalian target of rapamycin and are in clinical trials for diabetic nephropathy. Commonly used drugs such as insulin, metformin, peroxisome proliferator-activated receptors, glucagon like peptide-1 agonists and dipeptidyl peptidase-4 inhibitors also decrease inflammation. Anti-inflammatory therapies represent a potential approach for the therapy of diabetes and its complications. PMID:25317247

Protection of cultured brain endothelial cells from cytokine-induced damage by α-melanocyte stimulating hormone.

PubMed

Harazin, András; Bocsik, Alexandra; Barna, Lilla; Kincses, András; Váradi, Judit; Fenyvesi, Ferenc; Tubak, Vilmos; Deli, Maria A; Vecsernyés, Miklós

2018-01-01

The blood-brain barrier (BBB), an interface between the systemic circulation and the nervous system, can be a target of cytokines in inflammatory conditions. Pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) induce damage in brain endothelial cells and BBB dysfunction which contribute to neuronal injury. The neuroprotective effects of α-melanocyte stimulating hormone (α-MSH) were investigated in experimental models, but there are no data related to the BBB. Based on our recent study, in which α-MSH reduced barrier dysfunction in human intestinal epithelial cells induced by TNF-α and IL-1β, we hypothesized a protective effect of α-MSH on brain endothelial cells. We examined the effect of these two pro-inflammatory cytokines, and the neuropeptide α-MSH on a culture model of the BBB, primary rat brain endothelial cells co-cultured with rat brain pericytes and glial cells. We demonstrated the expression of melanocortin-1 receptor in isolated rat brain microvessels and cultured brain endothelial cells by RT-PCR and immunohistochemistry. TNF-α and IL-1β induced cell damage, measured by impedance and MTT assay, which was attenuated by α-MSH (1 and 10 pM). The peptide inhibited the cytokine-induced increase in brain endothelial permeability, and restored the morphological changes in cellular junctions visualized by immunostaining for claudin-5 and β-catenin. Elevated production of reactive oxygen species and the nuclear translocation of NF-κB were also reduced by α-MSH in brain endothelial cells stimulated by cytokines. We demonstrated for the first time the direct beneficial effect of α-MSH on cultured brain endothelial cells, indicating that this neurohormone may be protective at the BBB.

Protection of cultured brain endothelial cells from cytokine-induced damage by α-melanocyte stimulating hormone

PubMed Central

Barna, Lilla; Kincses, András; Váradi, Judit; Fenyvesi, Ferenc; Tubak, Vilmos

2018-01-01

The blood–brain barrier (BBB), an interface between the systemic circulation and the nervous system, can be a target of cytokines in inflammatory conditions. Pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) induce damage in brain endothelial cells and BBB dysfunction which contribute to neuronal injury. The neuroprotective effects of α-melanocyte stimulating hormone (α-MSH) were investigated in experimental models, but there are no data related to the BBB. Based on our recent study, in which α-MSH reduced barrier dysfunction in human intestinal epithelial cells induced by TNF-α and IL-1β, we hypothesized a protective effect of α-MSH on brain endothelial cells. We examined the effect of these two pro-inflammatory cytokines, and the neuropeptide α-MSH on a culture model of the BBB, primary rat brain endothelial cells co-cultured with rat brain pericytes and glial cells. We demonstrated the expression of melanocortin-1 receptor in isolated rat brain microvessels and cultured brain endothelial cells by RT-PCR and immunohistochemistry. TNF-α and IL-1β induced cell damage, measured by impedance and MTT assay, which was attenuated by α-MSH (1 and 10 pM). The peptide inhibited the cytokine-induced increase in brain endothelial permeability, and restored the morphological changes in cellular junctions visualized by immunostaining for claudin-5 and β-catenin. Elevated production of reactive oxygen species and the nuclear translocation of NF-κB were also reduced by α-MSH in brain endothelial cells stimulated by cytokines. We demonstrated for the first time the direct beneficial effect of α-MSH on cultured brain endothelial cells, indicating that this neurohormone may be protective at the BBB. PMID:29780671

Hemin controls T cell polarization in sickle cell alloimmunization.

PubMed

Zhong, Hui; Bao, Weili; Friedman, David; Yazdanbakhsh, Karina

2014-07-01

Patients with sickle cell disease (SCD) often require transfusions to treat and prevent worsening anemia and other SCD complications. However, transfusions can trigger alloimmunization against transfused RBCs with serious clinical sequelae. Risk factors for alloimmunization in SCD remain poorly understood. We recently reported altered regulatory T cell (Treg) and Th responses with higher circulating Th1 (IFN-γ(+)) cytokines in chronically transfused SCD patients with alloantibodies as compared with those without alloantibodies. Because monocytes play a critical role in polarization of T cell subsets and participate in clearance of transfused RBCs, we tested the hypothesis that in response to the RBC breakdown product hemin, monocyte control of T cell polarization will differ between alloimmunized and non-alloimmunized SCD patients. Exogenous hemin induced Treg polarization in purified T cell/monocyte cocultures from healthy volunteers through the monocyte anti-inflammatory heme-degrading enzyme heme oxygenase-1. Importantly, hemin primarily through its effect on CD16+ monocytes induced an anti-inflammatory (higher Treg/lower Th1) polarization state in the non-alloimmunized SCD group, whereas it had little effect in the alloimmunized group. Non-alloimmunized SCD CD16+ monocytes expressed higher basal levels of heme oxygenase-1. Furthermore, IL-12, which contributed to a proinflammatory polarization state (low Treg/high Th1) in SCD, was dampened in hemin-treated stimulated monocytes from non-alloimmunized SCD patients, but not in the alloimmunized group. These data suggest that unlike alloimmunized patients, non-alloimmunized SCD CD16+ monocytes in response to transfused RBC breakdown products promote an anti-inflammatory state that is less conducive to alloimmunization. Copyright © 2014 by The American Association of Immunologists, Inc.

Citrus Polyphenol Hesperidin Stimulates Production of Nitric Oxide in Endothelial Cells while Improving Endothelial Function and Reducing Inflammatory Markers in Patients with Metabolic Syndrome

PubMed Central

Rizza, Stefano; Muniyappa, Ranganath; Iantorno, Micaela; Kim, Jeong-a; Chen, Hui; Pullikotil, Philomena; Senese, Nicoletta; Tesauro, Manfredi; Lauro, Davide; Cardillo, Carmine

2011-01-01

Context: Hesperidin, a citrus flavonoid, and its metabolite hesperetin may have vascular actions relevant to their health benefits. Molecular and physiological mechanisms of hesperetin actions are unknown. Objective: We tested whether hesperetin stimulates production of nitric oxide (NO) from vascular endothelium and evaluated endothelial function in subjects with metabolic syndrome on oral hesperidin therapy. Design, Setting, and Interventions: Cellular mechanisms of action of hesperetin were evaluated in bovine aortic endothelial cells (BAEC) in primary culture. A randomized, placebo-controlled, double-blind, crossover trial examined whether oral hesperidin administration (500 mg once daily for 3 wk) improves endothelial function in individuals with metabolic syndrome (n = 24). Main Outcome Measure: We measured the difference in brachial artery flow-mediated dilation between placebo and hesperidin treatment periods. Results: Treatment of BAEC with hesperetin acutely stimulated phosphorylation of Src, Akt, AMP kinase, and endothelial NO synthase to produce NO; this required generation of H2O2. Increased adhesion of monocytes to BAEC and expression of vascular cell adhesion molecule-1 in response to TNF-α treatment was reduced by pretreatment with hesperetin. In the clinical study, when compared with placebo, hesperidin treatment increased flow-mediated dilation (10.26 ± 1.19 vs. 7.78 ± 0.76%; P = 0.02) and reduced concentrations of circulating inflammatory biomarkers (high-sensitivity C-reactive protein, serum amyloid A protein, soluble E-selectin). Conclusions: Novel mechanisms for hesperetin action in endothelial cells inform effects of oral hesperidin treatment to improve endothelial dysfunction and reduce circulating markers of inflammation in our exploratory clinical trial. Hesperetin has vasculoprotective actions that may explain beneficial cardiovascular effects of citrus consumption. PMID:21346065

Sirtuin-2 Regulates Sepsis Inflammation in ob/ob Mice

PubMed Central

Wang, Xianfeng; Buechler, Nancy L.; Martin, Ayana; Wells, Jonathan; Yoza, Barbara; McCall, Charles E.; Vachharajani, Vidula

2016-01-01

Objective Obesity increases morbidity and resource utilization in sepsis patients. Sepsis transitions from early/hyper-inflammatory to late/hypo-inflammatory phase. Majority of sepsis-mortality occurs during the late sepsis; no therapies exist to treat late sepsis. In lean mice, we have shown that sirtuins (SIRTs) modulate this transition. Here, we investigated the role of sirtuins, especially the adipose-tissue abundant SIRT-2 on transition from early to late sepsis in obese with sepsis. Methods Sepsis was induced using cecal ligation and puncture (CLP) in ob/ob mice. We measured microvascular inflammation in response to lipopolysaccharide/normal saline re-stimulation as a “second-hit” (marker of immune function) at different time points to track phases of sepsis in ob/ob mice. We determined SIRT-2 expression during different phases of sepsis. We studied the effect of SIRT-2 inhibition during the hypo-inflammatory phase on immune function and 7-day survival. We used a RAW264.7 (RAW) cell model of sepsis for mechanistic studies. We confirmed key findings in diet induced obese (DIO) mice with sepsis. Results We observed that the ob/ob-septic mice showed an enhanced early inflammation and a persistent and prolonged hypo-inflammatory phase when compared to WT mice. Unlike WT mice that showed increased SIRT1 expression, we found that SIRT2 levels were increased in ob/ob mice during hypo-inflammation. SIRT-2 inhibition in ob/ob mice during the hypo-inflammatory phase of sepsis reversed the repressed microvascular inflammation in vivo via activation of endothelial cells and circulating leukocytes and significantly improved survival. We confirmed the key finding of the role of SIRT2 during hypo-inflammatory phase of sepsis in this project in DIO-sepsis mice. Mechanistically, in the sepsis cell model, SIRT-2 expression modulated inflammatory response by deacetylation of NFκBp65. Conclusion SIRT-2 regulates microvascular inflammation in obese mice with sepsis and may provide a novel treatment target for obesity with sepsis. PMID:27500833

[The present and future state of minimized extracorporeal circulation].

PubMed

Meng, Fan; Yang, Ming

2013-05-01

Minimized extracorporeal circulation improved in the postoperative side effects of conventional extracorporeal circulation is a kind of new extracorporeal circulation. This paper introduces the principle, characteristics, applications and related research of minimized extracorporeal circulation. For the problems of systemic inflammatory response syndrome and limited assist time, the article proposes three development direction including system miniaturization and integration, pulsatile blood pump and the adaptive control by human parameter identification.

Metabolites associated with circulating interleukin-6 in older adults

USDA-ARS?s Scientific Manuscript database

Background: Circulating levels of the pro-inflammatory cytokine interleukin-6 (IL-6) levels are elevated in older adults, but mechanisms are unclear. In the current study, we used an untargeted metabolomic approach to develop an improved understanding about mechanisms related to circulating IL-6 in ...

Differential adipokine receptor expression on circulating leukocyte subsets in lean and obese children.

PubMed

Keustermans, Genoveva; van der Heijden, Laila B; Boer, Berlinda; Scholman, Rianne; Nuboer, Roos; Pasterkamp, Gerard; Prakken, Berent; de Jager, Wilco; Kalkhoven, Eric; Janse, Arieke J; Schipper, Henk S

2017-01-01

Childhood obesity prevalence has increased worldwide and is an important risk factor for type 2 diabetes (T2D) and cardiovascular disease (CVD). The production of inflammatory adipokines by obese adipose tissue contributes to the development of T2D and CVD. While levels of circulating adipokines such as adiponectin and leptin have been established in obese children and adults, the expression of adiponectin and leptin receptors on circulating immune cells can modulate adipokine signalling, but has not been studied so far. Here, we aim to establish the expression of adiponectin and leptin receptors on circulating immune cells in obese children pre and post-lifestyle intervention compared to normal weight control children. 13 obese children before and after a 1-year lifestyle intervention were compared with an age and sex-matched normal weight control group of 15 children. Next to routine clinical and biochemical parameters, circulating adipokines were measured, and flow cytometric analysis of adiponectin receptor 1 and 2 (AdipoR1, AdipoR2) and leptin receptor expression on peripheral blood mononuclear cell subsets was performed. Obese children exhibited typical clinical and biochemical characteristics compared to controls, including a higher BMI-SD, blood pressure and circulating leptin levels, combined with a lower insulin sensitivity index (QUICKI). The 1-year lifestyle intervention resulted in stabilization of their BMI-SD. Overall, circulating leukocyte subsets showed distinct adipokine receptor expression profiles. While monocytes expressed high levels of all adipokine receptors, NK and iNKT cells predominantly expressed AdipoR2, and B-lymphocytes and CD4+ and CD8+ T-lymphocyte subsets expressed AdipoR2 as well as leptin receptor. Strikingly though, leukocyte subset numbers and adipokine receptor expression profiles were largely similar in obese children and controls. Obese children showed higher naïve B-cell numbers, and pre-intervention also higher numbers of immature transition B-cells and intermediate CD14++CD16+ monocytes combined with lower total monocyte numbers, compared to controls. Furthermore, adiponectin receptor 1 expression on nonclassical CD14+CD16++ monocytes was consistently upregulated in obese children pre-intervention, compared to controls. However, none of the differences in leukocyte subset numbers and adipokine receptor expression profiles between obese children and controls remained significant after multiple testing correction. First, the distinct adipokine receptor profiles of circulating leukocyte subsets may partly explain the differential impact of adipokines on leukocyte subsets. Second, the similarities in adipokine receptor expression profiles between obese children and normal weight controls suggest that adipokine signaling in childhood obesity is primarily modulated by circulating adipokine levels, instead of adipokine receptor expression.

Shift Work in Rats Results in Increased Inflammatory Response after Lipopolysaccharide Administration: A Role for Food Consumption.

PubMed

Guerrero-Vargas, Natalí N; Guzmán-Ruiz, Mara; Fuentes, Rebeca; García, Joselyn; Salgado-Delgado, Roberto; Basualdo, María del Carmen; Escobar, Carolina; Markus, Regina P; Buijs, Ruud M

2015-08-01

The suprachiasmatic nucleus (SCN) drives circadian rhythms in behavioral and physiological variables, including the inflammatory response. Shift work is known to disturb circadian rhythms and is associated with increased susceptibility to develop disease. In rodents, circadian disruption due to shifted light schedules (jet lag) induced increased innate immune responses. To gain more insight into the influence of circadian disruption on the immune response, we characterized the inflammatory response in a model of rodent shift work and demonstrated that circadian disruption affected the inflammatory response to lipopolysaccharide (LPS) both in vivo and in vitro. Since food consumption is a main disturbing element in the shift work schedule, we also evaluated the inflammatory response to LPS in a group of rats that had no access to food during their working hours. Our results demonstrated that the shift work schedule decreased basal TNF-α levels in the liver but not in the circulation. Despite this, we observed that shift work induced increased cytokine response after LPS stimulation in comparison to control rats. Also, Kupffer cells (liver macrophages) isolated from shift work rats produced more TNF-α in response to in vitro LPS stimulation, suggesting important effects of circadian desynchronization on the functionality of this cell type. Importantly, the effects of shift work on the inflammatory response to LPS were prevented when food was not available during the working schedule. Together, these results show that dissociating behavior and food intake from the synchronizing drive of the SCN severely disturbs the immune response. © 2015 The Author(s).

Systemic immune cell response in rats after pulmonary exposure to manganese-containing particles collected from welding aerosols.

PubMed

Antonini, James M; Zeidler-Erdely, Patti C; Young, Shih-Houng; Roberts, Jenny R; Erdely, Aaron

2012-01-01

Welding fume inhalation affects the immune system of exposed workers. Manganese (Mn) in welding fume may induce immunosuppressive effects. The goal was to determine if Mn in welding fume alters immunity by reducing the number of circulating total leukocytes and specific leukocyte sub-populations. Sprague-Dawley rats were treated by intratracheal instillation (ITI) with either a single dose (2.00 mg/rat) or repeated doses (0.125 or 2.00 mg/rat for 7 weeks) with welding fumes that contained different levels of Mn. Additional rats were treated by ITI once a week for 7 weeks with the two doses of manganese chloride (MnCl₂). Bronchoalveolar lavage was performed to assess lung inflammation. Also, whole blood was recovered, and the number of circulating total leukocytes, as well as specific lymphocyte subsets, was determined by flow cytometry. The welding fume highest in Mn content significantly increased lung inflammation, injury, and production of inflammatory cytokines and chemokines compared to all other treatment groups. In addition, the same group expressed significant decreases in the number of circulating CD4⁺ and CD8⁺ T-lymphocytes after a single exposure, and significant reductions in the number of circulating total lymphocytes, primarily CD4⁺ and CD8⁺ T-lymphocytes, after repeated exposures (compared to control values). Repeated MnCl₂ exposure led to a trend of a reduction (but not statistically significant) in circulating total lymphocytes, attributable to the changes in the CD4⁺ T-lymphocyte population levels. The welding fume with the lower concentration of Mn had no significant effect on the numbers of blood lymphocytes and lymphocyte subsets compared to control values. Evidence from this study indicates that pulmonary exposure to certain welding fumes cause decrements in systemic immune cell populations, specifically circulating T-lymphocytes, and these alterations in immune cell number are not dependent exclusively on Mn, but likely a combination of other metals present in welding fume.

Blood-brain barrier and its function during inflammation and autoimmunity.

PubMed

Sonar, Sandip Ashok; Lal, Girdhari

2018-05-01

The blood-brain barrier (BBB) is an important physiologic barrier that separates CNS from soluble inflammatory mediators and effector immune cells from peripheral circulation. The optimum function of the BBB is necessary for the homeostasis, maintenance, and proper neuronal function. The clinical and experimental findings have shown that BBB dysfunction is an early hallmark of various neurologic disorders ranging from inflammatory autoimmune, neurodegenerative, and traumatic diseases to neuroinvasive infections. Significant progress has been made in the understanding of the regulation of BBB function under homeostatic and neuroinflammatory conditions. Several neurologic disease-modifying drugs have shown to improve the BBB function. However, they have a broad-acting immunomodulatory function and can increase the risk of life-threatening infections. The recent development of in vitro multicomponent 3-dimensional BBB models coupled with fluidics chamber as well as a cell-type specific reporter and knockout mice gave a new boost to our understanding of the dynamics of the BBB. In the review, we discuss the current understanding of BBB composition and recent findings that illustrate the critical regulatory elements of the BBB function under physiologic and inflammatory conditions, and also suggested the strategies to control BBB structure and function. ©2018 Society for Leukocyte Biology.

Immune Modulation of Cardiac Repair and Regeneration: The Art of Mending Broken Hearts

PubMed Central

Zlatanova, Ivana; Pinto, Cristina; Silvestre, Jean-Sébastien

2016-01-01

The accumulation of immune cells is among the earliest responses that manifest in the cardiac tissue after injury. Both innate and adaptive immunity coordinate distinct and mutually non-exclusive events governing cardiac repair, including elimination of the cellular debris, compensatory growth of the remaining cardiac tissue, activation of resident or circulating precursor cells, quantitative and qualitative modifications of the vascular network, and formation of a fibrotic scar. The present review summarizes the mounting evidence suggesting that the inflammatory response also guides the regenerative process following cardiac damage. In particular, recent literature has reinforced the central role of monocytes/macrophages in poising the refreshment of cardiomyocytes in myocardial infarction- or apical resection-induced cardiac insult. Macrophages dictate cardiac myocyte renewal through stimulation of preexisting cardiomyocyte proliferation and/or neovascularization. Nevertheless, substantial efforts are required to identify the nature of these macrophage-derived factors as well as the molecular mechanisms engendered by the distinct subsets of macrophages pertaining in the cardiac tissue. Among the growing inflammatory intermediaries that have been recognized as essential player in heart regeneration, we will focus on the role of interleukin (IL)-6 and IL-13. Finally, it is likely that within the mayhem of the injured cardiac tissue, additional types of inflammatory cells, such as neutrophils, will enter the dance to ignite and refresh the broken heart. However, the protective and detrimental inflammatory pathways have been mainly deciphered in animal models. Future research should be focused on understanding the cellular effectors and molecular signals regulating inflammation in human heart to pave the way for the development of factual therapies targeting the inflammatory compartment in cardiac diseases. PMID:27790620

Immune Modulation of Cardiac Repair and Regeneration: The Art of Mending Broken Hearts.

PubMed

Zlatanova, Ivana; Pinto, Cristina; Silvestre, Jean-Sébastien

2016-01-01

The accumulation of immune cells is among the earliest responses that manifest in the cardiac tissue after injury. Both innate and adaptive immunity coordinate distinct and mutually non-exclusive events governing cardiac repair, including elimination of the cellular debris, compensatory growth of the remaining cardiac tissue, activation of resident or circulating precursor cells, quantitative and qualitative modifications of the vascular network, and formation of a fibrotic scar. The present review summarizes the mounting evidence suggesting that the inflammatory response also guides the regenerative process following cardiac damage. In particular, recent literature has reinforced the central role of monocytes/macrophages in poising the refreshment of cardiomyocytes in myocardial infarction- or apical resection-induced cardiac insult. Macrophages dictate cardiac myocyte renewal through stimulation of preexisting cardiomyocyte proliferation and/or neovascularization. Nevertheless, substantial efforts are required to identify the nature of these macrophage-derived factors as well as the molecular mechanisms engendered by the distinct subsets of macrophages pertaining in the cardiac tissue. Among the growing inflammatory intermediaries that have been recognized as essential player in heart regeneration, we will focus on the role of interleukin (IL)-6 and IL-13. Finally, it is likely that within the mayhem of the injured cardiac tissue, additional types of inflammatory cells, such as neutrophils, will enter the dance to ignite and refresh the broken heart. However, the protective and detrimental inflammatory pathways have been mainly deciphered in animal models. Future research should be focused on understanding the cellular effectors and molecular signals regulating inflammation in human heart to pave the way for the development of factual therapies targeting the inflammatory compartment in cardiac diseases.

[T-lymphocytes--do they control rheumatic immune responses?].

PubMed

Wagner, U; Schulze-Koops, H

2005-09-01

T cells, in particular CD4(+) T cells, have been implicated in mediating many aspects of rheumatoid inflammation. In rheumatoid arthritis (RA), CD4(+) T cells display various functional abnormalities in the synovium as well as in the peripheral circulation. Current evidence suggests, however, that the role of CD4(+) T cells in the development of rheumatoid inflammation exceeds that of activated pro-inflammatory effector T cells that drive the chronic autoimmune response. Subsets of CD4(+) T cells with regulatory capacity, such as CD25(+) Tregs, have been identified in mice and man, and recent observations suggest that in RA, the function of these regulatory T cells is severely impaired. Thus, in RA, defective regulatory immune mechanisms might allow the breakdown of peripheral tolerance, following which the detrimental CD4(+) T-cell-driven immune response evolves and proceeds to chronic inflammation. Here, we review the functional abnormalities and the contribution of different T-cell subsets to rheumatoid inflammation.

Circulating blood and platelets supply glycosyltransferases that enable extrinsic extracellular glycosylation.

PubMed

Lee-Sundlov, Melissa M; Ashline, David J; Hanneman, Andrew J; Grozovsky, Renata; Reinhold, Vernon N; Hoffmeister, Karin M; Lau, Joseph Ty

2017-01-01

Glycosyltransferases, usually residing within the intracellular secretory apparatus, also circulate in the blood. Many of these blood-borne glycosyltransferases are associated with pathological states, including malignancies and inflammatory conditions. Despite the potential for dynamic modifications of glycans on distal cell surfaces and in the extracellular milieu, the glycan-modifying activities present in systemic circulation have not been systematically examined. Here, we describe an evaluation of blood-borne sialyl-, galactosyl- and fucosyltransferase activities that act upon the four common terminal glycan precursor motifs, GlcNAc monomer, Gal(β3)GlcNAc, Gal(β4)GlcNAc and Gal(β3)GalNAc, to produce more complex glycan structures. Data from radioisotope assays and detailed product analysis by sequential tandem mass spectrometry show that blood has the capacity to generate many of the well-recognized and important glycan motifs, including the Lewis, sialyl-Lewis, H- and Sialyl-T antigens. While many of these glycosyltransferases are freely circulating in the plasma, human and mouse platelets are important carriers for others, including ST3Gal-1 and β4GalT. Platelets compartmentalize glycosyltransferases and release them upon activation. Human platelets are also carriers for large amounts of ST6Gal-1 and the α3-sialyl to Gal(β4)GlcNAc sialyltransferases, both of which are conspicuously absent in mouse platelets. This study highlights the capability of circulatory glycosyltransferases, which are dynamically controlled by platelet activation, to remodel cell surface glycans and alter cell behavior. © The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Modulation of Endothelial Glycocalyx Structure under Inflammatory Conditions

PubMed Central

Kolářová, Hana; Ambrůzová, Barbora; Švihálková Šindlerová, Lenka; Klinke, Anna; Kubala, Lukáš

2014-01-01

The glycocalyx of the endothelium is an intravascular compartment that creates a barrier between circulating blood and the vessel wall. The glycocalyx is suggested to play an important role in numerous physiological processes including the regulation of vascular permeability, the prevention of the margination of blood cells to the vessel wall, and the transmission of shear stress. Various theoretical models and experimental approaches provide data about changes to the structure and functions of the glycocalyx under various types of inflammatory conditions. These alterations are suggested to promote inflammatory processes in vessels and contribute to the pathogenesis of number of diseases. In this review we summarize current knowledge about the modulation of the glycocalyx under inflammatory conditions and the consequences for the course of inflammation in vessels. The structure and functions of endothelial glycocalyx are briefly discussed in the context of methodological approaches regarding the determination of endothelial glycocalyx and the uncertainty and challenges involved in glycocalyx structure determination. In addition, the modulation of glycocalyx structure under inflammatory conditions and the possible consequences for pathogenesis of selected diseases and medical conditions (in particular, diabetes, atherosclerosis, ischemia/reperfusion, and sepsis) are summarized. Finally, therapeutic strategies to ameliorate glycocalyx dysfunction suggested by various authors are discussed. PMID:24803742

Circulating follicular helper T cells in Crohn's disease (CD) and CD-associated colorectal cancer.

PubMed

Wang, Zhenlong; Wang, Zhiming; Diao, Yanqing; Qian, Xiaoli; Zhu, Nan; Dong, Wen

2014-09-01

Follicular helper T cells (Tfh) represent a distinct subset of CD4+ T cells specialized in providing help to B lymphocytes. Studies have indicated that Tfh in circulating blood can act as a prognostic marker for diseases. In the current study, we investigated the percentages of circulating Tfh (CTfh) in Crohn's disease (CD) and CD-associated colorectal cancer (CRC). CTfh and it subtypes were determined by measuring CD3, CD4, CXCR5, CXCR3, and CCR6 using flow cytometry in 32 healthy controls and 78 CD patients, which included 16 CD-associated CRC. Data showed that proportion of CTfh in CD4+ T cells was significantly increased in CD patients (9.8 %) than in controls (5.1 %) (p < 0.01). Further analysis revealed that the upregulation of CTfh was contributed by CTfh-Th1 subtype and CTfh-Th17 subtype. Investigating the behavior of the patients demonstrated that prevalence of CTfh was significantly elevated in penetrating CD (20.9 %) than inflammatory CD (8.2 %) or stricturing CD (7.5 %). In addition, we analyzed CTfh in CD-associated CRC, and identified that patients with CRC had 1.59-fold higher percentage of CTfh than patients without CRC (p < 0.01). Furthermore, the distribution of CTfh subsets was significantly altered in patients with the cancer. This study suggests the involvement of CTfh in CD and CD-associated CRC, in which the effect of CTfh is partially different between these two diseases.

Oxidative stress and inflammatory response increase during coronary artery bypass grafting with extracorporeal circulation.

PubMed

Melek, Flora Eli; Baroncini, Liz Andréa Villela; Repka, João Carlos Domingus; Nascimento, Celso Soares; Précoma, Dalton Bertolim

2012-01-01

Thiobarbituric acid-reactive substance is a marker of oxidative stress and has cytotoxic and genotoxic actions. C- reactive protein is used to evaluate the acute phase of inflammatory response. To assess the thiobarbituric acid-reactive substance and C-reactive protein levels during extracorporeal circulation in patients submitted to cardiopulmonary bypass. Twenty-five consecutive surgical patients (16 men and nine women; mean age 61.2 ± 9.7 years) with severe coronary artery disease diagnosed by angiography scheduled for myocardial revascularization surgery with extracorporeal circulation were selected. Blood samples were collected immediately before initializing extracorporeal circulation, T0; in 10 minutes, T10; and in 30 minutes, T30. The thiobarbituric acid-reactive substance levels increased after extracorporeal circulation (P=0.001), with average values in T0=1.5 ± 0.07; in T10=5.54 ± 0.35; and in T30=3.36 ± 0.29 mmoles/mg of serum protein. The C-reactive protein levels in T0 were negative in all samples; in T10 average was 0.96 ± 0.7 mg/dl; and in T30 average was 0.99 ± 0.76 mg/dl. There were no significant differences between the dosages in T10 and T30 (P=0.83). C-reactive protein and thiobarbituric acid-reactive substance plasma levels progressively increased during extracorporeal circulation, with maximum values of thiobarbituric acid-reactive substance at 10 min and of C-reactive protein at 30 min. It suggests that there are an inflammatory response and oxidative stress during extracorporeal circulation.

CD31+ Cells From Peripheral Blood Facilitate Bone Regeneration in Biologically Impaired Conditions Through Combined Effects on Immunomodulation and Angiogenesis.

PubMed

Sass, F Andrea; Schmidt-Bleek, Katharina; Ellinghaus, Agnes; Filter, Sebastian; Rose, Alexander; Preininger, Bernd; Reinke, Simon; Geissler, Sven; Volk, Hans-Dieter; Duda, Georg N; Dienelt, Anke

2017-05-01

Controlled revascularization and inflammation are key elements regulating endogenous regeneration after (bone) tissue trauma. Peripheral blood-derived cell subsets, such as regulatory T-helper cells and circulating (endothelial) progenitor cells, respectively, can support endogenous tissue healing, whereas effector T cells that are associated with an aged immune system can hinder bone regeneration. CD31 is expressed by diverse leukocytes and is well recognized as a marker of circulating endothelial (precursor) cells; however, CD31 is absent from the surface of differentiated effector T cells. Thus, we hypothesized that by separating the inhibitory fractions from the supportive fractions of circulating cells within the peripheral blood (PB) using the CD31 marker, bone regeneration in biologically compromised conditions, such as those observed in aged patients, could be improved. In support of our hypothesis, we detected an inverse correlation between CD31+ cells and effector T cells in the hematomas of human fracture patients, dependent on the age of the patient. Furthermore, we demonstrated the regenerative capacity of human PB-CD31+ cells in vitro. These findings were translated to a clinically relevant rat model of impaired bone healing. The transplantation of rat PB-CD31+ cells advanced bone tissue restoration in vivo and was associated with an early anti-inflammatory response, the stimulation of (re)vascularization, and reduced fibrosis. Interestingly, the depletion or enrichment of the highly abundant CD31+/14+ monocytes from the mixed CD31+ cell population diminished tissue regeneration at different levels, suggesting combined effects within the PB-CD31+ subsets. In summary, an intraoperative enrichment of PB-CD31+ cells might be a novel option to facilitate endogenous regeneration under biologically impaired situations by supporting immunomodulation and vascularization. © 2016 American Society for Bone and Mineral Research. © 2016 American Society for Bone and Mineral Research.

Acute effects of exercise on the inflammatory state in patients with idiopathic pulmonary arterial hypertension.

PubMed

Harbaum, Lars; Renk, Emilia; Yousef, Sara; Glatzel, Antonia; Lüneburg, Nicole; Hennigs, Jan K; Oqueka, Tim; Baumann, Hans J; Atanackovic, Djordje; Grünig, Ekkehard; Böger, Rainer H; Bokemeyer, Carsten; Klose, Hans

2016-11-11

Exercise training positively influences exercise tolerance and functional capacity of patients with idiopathic pulmonary arterial hypertension (IPAH). However, the underlying mechanisms are unclear. We hypothesized that exercise modulates the activated inflammatory state found in IPAH patients. Single cardiopulmonary exercise testing was performed in 16 IPAH patients and 10 healthy subjects. Phenotypic characterization of peripheral blood mononuclear cells and circulating cytokines were assessed before, directly after and 1 h after exercise. Before exercise testing, IPAH patients showed elevated Th2 lymphocytes, regulatory T lymphocytes, IL-6, and TNF-alpha, whilst Th1/Th17 lymphocytes and IL-4 were reduced. In IPAH patients but not in healthy subject, exercise caused an immediate relative decrease of Th17 lymphocytes and a sustained reduction of IL-1-beta and IL-6. The higher the decrease of IL-6 the higher was the peak oxygen consumption of IPAH patients. Exercise seems to be safe from an immune and inflammatory point of view in IPAH patients. Our results demonstrate that exercise does not aggravate the inflammatory state and seems to elicit an immune-modulating effect in IPAH patients.

It May Seem Inflammatory, but Some T Cells Are Innately Healing to the Bone.

PubMed

Kalyan, Shirin

2016-11-01

Among the most significant developments to have taken place in osteology over the last few decades is an evolution from treating and viewing bone disorders primarily through an endocrine lens to instead seeing them as metabolic disorders that interface at the molecular and cellular level with the immune system. Osteoimmunology was officially born in response to accumulating evidence that the immune system is integrally involved in bone remodeling, but much of the early work focused on the role of conventional αβ T cells in driving bone loss. There is, however, emerging data indicating that innate lymphocytes, in particular γδ T cells, may in fact be important for bone regeneration. We first observed that bisphosphonate-associated osteonecrosis of the jaw (ONJ), a rare but serious adverse drug effect characterized by nonhealing necrotic bone tissue of the mandible or maxilla, was linked to a deficiency in a subset of γδ T cells found in human peripheral blood. Patients who developed ONJ while on bisphosphonate therapy not only lacked the main subset of circulating γδ T cells, but they also all had underlying conditions that compromised their immune integrity. A number of recent studies have unraveled the role of γδ T cells (and lymphocytes sharing their characteristics) in bone regeneration-particularly for fracture healing. These findings seem to contradict the prevailing view of such "inflammatory" T cells as being bone degenerative rather than restorative. This viewpoint melds together the emerging evidence of these so-called inflammatory T cells in bone remodeling and healing-showing that they are not in fact "all bad to the bone." © 2016 American Society for Bone and Mineral Research. © 2016 American Society for Bone and Mineral Research.

Patterns of Circulating Inflammatory Biomarkers in Older Persons with Varying Levels of Physical Performance: A Partial Least Squares-Discriminant Analysis Approach

PubMed Central

Marzetti, Emanuele; Landi, Francesco; Marini, Federico; Cesari, Matteo; Buford, Thomas W.; Manini, Todd M.; Onder, Graziano; Pahor, Marco; Bernabei, Roberto; Leeuwenburgh, Christiaan; Calvani, Riccardo

2014-01-01

Background: Chronic, low-grade inflammation and declining physical function are hallmarks of the aging process. However, previous attempts to correlate individual inflammatory biomarkers with physical performance in older people have produced mixed results. Given the complexity of the inflammatory response, the simultaneous analysis of an array of inflammatory mediators may provide more insights into the relationship between inflammation and age-related physical function decline. This study was designed to explore the association between a panel of inflammatory markers and physical performance in older adults through a multivariate statistical approach. Methods: Community-dwelling older persons were categorized into “normal walkers” (NWs; n = 27) or “slow walkers” (SWs; n = 11) groups using 0.8 m s−1 as the 4-m gait speed cutoff. A panel of 14 circulating inflammatory biomarkers was assayed by multiplex analysis. Partial least squares-discriminant analysis (PLS-DA) was used to identify patterns of inflammatory mediators associated with gait speed categories. Results: The optimal complexity of the PLS-DA model was found to be five latent variables. The proportion of correct classification was 88.9% for NW subjects (74.1% in cross-validation) and 90.9% for SW individuals (81.8% in cross-validation). Discriminant biomarkers in the model were interleukin 8, myeloperoxidase, and tumor necrosis factor alpha (all higher in the SW group), and P-selectin, interferon gamma, and granulocyte–macrophage colony-stimulating factor (all higher in the NW group). Conclusion: Distinct profiles of circulating inflammatory biomarkers characterize older subjects with different levels of physical performance. The dissection of these patterns may provide novel insights into the role played by inflammation in the disabling cascade and possible new targets for interventions. PMID:25593902

Cerebral Autoregulation in Hypertension and Ischemic Stroke: A Mini Review

PubMed Central

Shekhar, Shashank; Liu, Ruen; Travis, Olivia K; Roman, Richard J; Fan, Fan

2017-01-01

Aging and chronic hypertension are associated with dysfunction in vascular smooth muscle, endothelial cells, and neurovascular coupling. These dysfunctions induce impaired myogenic response and cerebral autoregulation, which diminish the protection of cerebral arterioles to the cerebral microcirculation from elevated pressure in hypertension. Chronic hypertension promotes cerebral focal ischemia in response to reductions in blood pressure that are often seen in sedentary elderly patients on antihypertensive therapy. Cerebral autoregulatory dysfunction evokes Blood-Brain Barrier (BBB) leakage, allowing the circulating inflammatory factors to infiltrate the brain to activate glia. The impaired cerebral autoregulation-induced inflammatory and ischemic injury could cause neuronal cell death and synaptic dysfunction which promote cognitive deficits. In this brief review, we summarize the pathogenesis and signaling mechanisms of cerebral autoregulation in hypertension and ischemic stroke-induced cognitive deficits, and discuss our new targets including 20-Hydroxyeicosatetraenoic acid (20-HETE), Gamma-Adducin (Add3) and Matrix Metalloproteinase-9 (MMP-9) that may contribute to the altered cerebral vascular function. PMID:29333537

Update on the pathogenesis of Scleroderma: focus on circulating progenitor cells

PubMed Central

Brunasso, Alexandra Maria Giovanna; Massone, Cesare

2016-01-01

In systemic sclerosis (SSc), the development of fibrosis seems to be a consequence of the initial ischemic process related to an endothelial injury. The initial trigger event in SSc is still unknown, but circulating progenitor cells (CPCs) might play a key role. Such cells have the ability to traffic into injury sites, exhibiting inflammatory features of macrophages, tissue remodeling properties of fibroblasts, and vasculogenesis functions of endothelial cells. The different subsets of CPCs described thus far in SSc arise from a pool of circulating monocyte precursors (CD14 + cells) and probably correspond to a different degree of differentiation of a single cell of origin. Several subsets of CPCs have been described in patients with SSc, all have a monocytic origin but may or may not express CD14, and all of these cells have the ability to give origin to endothelial cells, or collagen (Col)-producing cells, or both. We were able to identify six subsets of CPCs: pluripotent stem cells (CD14 +, CD45 +, and CD34 +), monocyte-derived multipotential cells (MOMCs) or monocyte-derived mesenchymal progenitors (CD14 +, CD45 +, CD34 +, Col I +, CD11b +, CD68 +, CD105 +, and VEGFR1 +), early endothelial progenitor cells (EPCs) or monocytic pro-angiogenic hematopoietic cells or circulating hematopoietic cells (CD14 +, CD45 +, CD34 low/−, VEGFR2 +/−, CXCR4 +, c-kit +, and DC117 +), late EPCs (CD14 −, CD133 +, VEGFR2 +, CD144 + [VE-cadherin +], and CD146 +), fibroblast-like cells (FLCs)/circulating Col-producing monocytes (CD14 +, CD45 +, CD34 +/−, and Col I +), and fibrocytes (CD14 −, CD45 +, CD34 +, Col I +, and CXCR4 +). It has been demonstrated that circulating CD14 + monocytes with an activated phenotype are increased in patients with SSc when compared with normal subjects. CD14 +, CD34 +, and Col I + spindle-shaped cells have been found in increased numbers in lungs of SSc patients with interstitial lung disease. Elevated blood amounts of early EPCs have been found in patients with SSc by different groups of researchers and such levels correlate directly with the interstitial lung involvement. The prevalence of hematopoietic markers expressed by CPCs that migrate from blood into injury sites in SSc differs and changes according to the degree of differentiation. CXCR4 is the most commonly expressed marker, followed by CD34 and CD45 at an end stage of differentiation. Such difference also indicates a continuous process of cell differentiation that might relate to the SSc clinical phenotype (degree of fibrosis and vascular involvement). A deeper understanding of the role of each subtype of CPCs in the development of the disease will help us to better classify patients in order to offer them targeted approaches in the future. PMID:27158466

Apoptotic cell-mediated suppression of streptococcal cell wall-induced arthritis is associated with alteration of macrophage function and local regulatory T-cell increase: a potential cell-based therapy?

PubMed Central

Perruche, Sylvain; Saas, Philippe; Chen, Wanjun

2009-01-01

Introduction Experimental streptococcal cell wall (SCW)-induced arthritis is characterized by two successive phases of the disease. The acute phase occurs early and is associated with an inflammatory process and neutrophil infiltration into the synovium. The second chronic phase is related to effector T-cell activation and the dysregulation of macrophage function. Creation of an immunomodulatory environment has been attributed to apoptotic cells themselves, apoptotic cell uptake by phagocytes as well as a less sensibility of phagocytes capturing apoptotic bodies to activation. Therefore we evaluated the potential of apoptotic cell injection to influence the course of inflammation in SCW-induced arthritis in rats. Methods Rat apoptotic thymocytes were injected intraperitoneally (2 × 108) in addition to an arthritogenic dose of systemic SCW in LEW female rats. Control rats received SCW immunization and PBS. Rats were then followed for arthritis occurrence and circulating cytokine detection. At sacrifice, regulatory T cells (Tregs) and macrophages were analyzed. Results Apoptotic cell injection profoundly suppressed joint swelling and destruction typically observed during the acute and chronic phases of SCW-induced arthritis. Synovial inflammatory cell infiltration and bone destruction were also markedly suppressed. Ex vivo experiments revealed reduced levels of TNF in cultures of macrophages from rats challenged with SCW in the presence of apoptotic thymocytes as well as reduced macrophage response to lipopolysaccharide. Moreover, apoptotic cell injection induced higher Foxp3+ Tregs in the lymphoid organs, especially in the draining lymph nodes. Conclusions Our data indicate that apoptotic cells modulate macrophage function and result in Treg generation/increase. This may be involved in inhibition of inflammation and amelioration of arthritis. This highlights and confirms previous studies showing that in vivo generation of Tregs using apoptotic cell injection may be a useful tool to prevent and treat inflammatory autoimmune responses. PMID:19570235

Avoidance-related EEG asymmetry predicts circulating interleukin-6.

PubMed

Shields, Grant S; Moons, Wesley G

2016-03-01

Recent research has linked avoidance-oriented motivational states to elevated pro-inflammatory cytokine levels. According to one of many theories regarding the association between avoidance and cytokine levels, because the evolutionarily basic avoidance system may be activated when an organism is threatened or overwhelmed, an associated inflammatory response may be adaptive for dealing with potential injury in such threatening situations. To examine this hypothesis, we tested whether the neural correlate of avoidance motivation associates with baseline levels of the circulating pro-inflammatory cytokine interleukin-6 (IL-6). Controlling for covariates, greater resting neural activity in the right frontal cortex relative to the left frontal cortex-the neural correlate of avoidance motivation-was associated with baseline IL-6. These results thus support the hypothesis that the avoidance motivational system may be closely linked to systemic inflammatory activity. (c) 2016 APA, all rights reserved).

A Double-Blinded Randomized Study Investigating a Possible Anti-Inflammatory Effect of Saxagliptin versus Placebo as Add-On Therapy in Patients with Both Type 2 Diabetes And Stable Coronary Artery Disease

PubMed Central

Åkra, Sissel; Weiss, Thomas W.; Øvstebø, Reidun; Aass, Hans Christian D.; Byrkjeland, Rune; Arnesen, Harald

2017-01-01

Background Promising results regarding potential anti-inflammatory and antiatherosclerotic effects of gliptins have been reported. Our aim was to investigate whether saxagliptin treatment modifies expression of inflammatory markers, primarily in peripheral blood mononuclear cells (PBMCs) and in circulating leukocytes in patients with stable coronary artery disease (CAD) and T2DM. Methods Patients (n = 12) were randomized to saxagliptin 5 mg daily or placebo for 3 months. Samples were taken at baseline and end of study in fasting state prior to intake of medications. PBMCs were isolated and cryopreserved at −150°C until ex vivo exposed to 1 ng/mL of lipopolysaccharide (LPS) for 4 hours. Gene expression was performed with custom-designed TaqMan® Arrays and relative quantification by real-time PCR (RT-qPCR). Results HbA1c was reduced in the saxagliptin-treated group compared to that in the change with placebo (p = 0.042). In unstimulated PBMCs and in circulating leukocytes, we observed a significant increase in IL-10 expression in the saxagliptin group (p = 0.043, both), significantly different from that in the placebo (p = 0.009 and p = 0.032, resp.). No between group differences in changes were observed in any of the selected proinflammatory markers. Conclusion In our small cohort of patients with combined T2DM and CAD, a possible anti-inflammatory effect of saxagliptin, observed in the present study by upregulation of IL-10 in leukocytes, needs to be confirmed in larger studies. PMID:28596642

Perioperative Outcomes, Transfusion Requirements, and Inflammatory Response After Coronary Artery Bypass Grafting With Off-Pump, Mini-Extracorporeal, and On-Pump Circulation Techniques.

PubMed

Brinkman, William T; Squiers, John J; Filardo, Giovanni; Arsalan, Mani; Smith, Robert L; Moore, David; Mack, Michael J; DiMaio, J Michael

2015-12-01

Mini-extracorporeal circulation (MECC) units were developed to reduce postoperative morbidity, transfusion requirements, and inflammation associated with conventional on-pump coronary artery bypass (ONCAB) surgery without the technical demands of the off-pump (OPCAB) technique. We compared perioperative outcomes and inflammatory mediation among OPCAB, MECC, and ONCAB techniques. We prospectively enrolled 102 patients undergoing elective isolated coronary bypass grafting. Perfusion methods were OPCAB (n = 34), MECC (n = 34), and ONCAB (n = 34). Serial blood samples were collected to measure serum inflammatory markers. There were no operative deaths or strokes. Total red blood cell (RBC) products used in OPCAB, MECC, and ONCAB patients were 0.676, 1.000, and 1.235 units, respectively. Adjusted (by splined Society of Thoracic Surgeons operative risk score) analysis showed no statistically significant differences in mean RBC product use among the different operative systems (OPCAB vs MECC, P = 0.580; OPCAB vs ONCAB, P = 0.311; MECC vs ONCAB, P = 0.633). Adjusted (by Society of Thoracic Surgeons risk score and baseline level) mean plasma level differences (24 hours postoperative - baseline) of C-reactive protein for OPCAB (117.89; 95% confidence interval [95% CI], 106.23-129.54) and for MECC (124.88; 95% CI, 113.45-136.32) were significantly higher than for ONCAB (98.82; 95% CI, 86.40-111.24). No significant adjusted differences (P = 0.304) in interleukin-6 level changes were observed. Off-pump coronary artery bypass and MECC did not significantly reduce mean total RBC transfusion requirements. Off-pump coronary artery bypass and MECC were associated with greater C-reactive protein elevation than ONCAB, suggestive of an increased inflammatory response to each of these techniques.

Development and characterization of targeted poly(NIPAm) nanoparticles for delivery of anti-inflammatory peptides in peripheral artery disease and osteoarthritis

NASA Astrophysics Data System (ADS)

McMasters, James F.

Inflammation is the underlying cause of several severe diseases including cardiovascular disease and osteoarthritis. Peripheral artery disease (PAD) is characterized by atherosclerotic occlusions within the peripheral vasculature. Current treatment for severe PAD involves mechanical widening of the artery via percutaneous transluminal angioplasty. Unfortunately, deployment of the balloon damages the endothelial layer, exposing the underlying collagenous matrix. Circulating platelets can bind to this collagen and become activated, releasing proinflammatory cytokines that promote proliferation of local smooth muscle cells. These proliferating cells eventually reocclude the vessel, resulting in restenosis and necessitating the need for a second procedure to reopen the vessel. Current treatments for moderate osteoarthritis include local injection of anti-inflammatory compounds such as glucocorticoids. Unfortunately, prolonged treatment carries with it significant side effects including osteoporosis, and cardiovascular complications. Our lab has developed an anti-inflammatory cell-penetrating peptide that inhibits mitogen-activated protein kinase activated protein kinase 2 (MK2). MK2 is implicated in the inflammatory cascade of atherosclerosis and osteoarthritis, making it a potentially effective strategy for reducing inflammation in both disease states. Unfortunately, these peptides are untargeted and quickly degraded in the presence of serum proteases, making the development of an effective delivery system of paramount importance. The overall goal of the research presented here is to detail the development of a poly(N-isopropylacrylamide) nanoparticle that is able to effectively load and release anti-inflammatory peptides for the treatment of these inflammatory diseases. In this dissertation, I will discuss the development of a collagen-binding nanoparticle that is able to inhibit platelet binding following angioplasty, thereby halting the initial inflammatory cascade. Additionally, these particles demonstrate the ability to reduce inflammation by through the loading and release of MK2-inhibiting cell-penetrating peptides. Additionally, I will cover the development of a hollow nanoparticle system that is designed to load increased quantities of these anti-inflammatory peptides for the treatment of osteoarthritis. This particle demonstrated increased macrophage uptake and prolonged drug release, resulting in a progressive inhibition of osteoarthritic inflammation over 8 days. The results presented here advance our understanding of these nanoparticle platforms, and suggest that they may serve at effective platforms for the treatment of restenosis following angioplasty, as well as osteoarthritis.

Chemokine expression in rheumatoid arthritis (RA): evidence of RANTES and macrophage inflammatory protein (MIP)-1 beta production by synovial T cells.

PubMed Central

Robinson, E; Keystone, E C; Schall, T J; Gillett, N; Fish, E N

1995-01-01

Earlier studies from this laboratory provided evidence for restricted cytokine expression in the T cell population in RA tissues. Specifically, IL-2, IL-4, IL-6 and interferon-gamma (IFN-gamma) gene expression levels were low. The selective chemoattractant and activation effects of chemokines on leucocytes identify them as potentially ideal candidates in mediating selective inflammatory processes in RA. Accordingly, we undertook studies to examine constitutive chemokine gene expression in RA tissues. RANTES, monocyte chemotactic protein-1 (MCP-1) and MIP-1 beta gene expression was examined in both the T and non-T cell populations in RA peripheral blood (PB), synovial fluid (SF) and synovial tissues (ST). Our results identified elevated levels of both RANTES and MIP-1 beta gene expression in circulating RA PB and SF T cells. By contrast, MCP-1 expression was virtually absent in RA PB, yet elevated MCP-1 mRNA levels were detected primarily in the non-T cell populations of the SF and ST samples. Histological examination of affected rheumatoid joints revealed extensive RANTES and MIP-1 beta expression in sites of lymphocyte infiltration and cell proliferation, namely the synovial lining and sublining layers. Fractionation or RA ST patient samples revealed that RANTES expression was restricted to the T cells, whereas MIP-1 beta expression was detected in both T and non-T fractions. These data suggest that MCP-1, MIP-1 beta and RANTES may have a central role in the trafficking of reactive molecules involved in immunoregulation and in the inflammatory processes in RA. Images Fig. 4 PMID:7545093

Interleukin-17 Promotes Neutrophil-Mediated Immunity by Activating Microvascular Pericytes and Not Endothelium

PubMed Central

Liu, Rebecca; Lauridsen, Holly M.; Amezquita, Robert A.; Pierce, Richard W.; Jane-wit, Dan; Fang, Caodi; Pellowe, Amanda S.; Kirkiles-Smith, Nancy C.; Gonzalez, Anjelica L.; Pober, Jordan S.

2016-01-01

A classical hallmark of acute inflammation is neutrophil infiltration of tissues, a multi-step process that involves sequential cell-cell interactions of circulating leukocytes with interleukin (IL)-1- or tumor necrosis factor-α (TNF)-activated microvascular endothelial cells (ECs) and pericytes (PCs) that form the wall of the postcapillary venules. The initial infiltrating cells accumulate perivascularly in close proximity to PCs. IL-17, a pro-inflammatory cytokine that acts on target cells via a heterodimeric receptor formed by IL-17RA and IL-17RC subunits, also promotes neutrophilic inflammation but its effects on vascular cells are less clear. We report that both cultured human ECs and PCs strongly express IL-17RC and, while neither cell type expresses much IL-17RA, PCs express significantly more than ECs. IL-17, alone or synergistically with TNF, significantly alters inflammatory gene expression in cultured human PCs but not ECs. RNA-seq analysis identifies many IL-17-induced transcripts in PCs encoding proteins known to stimulate neutrophil-mediated immunity. Conditioned media (CM) from IL-17-activated PCs, but not ECs, induce pertussis toxin-sensitive neutrophil polarization, likely mediated by PC-secreted chemokines, and also stimulate neutrophil production of pro-inflammatory molecules, including TNF, IL-1α, IL-1β, and IL-8. Furthermore, IL-17-activated PCs but not ECs can prolong neutrophil survival by producing G-CSF and GM-CSF, delaying the mitochondria outer membrane permeabilization and caspase 9 activation. Importantly, neutrophils exhibit enhanced phagocytic capacity after activation by CM from IL-17-treated PCs. We conclude that PCs, not ECs, are the major target of IL-17 within the microvessel wall and that IL-17-activated PCs can modulate neutrophil functions within the perivascular tissue space. PMID:27534549

Cortisol-induced immune suppression by a blockade of lymphocyte egress in traumatic brain injury.

PubMed

Dong, Tingting; Zhi, Liang; Bhayana, Brijesh; Wu, Mei X

2016-08-25

Acute traumatic brain injury (TBI) represents one of major causes of mortality and disability in the USA. Neuroinflammation has been regarded both beneficial and detrimental, probably in a time-dependent fashion. To address a role for neuroinflammation in brain injury, C57BL/6 mice were subjected to a closed head mild TBI (mTBI) by a standard controlled cortical impact, along with or without treatment of sphingosine 1-phosphate (S1P) or rolipram, after which the brain tissue of the impact site was evaluated for cell morphology via histology, inflammation by qRT-PCR and T cell staining, and cell death with Caspase-3 and TUNEL staining. Circulating lymphocytes were quantified by flow cytometry, and plasma hydrocortisone was analyzed by LC-MS/MS. To investigate the mechanism whereby cortisol lowered the number of peripheral T cells, T cell egress was tracked in lymph nodes by intravital confocal microscopy after hydrocortisone administration. We detected a decreased number of circulating lymphocytes, in particular, T cells soon after mTBI, which was inversely correlated with a transient and robust increase of plasma cortisol. The transient lymphocytopenia might be caused by cortisol in part via a blockade of lymphocyte egress as demonstrated by the ability of cortisol to inhibit T cell egress from the secondary lymphoid tissues. Moreover, exogenous hydrocortisone severely suppressed periphery lymphocytes in uninjured mice, whereas administering an egress-promoting agent S1P normalized circulating T cells in mTBI mice and increased T cells in the injured brain. Likewise, rolipram, a cAMP phosphodiesterase inhibitor, was also able to elevate cAMP levels in T cells in the presence of hydrocortisone in vitro and abrogate the action of cortisol in mTBI mice. The investigation demonstrated that the number of circulating T cells in the early phase of TBI was positively correlated with T cell infiltration and inflammatory responses as well as cell death at the cerebral cortex and hippocampus beneath the impact site. Decreases in intracellular cAMP might be part of the mechanism behind cortisol-mediated blockade of T cell egress. The study argues strongly for a protective role of cortisol-induced immune suppression in the early stage of TBI.

Metabolite Profiling and Pharmacokinetic Evaluation of Hydrocortisone in a Perfused Three-Dimensional Human Liver Bioreactor

PubMed Central

Sarkar, Ujjal; Rivera-Burgos, Dinelia; Large, Emma M.; Hughes, David J.; Ravindra, Kodihalli C.; Dyer, Rachel L.; Ebrahimkhani, Mohammad R.; Griffith, Linda G.

2015-01-01

Endotoxin lipopolysaccharide (LPS) is known to cause liver injury primarily involving inflammatory cells such as Kupffer cells, but few in vitro culture models are applicable for investigation of inflammatory effects on drug metabolism. We have developed a three-dimensional human microphysiological hepatocyte–Kupffer cell coculture system and evaluated the anti-inflammatory effect of glucocorticoids on liver cultures. LPS was introduced to the cultures to elicit an inflammatory response and was assessed by the release of proinflammatory cytokines, interleukin 6 and tumor necrosis factor α. A sensitive and specific reversed-phase–ultra high-performance liquid chromatography–quadrupole time of flight–mass spectrometry method was used to evaluate hydrocortisone disappearance and metabolism at near physiologic levels. For this, the systems were dosed with 100 nM hydrocortisone and circulated for 2 days; hydrocortisone was depleted to approximately 30 nM, with first-order kinetics. Phase I metabolites, including tetrahydrocortisone and dihydrocortisol, accounted for 8–10% of the loss, and 45–52% consisted of phase II metabolites, including glucuronides of tetrahydrocortisol and tetrahydrocortisone. Pharmacokinetic parameters, i.e., half-life, rate of elimination, clearance, and area under the curve, were 23.03 hours, 0.03 hour−1, 6.6 × 10−5 l⋅hour−1, and 1.03 (mg/l)*h, respectively. The ability of the bioreactor to predict the in vivo clearance of hydrocortisone was characterized, and the obtained intrinsic clearance values correlated with human data. This system offers a physiologically relevant tool for investigating hepatic function in an inflamed liver. PMID:25926431

Metabolite profiling and pharmacokinetic evaluation of hydrocortisone in a perfused three-dimensional human liver bioreactor.

PubMed

Sarkar, Ujjal; Rivera-Burgos, Dinelia; Large, Emma M; Hughes, David J; Ravindra, Kodihalli C; Dyer, Rachel L; Ebrahimkhani, Mohammad R; Wishnok, John S; Griffith, Linda G; Tannenbaum, Steven R

2015-07-01

Endotoxin lipopolysaccharide (LPS) is known to cause liver injury primarily involving inflammatory cells such as Kupffer cells, but few in vitro culture models are applicable for investigation of inflammatory effects on drug metabolism. We have developed a three-dimensional human microphysiological hepatocyte-Kupffer cell coculture system and evaluated the anti-inflammatory effect of glucocorticoids on liver cultures. LPS was introduced to the cultures to elicit an inflammatory response and was assessed by the release of proinflammatory cytokines, interleukin 6 and tumor necrosis factor α. A sensitive and specific reversed-phase-ultra high-performance liquid chromatography-quadrupole time of flight-mass spectrometry method was used to evaluate hydrocortisone disappearance and metabolism at near physiologic levels. For this, the systems were dosed with 100 nM hydrocortisone and circulated for 2 days; hydrocortisone was depleted to approximately 30 nM, with first-order kinetics. Phase I metabolites, including tetrahydrocortisone and dihydrocortisol, accounted for 8-10% of the loss, and 45-52% consisted of phase II metabolites, including glucuronides of tetrahydrocortisol and tetrahydrocortisone. Pharmacokinetic parameters, i.e., half-life, rate of elimination, clearance, and area under the curve, were 23.03 hours, 0.03 hour(-1), 6.6 × 10(-5) l⋅hour(-1), and 1.03 (mg/l)*h, respectively. The ability of the bioreactor to predict the in vivo clearance of hydrocortisone was characterized, and the obtained intrinsic clearance values correlated with human data. This system offers a physiologically relevant tool for investigating hepatic function in an inflamed liver. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

Residential proximity to abandoned uranium mines and serum inflammatory potential in chronically exposed Navajo communities.

PubMed

Harmon, Molly E; Lewis, Johnnye; Miller, Curtis; Hoover, Joseph; Ali, Abdul-Mehdi S; Shuey, Chris; Cajero, Miranda; Lucas, Selita; Zychowski, Katherine; Pacheco, Bernadette; Erdei, Esther; Ramone, Sandy; Nez, Teddy; Gonzales, Melissa; Campen, Matthew J

2017-07-01

Members of the Navajo Nation, who possess a high prevalence of cardiometabolic disease, reside near hundreds of local abandoned uranium mines (AUM), which contribute uranium, arsenic and other metals to the soil, water and air. We recently reported that hypertension is associated with mine waste exposures in this population. Inflammation is a major player in the development of numerous vascular ailments. Our previous work establishing that specific transcriptional responses of cultured endothelial cells treated with human serum can reveal relative circulating inflammatory potential in a manner responsive to pollutant exposures, providing a model to assess responses associated with exposure to these waste materials in this population. To investigate a potential link between exposures to AUM and serum inflammatory potential in affected communities, primary human coronary artery endothelial cells were treated for 4 h with serum provided by Navajo study participants (n=145). Endothelial transcriptional responses of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and chemokine ligand 2 (CCL2) were measured. These transcriptional responses were then linked to AUM exposure metrics, including surface area-weighted AUM proximity and estimated oral intake of metals. AUM proximity strongly predicted endothelial transcriptional responses to serum including CCL2, VCAM-1 and ICAM-1 (P<0.0001 for each), whereas annual water intakes of arsenic and uranium did not, even after controlling for all major effect modifiers. Inflammatory potential associated with proximity to AUMs, but not oral intake of specific metals, additionally suggests a role for inhalation exposure as a contributor to cardiovascular disease.

The ectoenzyme-side of matrix metalloproteinases (MMPs) makes inflammation by serum amyloid A (SAA) and chemokines go round.

PubMed

De Buck, Mieke; Gouwy, Mieke; Struyf, Sofie; Opdenakker, Ghislain; Van Damme, Jo

2018-06-02

During an inflammatory response, a large number of distinct mediators appears in the affected tissues or in the blood circulation. These include acute phase proteins such as serum amyloid A (SAA), cytokines and chemokines and proteolytic enzymes. Although these molecules are generated within a cascade sequence in specific body compartments allowing for independent action, their co-appearance in space and time during acute or chronic inflammation points toward important mutual interactions. Pathogen-associated molecular patterns lead to fast induction of the pro-inflammatory endogenous pyrogens, which are evoking the acute phase response. Interleukin-1, tumor necrosis factor-α and interferons simultaneously trigger different cell types, including leukocytes, endothelial cells and fibroblasts for tissue-specific or systemic production of chemokines and matrix metalloproteinases (MMPs). In addition, SAA induces chemokines and both stimulate secretion of MMPs from multiple cell types. As a consequence, these mediators may cooperate to enhance the inflammatory response. Indeed, SAA synergizes with chemokines to increase chemoattraction of monocytes and granulocytes. On the other hand, MMPs post-translationally modify chemokines and SAA to reduce their activity. Indeed, MMPs internally cleave SAA with loss of its cytokine-inducing and direct chemotactic potential whilst retaining its capacity to synergize with chemokines in leukocyte migration. Finally, MMPs truncate chemokines at their NH 2 - or COOH-terminal end, resulting in reduced or enhanced chemotactic activity. Therefore, the complex interactions between chemokines, SAA and MMPs either maintain or dampen the inflammatory response. Copyright © 2018. Published by Elsevier B.V.

Reduction of Breast Cancer Relapses with Perioperative Non-Steroidal Anti-Inflammatory Drugs: New Findings and a Review

PubMed Central

Retsky, Michael; Demicheli, Romano; Hrushesky, William J.M; Forget, Patrice; Kock, Marc De; Gukas, Isaac; Rogers, Rick A; Baum, Michael; Sukhatme, Vikas; Vaidya, Jayant S

2013-01-01

To explain a bimodal pattern of hazard of relapse among early stage breast cancer patients identified in multiple databases, we proposed that late relapses result from steady stochastic progressions from single dormant malignant cells to avascular micrometastases and then on to growing deposits. However in order to explain early relapses, we had to postulate that something happens at about the time of surgery to provoke sudden exits from dormant phases to active growth and then to detection. Most relapses in breast cancer are in the early category. Recent data from Forget et al. suggest an unexpected mechanism. They retrospectively studied results from 327 consecutive breast cancer patients comparing various perioperative analgesics and anesthetics in one Belgian hospital and one surgeon. Patients were treated with mastectomy and conventional adjuvant therapy. Relapse hazard updated Sept 2011 are presented. A common Non-Steroidal Anti-Inflammatory Drug (NSAID) analgesic used in surgery produced far superior disease-free survival in the first 5 years after surgery. The expected prominent early relapse events in months 9-18 are reduced 5-fold. If this observation holds up to further scrutiny, it could mean that the simple use of this safe, inexpensive and effective anti-inflammatory agent at surgery might eliminate early relapses. Transient systemic inflammation accompanying surgery could facilitate angiogenesis of dormant micrometastases, proliferation of dormant single cells, and seeding of circulating cancer stem cells (perhaps in part released from bone marrow) resulting in early relapse and could have been effectively blocked by the perioperative anti-inflammatory agent. PMID:23992307

Polymer-Based Therapeutics: Nanoassemblies and Nanoparticles for Management of Atherosclerosis

PubMed Central

Lewis, Daniel R.; Kamisoglu, Kubra; York, Adam; Moghe, Prabhas V.

2012-01-01

Coronary arterial disease, one of the leading causes of adult mortality, is triggered by atherosclerosis. A disease with complex etiology, atherosclerosis results from the progressive long-term combination of atherogenesis, the accumulation of modified lipoproteins within blood vessel walls, along with vascular and systemic inflammatory processes. The management of atherosclerosis is challenged by the localized flare-up of several multipronged signaling interactions between activated monocytes, atherogenic macrophages and inflamed or dysfunctional endothelial cells. A new generation of approaches is now emerging founded on multifocal, targeted therapies that seek to reverse or ameliorate the athero-inflammatory cascade within the vascular intima. This article reviews the various classes and primary examples of bioactive configurations of nanoscale assemblies. Of specific interest are polymer-based or polymer-lipid micellar assemblies designed as multimodal receptor-targeted blockers or drug carriers whose activity can be tuned by variations in polymer hydrophobicity, charge, and architecture. Also reviewed are emerging reports on multifunctional nanoassemblies and nanoparticles for improved circulation and enhanced targeting to athero-inflammatory lesions and atherosclerotic plaques. PMID:21523920

Non-Lethal Endotoxin Injection: A Rat Model of Hypercoagulability.

PubMed

Brooks, Marjory B; Turk, James R; Guerrero, Abraham; Narayanan, Padma K; Nolan, John P; Besteman, Elizabeth G; Wilson, Dennis W; Thomas, Roberta A; Fishman, Cindy E; Thompson, Karol L; Ellinger-Ziegelbauer, Heidrun; Pierson, Jennifer B; Paulman, April; Chiang, Alan Y; Schultze, Albert E

2017-01-01

Systemic inflammation co-activates coagulation, which unchecked culminates in a lethal syndrome of multi-organ microvascular thrombosis known as disseminated intravascular coagulation (DIC). We studied an endotoxin-induced inflammatory state in rats to identify biomarkers of hemostatic imbalance favoring hypercoagulability. Intraperitoneal injection of LPS at 15 mg/kg body weight resulted in peripheral leukopenia and widespread neutrophilic sequestration characteristic of an acute systemic inflammatory response. Early indicators of hemostatic pathway activation developed within 4 hours, including increased circulating concentrations of procoagulant extracellular vesicles (EVs), EVs expressing endothelial cell and platelet membrane markers, and high concentration of soluble intercellular adhesion molecule-1 (sICAM-1), plasminogen activator inhibitor-1 (PAI-1), and D-dimers. Inflammation persisted throughout the 48-hour observation period; however, increases were found in a subset of serum microRNA (miRNA) that coincided with gradual resolution of hemostatic protein abnormalities and reduction in EV counts. Dose-adjusted LPS treatment in rats provides a time-course model to develop biomarker profiles reflecting procoagulant imbalance and rebalance under inflammatory conditions.

The Transcriptomic Response of Rat Hepatic Stellate Cells to Endotoxin: Implications for Hepatic Inflammation and Immune Regulation

PubMed Central

Tandon, Ashish; Gandhi, Chandrashekhar R.

2013-01-01

With their location in the perisinusoidal space of Disse, hepatic stellate cells (HSCs) communicate with all of the liver cell types both by physical association (cell body as well as cytosolic processes penetrating into sinusoids through the endothelial fenestrations) and by producing several cytokines and chemokines. Bacterial lipopolysaccharide (LPS), circulating levels of which are elevated in liver diseases and transplantation, stimulates HSCs to produce increased amounts of cytokines and chemokines. Although recent research provides strong evidence for the role of HSCs in hepatic inflammation and immune regulation, the number of HSC-elaborated inflammatory and immune regulatory molecules may be much greater then known at the present time. Here we report time-dependent changes in the gene expression profile of inflammatory and immune-regulatory molecules in LPS-stimulated rat HSCs, and their validation by biochemical analyses. LPS strongly up-regulated LPS-response elements (TLR2 and TLR7) but did not affect TLR4 and down-regulated TLR9. LPS also up-regulated genes in the MAPK, NFκB, STAT, SOCS, IRAK and interferon signaling pathways, numerous CC and CXC chemokines and IL17F. Interestingly, LPS modulated genes related to TGFβ and HSC activation in a manner that would limit their activation and fibrogenic activity. The data indicate that LPS-stimulated HSCs become a major cell type in regulating hepatic inflammatory and immunological responses by altering expression of numerous relevant genes, and thus play a prominent role in hepatic pathophysiology including liver diseases and transplantation. PMID:24349206

Intravenous immunoglobulins reverse acute vaso-occlusive crises in sickle cell mice through rapid inhibition of neutrophil adhesion

PubMed Central

Chang, Jungshan; Shi, Patricia A.; Chiang, Elaine Y.

2008-01-01

Previous studies using intravital microscopy in a sickle cell disease (SCD) mouse model suggest that adherent white blood cells (WBCs) play a key role in vaso-occlusion by capturing circulating red blood cells (RBCs) in venules. Commercial intravenous immunoglobulin (IVIG) given before the inflammatory stimuli increased microcirculatory blood flow and survival. To mimic the clinical situation in which SCD patients seek medical attention after the onset of symptoms, we developed an in vivo model in which the therapeutic intervention (eg, IVIG) was administered after in the inflammatory challenge. In this setting, IVIG rapidly (< 10 minutes) reduced adherent leukocyte numbers and dramatically inhibited interactions between RBCs and WBCs, resulting in improved microcirculatory blood flow and survival of sickle cell “Berkeley” mice. Longer survival correlated positively with blood flow (P = .001) and negatively with the number of adherent leukocytes (P = .001) and RBC-WBC interactions (P = .002). Using multichannel digital fluorescence videomicroscopy, we found that IVIG affected specifically the recruitment of neutrophils. Moreover, further analyses of leukocyte behavior revealed that IVIG significantly increased rolling velocities, indicating that it alters adhesion pathways involved in slow rolling. These data suggest that the potential therapeutic benefits of IVIG in SCD crises should be evaluated in a clinical trial. PMID:17932253

Triple selectin knockout (ELP-/-) mice fail to develop OVA-induced acute asthma phenotype

PubMed Central

2011-01-01

Objective The recruitment of leukocytes from circulation to sites of inflammation requires several families of adhesion molecules among which are selectins expressed on a variety of cells. In addition, they have also been shown to play key roles in the activation of cells in inflammation. Methods To explore the collective role of E-, L-, and P- selectins in OVA-induced Th2 mediated response in acute asthma pathophysiology, ELP-/- mice were used and compared with age-matched wildtype (WT). Results Asthma phenotype was assessed by measuring pulmonary function, inflammation and OVA-specific serum IgE, which were completely abrogated in ELP-/- mice. Adoptive transfer of sensitized L selectin+CD4+ T cells into naïve ELP-/- mice which post-OVA challenge, developed asthma, suggesting that L-selectin may be critically involved in the onset of Th2 response in asthma. Tissue resident ELP-deficient cells were otherwise functionally competent as proved by normal proliferative response. Conclusions: Comparative studies between ELP-/- and WT mice uncovered functional roles of these three integrins in inflammatory response in allergic asthma. All three selectins seem to impede inflammatory migration while only L-selectin also possibly regulates activation of specific T cell subsets in lung and airways. PMID:21835035

CIRCULATING CD11B EXPRESSION CORRELATES WITH THE NEUTROPHIL RESPONSE AND AIRWAY MCD-14 EXPRESSION IS ENHANCED FOLLOWING OZONE EXPOSURE IN HUMANS

EPA Science Inventory

We recently reported that baseline expression of circulating CD11b is associated with the magnitude of the neutrophil response following inhaled endotoxin. In this study, we examined whether circulating CD11b plays a similar role in the inflammatory response following inhaled ozo...

Cynomolgus macaques naturally infected with Trypanosoma cruzi-I exhibit an overall mixed pro-inflammatory/modulated cytokine signature characteristic of human Chagas disease.

PubMed

Vitelli-Avelar, Danielle Marquete; Sathler-Avelar, Renato; Mattoso-Barbosa, Armanda Moreira; Gouin, Nicolas; Perdigão-de-Oliveira, Marcelo; Valério-Dos-Reis, Leydiane; Costa, Ronaldo Peres; Elói-Santos, Silvana Maria; Gomes, Matheus de Souza; Amaral, Laurence Rodrigues do; Teixeira-Carvalho, Andréa; Martins-Filho, Olindo Assis; Dick, Edward J; Hubbard, Gene B; VandeBerg, Jane F; VandeBerg, John L

2017-02-01

Non-human primates have been shown to be useful models for Chagas disease. We previously reported that natural T. cruzi infection of cynomolgus macaques triggers clinical features and immunophenotypic changes of peripheral blood leukocytes resembling those observed in human Chagas disease. In the present study, we further characterize the cytokine-mediated microenvironment to provide supportive evidence of the utility of cynomolgus macaques as a model for drug development for human Chagas disease. In this cross-sectional study design, flow cytometry and systems biology approaches were used to characterize the ex vivo and in vitro T. cruzi-specific functional cytokine signature of circulating leukocytes from TcI-T. cruzi naturally infected cynomolgus macaques (CH). Results showed that CH presented an overall CD4+-derived IFN-γ pattern regulated by IL-10-derived from CD4+ T-cells and B-cells, contrasting with the baseline profile observed in non-infected hosts (NI). Homologous TcI-T. cruzi-antigen recall in vitro induced a broad pro-inflammatory cytokine response in CH, mediated by TNF from innate/adaptive cells, counterbalanced by monocyte/B-cell-derived IL-10. TcIV-antigen triggered a more selective cytokine signature mediated by NK and T-cell-derived IFN-γ with modest regulation by IL-10 from T-cells. While NI presented a cytokine network comprised of small number of neighborhood connections, CH displayed a complex cross-talk amongst network elements. Noteworthy, was the ability of TcI-antigen to drive a complex global pro-inflammatory network mediated by TNF and IFN-γ from NK-cells, CD4+ and CD8+ T-cells, regulated by IL-10+CD8+ T-cells, in contrast to the TcIV-antigens that trigger a modest network, with moderate connecting edges. Altogether, our findings demonstrated that CH present a pro-inflammatory/regulatory cytokine signature similar to that observed in human Chagas disease. These data bring additional insights that further validate these non-human primates as experimental models for Chagas disease.

Interleukin-18: Biological properties and role in disease pathogenesis.

PubMed

Kaplanski, Gilles

2018-01-01

Initially described as an interferon (IFN)γ-inducing factor, interleukin (IL)-18 is indeed involved in Th1 and NK cell activation, but also in Th2, IL-17-producing γδ T cells and macrophage activation. IL-18, a member of the IL-1 family, is similar to IL-1β for being processed by caspase 1 to an 18 kDa-biologically active mature form. IL-18 binds to its specific receptor (IL-18Rα, also known as IL-1R7) forming a low affinity ligand chain. This is followed by recruitment of the IL-18Rβ chain. IL-18 then uses the same signaling pathway as IL-1 to activate NF-kB and induce inflammatory mediators such as adhesion molecules, chemokines and Fas ligand. IL-18 also binds to the circulating high affinity IL-18 binding protein (BP), such as only unbound free IL-18 is active. IL-18Rα may also bind IL-37, another member of the IL-1 family, but in association with the negative signaling chain termed IL-1R8, which transduces an anti-inflammatory signal. IL-18BP also binds IL-37 and this acts as a sink for the anti-inflammatory properties of IL-37. There is now ample evidence for a role of IL-18 in various infectious, metabolic or inflammatory diseases such as influenza virus infection, atheroma, myocardial infarction, chronic obstructive pulmonary disease, or Crohn's disease. However, IL-18 plays a very specific role in the pathogenesis of hemophagocytic syndromes (HS) also termed Macrophage Activation Syndrome. In children affected by NLRC4 gain-of-function mutations, IL-18 circulates in the range of tens of nanograms/mL. HS is treated with the IL-1 Receptor antagonist (anakinra) but also specifically with IL-18BP. Systemic juvenile idiopathic arthritis or adult-onset Still's disease are also characterized by high serum IL-18 concentrations and are treated by IL-18BP. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Circulating cytotoxic T cells and natural killer cells as potential predictors for antidepressant response in melancholic depression. Restoration of T regulatory cell populations after antidepressant therapy.

PubMed

Grosse, Laura; Carvalho, Livia A; Birkenhager, Tom K; Hoogendijk, Witte J; Kushner, Steven A; Drexhage, Hemmo A; Bergink, Veerle

2016-05-01

There is a substantial unmet need for biomarkers to predict treatment response in major depressive disorder (MDD). Evidence has converged on activation of the inflammatory response system as a fundamental mechanism underlying MDD. By investigating circulating leukocyte subsets quantified by fluorescence-activated cell sorting (FACS) analysis before treatment, we aim to predict antidepressant response. Forty medication-free inpatients with melancholic, non-psychotic depression before treatment with either venlafaxine or imipramine and 40 age- and gender-matched healthy controls were included. Leukocyte subsets were quantified by FACS analysis using frozen peripheral blood mononuclear cells (PBMC) collected prior to and after 7 weeks of treatment with either venlafaxine (375 mg/day) or imipramine (blood level 200-300 ng/ml). Response was defined as at least 50 % reduction of the baseline Hamilton Rating Scale for Depression (HAM-D) score. Prior to treatment, MDD patients showed reduced percentages of CD4(+)CD25(high)Foxp3(+) T regulatory (Treg) cells when compared with controls (1.5 ± 0.6 vs. 1.8 ± 0.6, p = .037). After treatment, robust rises in Treg cells were observed in patients (1.8 ± 0.7, p < .001), yet Treg cells were not predictors of the clinical outcome of treatment. Antidepressant non-responders showed increased CD8(+) cytotoxic T cell percentages (24.0 ± 8.6 vs. 15.9 ± 5.9, p = .004) and decreased natural killer (NK) cell percentages (14.0 ± 6.9 vs. 21.4 ± 11.9, p = .020) compared with responders before treatment. Both lymphocyte levels were not significantly modulated by treatment. In melancholic MDD, FACS analysis of circulating leukocyte subpopulations might help to discriminate between patients with high or low responsiveness to antidepressant treatment.

Pharmacological inhibition of myostatin suppresses systemic inflammation and muscle atrophy in mice with chronic kidney disease

PubMed Central

Zhang, Liping; Rajan, Vik; Lin, Eugene; Hu, Zhaoyong; Han, H. Q.; Zhou, Xiaolan; Song, Yanping; Min, Hosung; Wang, Xiaonan; Du, Jie; Mitch, William E.

2011-01-01

Chronic kidney disease (CKD) and several other catabolic conditions are characterized by increased circulating inflammatory cytokines, defects in IGF-1 signaling, abnormal muscle protein metabolism, and progressive muscle atrophy. In these conditions, no reliable treatments successfully block the development of muscle atrophy. In mice with CKD, we found a 2- to 3-fold increase in myostatin expression in muscle. Its pharmacological inhibition by subcutaneous injections of an anti-myostatin peptibody into CKD mice (IC50 ∼1.2 nM) reversed the loss of body weight (≈5–7% increase in body mass) and muscle mass (∼10% increase in muscle mass) and suppressed circulating inflammatory cytokines vs. results from CKD mice injected with PBS. Pharmacological myostatin inhibition also decreased the rate of protein degradation (16.38±1.29%; P<0.05), increased protein synthesis in extensor digitorum longus muscles (13.21±1.09%; P<0.05), markedly enhanced satellite cell function, and improved IGF-1 intracellular signaling. In cultured muscle cells, TNF-α increased myostatin expression via a NF-κB-dependent pathway, whereas muscle cells exposed to myostatin stimulated IL-6 production via p38 MAPK and MEK1 pathways. Because IL-6 stimulates muscle protein breakdown, we conclude that CKD increases myostatin through cytokine-activated pathways, leading to muscle atrophy. Myostatin antagonism might become a therapeutic strategy for improving muscle growth in CKD and other conditions with similar characteristics.—Zhang, L., Rajan, V., Lin, E., Hu, Z., Han, H.Q., Zhou, X., Song, Y., Min, H., Wang, X., Du, J., Mitch, W. E. Pharmacological inhibition of myostatin suppresses systemic inflammation and muscle atrophy in mice with chronic kidney disease. PMID:21282204

Unopposed Estrogen Supplementation/Progesterone Deficiency in Post-Reproductive Age Affects the Secretory Profile of Resident Macrophages in a Tissue-Specific Manner in the Rat.

PubMed

Stanojević, Stanislava; Kovačević-Jovanović, Vesna; Dimitrijević, Mirjana; Vujić, Vesna; Ćuruvija, Ivana; Blagojević, Veljko; Leposavić, Gordana

2015-11-01

The influence of unopposed estrogen replacement/isolated progesterone deficiency on macrophage production of pro-inflammatory/anti-inflammatory mediators in the post-reproductive age was studied. Considering that in the rats post-ovariectomy the circulating estradiol, but not progesterone level rises to the values in sham-operated controls, 20-month-old rats ovariectomized at the age of 10 months served as an experimental model. Estrogen and progesterone receptor expression, secretion of pro- and anti-inflammatory cytokines, and arginine metabolism end-products were examined in splenic and peritoneal macrophages under basal conditions and following lipopolysaccharide (LPS) stimulation in vitro. Almost all peritoneal and a subset of splenic macrophages expressed the intracellular progesterone receptor. Ovariectomy diminished cytokine production by splenic (IL-1β) and peritoneal (TNF-α, IL-1β, IL-10) macrophages and increased the production of IL-10 by splenic and TGF-β by peritoneal cells under basal conditions. Following LPS stimulation, splenic macrophages from ovariectomized rats produced less TNF-α and more IL-10, whereas peritoneal macrophages produced less IL-1β and TGF-β than the corresponding cells from sham-operated rats. Ovariectomy diminished urea production in both subpopulations of LPS-stimulated macrophages. Although long-lasting isolated progesterone deficiency in the post-reproductive age differentially affects cytokine production in the macrophages from distinct tissue compartments, in both subpopulations, it impairs the pro-inflammatory/anti-inflammatory cytokine secretory balance. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Platelet “First Responders” in Wound Response, Cancer, and Metastasis

PubMed Central

Menter, David G.; Kopetz, Scott; Hawk, Ernest; Sood, Anil K.; Loree, Jonathan M; Gresele, Paolo; Honn, Kenneth V.

2017-01-01

Platelets serve as “First Responders” during normal wounding and homeostasis. Arising from bone marrow stem cell lineage megakaryocytes, anucleate platelets can influence inflammation and immune regulation. Biophysically, platelets are optimized due to size and discoid morphology to distribute near vessel walls, monitor vascular integrity and initiate quick responses to vascular lesions. Adhesion receptors linked to a highly reactive filopodia-generating cytoskeleton maximizes their vascular surface contact allowing rapid response capabilities. Functionally, platelets normally initiate rapid clotting, vasoconstriction, inflammation and wound biology that leads to sterilization, tissue repair and resolution. Platelets also are among the first to sense, phagocytize, decorate, or react to pathogens in the circulation. These platelet first responder properties are commandeered during chronic inflammation, cancer progression and metastasis. Leaky or inflammatory reaction blood vessel genesis during carcinogenesis provides opportunities for platelet invasion into tumors. Cancer is thought of as a non-healing or chronic wound that can be actively aided by platelet mitogenic properties to stimulate tumor growth. This growth ultimately outstrips circulatory support leads to angiogenesis and intravasation of tumor cells into the blood stream. Circulating tumor cells reengage additional platelets, which facilitates tumor cell adhesion, arrest and extravasation and metastasis. This process, along with the hypercoagulable states associated with malignancy is amplified by IL6 production in tumors that stimulate liver thrombopoietin production and elevates circulating platelet numbers by thrombopoiesis in the bone marrow. These complex interactions and the “First Responder” role of platelets during diverse physiologic stresses provides a useful therapeutic target that deserves further exploration. PMID:28730545

Granzyme M and K release in human experimental endotoxemia.

PubMed

Wensink, Annette C; Wiewel, Maryse A; Jongeneel, Lieneke H; Boes, Marianne; van der Poll, Tom; Hack, C Erik; Bovenschen, Niels

2016-07-01

Granzymes are serine proteases involved in killing of tumor cells and virally infected cells. However, granzymes are also upregulated in blood under inflammatory conditions and contribute to cytokine release and processing. Here, we show that granzyme M (GrM) and to a lesser extent GrK are transiently elevated in the circulation following LPS administration in humans. GrM is released upon stimulation of whole blood with LPS or the gram-negative bacteria Escherichia coli BL21, Pseudomonas aeruginosa, and Neisseria meningitidis. GrK is only released upon stimulation with P. aeruginosa. Thus, GrM and GrK are differentially released in response to LPS and gram-negative bacteria. Copyright © 2016 Elsevier GmbH. All rights reserved.

Exosome platform for diagnosis and monitoring of traumatic brain injury

PubMed Central

Taylor, Douglas D.; Gercel-Taylor, Cicek

2014-01-01

We have previously demonstrated the release of membranous structures by cells into their extracellular environment, which are termed exosomes, microvesicles or extracellular vesicles depending on specific characteristics, including size, composition and biogenesis pathway. With activation, injury, stress, transformation or infection, cells express proteins and RNAs associated with the cellular responses to these events. The exosomes released by these cells can exhibit an array of proteins, lipids and nucleic acids linked to these physiologic events. This review focuses on exosomes associated with traumatic brain injury, which may be both diagnostic and a causative factor in the progression of the injury. Based on current data, exosomes play essential roles as conveyers of intercellular communication and mediators of many of the pathological conditions associated with development, progression and therapeutic failures and cellular stress in a variety of pathologic conditions. These extracellular vesicles express components responsible for angiogenesis promotion, stromal remodelling, signal pathway activation through growth factor/receptor transfer, chemoresistance, immunologic activation and genetic exchange. These circulating exosomes not only represent a central mediator of the pro-inflammatory microenvironment linked with secondary brain injury, but their presence in the peripheral circulation may serve as a surrogate for biopsies, enabling real-time diagnosis and monitoring of neurodegenerative progression. PMID:25135964

Effects of fish and krill oil on gene expression in peripheral blood mononuclear cells and circulating markers of inflammation: a randomised controlled trial.

PubMed

Rundblad, Amanda; Holven, Kirsten B; Bruheim, Inge; Myhrstad, Mari C; Ulven, Stine M

2018-01-01

Marine n -3 (omega-3) fatty acids alter gene expression by regulating the activity of transcription factors. Krill oil is a source of marine n -3 fatty acids that has been shown to modulate gene expression in animal studies; however, the effect in humans is not known. Hence, we aimed to compare the effect of intake of krill oil, lean and fatty fish with a similar content of n -3 fatty acids, and high-oleic sunflower oil (HOSO) with added astaxanthin on the expression of genes involved in glucose and lipid metabolism and inflammation in peripheral blood mononuclear cells (PBMC) as well as circulating inflammatory markers. In an 8-week trial, healthy men and women aged 18-70 years with fasting TAG of 1·3-4·0 mmol/l were randomised to receive krill oil capsules ( n 12), HOSO capsules ( n 12) or lean and fatty fish ( n 12). The weekly intakes of marine n -3 fatty acids from the interventions were 4654, 0 and 4103 mg, respectively. The mRNA expression of four genes, PPAR γ coactivator 1A ( PPARGC1A ), steaoryl-CoA desaturase ( SCD ), ATP binding cassette A1 ( ABCA1 ) and cluster of differentiation 40 ( CD40 ), were differently altered by the interventions. Furthermore, within-group analyses revealed that krill oil down-regulated the mRNA expression of thirteen genes, including genes involved in glucose and cholesterol metabolism and β-oxidation. Fish altered the mRNA expression of four genes and HOSO down-regulated sixteen genes, including several inflammation-related genes. There were no differences between the groups in circulating inflammatory markers after the intervention. In conclusion, the intake of krill oil and HOSO with added astaxanthin alter the PBMC mRNA expression of more genes than the intake of fish.

Potential Role of Axonal Chemorepellent Slit2 in Modulating Adventitial Inflammation in a Rat Carotid Artery Balloon Injury Model

PubMed Central

Liu, Dong; Xiao, Yan; Subramanian, Romesh R.; Okamoto, Ei-ichi; Wilcox, Josiah N.; Anderson, Leonard; De Leon, Hector

2016-01-01

Leukocyte infiltration of adventitial and perivascular tissues is an early event in the development of vascular remodeling after injury. We investigated whether Slit/Robo—an axonal chemorepellent system in vertebrate and invertebrate development—is activated during the inflammatory phase that follows endothelial denudation. Using the rat carotid artery model of angioplasty, we conducted a time course analysis of mRNAs encoding Slit ligands (Slit2 and Slit3) and Robo receptors (Robo1, Robo2 and Robo4), as well as proinflammatory cell adhesion molecule (CAM) genes. Adventitial inflammatory cells were counted in immunostained arterial sections. E-selectin, vascular CAM-1 (VCAM-1), and intercellular CAM-1 (ICAM-1) were upregulated 2–3 hr after injury, followed by infiltration of neutrophils and monocytes as evidenced by real-time PCR, in situ hybridization, and immunohistochemistry. Slit2, Slit3, and Robo genes exhibited no expression changes at 3 hr; however, they were markedly upregulated 1 day after angioplasty. ICAM-1 expression was reduced by 50%, and the number of adventitial neutrophils decreased by >75% one day after angioplasty. Slit2 has been shown to be a potent chemorepelent of leukocytes, endothelial cells and smooth muscle cells. Thus, we decided to further investigate the localization of Slit2 in injured vessels. Immunohistochemical stainings revealed the presence of Slit2 within the vessel wall and in the perivascular vasa vasorum of naive and injured arteries. Double immunohistochemical analyses showed that infiltrating monocytes expressed Slit2 in the perivascular and adventitial tissues of injured arteries 1 and 3 days postangioplasty. In addition, recombinant full-length Slit2 and Slit2-N/1118, an N-terminal fragment of Slit2, inhibited stromal cell-derived factor 1 (SDF-1)-mediated migration of circulating rat peripheral blood mononuclear cells. In summary, adventitial activation of CAM genes and neutrophil infiltration preceded upregulation of Slit/Robo genes. Sli2 expression colocalized with infiltrating inflammatory cells in the adventitial layer. This temporospatial association suggests that leukocyte chemorepellent Slit2 may be involved in halting the adventitial accumulation of inflammatory cells in injured vessels. PMID:26841069

Ghrelin receptor regulates adipose tissue inflammation in aging.

PubMed

Lin, Ligen; Lee, Jong Han; Buras, Eric D; Yu, Kaijiang; Wang, Ruitao; Smith, C Wayne; Wu, Huaizhu; Sheikh-Hamad, David; Sun, Yuxiang

2016-01-01

Aging is commonly associated with low-grade adipose inflammation, which is closely linked to insulin resistance. Ghrelin is the only circulating orexigenic hormone which is known to increase obesity and insulin resistance. We previously reported that the expression of the ghrelin receptor, growth hormone secretagogue receptor (GHS-R), increases in adipose tissues during aging, and old Ghsr(-/-) mice exhibit a lean and insulin-sensitive phenotype. Macrophages are major mediators of adipose tissue inflammation, which consist of pro-inflammatory M1 and anti-inflammatory M2 subtypes. Here, we show that in aged mice, GHS-R ablation promotes macrophage phenotypical shift toward anti-inflammatory M2. Old Ghsrp(-/-) mice have reduced macrophage infiltration, M1/M2 ratio, and pro-inflammatory cytokine expression in white and brown adipose tissues. We also found that peritoneal macrophages of old Ghsrp(-/-) mice produce higher norepinephrine, which is in line with increased alternatively-activated M2 macrophages. Our data further reveal that GHS-R has cell-autonomous effects in macrophages, and GHS-R antagonist suppresses lipopolysaccharide (LPS)-induced inflammatory responses in macrophages. Collectively, our studies demonstrate that ghrelin signaling has an important role in macrophage polarization and adipose tissue inflammation during aging. GHS-R antagonists may serve as a novel and effective therapeutic option for age-associated adipose tissue inflammation and insulin resistance.

Ghrelin receptor regulates adipose tissue inflammation in aging

PubMed Central

Buras, Eric D.; Yu, Kaijiang; Wang, Ruitao; Smith, C. Wayne; Wu, Huaizhu; Sheikh-Hamad, David; Sun, Yuxiang

2016-01-01

Aging is commonly associated with low-grade adipose inflammation, which is closely linked to insulin resistance. Ghrelin is the only circulating orexigenic hormone which is known to increase obesity and insulin resistance. We previously reported that the expression of the ghrelin receptor, growth hormone secretagogue receptor (GHS-R), increases in adipose tissues during aging, and old Ghsr−/− mice exhibit a lean and insulin-sensitive phenotype. Macrophages are major mediators of adipose tissue inflammation, which consist of pro-inflammatory M1 and anti-inflammatory M2 subtypes. Here, we show that in aged mice, GHS-R ablation promotes macrophage phenotypical shift toward anti-inflammatory M2. Old Ghsr−/− mice have reduced macrophage infiltration, M1/M2 ratio, and pro-inflammatory cytokine expression in white and brown adipose tissues. We also found that peritoneal macrophages of old Ghsr−/− mice produce higher norepinephrine, which is in line with increased alternatively-activated M2 macrophages. Our data further reveal that GHS-R has cell-autonomous effects in macrophages, and GHS-R antagonist suppresses lipopolysaccharide (LPS)-induced inflammatory responses in macrophages. Collectively, our studies demonstrate that ghrelin signaling has an important role in macrophage polarization and adipose tissue inflammation during aging. GHS-R antagonists may serve as a novel and effective therapeutic option for age-associated adipose tissue inflammation and insulin resistance. PMID:26837433

Nitric oxide-donating statin improves multiple functions of circulating angiogenic cells

PubMed Central

Mangialardi, G; Monopoli, A; Ongini, E; Spinetti, G; Fortunato, O; Emanueli, C; Madeddu, P

2011-01-01

BACKGROUND AND PURPOSE Statins, a major component of the prevention of cardiovascular disease, aid progenitor cell functions in vivo and in vitro. Statins bearing a NO-releasing moiety were developed for their enhanced anti-inflammatory/anti-thrombotic properties. Here, we investigated if the NO-donating atorvastatin (NCX 547) improved the functions of circulating angiogenic cells (CACs). EXPERIMENTAL APPROACH Circulating angiogenic cells (CACs) were prepared from peripheral blood monocytes of healthy volunteers and type-2 diabetic patients and were cultured in low (LG) or high glucose (HG) conditions, in presence of atorvastatin or NCX 547 (both at 0.1 µM) or vehicle. Functional assays (outgrowth, proliferation, viability, senescence and apoptosis) were performed in presence of the endothelial NOS inhibitor L-NIO, the NO scavenger c-PTIO or vehicle. KEY RESULTS Culturing in HG conditions lowered NO in CACs, inhibited outgrowth, proliferation, viability and migration, and induced cell senescence and apoptosis. NCX 547 fully restored NO levels and functions of HG-cultured CACs, while atorvastatin prevented only apoptosis in CACs. The activity of Akt, a pro-survival kinase, was increased by atorvastatin in LG-cultured but not in HG-cultured CACs, whereas NCX 547 increased Akt activity in both conditions. L-NIO partially blunted and c-PTIO prevented NCX 547-induced improvements in CAC functions. Finally, NCX 547 improved outgrowth and migration of CACs prepared from patients with type 2 diabetes. CONCLUSIONS AND IMPLICATIONS NCX 547 was more effective than atorvastatin in preserving functions of CACs. This property adds to the spectrum of favourable actions that would make NO-releasing statins more effective agents for treating cardiovascular disease. PMID:21486281

Inflammaging and human longevity in the omics era.

PubMed

Monti, Daniela; Ostan, Rita; Borelli, Vincenzo; Castellani, Gastone; Franceschi, Claudio

2017-07-01

Inflammaging is a recent theory of aging originally proposed in 2000 where data and conceptualizations regarding the aging of the immune system (immunosenescence) and the evolution of immune responses from invertebrates to mammals converged. This theory has received an increasing number of citations and experimental confirmations. Here we present an updated version of inflammaging focused on omics data - particularly on glycomics - collected on centenarians, semi-supercentenarians and their offspring. Accordingly, we arrived to the following conclusions: i) inflammaging has a structure where specific combinations of pro- and anti-inflammatory mediators are involved; ii) inflammaging is systemic and more complex than we previously thought, as many organs, tissues and cell types participate in producing pro- and anti-inflammatory stimuli defined "molecular garbage"; iii) inflammaging is dynamic, can be propagated locally to neighboring cells and systemically from organ to organ by circulating products and microvesicles, and amplified by chronic age-related diseases constituting a "local fire", which in turn produces additional inflammatory stimuli and molecular garbage; iv) an integrated Systems Medicine approach is urgently needed to let emerge a robust and highly informative set/combination of omics markers able to better grasp the complex molecular core of inflammaging in elderly and centenarians. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Doxycycline attenuates breast cancer related inflammation by decreasing plasma lysophosphatidate concentrations and inhibiting NF-κB activation.

PubMed

Tang, Xiaoyun; Wang, Xianyan; Zhao, Yuan Y; Curtis, Jonathan M; Brindley, David N

2017-02-08

We previously discovered that tetracyclines increase the expression of lipid phosphate phosphatases at the surface of cells. These enzymes degrade circulating lysophosphatidate and therefore doxycycline increases the turnover of plasma lysophosphatidate and decreases its concentration. Extracellular lysophosphatidate signals through six G protein-coupled receptors and it is a potent promoter of tumor growth, metastasis and chemo-resistance. These effects depend partly on the stimulation of inflammation that lysophosphatidate produces. In this work, we used a syngeneic orthotopic mouse model of breast cancer to determine the impact of doxycycline on circulating lysophosphatidate concentrations and tumor growth. Cytokine/chemokine concentrations in tumor tissue and plasma were measured by multiplexing laser bead technology. Leukocyte infiltration in tumors was analyzed by immunohistochemistry. The expression of IL-6 in breast cancer cell lines was determined by RT-PCR. Cell growth was measured in Matrigel™ 3D culture. The effects of doxycycline on NF-κB-dependent signaling were analyzed by Western blotting. Doxycycline decreased plasma lysophosphatidate concentrations, delayed tumor growth and decreased the concentrations of several cytokines/chemokines (IL-1β, IL-6, IL-9, CCL2, CCL11, CXCL1, CXCL2, CXCL9, G-CSF, LIF, VEGF) in the tumor. These results were compatible with the effects of doxycycline in decreasing the numbers of F4/80 + macrophages and CD31 + blood vessel endothelial cells in the tumor. Doxycycline also decreased the lysophosphatidate-induced growth of breast cancer cells in three-dimensional culture. Lysophosphatidate-induced Ki-67 expression was inhibited by doxycycline. NF-κB activity in HEK293 cells transiently expressing a NF-κB-luciferase reporter vectors was also inhibited by doxycycline. Treatment of breast cancer cells with doxycycline also decreased the translocation of NF-κB to the nucleus and the mRNA levels for IL-6 in the presence or absence of lysophosphatidate. These results contribute a new dimension for understanding the anti-inflammatory effects of tetracyclines, which make them potential candidates for adjuvant therapy of cancers and other inflammatory diseases.

PPAR-γ in the Cardiovascular System

PubMed Central

Duan, Sheng Zhong; Ivashchenko, Christine Y.; Usher, Michael G.; Mortensen, Richard M.

2008-01-01

Peroxisome proliferator-activated receptor-γ (PPAR-γ), an essential transcriptional mediator of adipogenesis, lipid metabolism, insulin sensitivity, and glucose homeostasis, is increasingly recognized as a key player in inflammatory cells and in cardiovascular diseases (CVD) such as hypertension, cardiac hypertrophy, congestive heart failure, and atherosclerosis. PPAR-γ agonists, the thiazolidinediones (TZDs), increase insulin sensitivity, lower blood glucose, decrease circulating free fatty acids and triglycerides, lower blood pressure, reduce inflammatory markers, and reduce atherosclerosis in insulin-resistant patients and animal models. Human genetic studies on PPAR-γ have revealed that functional changes in this nuclear receptor are associated with CVD. Recent controversial clinical studies raise the question of deleterious action of PPAR-γ agonists on the cardiovascular system. These complex interactions of metabolic responsive factors and cardiovascular disease promise to be important areas of focus for the future. PMID:18288291

Dermal γδ T Cells Do Not Freely Re-Circulate Out of Skin and Produce IL-17 to Promote Neutrophil Infiltration during Primary Contact Hypersensitivity

PubMed Central

Jiang, Xiaodong; Park, Chang Ook; Geddes Sweeney, Jenna; Yoo, Min Jae; Gaide, Olivier; Kupper, Thomas Seth

2017-01-01

The role of mouse dermal γδ T cells in inflammatory skin disorders and host defense has been studied extensively. It is known that dendritic epidermal T cells (DETC) have a monomorphic γδ T cell receptor (TCR) and reside in murine epidermis from birth. We asked if dermal γδ cells freely re-circulated out of skin, or behaved more like dermal resident memory T cells (TRM) in mice. We found that, unlike epidermal γδ T cells (DETC), dermal γδ cells are not homogeneous with regard to TCR, express the tissue resident T cell markers CD69 and CD103, bear skin homing receptors, and produce IL-17 and IL-22. We created GFP+: GFP− parabiotic mice and found that dermal γδ T cells re-circulate very slowly—more rapidly than authentic αβ TCR TRM, but more slowly than the recently described dermal αβ TCR T migratory memory cells (TMM). Mice lacking the TCR δ gene (δ-/-) had a significant reduction of 2,4-dinitrofluorobenzene (DNFB)-induced contact hypersensitivity (CHS). We created mice deficient in dermal γδ T cells but not DETC, and these mice also showed a markedly reduced CHS response after DNFB challenge. The infiltration of effector T cells during CHS was not reduced in dermal γδ T cell-deficient mice; however, infiltration of Gr-1+CD11b+ neutrophils, as well as ear swelling, was reduced significantly. We next depleted Gr-1+ neutrophils in vivo, and demonstrated that neutrophils are required for ear swelling, the accepted metric for a CHS response. Depletion of IL-17-producing dermal Vγ4+ cells and neutralization of IL-17 in vivo, respectively, also led to a significantly reduced CHS response and diminished neutrophil infiltration. Our findings here suggest that dermal γδ T cells have an intermediate phenotype of T cell residence, and play an important role in primary CHS through producing IL-17 to promote neutrophil infiltration. PMID:28081153

Colchicine to decrease NLRP3-activated inflammation and improve obesity-related metabolic dysregulation

PubMed Central

Demidowich, Andrew P.; Davis, Angela I.; Dedhia, Nicket; Yanovski, Jack A.

2016-01-01

Obesity is a major risk-factor for the development of insulin resistance, type 2 diabetes, and cardiovascular disease. Circulating molecules associated with obesity, such as saturated fatty acids and cholesterol crystals, stimulate the innate immune system to incite a chronic inflammatory state. Studies in mouse models suggest that suppressing the obesity-induced chronic inflammatory state may prevent or reverse obesity-associated metabolic dysregulation. Human studies, however, have been far less positive, possibly because targeted interventions were too far downstream of the inciting inflammatory events. Recently, it has been shown that, within adipose tissue macrophages, assembly of a multi-protein member of the innate immune system, the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, is essential for the induction of this inflammatory state. Microtubules enable the necessary spatial arrangement of the components of the NLRP3 inflammasome in the cell, leading to its activation and propagation of the inflammatory cascade. Colchicine, a medication classically used for gout, mediates its anti-inflammatory effect by inhibiting tubulin polymerization, and has been shown to attenuate macrophage NLRP3 inflammasome arrangement and activation in vitro and in vivo. Given these findings, we hypothesize that, in at-risk individuals (those with obesity-induced inflammation and metabolic dysregulation), long-term colchicine use will lead to suppression of inflammation and thus cause improvements in insulin sensitivity and other obesity-related metabolic impairments. PMID:27241260

Colchicine to decrease NLRP3-activated inflammation and improve obesity-related metabolic dysregulation.

PubMed

Demidowich, Andrew P; Davis, Angela I; Dedhia, Nicket; Yanovski, Jack A

2016-07-01

Obesity is a major risk-factor for the development of insulin resistance, type 2 diabetes, and cardiovascular disease. Circulating molecules associated with obesity, such as saturated fatty acids and cholesterol crystals, stimulate the innate immune system to incite a chronic inflammatory state. Studies in mouse models suggest that suppressing the obesity-induced chronic inflammatory state may prevent or reverse obesity-associated metabolic dysregulation. Human studies, however, have been far less positive, possibly because targeted interventions were too far downstream of the inciting inflammatory events. Recently, it has been shown that, within adipose tissue macrophages, assembly of a multi-protein member of the innate immune system, the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, is essential for the induction of this inflammatory state. Microtubules enable the necessary spatial arrangement of the components of the NLRP3 inflammasome in the cell, leading to its activation and propagation of the inflammatory cascade. Colchicine, a medication classically used for gout, mediates its anti-inflammatory effect by inhibiting tubulin polymerization, and has been shown to attenuate macrophage NLRP3 inflammasome arrangement and activation in vitro and in vivo. Given these findings, we hypothesize that, in at-risk individuals (those with obesity-induced inflammation and metabolic dysregulation), long-term colchicine use will lead to suppression of inflammation and thus cause improvements in insulin sensitivity and other obesity-related metabolic impairments. Published by Elsevier Ltd.

Macrophage migration inhibitory factor (MIF) supports homing of osteoclast precursors to peripheral osteolytic lesions

PubMed Central

Movila, Alexandru; Ishii, Takenobu; Albassam, Abdullah; Wisitrasameewong, Wichaya; Howait, Mohammed; Yamaguchi, Tsuguno; Ruiz-Torruella, Montserrat; Bahammam, Laila; Nishimura, Kazuaki; Van Dyke, Thomas; Kawai, Toshihisa

2016-01-01

By binding to its chemokine receptor CXCR4 on osteoclast precursor cells (OCPs), it is well known that SDF-1 promotes the chemotactic recruitment of circulating OCPs to the homeostatic bone remodeling site. However, the engagement of circulating OCPs in pathogenic bone resorption remains to be elucidated. The present study investigated a possible chemoattractant role of MIF, another ligand for CXCR4, in the recruitment of circulating OCPs to the bone lytic lesion. To accomplish this, we used Csf1r-eGFP-KI mice to establish an animal model of Polymethyl methacrylate (PMMA) particle-induced calvarial osteolysis. In the circulating Csf1r-eGFP+ cells of healthy Csf1r-eGFP-KI mice, Csf1r+/CD11b+ cells showed a greater degree of RANKL-induced osteoclastogenesis compared to a subset of Csf1r+/RANK+ cells in vitro. Therefore, Csf1r-eGFP+/CD11b+ cells were targeted as functionally relevant OCPs in the present study. While expression of the two cognate receptors for MIF, CXCR2 and CXCR4, was elevated on Csf1r+/CD11b+ cells, transmigration of OCPs toward recombinant MIF in vitro was facilitated by ligation with CXCR4, but not CXCR2. Meanwhile, the level of PMMA-induced bone resorption in calvaria was markedly greater in wild-type mice compared to that detected in MIF-KO mice. Interestingly, in contrast to the elevated MIF, diminished SDF-1 was detected in a particle-induced bone lytic lesion of wild-type mice in conjunction with an increased number of infiltrating CXCR4+ OCPs. However, such diminished SDF-1 was not found in the PMMA-injected calvaria of MIF-KO mice. Furthermore, stimulation of osteoblasts with MIF in vitro suppressed their production of SDF-1, suggesting that MIF can down-modulate SDF-1 production in bone tissue. Systemically administered anti-MIF neutralizing mAb inhibited the homing of CXCR4+ OCPs, as well as bone resorption, in the PMMA-injected calvaria, while increasing locally produced SDF-1. Collectively, these data suggest that locally produced MIF in the inflammatory bone lytic site is engaged in the chemoattraction of circulating CXCR4+ OCPs. PMID:27082509

Usefulness of elevated red cell distribution width for predicting systemic inflammatory response syndrome after extracorporeal circulation.

PubMed

Özeren, M; Aytaçoğlu, B; Vezir, Ö; Karaca, K; Akın, R; Sucu, N

2015-10-01

Cardiac surgical operations performed by using extracorporeal circulation (ECC) lead to a systemic inflammatory response (SIR). Sometimes SIR may turn into a severe state, the systemic inflammatory response syndrome (SIRS) that usually has a poor outcome with no specific clinical tools described for its prediction. Red cell distribution width (RDW) is a routine hematological parameter. It has been proposed as a marker of morbidity and mortality in various clinical conditions. We aimed to investigate the relationship between high RDW and SIRS which is triggered by ECC. Eleven hundred consecutive patients who underwent elective heart surgery with the use of ECC were retrospectively analyzed. A total of 19 patients fulfilled the described SIRS criteria and 20 consecutive patients were selected as the control group. RDW and other laboratory parameters, preoperative clinical status, operative data and postoperative data were compared between the SIRS and the control groups. Baseline characteristics of the patient groups were similar. Significant mortality was found in the SIRS group; 18 (94.73%) patients and 2 (10%) patients in the control group (p < 0.002). RDW was found to be significantly higher in the SIRS group vs the control group (15.02 ± 2.03 vs 13.01 ± 1.93, respectively, p < 0.003). Multiple logistic regression analyses showed an association between high RDW levels and SIRS development (OR for RDW levels exceeding 13.5%; 95% confidence limits of 1.0-1.3; p < 0.04). Total operation time and the need for inotropic support were also found to be significant against the SIRS group (p = 0.049). Increased RDW was significantly associated with increased risk of SIRS after ECC. The results of this study suggest that paying attention to RDW might provide valuable clinical information for predicting SIRS development among patients who are candidates for open heart surgery, without incurring additional costs. © The Author(s) 2015.

Myeloid protein tyrosine phosphatase 1B (PTP1B) deficiency protects against atherosclerotic plaque formation in the ApoE-/- mouse model of atherosclerosis with alterations in IL10/AMPKα pathway.

PubMed

Thompson, D; Morrice, N; Grant, L; Le Sommer, S; Ziegler, K; Whitfield, P; Mody, N; Wilson, H M; Delibegović, M

2017-08-01

Cardiovascular disease (CVD) is the most prevalent cause of mortality among patients with Type 1 or Type 2 diabetes, due to accelerated atherosclerosis. Recent evidence suggests a strong link between atherosclerosis and insulin resistance due to impaired insulin receptor (IR) signaling. Moreover, inflammatory cells, in particular macrophages, play a key role in pathogenesis of atherosclerosis and insulin resistance in humans. We hypothesized that inhibiting the activity of protein tyrosine phosphatase 1B (PTP1B), the major negative regulator of the IR, specifically in macrophages, would have beneficial anti-inflammatory effects and lead to protection against atherosclerosis and CVD. We generated novel macrophage-specific PTP1B knockout mice on atherogenic background (ApoE -/- /LysM-PTP1B). Mice were fed standard or pro-atherogenic diet, and body weight, adiposity (echoMRI), glucose homeostasis, atherosclerotic plaque development, and molecular, biochemical and targeted lipidomic eicosanoid analyses were performed. Myeloid-PTP1B knockout mice on atherogenic background (ApoE -/- /LysM-PTP1B) exhibited a striking improvement in glucose homeostasis, decreased circulating lipids and decreased atherosclerotic plaque lesions, in the absence of body weight/adiposity differences. This was associated with enhanced phosphorylation of aortic Akt, AMPKα and increased secretion of circulating anti-inflammatory cytokine interleukin-10 (IL-10) and prostaglandin E2 (PGE 2 ), without measurable alterations in IR phosphorylation, suggesting a direct beneficial effect of myeloid-PTP1B targeting. Here we demonstrate that inhibiting the activity of PTP1B specifically in myeloid lineage cells protects against atherosclerotic plaque formation, under atherogenic conditions, in an ApoE -/- mouse model of atherosclerosis. Our findings suggest for the first time that macrophage PTP1B targeting could be a therapeutic target for atherosclerosis treatment and reduction of CVD risk.

Activation of Cell Surface Bound 20S Proteasome Inhibits Vascular Cell Growth and Arteriogenesis

PubMed Central

Ito, Wulf D.; Lund, Natalie; Zhang, Ziyang; Buck, Friedrich; Lellek, Heinrich; Horst, Andrea; Machens, Hans-Günther; Schunkert, Heribert; Schaper, Wolfgang; Meinertz, Thomas

2015-01-01

Arteriogenesis is an inflammatory process associated with rapid cellular changes involving vascular resident endothelial progenitor cells (VR-EPCs). Extracellular cell surface bound 20S proteasome has been implicated to play an important role in inflammatory processes. In our search for antigens initially regulated during collateral growth mAb CTA 157-2 was generated against membrane fractions of growing collateral vessels. CTA 157-2 stained endothelium of growing collateral vessels and the cell surface of VR-EPCs. CTA 157-2 bound a protein complex (760 kDa) that was identified as 26 kDa α7 and 21 kDa β3 subunit of 20S proteasome in mass spectrometry. Furthermore we demonstrated specific staining of 20S proteasome after immunoprecipitation of VR-EPC membrane extract with CTA 157-2 sepharose beads. Functionally, CTA 157-2 enhanced concentration dependently AMC (7-amino-4-methylcoumarin) cleavage from LLVY (N-Succinyl-Leu-Leu-Val-Tyr) by recombinant 20S proteasome as well as proteasomal activity in VR-EPC extracts. Proliferation of VR-EPCs (BrdU incorporation) was reduced by CTA 157-2. Infusion of the antibody into the collateral circulation reduced number of collateral arteries, collateral proliferation, and collateral conductance in vivo. In conclusion our results indicate that extracellular cell surface bound 20S proteasome influences VR-EPC function in vitro and collateral growth in vivo. PMID:26146628

Activation of VIP signaling enhances immunosuppressive effect of MDSCs on CMV-induced adaptive immunity.

PubMed

Forghani, Parvin; Petersen, Christopher T; Waller, Edmund K

2017-10-10

Vasoactive intestinal peptide (VIP) is recognized as a potent anti-inflammatory factor which affects both the innate and adaptive arms of the immune system. These effects include, but are not limited to, inhibition of T cell proliferation and disruption of immune homeostasis. Myeloid-derived suppressor cells (MDSC) are an immune regulatory cell type that has been described in settings of cancer and infectious disease._Here we demonstrate a reduced circulating monocytic MDSCs in the VIP -/- vs. wild type MCMV. VIP-/- MDSCs secretes less NO upon stimulation with LPS and interferon that relatively lose the ability to suppress T cells activation in vitro compared to wild type MDSCs._Considering the importance of VIP in immunomodulation, the possible effect of VIP in the suppressive function of MDSC populations following CMV infection remains unknown. We describe the possible role of VIP in the regulation of anti-CMV activity of T cells through the activation of MDSCs.

Porphyromonas gingivalis-dendritic cell interactions: consequences for coronary artery disease.

PubMed

Zeituni, Amir E; Carrion, Julio; Cutler, Christopher W

2010-12-21

An estimated 80 million US adults have one or more types of cardiovascular diseases. Atherosclerosis is the single most important contributor to cardiovascular diseases; however, only 50% of atherosclerosis patients have currently identified risk factors. Chronic periodontitis, a common inflammatory disease, is linked to an increased cardiovascular risk. Dendritic cells (DCs) are potent antigen presenting cells that infiltrate arterial walls and may destabilize atherosclerotic plaques in cardiovascular disease. While the source of these DCs in atherosclerotic plaques is presently unclear, we propose that dermal DCs from peripheral inflamed sites such as CP tissues are a potential source. This review will examine the role of the opportunistic oral pathogen Porphyromonas gingivalis in invading DCs and stimulating their mobilization and misdirection through the bloodstream. Based on our published observations, combined with some new data, as well as a focused review of the literature we will propose a model for how P. gingivalis may exploit DCs to gain access to systemic circulation and contribute to coronary artery disease. Our published evidence supports a significant role for P. gingivalis in subverting normal DC function, promoting a semimature, highly migratory, and immunosuppressive DC phenotype that contributes to the inflammatory development of atherosclerosis and, eventually, plaque rupture.

Hfe Deficiency Impairs Pulmonary Neutrophil Recruitment in Response to Inflammation

PubMed Central

Benesova, Karolina; Vujić Spasić, Maja; Schaefer, Sebastian M.; Stolte, Jens; Baehr-Ivacevic, Tomi; Waldow, Katharina; Zhou, Zhe; Klingmueller, Ursula; Benes, Vladimir; Mall, Marcus A.; Muckenthaler, Martina U.

2012-01-01

Regulation of iron homeostasis and the inflammatory response are tightly linked to protect the host from infection. Here we investigate how imbalanced systemic iron homeostasis in a murine disease model of hereditary hemochromatosis (Hfe−/− mice) affects the inflammatory responses of the lung. We induced acute pulmonary inflammation in Hfe−/− and wild-type mice by intratracheal instillation of 20 µg of lipopolysaccharide (LPS) and analyzed local and systemic inflammatory responses and iron-related parameters. We show that in Hfe−/− mice neutrophil recruitment to the bronchoalveolar space is attenuated compared to wild-type mice although circulating neutrophil numbers in the bloodstream were elevated to similar levels in Hfe−/− and wild-type mice. The underlying molecular mechanisms are likely multifactorial and include elevated systemic iron levels, alveolar macrophage iron deficiency and/or hitherto unexplored functions of Hfe in resident pulmonary cell types. As a consequence, pulmonary cytokine expression is out of balance and neutrophils fail to be recruited efficiently to the bronchoalveolar compartment, a process required to protect the host from infections. In conclusion, our findings suggest a novel role for Hfe and/or imbalanced iron homeostasis in the regulation of the inflammatory response in the lung and hereditary hemochromatosis. PMID:22745741

Influence of vitamin C supplementation on oxidative stress and neutrophil inflammatory response in acute and regular exercise.

PubMed

Popovic, Ljiljana M; Mitic, Nebojsa R; Miric, Dijana; Bisevac, Boban; Miric, Mirjana; Popovic, Brankica

2015-01-01

Exercise induces a multitude of physiological and biochemical changes in blood affecting its redox status. Tissue damage resulting from exercise induces activation of inflammatory cells followed by the increased activity of myeloperoxidase (MPO) in circulation. Vitamin C readily scavenges free radicals and may thereby prevent oxidative damage of important biological macromolecules. The aim of this study was to examine the effect of vitamin C supplementation on oxidative stress and neutrophil inflammatory response induced by acute and regular exercise. Experiment was conducted on acute exercise group (performing Bruce Treadmill Protocol (BTP)) and regular training group. Markers of lipid peroxidation, malondialdehyde (MDA), MPO activity, and vitamin C status were estimated at rest and after BTP (acute exercise group) and before and after vitamin C supplementation in both groups. Our results showed increased postexercise Asc in serum independently of vitamin supplementation. They also showed that vitamin C can significantly decrease postexercise MDA level in both experimental groups. Increased postexercise MPO activity has been found in both groups and was not affected by vitamin C supplementation. We concluded that vitamin C supplementation can suppress lipid peroxidation process during exercise but cannot affect neutrophil inflammatory response in either exercise group.

Advances in understanding the pathogenesis of HLH.

PubMed

Usmani, G Naheed; Woda, Bruce A; Newburger, Peter E

2013-06-01

Haemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory disorder resulting from immune dysfunction reflecting either primary immune deficiency or acquired failure of normal immune homeostasis. Familial HLH includes autosomal recessive and X-linked disorders characterized by uncontrolled activation of T cells and macrophages and overproduction of inflammatory cytokines, secondary to defects in genes encoding proteins involved in granule-dependent cytolytic pathways. In older children and adults, HLH is associated more often with infections, malignancies, autoimmune diseases, and acquired immune deficiencies. HLH, macrophage activation syndrome, sepsis, and systemic inflammatory response syndrome are different clinical entities that probably represent a common immunopathological state, termed cytokine storm. These conditions may be clinically indistinguishable; all include massive inflammatory response, elevated serum cytokine levels, multi-organ involvement, haemophagocytic macrophages, and often death. Tissues of haematopoietic and lymphoid function are directly involved; other organs are secondarily damaged by circulating cytokines and chemokines. Haemophagocytic disorders are now increasingly diagnosed in the context of severe inflammatory reactions to viruses, malignancies and systemic connective tissue diseases. Many of these cases may reflect underlying genetic predispositions to HLH. The detection of gene defects has contributed considerably to our understanding of HLH, but the mechanisms leading to acquired HLH have yet to be fully determined. © 2013 John Wiley & Sons Ltd.

Host response biomarkers in the diagnosis of sepsis: a general overview.

PubMed

Parlato, Marianna; Cavaillon, Jean-Marc

2015-01-01

Critically ill patients who display a systemic inflammatory response syndrome (SIRS) are prone to develop nosocomial infections. The challenge remains to distinguish as early as possible among SIRS patients those who are developing sepsis. Following a sterile insult, damage-associated molecular patterns (DAMPs) released by damaged tissues and necrotic cells initiate an inflammatory response close to that observed during sepsis. During sepsis, pathogen-associated molecular patterns (PAMPs) trigger the release of host mediators involved in innate immunity and inflammation through identical receptors as DAMPs. In both clinical settings, a compensatory anti-inflammatory response syndrome (CARS) is concomitantly initiated. The exacerbated production of pro- or anti-inflammatory mediators allows their detection in biological fluids and particularly within the bloodstream. Some of these mediators can be used as biomarkers to decipher among the patients those who developed sepsis, and eventually they can be used as prognosis markers. In addition to plasma biomarkers, the analysis of some surface markers on circulating leukocytes or the study of mRNA and miRNA can be helpful. While there is no magic marker, a combination of few biomarkers might offer a high accuracy for diagnosis.

Circulating tumour cells and pathological complete response: independent prognostic factors in inflammatory breast cancer in a pooled analysis of two multicentre phase II trials (BEVERLY-1 and -2) of neoadjuvant chemotherapy combined with bevacizumab.

PubMed

Pierga, J-Y; Bidard, F-C; Autret, A; Petit, T; Andre, F; Dalenc, F; Levy, C; Ferrero, J-M; Romieu, G; Bonneterre, J; Lerebours, F; Bachelot, T; Kerbrat, P; Campone, M; Eymard, J-C; Mouret-Reynier, M-A; Gligorov, J; Hardy-Bessard, A-C; Lortholary, A; Soulie, P; Boher, J-M; Proudhon, C; Charafe-Jaufret, E; Lemonnier, J; Bertucci, F; Viens, P

2017-01-01

We present a pooled analysis of predictive and prognostic values of circulating tumour cells (CTC) and circulating endothelial cells (CEC) in two prospective trials of patients with inflammatory breast cancer (IBC) treated with neoadjuvant chemotherapy combined with neoadjuvant and adjuvant bevacizumab. Nonmetastatic T4d patients were enrolled in two phase II multicentre trials, evaluating bevacizumab in combination with sequential neoadjuvant chemotherapy of four cycles of FEC followed by four cycles of docetaxel in HER2-negative tumour (BEVERLY-1) or docetaxel and trastuzumab in HER2-positive tumour (BEVERLY-2). CTC and CEC were detected in 7.5 and 4 ml of blood, respectively, with the CellSearch System. From October 2008 to September 2010, 152 patients were included and 137 were evaluable for CTC and CEC. At baseline, 55 patients had detectable CTC (39%). After four cycles of chemotherapy, a dramatic drop in CTC to a rate of 9% was observed (P < 0.01). Pathological complete response (pCR) rate was 40%. No correlation was found between CTC or CEC levels and pCR rate. Median follow-up was 43 months. CTC detection (≥1 CTC/7.5 ml) at baseline was associated with shorter 3-year disease-free survival (39% versus 70% for patients without CTC, P < 0.01, HR 2.80) and shorter 3-year overall survival (OS) (P < 0.01). In multivariate analysis, independent prognostic parameters for shorter survival were absence of hormonal receptors, no pCR and CTC detection at baseline. CEC level at baseline or variations during treatment had no prognostic value. In this pooled analysis of two prospective trials in nonmetastatic IBC, detection rate of CTC was 39% with a strong and independent prognostic value for survival. Combination of pCR after neoadjuvant treatment with no CTC detection at baseline isolated a subgroup of IBC with excellent OS (94% 3-year OS), suggesting that CTC count could be part of IBC stratification in prospective trials. © The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Emodin Inhibits Homocysteine-Induced C-Reactive Protein Generation in Vascular Smooth Muscle Cells by Regulating PPARγ Expression and ROS-ERK1/2/p38 Signal Pathway

PubMed Central

Pang, Xiaoming; Liu, Juntian; Li, Yuxia; Zhao, Jingjing; Zhang, Xiaolu

2015-01-01

Atherosclerosis is an inflammatory disease. As an inflammatory molecule, C-reactive protein (CRP) plays a direct role in atherogenesis. It is known that the elevated plasma homocysteine (Hcy) level is an independent risk factor for atherosclerosis. We previously reported that Hcy produces a pro-inflammatory effect by inducing CRP expression in vascular smooth muscle cells (VSMCs). In the present study, we observed effect of emodin on Hcy-induced CRP expression in rat VSMCs and molecular mechanisms. The in vitro results showed that pretreatment of VSMCs with emodin inhibited Hcy-induced mRNA and protein expression of CRP in a concentration-dependent manner. The in vivo experiments displayed that emodin not only inhibited CRP expression in the vessel walls in mRNA and protein levels, but also reduced the circulating CRP level in hyperhomocysteinemic rats. Further study revealed that emodin diminished Hcy-stimulated generation of reactive oxygen species (ROS), attenuated Hcy-activated phosphorylation of ERK1/2 and p38, and upregulated Hcy-inhibited expression of peroxisome proliferator-activated receptor gamma (PPARγ) in VSMCs. These demonstrate that emodin is able to inhibit Hcy-induced CRP generation in VSMCs, which is related to interfering with ROS-ERK1/2/p38 signal pathway and upregulating PPARγ expression. The present study provides new evidence for the anti-inflammatory and anti-atherosclerotic effects of emodin. PMID:26131983

Diabetic retinopathy: could the alpha-1 antitrypsin be a therapeutic option?

PubMed

Ortiz, Gustavo; Salica, Juan P; Chuluyan, Eduardo H; Gallo, Juan E

2014-11-18

Diabetic retinopathy is one of the most important causes of blindness. The underlying mechanisms of this disease include inflammatory changes and remodeling processes of the extracellular-matrix (ECM) leading to pericyte and vascular endothelial cell damage that affects the retinal circulation. In turn, this causes hypoxia leading to release of vascular endothelial growth factor (VEGF) to induce the angiogenesis process. Alpha-1 antitrypsin (AAT) is the most important circulating inhibitor of serine proteases (SERPIN). Its targets include elastase, plasmin, thrombin, trypsin, chymotrypsin, proteinase 3 (PR-3) and plasminogen activator (PAI). AAT modulates the effect of protease-activated receptors (PARs) during inflammatory responses. Plasma levels of AAT can increase 4-fold during acute inflammation then is so-called acute phase protein (APPs). Individuals with low serum levels of AAT could develop disease in lung, liver and pancreas. AAT is involved in extracellular matrix remodeling and inflammation, particularly migration and chemotaxis of neutrophils. It can also suppress nitric oxide (NO) by nitric oxide sintase (NOS) inhibition. AAT binds their targets in an irreversible way resulting in product degradation. The aim of this review is to focus on the points of contact between multiple factors involved in diabetic retinopathy and AAT resembling pleiotropic effects that might be beneficial.

Bilirubin nanoparticles ameliorate allergic lung inflammation in a mouse model of asthma.

PubMed

Kim, Dong Eon; Lee, Yonghyun; Kim, MinGyo; Lee, Soyoung; Jon, Sangyong; Lee, Seung-Hyo

2017-09-01

Although asthma, a chronic inflammatory airway disease, is relatively well-managed by inhaled corticosteroids, the side effects associated with the long-term use of these agents precipitate the need for alternative therapeutic options based on differing modes of action. Bilirubin, a potent endogenous antioxidant, and anti-inflammatory molecule have been shown to ameliorate asthmatic symptoms; however, its clinical translation has been limited owing to its water insolubility and associated potential toxicity. Here we report the first application of bilirubin-based nanoparticles (BRNPs) as a nanomedicine for the treatment of allergic lung inflammatory disease. BRNPs were prepared directly from self-assembly of PEGylated bilirubin in aqueous solution and had a hydrodynamic diameter of ∼100 nm. Because allergen-specific type 2 T-helper (Th2) cells play a key role in the pathogenesis and progression of allergic asthma, the effects of BRNPs on Th2 immune responses were investigated both in vivo and in vitro. BRNPs after intravenous injection (i.v.) showed much higher serum concentration and a longer circulation time of bilirubin than the intraperitoneal injection (i.p.) of BRNPs or unconjugated bilirubin (UCB). The anti-asthmatic effects of BRNPs were assessed in a mouse model of allergen-induced asthma. Compared with UCB, treatment with BRNPs suppressed the symptoms of experimental allergic asthma and dramatically ameliorated Th2-related allergic lung inflammation. Consistent with these results, BRNPs caused a reduction of Th2 cell populations and the expression of related cytokines by antibody-stimulated CD4 + T cells in vitro. Therefore, our results establish BRNPs as an important immunomodulatory agent that may be useful as a therapeutic for allergic lung inflammatory disease and other immune-mediated disorders. Copyright © 2017 Elsevier Ltd. All rights reserved.

Loss of CX3CR1 increases accumulation of inflammatory monocytes and promotes gliomagenesis

PubMed Central

Feng, Xi; Chen, Zhihong; Heinzmann, David; Rasmussen, Rikke Darling; Alvarez-Garcia, Virginia; Kim, Yeonghwan; Wang, Bingcheng; Tamagno, Ilaria; Zhou, Hao; Li, Xiaoxia; Kettenmann, Helmut; Ransohoff, Richard M.; Hambardzumyan, Dolores

2015-01-01

The most abundant populations of non-neoplastic cells in the glioblastoma (GBM) microenvironment are resident microglia, macrophages and infiltrating monocytes from the blood circulation. The mechanisms by which monocytes infiltrate into GBM, their fate following infiltration, and their role in GBM growth are not known. Here we tested the hypothesis that loss of the fractalkine receptor CX3CR1 in microglia and monocytes would affect gliomagenesis. Deletion of Cx3cr1 from the microenvironment resulted in increased tumor incidence and shorter survival times in glioma-bearing mice. Loss of Cx3cr1 did not affect accumulation of microglia/macrophages in peri-tumoral areas, but instead indirectly promoted the trafficking of CD11b+CD45hiCX3CR1lowLy-6ChiLy-6G−F4/80−/low circulating inflammatory monocytes into the CNS, resulting in their increased accumulation in the perivascular area. Cx3cr1-deficient microglia/macrophages and monocytes demonstrated upregulation of IL1β expression that was inversely proportional to Cx3cr1 gene dosage. The Proneural subgroup of the TCGA GBM patient dataset with high IL1β expression showed shorter survival compared to patients with low IL1β. IL1β promoted tumor growth and increased the cancer stem cell phenotype in murine and human Proneural glioma stem cells (GSCs). IL1β activated the p38 MAPK signaling pathway and expression of monocyte chemoattractant protein (MCP-1/CCL2) by tumor cells. Loss of Cx3cr1 in microglia in a monocyte-free environment had no impact on tumor growth and did not alter microglial migration. These data suggest that enhancing signaling to CX3CR1 or inhibiting IL1β signaling in intra-tumoral macrophages can be considered as potential strategies to decrease the tumor-promoting effects of monocytes in Proneural GBM. PMID:25987130

Proteinase 3 on apoptotic cells disrupts immune silencing in autoimmune vasculitis.

PubMed

Millet, Arnaud; Martin, Katherine R; Bonnefoy, Francis; Saas, Philippe; Mocek, Julie; Alkan, Manal; Terrier, Benjamin; Kerstein, Anja; Tamassia, Nicola; Satyanarayanan, Senthil Kumaran; Ariel, Amiram; Ribeil, Jean-Antoine; Guillevin, Loïc; Cassatella, Marco A; Mueller, Antje; Thieblemont, Nathalie; Lamprecht, Peter; Mouthon, Luc; Perruche, Sylvain; Witko-Sarsat, Véronique

2015-11-02

Granulomatosis with polyangiitis (GPA) is a systemic necrotizing vasculitis that is associated with granulomatous inflammation and the presence of anti-neutrophil cytoplasmic antibodies (ANCAs) directed against proteinase 3 (PR3). We previously determined that PR3 on the surface of apoptotic neutrophils interferes with induction of antiinflammatory mechanisms following phagocytosis of these cells by macrophages. Here, we demonstrate that enzymatically active membrane-associated PR3 on apoptotic cells triggered secretion of inflammatory cytokines, including granulocyte CSF (G-CSF) and chemokines. This response required the IL-1R1/MyD88 signaling pathway and was dependent on the synthesis of NO, as macrophages from animals lacking these pathways did not exhibit a PR3-associated proinflammatory response. The PR3-induced microenvironment facilitated recruitment of inflammatory cells, such as macrophages, plasmacytoid DCs (pDCs), and neutrophils, which were observed in close proximity within granulomatous lesions in the lungs of GPA patients. In different murine models of apoptotic cell injection, the PR3-induced microenvironment instructed pDC-driven Th9/Th2 cell generation. Concomitant injection of anti-PR3 ANCAs with PR3-expressing apoptotic cells induced a Th17 response, revealing a GPA-specific mechanism of immune polarization. Accordingly, circulating CD4+ T cells from GPA patients had a skewed distribution of Th9/Th2/Th17. These results reveal that PR3 disrupts immune silencing associated with clearance of apoptotic neutrophils and provide insight into how PR3 and PR3-targeting ANCAs promote GPA pathophysiology.

Proteinase 3 on apoptotic cells disrupts immune silencing in autoimmune vasculitis

PubMed Central

Millet, Arnaud; Martin, Katherine R.; Bonnefoy, Francis; Saas, Philippe; Mocek, Julie; Alkan, Manal; Terrier, Benjamin; Kerstein, Anja; Tamassia, Nicola; Satyanarayanan, Senthil Kumaran; Ariel, Amiram; Ribeil, Jean-Antoine; Guillevin, Loïc; Cassatella, Marco A.; Mueller, Antje; Thieblemont, Nathalie; Lamprecht, Peter; Mouthon, Luc; Perruche, Sylvain; Witko-Sarsat, Véronique

2015-01-01

Granulomatosis with polyangiitis (GPA) is a systemic necrotizing vasculitis that is associated with granulomatous inflammation and the presence of anti-neutrophil cytoplasmic antibodies (ANCAs) directed against proteinase 3 (PR3). We previously determined that PR3 on the surface of apoptotic neutrophils interferes with induction of antiinflammatory mechanisms following phagocytosis of these cells by macrophages. Here, we demonstrate that enzymatically active membrane-associated PR3 on apoptotic cells triggered secretion of inflammatory cytokines, including granulocyte CSF (G-CSF) and chemokines. This response required the IL-1R1/MyD88 signaling pathway and was dependent on the synthesis of NO, as macrophages from animals lacking these pathways did not exhibit a PR3-associated proinflammatory response. The PR3-induced microenvironment facilitated recruitment of inflammatory cells, such as macrophages, plasmacytoid DCs (pDCs), and neutrophils, which were observed in close proximity within granulomatous lesions in the lungs of GPA patients. In different murine models of apoptotic cell injection, the PR3-induced microenvironment instructed pDC-driven Th9/Th2 cell generation. Concomitant injection of anti-PR3 ANCAs with PR3-expressing apoptotic cells induced a Th17 response, revealing a GPA-specific mechanism of immune polarization. Accordingly, circulating CD4+ T cells from GPA patients had a skewed distribution of Th9/Th2/Th17. These results reveal that PR3 disrupts immune silencing associated with clearance of apoptotic neutrophils and provide insight into how PR3 and PR3-targeting ANCAs promote GPA pathophysiology. PMID:26436651

Social Regulation of Leukocyte Homeostasis: The Role of Glucocorticoid Sensitivity

PubMed Central

Cole, Steve W.

2010-01-01

Recent small-scale genomics analyses suggest that physiologic regulation of pro-inflammatory gene expression by endogenous glucocorticoids may be compromised in individuals who experience chronic social isolation. This could potentially contribute to the elevated prevalence of inflammation-related disease previously observed in social isolates. The present study assessed the relationship between leukocyte distributional sensitivity to glucocorticoid regulation and subjective social isolation in a large population-based sample of older adults. Initial analyses confirmed that circulating neutrophil percentages were elevated, and circulating lymphocyte and monocyte percentages were suppressed, in direct proportion to circulating cortisol levels. However, leukocyte distributional sensitivity to endogenous glucocorticoids was abrogated in individuals reporting either occasional or frequent experiences of subjective social isolation. This finding held in both nonparametric univariate analyses and in multivariate linear models controlling for a variety of biological, social, behavioral, and psychological confounders. The present results suggest that social factors may alter immune cell sensitivity to physiologic regulation by the hypothalamic-pituitary-adrenal axis in ways that could ultimately contribute to the increased physical health risks associated with social isolation. PMID:18394861

The link between inflammation, bugs, the intestine and the brain in alcohol dependence.

PubMed

Leclercq, S; de Timary, P; Delzenne, N M; Stärkel, P

2017-02-28

In recent years, some new processes have been proposed to explain how alcohol may influence behavior, psychological symptoms and alcohol seeking in alcohol-dependent subjects. In addition to its important effect on brain and neurotransmitters equilibrium, alcohol abuse also affects peripheral organs including the gut. By yet incompletely understood mechanisms, chronic alcohol abuse increases intestinal permeability and alters the composition of the gut microbiota, allowing bacterial components from the gut lumen to reach the systemic circulation. These gut-derived bacterial products are recognized by immune cells circulating in the blood or residing in target organs, which consequently synthesize and release pro-inflammatory cytokines. Circulating cytokines are considered important mediators of the gut-brain communication, as they can reach the central nervous system and induce neuroinflammation that is associated with change in mood, cognition and drinking behavior. These observations support the possibility that targeting the gut microbiota, by the use of probiotics or prebiotics, could restore the gut barrier function, reduce systemic inflammation and may have beneficial effect in treating alcohol dependence and in reducing alcohol relapse.

Stearidonic and γ-linolenic acids in echium oil improves glucose disposal in insulin resistant monkeys.

PubMed

Kavanagh, K; Flynn, D M; Jenkins, K A; Wilson, M D; Chilton, F H

2013-07-01

Echium oil (EO) contains stearidonic acid (18:4), a n-3 polyunsaturated fatty acids (PUFAs), and gamma-linolenic acids (18:3), a n-6 PUFA that can be converted to long chain (LC)-PUFAs. We aimed to compare a safflower oil (SO)-enriched diet to EO- and fish oil (FO)-enriched diets on circulating and tissue PUFAs levels and glycemic, inflammatory, and cardiovascular health biomarkers in insulin resistant African green monkeys. In a Latin-square cross-over study, eight monkeys consumed matched diets for 6 weeks with 3-week washout periods. Monkeys consuming FO had significantly higher levels of n-3 LC-PUFAs and EO supplementation resulted in higher levels of circulating n-3 LC-PUFAs and a significant increase in dihomo-gamma linolenic acid (DGLA) in red blood cells and muscle. Glucose disposal was improved after EO consumption. These data suggest that PUFAs in EO supplementation have the capacity to alter circulating, RBC and muscle LC-PUFA levels and improve glucose tolerance in insulin-resistant monkeys. Copyright © 2013 Elsevier Ltd. All rights reserved.

The link between inflammation, bugs, the intestine and the brain in alcohol dependence

PubMed Central

Leclercq, S; de Timary, P; Delzenne, N M; Stärkel, P

2017-01-01

In recent years, some new processes have been proposed to explain how alcohol may influence behavior, psychological symptoms and alcohol seeking in alcohol-dependent subjects. In addition to its important effect on brain and neurotransmitters equilibrium, alcohol abuse also affects peripheral organs including the gut. By yet incompletely understood mechanisms, chronic alcohol abuse increases intestinal permeability and alters the composition of the gut microbiota, allowing bacterial components from the gut lumen to reach the systemic circulation. These gut-derived bacterial products are recognized by immune cells circulating in the blood or residing in target organs, which consequently synthesize and release pro-inflammatory cytokines. Circulating cytokines are considered important mediators of the gut–brain communication, as they can reach the central nervous system and induce neuroinflammation that is associated with change in mood, cognition and drinking behavior. These observations support the possibility that targeting the gut microbiota, by the use of probiotics or prebiotics, could restore the gut barrier function, reduce systemic inflammation and may have beneficial effect in treating alcohol dependence and in reducing alcohol relapse. PMID:28244981

Inflammatory status in human hepatic cirrhosis

PubMed Central

Martínez-Esparza, María; Tristán-Manzano, María; Ruiz-Alcaraz, Antonio J; García-Peñarrubia, Pilar

2015-01-01

This review focuses on new findings about the inflammatory status involved in the development of human liver cirrhosis induced by the two main causes, hepatitis C virus (HCV) infection and chronic alcohol abuse, avoiding results obtained from animal models. When liver is faced to a persistent and/or intense local damage the maintained inflammatory response gives rise to a progressive replacement of normal hepatic tissue by non-functional fibrotic scar. The imbalance between tissue regeneration and fibrosis will determine the outcome toward health recovery or hepatic cirrhosis. In all cases progression toward liver cirrhosis is caused by a dysregulation of mechanisms that govern the balance between activation/homeostasis of the immune system. Detecting differences between the inflammatory status in HCV-induced vs alcohol-induced cirrhosis could be useful to identify specific targets for preventive and therapeutic intervention in each case. Thus, although survival of patients with alcoholic cirrhosis seems to be similar to that of patients with HCV-related cirrhosis (HCV-C), there are important differences in the altered cellular and molecular mechanisms implicated in the progression toward human liver cirrhosis. The predominant features of HCV-C are more related with those that allow viral evasion of the immune defenses, especially although not exclusively, inhibition of interferons secretion, natural killer cells activation and T cell-mediated cytotoxicity. On the contrary, the inflammatory status of alcohol-induced cirrhosis is determined by the combined effect of direct hepatotoxicity of ethanol metabolites and increases of the intestinal permeability, allowing bacteria and bacterial products translocation, into the portal circulation, mesenteric lymph nodes and peritoneal cavity. This phenomenon generates a stronger pro-inflammatory response compared with HCV-related cirrhosis. Hence, therapeutic intervention in HCV-related cirrhosis must be mainly focused to counteract HCV-immune system evasion, while in the case of alcohol-induced cirrhosis it must try to break the inflammatory loop established at the gut-mesenteric lymph nodes-peritoneal-systemic axis. PMID:26556984

Increase in cholinergic modulation with pyridostigmine induces anti-inflammatory cell recruitment soon after acute myocardial infarction in rats

PubMed Central

Rocha, Juraci Aparecida; Ribeiro, Susan Pereira; França, Cristiane Miranda; Coelho, Otávio; Alves, Gisele; Kallás, Esper Georges; Irigoyen, Maria Cláudia

2016-01-01

We tested the hypothesis that an increase in the anti-inflammatory cholinergic pathway, when induced by pyridostigmine (PY), may modulate subtypes of lymphocytes (CD4+, CD8+, FOXP3+) and macrophages (M1/M2) soon after myocardial infarction (MI) in rats. Wistar rats, randomly allocated to receive PY (40 mg·kg−1·day−1) in drinking water or to stay without treatment, were followed for 4 days and then were subjected to ligation of the left coronary artery. The groups—denominated as the pyridostigmine-treated infarcted (IP) and infarcted control (I) groups—were submitted to euthanasia 3 days after MI; the heart was removed for immunohistochemistry, and the peripheral blood and spleen were collected for flow cytometry analysis. Noninfarcted and untreated rats were used as controls (C Group). Echocardiographic measurements were registered on the second day after MI, and heart rate variability was measured on the third day after MI. The infarcted groups had similar MI areas, degrees of systolic dysfunction, blood pressures, and heart rates. Compared with the I Group, the IP Group showed a significant higher parasympathetic modulation and a lower sympathetic modulation, which were associated with a small, but significant, increase in diastolic function. The IP Group showed a significant increase in M2 macrophages and FOXP3+ cells in the infarcted and peri-infarcted areas, a significantly higher frequency of circulating Treg cells (CD4+CD25+FOXP3+), and a less extreme decrease in conventional T cells (CD25+FOXP3−) compared with the I Group. Therefore, increasing cholinergic modulation with PY induces greater anti-inflammatory cell recruitment soon after MY in rats. PMID:26791829

Increase in cholinergic modulation with pyridostigmine induces anti-inflammatory cell recruitment soon after acute myocardial infarction in rats.

PubMed

Rocha, Juraci Aparecida; Ribeiro, Susan Pereira; França, Cristiane Miranda; Coelho, Otávio; Alves, Gisele; Lacchini, Silvia; Kallás, Esper Georges; Irigoyen, Maria Cláudia; Consolim-Colombo, Fernanda M

2016-04-15

We tested the hypothesis that an increase in the anti-inflammatory cholinergic pathway, when induced by pyridostigmine (PY), may modulate subtypes of lymphocytes (CD4+, CD8+, FOXP3+) and macrophages (M1/M2) soon after myocardial infarction (MI) in rats. Wistar rats, randomly allocated to receive PY (40 mg·kg(-1)·day(-1)) in drinking water or to stay without treatment, were followed for 4 days and then were subjected to ligation of the left coronary artery. The groups-denominated as the pyridostigmine-treated infarcted (IP) and infarcted control (I) groups-were submitted to euthanasia 3 days after MI; the heart was removed for immunohistochemistry, and the peripheral blood and spleen were collected for flow cytometry analysis. Noninfarcted and untreated rats were used as controls (C Group). Echocardiographic measurements were registered on the second day after MI, and heart rate variability was measured on the third day after MI. The infarcted groups had similar MI areas, degrees of systolic dysfunction, blood pressures, and heart rates. Compared with the I Group, the IP Group showed a significant higher parasympathetic modulation and a lower sympathetic modulation, which were associated with a small, but significant, increase in diastolic function. The IP Group showed a significant increase in M2 macrophages and FOXP3(+)cells in the infarcted and peri-infarcted areas, a significantly higher frequency of circulating Treg cells (CD4(+)CD25(+)FOXP3(+)), and a less extreme decrease in conventional T cells (CD25(+)FOXP3(-)) compared with the I Group. Therefore, increasing cholinergic modulation with PY induces greater anti-inflammatory cell recruitment soon after MY in rats. Copyright © 2016 the American Physiological Society.

Multiple intravenous injections of allogeneic equine mesenchymal stem cells do not induce a systemic inflammatory response but do alter lymphocyte subsets in healthy horses.

PubMed

Kol, Amir; Wood, Joshua A; Carrade Holt, Danielle D; Gillette, Jessica A; Bohannon-Worsley, Laurie K; Puchalski, Sarah M; Walker, Naomi J; Clark, Kaitlin C; Watson, Johanna L; Borjesson, Dori L

2015-04-15

Intravenous (IV) injection of mesenchymal stem cells (MSCs) is used to treat systemic human diseases and disorders but is not routinely used in equine therapy. In horses, MSCs are isolated primarily from adipose tissue (AT) or bone marrow (BM) and used for treatment of orthopedic injuries through one or more local injections. The objective of this study was to determine the safety and lymphocyte response to multiple allogeneic IV injections of either AT-derived MSCs (AT-MSCs) or BM-derived MSCs (BM-MSCs) to healthy horses. We injected three doses of 25 × 10(6) allogeneic MSCs from either AT or BM (a total of 75 × 10(6) MSCs per horse) into five and five, respectively, healthy horses. Horses were followed up for 35 days after the first MSC infusion. We evaluated host inflammatory and immune response, including total leukocyte numbers, serum cytokine concentration, and splenic lymphocyte subsets. Repeated injection of allogeneic AT-MSCs or BM-MSCs did not elicit any clinical adverse effects. Repeated BM-MSC injection resulted in increased blood CD8(+) T-cell numbers. Multiple BM-MSC injections also increased splenic regulatory T cell numbers compared with AT-MSC-injected horses but not controls. These data demonstrate that multiple IV injections of allogeneic MSCs are well tolerated by healthy horses. No clinical signs or clinico-pathologic measurements of organ toxicity or systemic inflammatory response were recorded. Increased numbers of circulating CD8(+) T cells after multiple IV injections of allogeneic BM-MSCs may indicate a mild allo-antigen-directed cytotoxic response. Safety and efficacy of allogeneic MSC IV infusions in sick horses remain to be determined.

Human serum-derived hydroxy long-chain fatty acids exhibit anti-inflammatory and anti-proliferative activity

PubMed Central

2011-01-01

Background Circulating levels of novel long-chain hydroxy fatty acids (called GTAs) were recently discovered in the serum of healthy subjects which were shown to be reduced in subjects with colorectal cancer (CRC), independent of tumor burden or disease stage. The levels of GTAs were subsequently observed to exhibit an inverse association with age in the general population. The current work investigates the biological activity of these fatty acids by evaluating the effects of enriched human serum extracts on cell growth and inflammation. Methods GTAs were extracted from commercially available bulk human serum and then chromatographically separated into enriched (GTA-positive) and depleted (GTA-negative) fractions. SW620, MCF7 and LPS stimulated RAW264.7 cells were treated with various concentrations of the GTA-positive and GTA-negative extracts, and the effects on cell growth and inflammation determined. Results Enriched fractions resulted in poly-ADP ribose polymerase (PARP) cleavage, suppression of NFκB, induction of IκBα, and reduction in NOS2 mRNA transcript levels. In RAW264.7 mouse macrophage cells, incubation with enriched fractions prior to treatment with LPS blocked the induction of several pro-inflammatory markers including nitric oxide, TNFα, IL-1β, NOS2 and COX2. Conclusions Our results show that human serum extracts enriched with endogenous long-chain hydroxy fatty acids possess anti-inflammatory and anti-proliferative activity. These findings support a hypothesis that the reduction of these metabolites with age may result in a compromised ability to defend against uncontrolled cell growth and inflammation, and could therefore represent a significant risk for the development of CRC. PMID:21586136

HTLV-1 Integration into Transcriptionally Active Genomic Regions Is Associated with Proviral Expression and with HAM/TSP

PubMed Central

Meekings, Kiran N.; Leipzig, Jeremy; Bushman, Frederic D.; Taylor, Graham P.; Bangham, Charles R. M.

2008-01-01

Human T-lymphotropic virus type 1 (HTLV-1) causes leukaemia or chronic inflammatory disease in ∼5% of infected hosts. The level of proviral expression of HTLV-1 differs significantly among infected people, even at the same proviral load (proportion of infected mononuclear cells in the circulation). A high level of expression of the HTLV-1 provirus is associated with a high proviral load and a high risk of the inflammatory disease of the central nervous system known as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). But the factors that control the rate of HTLV-1 proviral expression remain unknown. Here we show that proviral integration sites of HTLV-1 in vivo are not randomly distributed within the human genome but are associated with transcriptionally active regions. Comparison of proviral integration sites between individuals with high and low levels of proviral expression, and between provirus-expressing and provirus non-expressing cells from within an individual, demonstrated that frequent integration into transcription units was associated with an increased rate of proviral expression. An increased frequency of integration sites in transcription units in individuals with high proviral expression was also associated with the inflammatory disease HAM/TSP. By comparing the distribution of integration sites in human lymphocytes infected in short-term cell culture with those from persistent infection in vivo, we infer the action of two selective forces that shape the distribution of integration sites in vivo: positive selection for cells containing proviral integration sites in transcriptionally active regions of the genome, and negative selection against cells with proviral integration sites within transcription units. PMID:18369476

Occurrence and biological activity of palmitoleic acid isomers in phagocytic cells.

PubMed

Astudillo, Alma M; Meana, Clara; Guijas, Carlos; Pereira, Laura; Lebrero, Patricia; Balboa, María A; Balsinde, Jesús

2018-02-01

Recent studies have highlighted the role of palmitoleic acid [16:1 n-7 ( cis -9-hexadecenoic acid)] as a lipid hormone that coordinates cross-talk between liver and adipose tissue and exerts anti-inflammatory protective effects on hepatic steatosis and insulin signaling in murine models of metabolic disease. More recently, a 16:1 n-7 isomer, cis -7-hexadecenoic acid (16:1 n-9 ), that also possesses marked anti-inflammatory effects, has been described in human circulating monocytes and monocyte-derived macrophages. By using gas chromatographic/mass spectrometric analyses of dimethyl disulfide derivatives of fatty acyl methyl esters, we describe in this study the presence of a third 16:1 isomer, sapienic acid [16:1 n-10 (6- cis -hexadecenoic acid)], in phagocytic cells. Cellular levels of 16:1 n-10 appear to depend not only on the cellular content of linoleic acid, but also on the expression level of fatty acid desaturase 2, thus revealing a complex regulation both at the enzyme level, via fatty acid substrate competition, and directly at the gene level. However, unlike 16:1 n-7 and 16:1 n-9 , 16:1 n-10 levels are not regulated by the activation state of the cell. Moreover, while 16:1 n-7 and 16:1 n-9 manifest strong anti-inflammatory activity when added to the cells at low concentrations (10 μM), notably higher concentrations of 16:1 n-10 are required to observe a comparable effect. Collectively, these results suggest the presence in phagocytic cells of an unexpected variety of 16:1 isomers, which can be distinguished on the basis of their biological activity and cellular regulation. Copyright © 2018 by the American Society for Biochemistry and Molecular Biology, Inc.

Host-mediated impairment of parasite maturation during blood-stage Plasmodium infection

PubMed Central

Khoury, David S.; Cromer, Deborah; Akter, Jasmin; Sebina, Ismail; Elliott, Trish; Thomas, Bryce S.; Soon, Megan S. F.; James, Kylie R.; Best, Shannon E.; Haque, Ashraful; Davenport, Miles P.

2017-01-01

Severe malaria and associated high parasite burdens occur more frequently in humans lacking robust adaptive immunity to Plasmodium falciparum. Nevertheless, the host may partly control blood-stage parasite numbers while adaptive immunity is gradually established. Parasite control has typically been attributed to enhanced removal of parasites by the host, although in vivo quantification of this phenomenon remains challenging. We used a unique in vivo approach to determine the fate of a single cohort of semisynchronous, Plasmodium berghei ANKA- or Plasmodium yoelii 17XNL-parasitized red blood cells (pRBCs) after transfusion into naive or acutely infected mice. As previously shown, acutely infected mice, with ongoing splenic and systemic inflammatory responses, controlled parasite population growth more effectively than naive controls. Surprisingly, however, this was not associated with accelerated removal of pRBCs from circulation. Instead, transfused pRBCs remained in circulation longer in acutely infected mice. Flow cytometric assessment and mathematical modeling of intraerythrocytic parasite development revealed an unexpected and substantial slowing of parasite maturation in acutely infected mice, extending the life cycle from 24 h to 40 h. Importantly, impaired parasite maturation was the major contributor to control of parasite growth in acutely infected mice. Moreover, by performing the same experiments in rag1−/− mice, which lack T and B cells and mount weak inflammatory responses, we revealed that impaired parasite maturation is largely dependent upon the host response to infection. Thus, impairment of parasite maturation represents a host-mediated, immune system-dependent mechanism for limiting parasite population growth during the early stages of an acute blood-stage Plasmodium infection. PMID:28673996

Omentin protects against LPS-induced ARDS through suppressing pulmonary inflammation and promoting endothelial barrier via an Akt/eNOS-dependent mechanism.

PubMed

Qi, Di; Tang, Xumao; He, Jing; Wang, Daoxin; Zhao, Yan; Deng, Wang; Deng, Xinyu; Zhou, Guoqi; Xia, Jing; Zhong, Xi; Pu, Shenglan

2016-09-08

Acute respiratory distress syndrome (ARDS) is characterized by increased pulmonary inflammation and endothelial barrier permeability. Omentin has been shown to benefit obesity-related systemic vascular diseases; however, its effects on ARDS are unknown. In the present study, the level of circulating omentin in patients with ARDS was assessed to appraise its clinical significance in ARDS. Mice were subjected to systemic administration of adenoviral vector expressing omentin (Ad-omentin) and one-shot treatment of recombinant human omentin (rh-omentin) to examine omentin's effects on lipopolysaccharide (LPS)-induced ARDS. Pulmonary endothelial cells (ECs) were treated with rh-omentin to further investigate its underlying mechanism. We found that a decreased level of circulating omentin negatively correlated with white blood cells and procalcitonin in patients with ARDS. Ad-omentin protected against LPS-induced ARDS by alleviating the pulmonary inflammatory response and endothelial barrier injury in mice, accompanied by Akt/eNOS pathway activation. Treatment of pulmonary ECs with rh-omentin attenuated inflammatory response and restored adherens junctions (AJs), and cytoskeleton organization promoted endothelial barrier after LPS insult. Moreover, the omentin-mediated enhancement of EC survival and differentiation was blocked by the Akt/eNOS pathway inactivation. Therapeutic rh-omentin treatment also effectively protected against LPS-induced ARDS via the Akt/eNOS pathway. Collectively, these data indicated that omentin protects against LPS-induced ARDS by suppressing inflammation and promoting the pulmonary endothelial barrier, at least partially, through an Akt/eNOS-dependent mechanism. Therapeutic strategies aiming to restore omentin levels may be valuable for the prevention or treatment of ARDS.

Olive oil and leaf extract prevent fluoxetine-induced hepatotoxicity by attenuating oxidative stress, inflammation and apoptosis.

PubMed

Elgebaly, Hassan A; Mosa, Nermeen M; Allach, Mariam; El-Massry, Khaled F; El-Ghorab, Ahmed H; Al Hroob, Amir M; Mahmoud, Ayman M

2018-02-01

Olive oil and leaf extract have several health benefits; however, their beneficial effect against fluoxetine-induced liver injury has not been investigated. The present study aimed to scrutinize the impact of fluoxetine on the liver of rats and to evaluate the protective effects of olive oil and leaf extract. Rats received fluoxetine orally at dose of 10 mg/kg body weight for 7 consecutive days. The fluoxetine-induced rats were concurrently treated with olive oil or leaf extract. At the end of the experiment, blood and liver samples were collected for analysis. Fluoxetine administration significantly increased circulating ALT, AST, ALP and the pro-inflammatory cytokines TNF-α and IL-1β levels in rats. Histological analysis showed several alterations, such as inflammatory cells infiltration, hepatocyte vacuolation and dilated sinusoids in the liver of fluoxetine-induced rats. Concurrent supplementation of olive oil and olive leaf extract significantly reduced circulating liver function marker enzymes and pro-inflammatory cytokines, and prevented fluoxetine-induced histological alterations. Both olive oil and leaf extract significantly decreased liver lipid peroxidation and nitric oxide, and ameliorated liver glutathione, superoxide dismutase, catalase and glutathione peroxidase. In addition, olive oil and leaf extract prevented fluoxetine-induced apoptosis in the liver of rats as evidenced by decreased expression of Bax and caspase-3, and up-regulated expression of Bcl-2. In conclusion, olive oil and leaf extract protect against fluoxetine-induced liver injury in rats through attenuation of oxidative stress, inflammation and apoptosis. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

From Osteoimmunology to Osteomicrobiology: How the Microbiota and the Immune System Regulate Bone.

PubMed

Hsu, Emory; Pacifici, Roberto

2018-05-01

Osteomicrobiology refers to the role of microbiota in bone health and the mechanisms by which the microbiota regulates post-natal skeletal development, bone aging, and pathologic bone loss. Here, we review recent reports linking gut microbiota to changes in bone phenotype. A pro-inflammatory cytokine milieu drives bone resorption in conditions such as sex steroid hormone deficiency. The response of the immune system to activation by the microbiome results in increased circulating osteoclastogenic cytokines in a T cell-dependent mechanism. Additionally, gut microbiota affect bone homeostasis through nutrient absorption, mediation of the IGF-1 pathway, and short chain fatty acid and metabolic products. Manipulation of microbiota through prebiotics or probiotics reduces inflammatory cytokine production, leading to changes in bone density. One mechanism of probiotic action is through upregulating tight junction proteins, increasing the strength of the gut epithelial layer, and leading to less antigen presentation and less activation of intestinal immune cells. Thus, prebiotics or probiotics may represent a future therapeutic avenue for ameliorating the risk of postmenopausal bone loss in humans.

Processing of CXCL12 impedes the recruitment of endothelial progenitor cells in diabetic wound healing.

PubMed

Feng, Guang; Hao, Daifeng; Chai, Jiake

2014-11-01

High blood sugar levels result in defective wound healing processes in diabetic patients. Endothelial progenitor cells (EPCs) play an important role in vasculogenesis, and thereby contribute to reconstitution of the microcirculation and healing. This study aimed to determine the possible mechanism by which the numbers of circulating EPCs are regulated in response to tissue wounding. In the streptozotocin-induced diabetic mouse model, we found that phagocytes activated by local inflammatory cytokines in the wound interfere with the mobilization and recruitment of EPCs to the lesion area. Specifically, the activated macrophages inactivate CXCL12, the major chemokine for EPC recruitment, via matrix metalloproteinases (MMPs), and thereby prevent local chemotaxis and subsequent homing of EPCs to the wound. The wound healing process is delayed by local administration of inflammatory cytokines, and its rate is increased by MMP inhibitors. This study indicates that local inhibition of MMPs is beneficial for regeneration of damaged vessels, and may explain poor wound healing in diabetic patients, thus demonstrating its potential utility as a local treatment therapy to promote diabetic wound healing. © 2014 FEBS.

Effects of calcitriol (1, 25-dihydroxy-vitamin D3) on the inflammatory response induced by H9N2 influenza virus infection in human lung A549 epithelial cells and in mice.

PubMed

Gui, Boxiang; Chen, Qin; Hu, Chuanxia; Zhu, Caihui; He, Guimei

2017-01-23

H9N2 influenza viruses circulate globally and are considered to have pandemic potential. The hyper-inflammatory response elicited by these viruses is thought to contribute to disease severity. Calcitriol plays an important role in modulating the immune response to viral infections. However, its unknown whether calcitriol can attenuate the inflammatory response elicited by H9N2 influenza virus infection. Human lung A549 epithelial cells were treated with calcitriol (100 nM) and then infected with an H9N2 influenza virus, or infected and then treated with calcitriol (30 nM). Culture supernatants were collected every 24 h post infection and the viral growth kinetics and inflammatory response were evaluated. Calcitriol (5 mg/kg) was administered daily by intraperitoneal injection to BABL/c mice for 15 days following H9N2 influenza virus infection. Mice were monitored for clinical signs of disease, lung pathology and inflammatory responses. Calcitriol treatment prior to and post infection with H9N2 influenza significantly decreased expression of the influenza M gene, IL-6, and IFN-β in A549 cells, but did not affect virus replication. In vivo, we found that calcitriol treatment significantly downregulated pulmonary inflammation in mice 2 days post-infection, but increased the inflammatory response 4 to 6 days post-infection. In contrast, the antiviral cytokine IFN-β was significantly higher in calcitriol-treated mice than in the untreated infected mice at 2 days post-infection, but lower than in untreated infected mice on days 4 and 8 post-infection. The elevated levels of pro-inflammatory cytokines and the decreased levels of antiviral cytokine are consistent with the period of maximum body weight loss and the lung damage in calcitriol-treated mice. These results suggest that calcitriol treatment might have a negative impact on the innate immune response elicited by H9N2 infection in mice, especially at the later stage of influenza virus infection. This study will provide some novel insights into the use of calcitriol to modulate the inflammatory response elicited by influenza virus infection in humans.

Serum Progranulin Concentrations May Be Associated With Macrophage Infiltration Into Omental Adipose Tissue

PubMed Central

Youn, Byung-Soo; Bang, Sa-Ik; Klöting, Nora; Park, Ji Woo; Lee, Namseok; Oh, Ji-Eun; Pi, Kyung-Bae; Lee, Tae Hee; Ruschke, Karen; Fasshauer, Mathias; Stumvoll, Michael; Blüher, Matthias

2009-01-01

OBJECTIVE—Progranulin is an important molecule in inflammatory response. Chronic inflammation is frequently associated with central obesity and associated disturbances; however, the role of circulating progranulin in human obesity, type 2 diabetes, and dyslipidemia is unknown. RESEARCH DESIGN AND METHODS—For the measurement of progranulin serum concentrations, we developed an enzyme-linked immunosorbent assay (ELISA). Using this ELISA, we assessed circulating progranulin in a cross-sectional study of 209 subjects with a wide range of obesity, body fat distribution, insulin sensitivity, and glucose tolerance and in 60 individuals with normal (NGT) or impaired (IGT) glucose tolerance or type 2 diabetes before and after a 4-week physical training program. Progranulin mRNA and protein expression was measured in paired samples of omental and subcutaneous adipose tissue (adipocytes and cells of the stromal vascular fraction) from 55 lean or obese individuals. Measurement of Erk activation and chemotactic activity induced by progranulin in vitro was performed using THP-1–based cell migration assays. RESULTS—Progranulin serum concentrations were significantly higher in individuals with type 2 diabetes compared with NGT and in obese subjects with predominant visceral fat accumulation. Circulating progranulin significantly correlates with BMI, macrophage infiltration in omental adipose tissue, C-reactive protein (CRP) serum concentrations, A1C values, and total cholesterol. Multivariable linear regression analyses revealed CRP levels as the strongest independent predictor of circulating progranulin. The extent of in vitro progranulin-mediated chemotaxis is similar to that of monocyte chemoattractant protein-1 but independent of Gα. Moreover, in type 2 diabetes, but not in IGT and NGT individuals, physical training for 4 weeks resulted in significantly decreased circulating progranulin levels. CONCLUSIONS—Elevated progranulin serum concentrations are associated with visceral obesity, elevated plasma glucose, and dyslipidemia. We identified progranulin as a novel marker of chronic inflammation in obesity and type 2 diabetes that closely reflects omental adipose tissue macrophage infiltration. Physical training significantly reduces elevated circulating progranulin in patients with type 2 diabetes. PMID:19056610

Aging-dependent decline of IL-10 producing B cells coincides with production of antinuclear antibodies but not rheumatoid factors.

PubMed

van der Geest, Kornelis S M; Lorencetti, Pedro G; Abdulahad, Wayel H; Horst, Gerda; Huitema, Minke; Roozendaal, Caroline; Kroesen, Bart-Jan; Brouwer, Elisabeth; Boots, Annemieke M H

2016-03-01

Aging is associated with development of autoimmunity. Loss of B cell tolerance in the elderly is suggested by an increased prevalence of anti-nuclear antibodies (ANAs) and rheumatoid factors (RFs). Accumulating evidence indicates that B cells also impact autoimmunity via secretion of cytokines. So far, few studies have directly assessed the effect of aging on the latter B cell function. Here, we determined if and how human aging influences the production of cytokines by B cells. In a cross-sectional study, we found that absolute numbers of circulating B cells were similar in 31 young (ages 19-39) and 73 old (age ≥ 60) individuals. Numbers of transitional B cells (CD19(+)CD27(-)CD38(High)CD24(High)) were decreased in old individuals, whereas numbers of naive and memory B cell subsets were comparable in young and old individuals. Short-term in vitro stimulation of whole blood samples revealed that numbers of B cells capable of producing TNF-α were similar in young and old individuals. In contrast, B cells capable of IL-10 production were decreased in old subjects. This decline of IL-10(+) B cells was observed in old individuals that were ANA positive, and in those that were negative for both ANAs and RFs. However, IL-10(+) B cells were remarkably well retained in the circulation of old subjects that were RF positive. Thus, pro-inflammatory TNF-α(+) B cells are retained in the elderly, whereas IL-10(+) B cells generally decline. In addition, our findings indicate that IL-10(+) B cells may differentially impact the development of ANAs and RFs in the elderly. Copyright © 2015 Elsevier Inc. All rights reserved.

Immunotherapy in inflammatory bowel disease: Novel and emerging treatments.

PubMed

Catalan-Serra, Ignacio; Brenna, Øystein

2018-04-06

Inflammatory bowel disease (IBD) is a chronic disabling inflammatory process that affects young individuals, with growing incidence. The etiopathogenesis of IBD remains poorly understood. A combination of genetic and environmental factors triggers an inadequate immune response against the commensal intestinal flora in IBD patients. Thus, a better understanding of the immunological mechanisms involved in IBD pathogenesis is central to the development of new therapeutic options. Current pharmacological treatments used in clinical practice like thiopurines or anti-TNF are effective but can produce significant side effects and their efficacy may diminish over time. In fact, up to one third of the patients do not have a satisfactory response to these therapies. Consequently, the search for new therapeutic strategies targeting alternative immunological pathways has intensified. Several new oral and parenteral substances are in the pipeline for IBD. In this review we discuss novel therapies targeting alternative pro-inflammatory pathways like IL-12/23 axis, IL-6 pathway or Janus Kinase inhibitors; as well as others modulating anti-inflammatory signalling pathways like transforming growth factor-β1 (TGF-β1). We also highlight new emerging therapies targeting the adhesion and migration of leukocytes into the inflamed intestinal mucosa by blocking selectively different subunits of α 4 β 7 integrins or binding alternative adhesion molecules like MAdCAM-1. Drugs reducing the circulating lymphocytes by sequestering them in secondary lymphoid organs (sphingosine-1-phosphate (S1P) receptor modulators) are also discussed. Finally, the latest advances in cell therapies using mesenchymal stem cells or engineered T regs are reviewed. In addition, we provide an update on the current status in clinical trials of these new immune-regulating therapies that open a new era in the treatment of IBD.

N-terminal fragment of cardiac myosin binding protein-C triggers pro-inflammatory responses in vitro

PubMed Central

Lipps, Christoph; Nguyen, Jenine H.; Pyttel, Lukas; Lynch, Thomas L.; Liebetrau, Christoph; Aleshcheva, Ganna; Voss, Sandra; Dörr, Oliver; Nef, Holger M.; Möllmann, Helge; Hamm, Christian W.; Sadayappan, Sakthivel; Troidl, Christian

2016-01-01

Myocardial infarction (MI) leads to loss and degradation of contractile cardiac tissue followed by sterile inflammation of the myocardium through activation and recruitment of innate and adaptive cells of the immune system. Recently, it was shown that cardiac myosin binding protein-C (cMyBP-C), a protein of the cardiac sarcomere, is degraded following MI, releasing a predominant N-terminal 40-kDa fragment (C0C1f) into myocardial tissue and the systemic circulation. We hypothesized that early release of C0C1f contributes to the initiation of inflammation and plays a key role in recruitment and activation of immune cells. Therefore, we investigated the role of C0C1f on macrophage / monocyte activation using both mouse bone marrow-derived macrophages and human monocytes. Here we demonstrate that C0C1f leads to macrophage / monocyte activation in vitro. Furthermore, C0C1f induces strong upregulation of pro-inflammatory cytokines (interleukin-6 (IL-6), tumor necrosis factor α (TNFα), and interleukin-1β (IL-1β)) in cultured murine macrophages and human monocytes, resulting in a pro-inflammatory phenotype. We identified the toll-like receptor 4 (TLR4), toll-like receptor 2 (TLR2), and Advanced Glycosylation End Product-Specific Receptor (RAGE) as potential receptors for C0C1f whose activation leads to mobilization of the NFκB signaling pathway, a central mediator of the pro-inflammatory signaling cascade. Thus, C0C1f appears to be a key player in the initiation of inflammatory processes and might also play an important role upon MI. PMID:27616755

Serum-borne bioactivity caused by pulmonary multiwalled carbon nanotubes induces neuroinflammation via blood-brain barrier impairment.

PubMed

Aragon, Mario J; Topper, Lauren; Tyler, Christina R; Sanchez, Bethany; Zychowski, Katherine; Young, Tamara; Herbert, Guy; Hall, Pamela; Erdely, Aaron; Eye, Tracy; Bishop, Lindsey; Saunders, Samantha A; Muldoon, Pretal P; Ottens, Andrew K; Campen, Matthew J

2017-03-07

Pulmonary exposure to multiwalled carbon nanotubes (MWCNTs) causes indirect systemic inflammation through unknown pathways. MWCNTs translocate only minimally from the lungs into the systemic circulation, suggesting that extrapulmonary toxicity may be caused indirectly by lung-derived factors entering the circulation. To assess a role for MWCNT-induced circulating factors in driving neuroinflammatory outcomes, mice were acutely exposed to MWCNTs (10 or 40 µg/mouse) via oropharyngeal aspiration. At 4 h after MWCNT exposure, broad disruption of the blood-brain barrier (BBB) was observed across the capillary bed with the small molecule fluorescein, concomitant with reactive astrocytosis. However, pronounced BBB permeation was noted, with frank albumin leakage around larger vessels (>10 µm), overlain by a dose-dependent astroglial scar-like formation and recruitment of phagocytic microglia. As affirmed by elevated inflammatory marker transcription, MWCNT-induced BBB disruption and neuroinflammation were abrogated by pretreatment with the rho kinase inhibitor fasudil. Serum from MWCNT-exposed mice induced expression of adhesion molecules in primary murine cerebrovascular endothelial cells and, in a wound-healing in vitro assay, impaired cell motility and cytokinesis. Serum thrombospondin-1 level was significantly increased after MWCNT exposure, and mice lacking the endogenous receptor CD36 were protected from the neuroinflammatory and BBB permeability effects of MWCNTs. In conclusion, acute pulmonary exposure to MWCNTs causes neuroinflammatory responses that are dependent on the disruption of BBB integrity.

B cell subset distribution is altered in patients with severe periodontitis.

PubMed

Demoersman, Julien; Pochard, Pierre; Framery, Camille; Simon, Quentin; Boisramé, Sylvie; Soueidan, Assem; Pers, Jacques-Olivier

2018-01-01

Several studies have recently highlighted the implication of B cells in physiopathogenesis of periodontal disease by showing that a B cell deficiency leads to improved periodontal parameters. However, the detailed profiles of circulating B cell subsets have not yet been investigated in patients with severe periodontitis (SP). We hypothesised that an abnormal distribution of B cell subsets could be detected in the blood of patients with severe periodontal lesions, as already reported for patients with chronic inflammatory diseases as systemic autoimmune diseases. Fifteen subjects with SP and 13 subjects without periodontitis, according to the definition proposed by the CDC periodontal disease surveillance work group, were enrolled in this pilot observational study. Two flow cytometry panels were designed to analyse the circulating B and B1 cell subset distribution in association with the RANKL expression. A significantly higher percentage of CD27+ memory B cells was observed in patients with SP. Among these CD27+ B cells, the proportion of the switched memory subset was significantly higher. At the same time, human B1 cells, which were previously associated with a regulatory function (CD20+CD69-CD43+CD27+CD11b+), decreased in SP patients. The RANKL expression increased in every B cell subset from the SP patients and was significantly greater in activated B cells than in the subjects without periodontitis. These preliminary results demonstrate the altered distribution of B cells in the context of severe periodontitis. Further investigations with a larger cohort of patients can elucidate if the analysis of the B cell compartment distribution can reflect the periodontal disease activity and be a reliable marker for its prognosis (clinical trial registration number: NCT02833285, B cell functions in periodontitis).

B cell subset distribution is altered in patients with severe periodontitis

PubMed Central

Demoersman, Julien; Pochard, Pierre; Framery, Camille; Simon, Quentin; Boisramé, Sylvie; Soueidan, Assem

2018-01-01

Several studies have recently highlighted the implication of B cells in physiopathogenesis of periodontal disease by showing that a B cell deficiency leads to improved periodontal parameters. However, the detailed profiles of circulating B cell subsets have not yet been investigated in patients with severe periodontitis (SP). We hypothesised that an abnormal distribution of B cell subsets could be detected in the blood of patients with severe periodontal lesions, as already reported for patients with chronic inflammatory diseases as systemic autoimmune diseases. Fifteen subjects with SP and 13 subjects without periodontitis, according to the definition proposed by the CDC periodontal disease surveillance work group, were enrolled in this pilot observational study. Two flow cytometry panels were designed to analyse the circulating B and B1 cell subset distribution in association with the RANKL expression. A significantly higher percentage of CD27+ memory B cells was observed in patients with SP. Among these CD27+ B cells, the proportion of the switched memory subset was significantly higher. At the same time, human B1 cells, which were previously associated with a regulatory function (CD20+CD69-CD43+CD27+CD11b+), decreased in SP patients. The RANKL expression increased in every B cell subset from the SP patients and was significantly greater in activated B cells than in the subjects without periodontitis. These preliminary results demonstrate the altered distribution of B cells in the context of severe periodontitis. Further investigations with a larger cohort of patients can elucidate if the analysis of the B cell compartment distribution can reflect the periodontal disease activity and be a reliable marker for its prognosis (clinical trial registration number: NCT02833285, B cell functions in periodontitis). PMID:29447240

Key endothelial cell angiogenic mechanisms are stimulated by the circulating milieu in sickle cell disease and attenuated by hydroxyurea

PubMed Central

Lopes, Flavia C. M.; Traina, Fabiola; Almeida, Camila B.; Leonardo, Flavia C.; Franco-Penteado, Carla F.; Garrido, Vanessa T.; Colella, Marina P.; Soares, Raquel; Olalla-Saad, Sara T.; Costa, Fernando F.; Conran, Nicola

2015-01-01

As hypoxia-induced inflammatory angiogenesis may contribute to the manifestations of sickle cell disease, we compared the angiogenic molecular profiles of plasma from sickle cell disease individuals and correlated these with in vitro endothelial cell-mediated angiogenesis-stimulating activity and in vivo neovascularization. Bioplex demonstrated that plasma from patients with steady-state sickle cell anemia contained elevated concentrations of pro-angiogenic factors (angiopoietin-1, basic fibroblast growth factor, vascular endothelial growth factor, vascular endothelial growth factor-D and placental growth factor) and displayed potent pro-angiogenic activity, significantly increasing endothelial cell proliferation, migration and capillary-like structure formation. In vivo neovascularization of Matrigel plugs was significantly greater in sickle cell disease mice than in non-sickle cell disease mice, consistent with an up-regulation of angiogenesis in the disease. In plasma from patients with hemoglobin SC disease without proliferative retinopathy, anti-angiogenic endostatin and thrombospondin-2 were significantly elevated. In contrast, plasma from hemoglobin SC individuals with proliferative retinopathy had a pro-angiogenic profile and more significant effects on endothelial cell proliferation and capillary formation than plasma from patients without retinopathy. Hydroxyurea therapy was associated with significant reductions in plasma angiogenic factors and inhibition of endothelial cell-mediated angiogenic mechanisms and neovascularization. Thus, individuals with sickle cell anemia or hemoglobin SC disease with retinopathy present a highly angiogenic circulating milieu, capable of stimulating key endothelial cell-mediated angiogenic mechanisms. Combination anti-angiogenic therapy to prevent the progression of unregulated neovascularization and associated manifestations in sickle cell disease, such as pulmonary hypertension, may be indicated; furthermore, the benefits and drawbacks of the potent anti-angiogenic effects of hydroxyurea should be clarified. PMID:25769545

Biophysics of selectin-ligand interactions in inflammation and cancer

NASA Astrophysics Data System (ADS)

Siu-Lun Cheung, Luthur; Raman, Phrabha S.; Balzer, Eric M.; Wirtz, Denis; Konstantopoulos, Konstantinos

2011-02-01

Selectins (l-, e- and p-selectin) are calcium-dependent transmembrane glycoproteins that are expressed on the surface of circulating leukocytes, activated platelets, and inflamed endothelial cells. Selectins bind predominantly to sialofucosylated glycoproteins and glycolipids (e-selectin only) present on the surface of apposing cells, and mediate transient adhesive interactions pertinent to inflammation and cancer metastasis. The rapid turnover of selectin-ligand bonds, due to their fast on- and off-rates along with their remarkably high tensile strengths, enables them to mediate cell tethering and rolling in shear flow. This paper presents the current body of knowledge regarding the role of selectins in inflammation and cancer metastasis, and discusses experimental methodologies and mathematical models used to resolve the biophysics of selectin-mediated cell adhesion. Understanding the biochemistry and biomechanics of selectin-ligand interactions pertinent to inflammatory disorders and cancer metastasis may provide insights for developing promising therapies and/or diagnostic tools to combat these disorders.

Effects of interventions on oxidative stress and inflammation of cardiovascular diseases

PubMed Central

Lee, Sewon; Park, Yoonjung; Zuidema, Mozow Yusof; Hannink, Mark; Zhang, Cuihua

2011-01-01

Excessive oxidative stress and low-grade chronic inflammation are major pathophysiological factors contributing to the development of cardiovascular diseases (CVD) such as hypertension, diabetes and atherosclerosis. Accumulating evidence suggests that a compromised anti-oxidant system can lead to excessive oxidative stress in cardiovascular related organs, resulting in cell damage and death. In addition, increased circulating levels of pro-inflammatory cytokines, such as tumor necrosis factor α, interleukin-6 and C-reactive protein, are closely related to morbidity and mortality of cardiovascular complications. Emerging evidence suggests that interventions including nutrition, pharmacology and exercise may activate expression of cellular anti-oxidant systems via the nuclear factor erythroid 2-related factor 2-Kelch-like ECH-associated protein 1 signaling pathway and play a role in preventing inflammatory processes in CVD. The focus of the present review is to summarize recent evidence showing the role of these anti-oxidant and anti-inflammatory interventions in cardiovascular disease. We believe that these findings may prompt new effective pathogenesis-oriented interventions, based on the exercise-induced protection from disease in the cardiovascular system, aimed at targeting oxidant stress and inflammation. PMID:21286214

Magnetic forces enable controlled drug delivery by disrupting endothelial cell-cell junctions

NASA Astrophysics Data System (ADS)

Qiu, Yongzhi; Tong, Sheng; Zhang, Linlin; Sakurai, Yumiko; Myers, David R.; Hong, Lin; Lam, Wilbur A.; Bao, Gang

2017-06-01

The vascular endothelium presents a major transport barrier to drug delivery by only allowing selective extravasation of solutes and small molecules. Therefore, enhancing drug transport across the endothelial barrier has to rely on leaky vessels arising from disease states such as pathological angiogenesis and inflammatory response. Here we show that the permeability of vascular endothelium can be increased using an external magnetic field to temporarily disrupt endothelial adherens junctions through internalized iron oxide nanoparticles, activating the paracellular transport pathway and facilitating the local extravasation of circulating substances. This approach provides a physically controlled drug delivery method harnessing the biology of endothelial adherens junction and opens a new avenue for drug delivery in a broad range of biomedical research and therapeutic applications.

Detection of FAM172A expressed in circulating tumor cells is a feasible method to predict high-risk subgroups of colorectal cancer.

PubMed

Cui, Chun-Hui; Chen, Ri-Hong; Zhai, Duan-Yang; Xie, Lang; Qi, Jia; Yu, Jin-Long

2017-06-01

Previous studies used to enumerate circulating tumor cells to predict prognosis and therapeutic effect of colorectal cancer. However, increasing studies have shown that only circulating tumor cells enumeration was not enough to reflect the heterogeneous condition of tumor. In this study, we classified different metastatic-potential circulating tumor cells from colorectal cancer patients and measured FAM172A expression in circulating tumor cells to improve accuracy of clinical diagnosis and treatment of colorectal cancer. Blood samples were collected from 45 primary colorectal cancer patients. Circulating tumor cells were enriched by blood filtration using isolation by size of epithelial tumor cells, and in situ hybridization with RNA method was used to identify and discriminate subgroups of circulating tumor cells. Afterwards, FAM172A expression in individual circulating tumor cells was measured. Three circulating tumor cell subgroups (epithelial/biophenotypic/mesenchymal circulating tumor cells) were identified using epithelial-mesenchymal transition markers. In our research, mesenchymal circulating tumor cells significantly increased along with tumor progression, development of distant metastasis, and vascular invasion. Furthermore, FAM172A expression rate in mesenchymal circulating tumor cells was significantly higher than that in epithelial circulating tumor cells, which suggested that FAM172A may correlate with malignant degree of tumor. This hypothesis was further verified by FAM172A expression in mesenchymal circulating tumor cells, which was strictly related to tumor aggressiveness factors. Mesenchymal circulating tumor cells and FAM172A detection may predict highrisk stage II colorectal cancer. Our research proved that circulating tumor cells were feasible surrogate samples to detect gene expression and could serve as a predictive biomarker for tumor evaluation.

An intermediate level of CD161 expression defines a novel activated, inflammatory, and pathogenic subset of CD8+ T cells involved in multiple sclerosis.

PubMed

Nicol, Bryan; Salou, Marion; Vogel, Isabel; Garcia, Alexandra; Dugast, Emilie; Morille, Jeremy; Kilens, Stéphanie; Charpentier, Eric; Donnart, Audrey; Nedellec, Steven; Jacq-Foucher, Marylène; Le Frère, Fabienne; Wiertlewski, Sandrine; Bourreille, Arnaud; Brouard, Sophie; Michel, Laure; David, Laurent; Gourraud, Pierre-Antoine; Degauque, Nicolas; Nicot, Arnaud B; Berthelot, Laureline; Laplaud, David-Axel

2018-03-01

Several lines of evidence support a key role for CD8 + T cells in central nervous system tissue damage of patients with multiple sclerosis. However, the precise phenotype of the circulating CD8 + T cells that may be recruited from the peripheral blood to invade the CNS remains largely undefined to date. It has been suggested that IL-17 secreting CD8 (Tc17) T cells may be involved, and in humans these cells are characterized by the expression of CD161. We focused our study on a unique and recently described subset of CD8 T cells characterized by an intermediate expression of CD161 as its role in neuroinflammation has not been investigated to date. The frequency, phenotype, and function of CD8 + T cells with an intermediate CD161 expression level were characterized ex-vivo, in vitro, and in situ using RNAseq, RT-PCR, flow cytometry, TCR sequencing, and immunohistofluorescence of cells derived from healthy volunteers (n = 61), MS subjects (n = 90), as well as inflammatory (n = 15) and non-inflammatory controls (n = 6). We report here that CD8 + CD161 int T cells present characteristics of effector cells, up-regulate cell-adhesion molecules and have an increased ability to cross the blood-brain barrier and to secrete IL-17, IFNγ, GM-CSF, and IL-22. We further demonstrate that these cells are recruited and enriched in the CNS of MS subjects where they produce IL-17. In the peripheral blood, RNAseq, RT-PCR, high-throughput TCR repertoire analyses, and flow cytometry confirmed an increased effector and transmigration pattern of these cells in MS patients, with the presence of supernumerary clones compared to healthy controls. Our data demonstrate that intermediate levels of CD161 expression identifies activated and effector CD8 + T cells with pathogenic properties that are recruited to MS lesions. This suggests that CD161 may represent a biomarker and a valid target for the treatment of neuroinflammation. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

An immune response manifested by the common occurrence of annexins I and II autoantibodies and high circulating levels of IL-6 in lung cancer

PubMed Central

Brichory, Franck M.; Misek, David E.; Yim, Anne-Marie; Krause, Melissa C.; Giordano, Thomas J.; Beer, David G.; Hanash, Samir M.

2001-01-01

The identification of circulating tumor antigens or their related autoantibodies provides a means for early cancer diagnosis as well as leads for therapy. The purpose of this study was to identify proteins that commonly induce a humoral response in lung cancer by using a proteomic approach and to investigate biological processes that may be associated with the development of autoantibodies. Aliquots of solubilized proteins from a lung adenocarcinoma cell line (A549) and from lung tumors were subjected to two-dimensional PAGE, followed by Western blot analysis in which individual sera were tested for primary antibodies. Sera from 54 newly diagnosed patients with lung cancer and 60 patients with other cancers and from 61 noncancer controls were analyzed. Sera from 60% of patients with lung adenocarcinoma and 33% of patients with squamous cell lung carcinoma but none of the noncancer controls exhibited IgG-based reactivity against proteins identified as glycosylated annexins I and/or II. Immunohistochemical analysis showed that annexin I was expressed diffusely in neoplastic cells in lung tumor tissues, whereas annexin II was predominant at the cell surface. Interestingly, IL-6 levels were significantly higher in sera of antibody-positive lung cancer patients compared with antibody-negative patients and controls. We conclude that an immune response manifested by annexins I and II autoantibodies occurs commonly in lung cancer and is associated with high circulating levels of an inflammatory cytokine. The proteomic approach we have implemented has utility for the development of serum-based assays for cancer diagnosis as we report in this paper on the discovery of antiannexins I and/or II in sera from patients with lung cancer. PMID:11504947

Increased CD39 Nucleotidase Activity on Microparticles from Patients with Idiopathic Pulmonary Arterial Hypertension

PubMed Central

Visovatti, Scott H.; Hyman, Matthew C.; Bouis, Diane; Neubig, Richard; McLaughlin, Vallerie V.; Pinsky, David J.

2012-01-01

Background Idiopathic pulmonary arterial hypertension (IPAH) is a devastating disease characterized by increased pulmonary vascular resistance, smooth muscle and endothelial cell proliferation, perivascular inflammatory infiltrates, and in situ thrombosis. Circulating intravascular ATP, ADP, AMP and adenosine activate purinergic cell signaling pathways and appear to induce many of the same pathologic processes that underlie IPAH. Extracellular dephosphorylation of ATP to ADP and AMP occurs primarily via CD39 (ENTPD1), an ectonucleotidase found on the surface of leukocytes, platelets, and endothelial cells [1]. Microparticles are micron-sized phospholipid vesicles formed from the membranes of platelets and endothelial cells. Objectives: Studies here examine whether CD39 is an important microparticle surface nucleotidase, and whether patients with IPAH have altered microparticle-bound CD39 activity that may contribute to the pathophysiology of the disease. Methodology/ Principal Findings Kinetic parameters, inhibitor blocking experiments, and immunogold labeling with electron microscopy support the role of CD39 as a major nucleotidase on the surface of microparticles. Comparison of microparticle surface CD39 expression and nucleotidase activity in 10 patients with advanced IPAH and 10 healthy controls using flow cytometry and thin layer chromatograph demonstrate the following: 1) circulating platelet (CD39+CD31+CD42b+) and endothelial (CD39+CD31+CD42b−) microparticle subpopulations in patients with IPAH show increased CD39 expression; 2) microparticle ATPase and ADPase activity in patients with IPAH is increased. Conclusions/ Significance We demonstrate for the first time increased CD39 expression and function on circulating microparticles in patients with IPAH. Further research is needed to elucidate whether these findings identify an important trigger for the development of the disease, or reflect a physiologic response to IPAH. PMID:22792409

The digestive tract as the origin of systemic inflammation.

PubMed

de Jong, Petrus R; González-Navajas, José M; Jansen, Nicolaas J G

2016-10-18

Failure of gut homeostasis is an important factor in the pathogenesis and progression of systemic inflammation, which can culminate in multiple organ failure and fatality. Pathogenic events in critically ill patients include mesenteric hypoperfusion, dysregulation of gut motility, and failure of the gut barrier with resultant translocation of luminal substrates. This is followed by the exacerbation of local and systemic immune responses. All these events can contribute to pathogenic crosstalk between the gut, circulating cells, and other organs like the liver, pancreas, and lungs. Here we review recent insights into the identity of the cellular and biochemical players from the gut that have key roles in the pathogenic turn of events in these organ systems that derange the systemic inflammatory homeostasis. In particular, we discuss the dangers from within the gastrointestinal tract, including metabolic products from the liver (bile acids), digestive enzymes produced by the pancreas, and inflammatory components of the mesenteric lymph.

[Interactions of fibroblasts, adipocytes and immunocompeent cells in the pathogenesis of endocrine ophthalmopathy].

PubMed

Heufelder, A E

2001-01-01

Graves' ophthalmopathy is thought to result from a complex interplay of genetic and environmental factors. Various genes including those coding for HLA may determine a patient's susceptibility to the disease and its severity, but in addition numerous and often unknown environmental factors may determine its course. The orbital immune process is thought to be initiated, on the background of a permissive immunogenetic milieu, by circulating T cells directed against certain antigens on thyroid follicular cells that also recognize antigenic epitopes which are shared by tissues contained in the orbital space. Analysis of variable region genes of T cell antigen receptors in orbital T cells of patients with active Graves' ophthalmopathy has revealed limited variability of TcR V gene usage, suggesting that antigen-driven selection and/or expansion of specific T cells may occur during the early stages of Graves' ophthalmopathy. T cell recruitment into the orbital tissues is facilitated by certain chemokines and cytokines, which attract T cells by stimulating the expression of several adhesion molecules (e.g. ICAM-1, VCAM-1, CD44) in vascular endothelium and connective tissue cells. Adhesion molecules are known to be important for a variety of interactions between immunocompetent cells, preadipocyte fibroblasts and adipocytes. In addition, these molecules play a central role in lymphocyte activation and localization, facilitating antigen recognition, T cell costimulation, and various effector-target cell functions at the inflammatory sites, which result in amplification of the cellular immune process in active Graves' ophthalmopathy. T cells and macrophages populate the orbital space and release a number of cytokines (most likely a Th-1-type spectrum) into the surrounding tissues. Cytokines, oxygen free radicals and fibrogenic growth factors, released both from infiltrating inflammatory and residential cells, act upon orbital preadipocytes in a paracrine and autocrine manner to stimulate adipogenesis, fibroblast proliferation, glycosaminoglycan synthesis, and the expression of immunomodulatory molecules. Smoking, a well-known aggravating factor in Graves' ophthalmopathy, may aggravate tissue hypoxia and exert important immunomodulatory and pro-oxidant effects. Differentiation of orbital preadipocyte fibroblasts into mature adipocytes expressing increased levels of TSHR may also be driven by stimulation with circulating or locally produced cytokines or effectors. TSHR-directed autoantibodies or T cells may thus play a direct role promoting adipogenesis, glycosaminoglycan synthesis and expression of immunomodulatory proteins within the orbits. Once the net effect of these changes has come to increase the volume of the fatty connective tissues within the orbit, then proptosis, extraocular muscle dysfunction, and periorbital congestion will ensue.

Cytokine-Mediated Loss of Blood Dendritic Cells During Epstein-Barr Virus-Associated Acute Infectious Mononucleosis: Implication for Immune Dysregulation.

PubMed

Panikkar, Archana; Smith, Corey; Hislop, Andrew; Tellam, Nick; Dasari, Vijayendra; Hogquist, Kristin A; Wykes, Michelle; Moss, Denis J; Rickinson, Alan; Balfour, Henry H; Khanna, Rajiv

2015-12-15

Acute infectious mononucleosis (IM) is associated with altered expression of inflammatory cytokines and disturbed T-cell homeostasis, however, the precise mechanism of this immune dysregulation remains unresolved. In the current study we demonstrated a significant loss of circulating myeloid and plasmacytoid dendritic cells (DCs) during acute IM, a loss correlated with the severity of clinical symptoms. In vitro exposure of blood DCs to acute IM plasma resulted in loss of plasmacytoid DCs, and further studies with individual cytokines showed that exposure to interleukin 10 could replicate this effect. Our data provide important mechanistic insight into dysregulated immune homeostasis during acute IM. © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

A proinflammatory CD4+ T cell phenotype in gestational diabetes mellitus.

PubMed

Sheu, Angela; Chan, Yixian; Ferguson, Angela; Bakhtyari, Mohammad B; Hawke, Wendy; White, Chris; Chan, Yuk Fun; Bertolino, Patrick J; Woon, Heng G; Palendira, Umaimainthan; Sierro, Frederic; Lau, Sue Mei

2018-07-01

Numerous adaptations of the maternal immune system are necessary during pregnancy to maintain immunological tolerance to the semi-allogeneic fetus. Several complications of pregnancy have been associated with dysregulation of these adaptive mechanisms. While gestational diabetes mellitus (GDM) has been associated with upregulation of circulating inflammatory factors linked to innate immunity, polarisation of the adaptive immune system has not been extensively characterised in this condition. We aimed to characterise pro- and anti-inflammatory CD4 + (T helper [Th]) T cell subsets in women with GDM vs women without GDM (of similar BMI), during and after pregnancy, and examine the relationship between CD4 + subsets and severity of GDM. This is a prospective longitudinal case-control study of 55 women with GDM (cases) and 65 women without GDM (controls) at a tertiary maternity hospital. Quantification of proinflammatory (Th17, Th17.1, Th1) and anti-inflammatory (regulatory T cell [Treg]) CD4 + T cell subsets was performed on peripheral blood at 37 weeks gestation and 7 weeks postpartum, and correlated with clinical characteristics and measures of blood glucose. Women with GDM had a significantly greater percentage of Th17 (median 2.49% [interquartile range 1.62-4.60] vs 1.85% [1.13-2.98], p = 0.012) and Th17.1 (3.06% [1.30-4.33] vs 1.55% [0.65-3.13], p = 0.006) cells compared with the control group of women without GDM. Women with GDM also had higher proinflammatory cell ratios (Th17:Treg, Th17.1:Treg and Th1:Treg) in pregnancy compared with the control group of women without GDM. In the control group, there was a statistically significant independent association between 1 h glucose levels in the GTT and Th17 cell percentages, and also between 2 h glucose levels and percentage of Th17 cells. The percentage of Th17 cells and the Th17:Treg ratio declined significantly after delivery in women with GDM, whereas this was not the case with the control group of women. Nevertheless, a milder inflammatory phenotype persisted after delivery (higher Th17:Treg ratio) in women with GDM vs women without. Dysregulation of adaptive immunity supports a novel paradigm of GDM that extends beyond hyperglycaemia and altered innate immunity.

CIRCULATING MICROPARTICLES IN PATIENTS WITH ANTIPHOSPHOLIPID ANTIBODIES: CHARACTERIZATION AND ASSOCIATIONS

PubMed Central

Chaturvedi, Shruti; Cockrell, Erin; Espinola, Ricardo; Hsi, Linda; Fulton, Stacey; Khan, Mohammad; Li, Liang; Fonseca, Fabio; Kundu, Suman; McCrae, Keith R.

2014-01-01

The antiphospholipid syndrome is characterized by venous or arterial thrombosis and/or recurrent fetal loss in the presence of circulating antiphospholipid antibodies. These antibodies cause activation of endothelial and other cell types leading to the release of microparticles with procoagulant and pro-inflammatory properties. The aims of this study were to characterize the levels of endothelial cell, monocyte, platelet derived, and tissue factor-bearing microparticles in patients with antiphospholipid antibodies, to determine the association of circulating microparticles with anticardiolipin and anti-β2-glycoprotein antibodies, and to define the cellular origin of microparticles that express tissue factor. Microparticle content within citrated blood from 47 patients with antiphospholipid antibodies and 144 healthy controls was analyzed within 2 hours of venipuncture. Levels of Annexin-V, CD105 and CD144 (endothelial derived), CD41 (platelet derived) and tissue factor positive microparticles were significantly higher in patients than controls. Though levels of CD14 (monocyte-derived) microparticles in patient plasma were not significantly increased, increased levels of CD14 and tissue factor positive microparticles were observed in patients. Levels of microparticles that stained for CD105 and CD144 showed a positive correlation with IgG (R = 0.60, p=0.006) and IgM anti-beta2-glycoprotein I antibodies (R=0.58, p=0.006). The elevation of endothelial and platelet derived microparticles in patients with APS and their correlation with anti-β2-glycoprotein I antibodies suggests a chronic state of vascular cell activation in these individuals and an important role for β2-glycoprotein I in development of the pro-thrombotic state associated with antiphospholipid antibodies. PMID:25467081

HMGB1 redox during sepsis.

PubMed

Abdulmahdi, Wasan; Patel, Devika; Rabadi, May M; Azar, Tala; Jules, Edson; Lipphardt, Mark; Hashemiyoon, Rameen; Ratliff, Brian B

2017-10-01

During sepsis, the alarmin HMGB1 is released from tissues and promotes systemic inflammation that results in multi-organ damage, with the kidney particularly susceptible to injury. The severity of inflammation and pro-damage signaling mediated by HMGB1 appears to be dependent on the alarmin's redox state. Therefore, we examined HMGB1 redox in kidney cells during sepsis. Using intravital microscopy, CellROX labeling of kidneys in live mice indicated increased ROS generation in the kidney perivascular endothelium and tubules during lipopolysaccharide (LPS)-induced sepsis. Subsequent CellROX and MitoSOX labeling of LPS-stressed endothelial and kidney proximal tubule cells demonstrated increased ROS generation in these cells as sepsis worsens. Consequently, HMGB1 oxidation increased in the cytoplasm of kidney cells during its translocation from the nucleus to the circulation, with the degree of oxidation dependent on the severity of sepsis, as measured in in vivo mouse samples using a thiol assay and mass spectrometry (LC-MS/MS). The greater the oxidation of HMGB1, the greater the ability of the alarmin to stimulate pro-inflammatory cyto-/chemokine release (measured by Luminex Multiplex) and alter mitochondrial ATP generation (Luminescent ATP Detection Assay). Administration of glutathione and thioredoxin inhibitors to cell cultures enhanced HMGB1 oxidation during sepsis in endothelial and proximal tubule cells, respectively. In conclusion, as sepsis worsens, ROS generation and HMGB1 oxidation increases in kidney cells, which enhances HMGB1's pro-inflammatory signaling. Conversely, the glutathione and thioredoxin systems work to maintain the protein in its reduced state. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Discrete microfluidics for the isolation of circulating tumor cell subpopulations targeting fibroblast activation protein alpha and epithelial cell adhesion molecule.

PubMed

Witek, Małgorzata A; Aufforth, Rachel D; Wang, Hong; Kamande, Joyce W; Jackson, Joshua M; Pullagurla, Swathi R; Hupert, Mateusz L; Usary, Jerry; Wysham, Weiya Z; Hilliard, Dawud; Montgomery, Stephanie; Bae-Jump, Victoria; Carey, Lisa A; Gehrig, Paola A; Milowsky, Matthew I; Perou, Charles M; Soper, John T; Whang, Young E; Yeh, Jen Jen; Martin, George; Soper, Steven A

2017-01-01

Circulating tumor cells consist of phenotypically distinct subpopulations that originate from the tumor microenvironment. We report a circulating tumor cell dual selection assay that uses discrete microfluidics to select circulating tumor cell subpopulations from a single blood sample; circulating tumor cells expressing the established marker epithelial cell adhesion molecule and a new marker, fibroblast activation protein alpha, were evaluated. Both circulating tumor cell subpopulations were detected in metastatic ovarian, colorectal, prostate, breast, and pancreatic cancer patients and 90% of the isolated circulating tumor cells did not co-express both antigens. Clinical sensitivities of 100% showed substantial improvement compared to epithelial cell adhesion molecule selection alone. Owing to high purity (>80%) of the selected circulating tumor cells, molecular analysis of both circulating tumor cell subpopulations was carried out in bulk, including next generation sequencing, mutation analysis, and gene expression. Results suggested fibroblast activation protein alpha and epithelial cell adhesion molecule circulating tumor cells are distinct subpopulations and the use of these in concert can provide information needed to navigate through cancer disease management challenges.

Microparticles in the blood of patients with systemic lupus erythematosus (SLE): phenotypic characterization and clinical associations

PubMed Central

Mobarrez, Fariborz; Vikerfors, Anna; Gustafsson, Johanna T.; Gunnarsson, Iva; Zickert, Agneta; Larsson, Anders; Pisetsky, David S.; Wallén, Håkan; Svenungsson, Elisabet

2016-01-01

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by circulating autoantibodies and the formation of immune complexes. In these responses, the selecting self-antigens likely derive from the remains of dead and dying cells, as well as from disturbances in clearance. During cell death/activation, microparticles (MPs) can be released to the circulation. Previous MP studies in SLE have been limited in size and differ regarding numbers and phenotypes. Therefore, to characterize MPs more completely, we investigated 280 SLE patients and 280 individually matched controls. MPs were measured with flow cytometry and phenotyped according to phosphatidylserine expression (PS+/PS−), cellular origin and inflammatory markers. MPs, regardless of phenotype, are 2–10 times more abundant in SLE blood compared to controls. PS− MPs predominated in SLE, but not in controls (66% vs. 42%). Selectively in SLE, PS− MPs were more numerous in females and smokers. MP numbers decreased with declining renal function, but no clear association with disease activity was observed. The striking abundance of MPs, especially PS− MPs, suggests a generalized disturbance in SLE. MPs may be regarded as “liquid biopsies” to assess the production and clearance of dead, dying and activated cells, i.e. pivotal events for SLE pathogenesis. PMID:27777414

Stimulation of monocytes, macrophages, and microglia by amphotericin B and macrophage colony-stimulating factor promotes remyelination.

PubMed

Döring, Axinia; Sloka, Scott; Lau, Lorraine; Mishra, Manoj; van Minnen, Jan; Zhang, Xu; Kinniburgh, David; Rivest, Serge; Yong, V Wee

2015-01-21

Approaches to stimulate remyelination may lead to recovery from demyelinating injuries and protect axons. One such strategy is the activation of immune cells with clinically used medications, since a properly directed inflammatory response can have healing properties through mechanisms such as the provision of growth factors and the removal of cellular debris. We previously reported that the antifungal medication amphotericin B is an activator of circulating monocytes, and their tissue-infiltrated counterparts and macrophages, and of microglia within the CNS. Here, we describe that amphotericin B activates these cells through engaging MyD88/TRIF signaling. When mice were subjected to lysolecithin-induced demyelination of the spinal cord, systemic injections of nontoxic doses of amphotericin B and another activator, macrophage colony-stimulating factor (MCSF), further elevated the representation of microglia/macrophages at the site of injury. Treatment with amphotericin B, particularly in combination with MCSF, increased the number of oligodendrocyte precursor cells and promoted remyelination within lesions; these pro-regenerative effects were mitigated in mice treated with clodronate liposomes to reduce circulating monocytes and tissue-infiltrated macrophages. Our results have identified candidates among currently used medications as potential therapies for the repair of myelin. Copyright © 2015 the authors 0270-6474/15/351136-13$15.00/0.

Neuroendocrine Factors in the Regulation of Inflammation: Excessive Adiposity and Calorie Restriction

PubMed Central

Fontana, Luigi

2009-01-01

Acute inflammation is usually a self-limited life preserving response, triggered by pathogens and/or traumatic injuries. This transient response normally leads to removal of harmful agents and to healing of the damaged tissues. In contrast, unchecked or chronic inflammation can lead to persistent tissue and organ damage by activated leukocytes, cytokines, or collagen deposition. Excessive energy intake and adiposity cause systemic inflammation, whereas calorie restriction without malnutrition exerts a potent anti-inflammatory effect. As individuals accumulate fat and their adipocytes enlarge, adipose tissue undergoes molecular and cellular alterations, macrophages accumulate, and inflammation ensues. Overweight/obese subjects have significantly higher plasma concentrations of C-reactive protein and several cytokines, including IL-6, IL-8, IL-18, and TNF-alpha. Experimental animals on a chronic CR regimen, instead, have low levels of circulating inflammatory cytokines, low blood lymphocyte levels, reduced production of inflammatory cytokines by the white blood cells in response to stimulation, and cortisol levels in the high normal range. Recent data demonstrate that CR exerts a powerful anti-inflammatory effect also in non-human primates and humans. Multiple metabolic and neuroendocrine mechanisms are responsible for the CR-mediated anti-inflammatory effects, including reduced adiposity and secretion of pro-inflammatory adipokines, enhanced glucocorticoid production, reduced plasma glucose and advanced glycation end-product concentrations, increased parasympathetic tone, and increased ghrelin production. Measuring tissue specific effects of CR using genomic, proteomic and metabolomic techniques in humans will foster the understanding of the complex biological processes involved in the anti-inflammatory and anti-aging effects of CR. PMID:18502597

Galectin-3 Shapes Antitumor Immune Responses by Suppressing CD8+ T Cells via LAG-3 and Inhibiting Expansion of Plasmacytoid Dendritic Cells.

PubMed

Kouo, Theodore; Huang, Lanqing; Pucsek, Alexandra B; Cao, Minwei; Solt, Sara; Armstrong, Todd; Jaffee, Elizabeth

2015-04-01

Galectin-3 is a 31-kDa lectin that modulates T-cell responses through several mechanisms, including apoptosis, T-cell receptor (TCR) cross-linking, and TCR downregulation. We found that patients with pancreatic ductal adenocarcinoma (PDA) who responded to a granulocyte-macrophage colony-stimulating factor-secreting allogeneic PDA vaccine developed neutralizing antibodies to galectin-3 after immunization. We show that galectin-3 binds activated antigen-committed CD8(+) T cells only in the tumor microenvironment. Galectin-3-deficient mice exhibit improved CD8(+) T-cell effector function and increased expression of several inflammatory genes. Galectin-3 binds to LAG-3, and LAG-3 expression is necessary for galectin-3-mediated suppression of CD8(+) T cells in vitro. Lastly, galectin-3-deficient mice have elevated levels of circulating plasmacytoid dendritic cells, which are superior to conventional dendritic cells in activating CD8(+) T cells. Thus, inhibiting galectin-3 in conjunction with CD8(+) T-cell-directed immunotherapies should enhance the tumor-specific immune response. ©2015 American Association for Cancer Research.

Chronic Ethanol Feeding Modulates Inflammatory Mediators, Activation of Nuclear Factor-κB, and Responsiveness to Endotoxin in Murine Kupffer Cells and Circulating Leukocytes

PubMed Central

Oppermann, Elsie; Jobin, Christian; Schleucher, Elke; Marzi, Ingo

2014-01-01

Chronic ethanol abuse is known to increase susceptibility to infections after injury, in part, by modification of macrophage function. Several intracellular signalling mechanisms are involved in the initiation of inflammatory responses, including the nuclear factor-κB (NF-κB) pathway. In this study, we investigated the systemic and hepatic effect of chronic ethanol feeding on in vivo activation of NF-κB in NF-κBEGFP reporter gene mice. Specifically, the study focused on Kupffer cell proinflammatory cytokines IL-6 and TNF-α and activation of NF-κB after chronic ethanol feeding followed by in vitro stimulation with lipopolysaccharide (LPS). We found that chronic ethanol upregulated NF-κB activation and increased hepatic and systemic proinflammatory cytokine levels. Similarly, LPS-stimulated IL-1β release from whole blood was significantly enhanced in ethanol-fed mice. However, LPS significantly increased IL-6 and TNF-α levels. These results demonstrate that chronic ethanol feeding can improve the responsiveness of macrophage LPS-stimulated IL-6 and TNF-α production and indicate that this effect may result from ethanol-induced alterations in intracellular signalling through NF-κB. Furthermore, LPS and TNF-α stimulated the gene expression of different inflammatory mediators, in part, in a NF-κB-dependent manner. PMID:24623963

Molecular and functional characterization of CD133+ stem/progenitor cells infused in patients with end-stage liver disease reveals their interplay with stromal liver cells.

PubMed

Catani, Lucia; Sollazzo, Daria; Bianchi, Elisa; Ciciarello, Marilena; Antoniani, Chiara; Foscoli, Licia; Caraceni, Paolo; Giannone, Ferdinando Antonino; Baldassarre, Maurizio; Giordano, Rosaria; Montemurro, Tiziana; Montelatici, Elisa; D'Errico, Antonia; Andreone, Pietro; Giudice, Valeria; Curti, Antonio; Manfredini, Rossella; Lemoli, Roberto Massimo

2017-12-01

Growing evidence supports the therapeutic potential of bone marrow (BM)-derived stem/progenitor cells for end-stage liver disease (ESLD). We recently demonstrated that CD133 + stem/progenitor cell (SPC) reinfusion in patients with ESLD is feasible and safe and improve, albeit transiently, liver function. However, the mechanism(s) through which BM-derived SPCs may improve liver function are not fully elucidated. Here, we characterized the circulating SPCs compartment of patients with ESLD undergoing CD133 + cell therapy. Next, we set up an in vitro model mimicking SPCs/liver microenvironment interaction by culturing granulocyte colony-stimulating factor (G-CSF)-mobilized CD133 + and LX-2 hepatic stellate cells. We found that patients with ESLD show normal basal levels of circulating hematopoietic and endothelial progenitors with impaired clonogenic ability. After G-CSF treatment, patients with ESLD were capable to mobilize significant numbers of functional multipotent SPCs, and interestingly, this was associated with increased levels of selected cytokines potentially facilitating SPC function. Co-culture experiments showed, at the molecular and functional levels, the bi-directional cross-talk between CD133 + SPCs and human hepatic stellate cells LX-2. Human hepatic stellate cells LX-2 showed reduced activation and fibrotic potential. In turn, hepatic stellate cells enhanced the proliferation and survival of CD133 + SPCs as well as their endothelial and hematopoietic function while promoting an anti-inflammatory profile. We demonstrated that the interaction between CD133 + SPCs from patients with ESLD and hepatic stellate cells induces significant functional changes in both cellular types that may be instrumental for the improvement of liver function in cirrhotic patients undergoing cell therapy. Copyright © 2017 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

Perinatal stress, brain inflammation and risk of autism-review and proposal.

PubMed

Angelidou, Asimenia; Asadi, Shahrzad; Alysandratos, Konstantinos-Dionysios; Karagkouni, Anna; Kourembanas, Stella; Theoharides, Theoharis C

2012-07-02

Autism Spectrum Disorders (ASD) are neurodevelopmental disorders characterized by varying deficits in social interactions, communication, and learning, as well as stereotypic behaviors. Despite the significant increase in ASD, there are few if any clues for its pathogenesis, hampering early detection or treatment. Premature babies are also more vulnerable to infections and inflammation leading to neurodevelopmental problems and higher risk of developing ASD. Many autism "susceptibility" genes have been identified, but "environmental" factors appear to play a significant role. Increasing evidence suggests that there are different ASD endophenotypes. We review relevant literature suggesting in utero inflammation can lead to preterm labor, while insufficient development of the gut-blood-brain barriers could permit exposure to potential neurotoxins. This risk apparently may increase in parents with "allergic" or autoimmune problems during gestation, or if they had been exposed to stressors. The presence of circulating auto-antibodies against fetal brain proteins in mothers is associated with higher risk of autism and suggests disruption of the blood-brain-barrier (BBB). A number of papers have reported increased brain expression or cerebrospinal fluid (CSF) levels of pro-inflammatory cytokines, especially TNF, which is preformed in mast cells. Recent evidence also indicates increased serum levels of the pro-inflammatory mast cell trigger neurotensin (NT), and of extracellular mitochondrial DNA (mtDNA), which is immunogenic. Gene mutations of phosphatase and tensin homolog (PTEN), the negative regulator of the mammalian target of rapamycin (mTOR), have been linked to higher risk of autism, but also to increased proliferation and function of mast cells. Premature birth and susceptibility genes may make infants more vulnerable to allergic, environmental, infectious, or stress-related triggers that could stimulate mast cell release of pro-inflammatory and neurotoxic molecules, thus contributing to brain inflammation and ASD pathogenesis, at least in an endophenotype of ASD patients.

Eosinophils as a novel cell source of prostaglandin D2: autocrine role in allergic inflammation

PubMed Central

Luna-Gomes, Tatiana; Magalhães, Kelly G; Mesquita-Santos, Fabio P.; Bakker-Abreu, Ilka; Samico, Rafaela F.; Molinaro, Raphael; Calheiros, Andrea S.; Diaz, Bruno L.; Bozza, Patrícia T.

2011-01-01

Prostaglandin (PG)D2 is a key mediator of allergic inflammatory diseases that is mainly synthesized by mast cells, which constitutively express high levels of the terminal enzyme involved in PGD2 synthesis, the hematopoietic PGD synthase (H-PGDS). Here, we investigated whether eosinophils are also able to synthesize, and therefore, supply biologically active PGD2. PGD2 synthesis was evaluated within human blood eosinophils, in vitro-differentiated mouse eosinophils, and eosinophils infiltrating inflammatory site of mouse allergic reaction. Biological function of eosinophil-derived PGD2 was studied by employing inhibitors of synthesis and activity. Constitutive expression of H-PGDS was found within non-stimulated human circulating eosinophils. Acute stimulation of human eosinophils with A23187 (0.1 – 5 μM) evoked PGD2 synthesis, which was located at the nuclear envelope and was inhibited by pre-treatment with HQL-79 (10 μM), a specific H-PGDS inhibitor. Pre-stimulation of human eosinophils with arachidonic acid (AA; 10 μM) or human eotaxin (6 nM) also enhanced HQL-79-sensitive PGD2 synthesis, which, by acting on membrane-expressed specific receptors (DP1 and DP2), displayed an autocrine/paracrine ability to trigger leukotriene (LT)C4 synthesis and lipid body biogenesis, hallmark events of eosinophil activation. In vitro-differentiated mouse eosinophils also synthesized paracrine/autocrine active PGD2 in response to AA stimulation. In vivo, at late time point of the allergic reaction, infiltrating eosinophils found at the inflammatory site appeared as an auxiliary PGD2-synthesizing cell population. Our findings reveal that eosinophils are indeed able to synthesize and secrete PGD2, hence representing during allergic inflammation an extra cell source of PGD2, which functions as an autocrine signal for eosinophil activation. PMID:22102725

Selective Granulocyte and Monocyte Apheresis as a Non-Pharmacological Option for Patients with Inflammatory Bowel Disease

PubMed Central

C. Leitner, Gerda; Worel, Nina; Vogelsang, Harald

2012-01-01

Ulcerative colitis and Crohn's disease are the two most prevalent inflammatory bowel diseases. In both cases, the medically refractory and steroid-dependent type presents a therapeutic challenge. To help resolve this problem, a mainly Japanese team developed a new therapeutic option. There are two systems, both of which are able to selectively remove the main mediators of the disease, namely the activated pro-inflammatory cytokine-producing granulocytes and monocytes/macrophages, from the patient's blood circulation (GMA = granulocyte monocyte apheresis). One of the two systems is the Adacolumn® (Immunoresearch Laboratories, Takasaki, Japan) consisting of the ADA-monitor and a single-use column, which contains approximately 35,000 cellulose acetate beads. The exact mode of action is not yet sufficiently understood, but however, a modulation of the immune system takes place. As a result, less pro-inflammatory cytokines are released. Furthermore, the production of anti-inflammatory interleukin-1 receptor antagonist is increased, and the apoptosis of granulocytes boosted. The decreased LECAM-1-expression on leukocytes impedes the leukotaxis to the inflamed tissue, and CD10-negative immature granulocytes appear in the peripheral blood. Another effect to be mentioned is the removal of the peripheral dendritic cells and the leachate of regulatory T cells (T-regs). The second system is the Cellsorba® FX Filter (Asahi Medical, Tokyo, Japan). The range of efficiency, the indication, and the procedure are very similar to the Adacolumn. Solely the additional removal of lymphocytes can possibly limit the implementation since lymphopenia can increase the risk of autoimmune disease. Both systems provide a low-risk therapy with few adverse reactions. ASFA recommendations for GMA in inflammatory bowel disease are 2B due to the fact that not enough randomized double-blind studies are available to proof the efficacy of this treatment. PMID:22969694

Clopidogrel, a P2Y12 Receptor Antagonist, Potentiates the Inflammatory Response in a Rat Model of Peptidoglycan Polysaccharide-Induced Arthritis

PubMed Central

Rico, Mario C.; Dela Cadena, Raul A.; Kunapuli, Satya P.

2011-01-01

The P2Y12 receptor plays a crucial role in the regulation of platelet activation by several agonists, which is irreversibly antagonized by the active metabolite of clopidogrel, a widely used anti-thrombotic drug. In this study, we investigated whether reduction of platelet reactivity leads to reduced inflammatory responses using a rat model of erosive arthritis. We evaluated the effect of clopidogrel on inflammation in Lewis rats in a peptidoglycan polysaccharide (PG-PS)-induced arthritis model with four groups of rats: 1) untreated, 2) clopidogrel-treated, 3) PG-PS-induced, and 4) PG-PS-induced and clopidogrel-treated. There were significant differences between the PG-PS+clopidogrel group when compared to the PG-PS group including: increased joint diameter and clinical manifestations of inflammation, elevated plasma levels of pro-inflammatory cytokines (IL-1 beta, interferon (IFN) gamma, and IL-6), an elevated neutrophil blood count and an increased circulating platelet count. Plasma levels of IL-10 were significantly lower in the PG-PS+clopidogrel group compared to the PG-PS group. Plasma levels of platelet factor 4 (PF4) were elevated in both the PG-PS and the PG-PS+clopidogrel groups, however PF4 levels showed no difference upon clopidogrel treatment, suggesting that the pro- inflammatory effect of clopidogrel may be due to its action on cells other than platelets. Histology indicated an increase in leukocyte infiltration at the inflammatory area of the joint, increased pannus formation, blood vessel proliferation, subsynovial fibrosis and cartilage erosion upon treatment with clopidogrel in PG-PS-induced arthritis animals. In summary, animals treated with clopidogrel showed a pro-inflammatory effect in the PG-PS-induced arthritis animal model, which might not be mediated by platelets. Elucidation of the mechanism of clopidogrel-induced cell responses is important to understand the role of the P2Y12 receptor in inflammation. PMID:22028806

Efficacy of Metreleptin in Obese Patients With Type 2 Diabetes: Cellular and Molecular Pathways Underlying Leptin Tolerance

PubMed Central

Moon, Hyun-Seuk; Matarese, Giuseppe; Brennan, Aoife M.; Chamberland, John P.; Liu, Xiaowen; Fiorenza, Christina G.; Mylvaganam, Geetha H.; Abanni, Luisa; Carbone, Fortunata; Williams, Catherine J.; De Paoli, Alex M.; Schneider, Benjamin E.; Mantzoros, Christos S.

2011-01-01

OBJECTIVE Metreleptin has been efficacious in improving metabolic control in patients with lipodystrophy, but its efficacy has not been tested in obese patients with type 2 diabetes. RESEARCH DESIGN AND METHODS We studied the role of leptin in regulating the endocrine adaptation to long-term caloric deprivation and weight loss in obese diabetic subjects over 16 weeks in the context of a double-blinded, placebo–controlled, randomized trial. We then performed detailed interventional and mechanistic signaling studies in humans in vivo, ex vivo, and in vitro. RESULTS In obese patients with diabetes, metreleptin administration for 16 weeks did not alter body weight or circulating inflammatory markers but reduced HbA1c marginally (8.01 ± 0.93–7.96 ± 1.12, P = 0.03). Total leptin, leptin-binding protein, and antileptin antibody levels increased, limiting free leptin availability and resulting in circulating free leptin levels of ∼50 ng/mL. Consistent with clinical observations, all metreleptin signaling pathways studied in human adipose tissue and peripheral blood mononuclear cells were saturable at ∼50 ng/mL, with no major differences in timing or magnitude of leptin-activated STAT3 phosphorylation in tissues from male versus female or obese versus lean humans in vivo, ex vivo, or in vitro. We also observed for the first time that endoplasmic reticulum (ER) stress in human primary adipocytes inhibits leptin signaling. CONCLUSIONS In obese patients with diabetes, metreleptin administration did not alter body weight or circulating inflammatory markers but reduced HbA1c marginally. ER stress and the saturable nature of leptin signaling pathways play a key role in the development of leptin tolerance in obese patients with diabetes. PMID:21617185

Hyperirisinemia is independently associated with subclinical hypothyroidism: correlations with cardiometabolic biomarkers and risk factors.

PubMed

Stratigou, Theodora; Dalamaga, Maria; Antonakos, Georgios; Marinou, Ioanna; Vogiatzakis, Evaggelos; Christodoulatos, Gerasimos Socrates; Karampela, Irene; Papavassiliou, Athanasios G

2018-02-17

Irisin, a newly discovered adipo-myokine, is implicated in the modulation of the adipose phenotype, increasing energy expenditure and ameliorating systemic metabolism. Our aim was to investigate circulating irisin in subclinical hypothyroidism (SH) and study its associations with cardiometabolic risk factors. In a large case-control study, serum irisin, insulin resistance and lipid parameters, classic adipokines, inflammatory and hepatic biomarkers, and cardiovascular risk factors were determined in 120 consecutive patients with SH and 120 healthy controls matched on age, gender, and date of blood draw. Sixteen patients with SH received L-T4 treatment and, after 6 months, serum irisin and other biomarkers were assessed. SH cases exhibited significantly higher circulating irisin than controls (p < 0.001). In all participants, irisin was positively associated with TSH, anti-TG, HOMA-IR, C-peptide, lipid and inflammatory biomarkers, leptin, and cardiovascular risk factors, including Framigham score and apolipoprotein B/apolipoprotein A-I. Irisin was negatively correlated with adiponectin, HDL-C, and thyroid hormones. Serum irisin was independently associated with SH, above and beyond body mass index and cardiometabolic factors (p = 0.02). TSH was an independent predictor of circulating irisin (p = 0.003). L-T4 therapy did not reverse considerably the hyperirisinemic status in treated SH patients (p = 0.09). Irisin may represent an adipo-myokine counterbalancing a potential, gradual deterioration of lipid metabolism and insulin sensitivity in SH as well as reflecting a protective compensatory mechanism against oxidative muscle and thyroid cell stress. More mechanistic and prospective studies shedding light on the pathogenetic role of irisin in SH are needed to confirm and extend these data.

Curcumin as a natural regulator of monocyte chemoattractant protein-1.

PubMed

Karimian, Maryam Saberi; Pirro, Matteo; Majeed, Muhammed; Sahebkar, Amirhossein

2017-02-01

Monocyte chemoattractant/chemotactic protein-1 (MCP-1), a member of the CC chemokine family, is one of the key chemokines that regulate migration and tissue infiltration of monocytes/macrophages. Its role in the pathophysiology of several inflammatory diseases has been widely recognized, thus making MCP-1 a possible target for anti-inflammatory treatments. Curcumin (diferuloylmethane) is a natural polyphenol derived from the rhizomes of Curcuma Longa L. (turmeric). Anti-inflammatory action underlies numerous pharmacological effects of curcumin in the control and prevention of several diseases. The purpose of this review is to evaluate the effects of curcumin on the regulation of MCP-1 as a key mediator of chemotaxis and inflammation, and the biological consequences thereof. In vitro studies have shown that curcumin can decrease MCP-1 production in various cell lines. Animal studies have also revealed that curcumin can attenuate MCP-1 expression and improve a range of inflammatory diseases through multiple molecular targets and mechanisms of action. There is limited data from human clinical trials showing the decreasing effect of curcumin on MCP-1 concentrations and improvement of the course of inflammatory diseases. Most of the in vitro and animal studies confirm that curcumin exert its MCP-1-lowering and anti-inflammatory effects by down-regulating the mitogen-activated protein kinase (MAPK) and NF-κB signaling pathway. As yet, there is limited data from human clinical trials showing the effect of curcumin on MCP-1 levels and improvement of the course of inflammatory diseases. More evidence, especially from human studies, is needed to better assess the effects of curcumin on circulating MCP-1 in different human diseases and the role of this modulatory effect in the putative anti-inflammatory properties of curcumin. Copyright © 2016 Elsevier Ltd. All rights reserved.

Resveratrol supplementation decreases blood glucose without changing the circulating CD14+CD16+ monocytes and inflammatory cytokines in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled study.

PubMed

Khodabandehloo, Hadi; Seyyedebrahimi, ShadiSadat; Esfahani, Ensieh Nasli; Razi, Farideh; Meshkani, Reza

2018-06-01

Chronic low-grade inflammation is the hallmark of type 2 diabetes (T2D). Although in vitro and animal studies have shown that resveratrol exerts anti-inflammatory effects, clinical trials addressing these effects in patients with T2D are limited. Therefore, in the present study, we hypothesized that supplementation of resveratrol might improve inflammatory markers in patients with T2D in a randomized, double-blind, placebo-controlled clinical trial. A total of 45 T2D patients were supplemented with either of 800 mg/d resveratrol or placebo capsules for 8 weeks. Percentage of CD14 + CD16 + monocytes, plasma levels of inflammatory cytokines (tumor necrosis factor α, interleukin [IL] 1β, IL-6, and monocyte chemoattractant protein-1), the expression levels of genes involved in the inflammatory responses (toll-like receptor 2, toll-like receptor 4, and nuclear factor κB), lipopolysaccharide-stimulated cytokine (tumor necrosis factor α, IL-1β, and IL-6) secretion from peripheral blood mononuclear cells, and metabolic and anthropometric parameters were assessed at both the baseline level and the end of the study. Compared with the placebo group, we could not detect any significant difference in the percentage of CD14 + CD16 + monocytes, lipopolysaccharide-induced cytokine secretion, plasma levels of inflammatory cytokines, and the expression of inflammatory genes in resveratrol group. Moreover, we did not find any significant change in the metabolic and anthropometric parameters except for a significant reduction in fasting blood glucose and blood pressure. In conclusion, 8-week supplementation of resveratrol reduces blood glucose level in patients with T2D without improving their inflammatory markers. Copyright © 2018 Elsevier Inc. All rights reserved.

Role of Polyamines in Asthma Pathophysiology

PubMed Central

2018-01-01

Asthma is a complex disease of airways, where the interactions of immune and structural cells result in disease outcomes with airway remodeling and airway hyper-responsiveness. Polyamines, which are small-sized, natural super-cations, interact with negatively charged intracellular macromolecules, and altered levels of polyamines and their interactions have been associated with different pathological conditions including asthma. Elevated levels of polyamines have been reported in the circulation of asthmatic patients as well as in the lungs of a murine model of asthma. In various studies, polyamines were found to potentiate the pathogenic potential of inflammatory cells, such as mast cells and granulocytes (eosinophils and neutrophils), by either inducing the release of their pro-inflammatory mediators or prolonging their life span. Additionally, polyamines were crucial in the differentiation and alternative activation of macrophages, which play an important role in asthma pathology. Importantly, polyamines cause airway smooth muscle contraction and thus airway hyper-responsiveness, which is the key feature in asthma pathophysiology. High levels of polyamines in asthma and their active cellular and macromolecular interactions indicate the importance of the polyamine pathway in asthma pathogenesis; therefore, modulation of polyamine levels could be a suitable approach in acute and severe asthma management. This review summarizes the possible roles of polyamines in different pathophysiological features of asthma. PMID:29316647

The Role of TLR2, TLR4, and TLR9 in the Pathogenesis of Atherosclerosis

PubMed Central

2016-01-01

Toll-like receptors (TLRs) are key players in the pathogenesis of inflammatory conditions including coronary arterial disease (CAD). They are expressed by a variety of immune cells where they recognize pathogen-associated molecular patterns (PAMPs). TLRs recruit adaptor molecules, including myeloid differentiation primary response protein (MYD88) and TIRF-related adaptor protein (TRAM), to mediate activation of MAPKs and NF-kappa B pathways. They are associated with the development of CAD through various mechanisms. TLR4 is expressed in lipid-rich and atherosclerotic plaques. In TLR2−/− and TLR4−/− mice, atherosclerosis-associated inflammation was diminished. Moreover, TLR2 and TLR4 may induce expression of Wnt5a in advanced staged atheromatous plaque leading to activation of the inflammatory processes. TLR9 is activated by CpG motifs in nucleic acids and have been implicated in macrophage activation and the uptake of oxLDL from the circulation. Furthermore, TLR9 also stimulates interferon-α (INF-α) secretion and increases cytotoxic activity of CD4+ T-cells towards coronary artery tunica media smooth muscle cells. This review outlines the pathophysiological role of TLR2, TLR4, and TLR9 in atherosclerosis, focusing on evidence from animal models of the disease. PMID:27795867

Discovery of a potent nanoparticle P-selectin antagonist with anti-inflammatory effects in allergic airway disease

PubMed Central

John, Alison E.; Lukacs, Nicholas W.; Berlin, Aaron A.; Palecanda, Aiyappa; Bargatze, Robert F.; Stoolman, Lloyd M.; Nagy, Jon O.

2010-01-01

The severity of allergic asthma is dependent, in part, on the intensity of peribronchial inflammation. P-selectin is known to play a role in the development of allergen-induced peribronchial inflammation and airway hyperreactivity. Selective inhibitors of P-selectin-mediated leukocyte endothelial-cell interactions may therefore attenuate the inflammatory processes associated with allergic airway disease. Novel P-selectin inhibitors were created using a polyvalent polymer nanoparticle capable of displaying multiple synthetic, low molecular weight ligands. By assembling a particle that presents an array of groups, which as monomers interact with only low affinity, we created a construct that binds extremely efficiently to P-selectin. The ligands acted as mimetics of the key binding elements responsible for the high-avidity adhesion of P-selectin to the physiologic ligand, PSGL-1. The inhibitors were initially evaluated using an in vitro shear assay system in which interactions between circulating cells and P-selectin-coated capillary tubes were measured. The nanoparticles were shown to preferentially bind to selectins expressed on activated endothelial cells. We subsequently demonstrated that nanoparticles displaying P-selectin blocking arrays were functionally active in vivo, significantly reducing allergen-induced airway hyperreactivity and peribronchial eosinophilic inflammation in a murine model of asthma. PMID:14563683

Role of CD11b+Gr-1+ myeloid cells in AGEs-induced myocardial injury in a mice model of acute myocardial infarction.

PubMed

Yao, Tongqing; Lu, Wenbin; Zhu, Jian; Jin, Xian; Ma, Genshan; Wang, Yuepeng; Meng, Shu; Zhang, Yachen; Li, Yigang; Shen, Chengxing

2015-01-01

Polymorph neutrophils are the predominant inflammatory cells and play a crucial role on the pathogenesis of myocardial injury at the early stage of acute myocardial infarction (AMI). However, the precursors and the differentiation of neutrophils are not fully understood. Here we explored the role of CD11b+Gr-1+ myeloid-derived suppressor cells (MDSCs) on myocardial injury in the absence and presence of advanced glycation end-products (AGEs) in a mice model of AMI. Male C57BL/6J mice were selected. Fluorescent actived cell sortor (FACS) data demonstrated significantly increased CD11b+Gr-1+ MDSCs both in peripheral blood circulation and in the ischemic myocardium at 24 hours post AMI. Quantitative-real-time PCR results also revealed significantly upregulated CD11b and Ly6G mRNA expression in the ischemic myocardium. AGEs treatment further aggravated these changes in AMI mice but not in sham mice. Moreover, AGEs treatment also significantly increased infarction size and enhanced cardiomyocyte apoptosis. The mRNA expression of pro-inflammatory cytokine IL-6 and iNOS2 was also significantly increased in AMI + AGEs group compared to AMI group. These data suggest enhanced infiltration of MDSCs by AGEs contributes to aggravated myocardial injury in AMI mice, which might be one of the mechanisms responsible for severer myocardial injury in AMI patients complicating diabetes.

Widespread activation of immunity and pro-inflammatory programs in peripheral blood leukocytes of HIV-infected patients with impaired lung gas exchange.

PubMed

Crothers, Kristina; Petrache, Irina; Wongtrakool, Cherry; Lee, Patty J; Schnapp, Lynn M; Gharib, Sina A

2016-04-01

HIV infection is associated with impaired lung gas transfer as indicated by a low diffusing capacity (DLCO), but the mechanisms are not well understood. We hypothesized that HIV-associated gas exchange impairment is indicative of system-wide perturbations that could be reflected by alterations in peripheral blood leukocyte (PBL) gene expression. Forty HIV-infected (HIV(+)) and uninfected (HIV(-)) men with preserved versus low DLCO were enrolled. All subjects were current smokers and those with acute illness, lung diseases other than COPD or asthma were excluded. Total RNA was extracted from PBLs and hybridized to whole-genome microarrays. Gene set enrichment analysis (GSEA) was performed between HIV(+) versus HIV(-) subjects with preserved DLCO and those with low DLCO to identify differentially activated pathways. Using pathway-based analyses, we found that in subjects with preserved DLCO, HIV infection is associated with activation of processes involved in immunity, cell cycle, and apoptosis. Applying a similar analysis to subjects with low DLCO, we identified a much broader repertoire of pro-inflammatory and immune-related pathways in HIV(+) patients relative to HIV(-) subjects, with up-regulation of multiple interleukin pathways, interferon signaling, and toll-like receptor signaling. We confirmed elevated circulating levels of IL-6 in HIV(+) patients with low DLCO relative to the other groups. Our findings reveal that PBLs of subjects with HIV infection and low DLCO are distinguished by widespread enrichment of immuno-inflammatory programs. Activation of these pathways may alter the biology of circulating leukocytes and play a role in the pathogenesis of HIV-associated gas exchange impairment. © 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

Anti-inflammatory IgG Production Requires Functional P1 Promoter in β-Galactoside α2,6-Sialyltransferase 1 (ST6Gal-1) Gene*

PubMed Central

Jones, Mark B.; Nasirikenari, Mehrab; Lugade, Amit A.; Thanavala, Yasmin; Lau, Joseph T. Y.

2012-01-01

The anti-inflammatory properties associated with intravenous immunoglobulin therapy require the sialic acid modification of the N-glycan of the Fc domain of IgG. Sialylation of the Fc fragment is mediated by β-galactoside α2,6-sialyltransferase 1 (ST6Gal-1), acting on the Gal(β4)GlcNAc terminal structure of the biantennary N-glycans on the Fc domain. However, little is known regarding the in vivo regulation of Fc sialylation and its role in the progression of inflammatory processes. Here, we report that decreased Fc sialylation of circulatory IgG accompanies the acute phase response elicited by turpentine exposure or upon acute exposure to either nontypeable Haemophilus influenzae or ovalbumin. However, Fc sialylation was increased 3-fold from the base line upon transition to chronic inflammation by repeated exposure to challenge. The P1 promoter of the ST6Gal-1 gene is critical for Fc sialylation, but P1 does not drive ST6Gal-1 expression in B cells. The Siat1ΔP1 mouse, with a dysfunctional P1 promoter, was unable to produce sialylated Fc in the systemic circulation, despite the presence of Gal(β4)GlcNAc termini on the Fc glycans. The major contribution of P1 action is to synthesize ST6Gal-1 enzymes that are deposited into the systemic circulation. The data strongly indicate that this pool of extracellular ST6Gal-1 in the blood impacts the sialylation of IgG Fc and that defective Fc sialylation is likely a major contributing mechanism for the proinflammatory tendencies previously noted in Siat1ΔP1 animals. PMID:22427662

Decreased number of steroid receptors of circulating lymphocytes in Crohn's disease and ulcerative colitis.

PubMed

Krasznai, A; Krajcsi, P; Arányi, P; Mészáros, K; Horváth, I

1986-01-01

The number of steroid receptors of circulating lymphocytes was determined in 13 patients with inflammatory bowel disease and in controls. Marked reduction of the number of receptors was observed both in Crohn's disease and in ulcerative colitis; no receptors were detected by radioactive hormone binding assay in 4 cases.

Endotoxin, Toll-like Receptor-4, and Atherosclerotic Heart Disease

PubMed Central

Horseman, Michael A.; Surani, Salim; Bowman, John D.

2017-01-01

Background: Endotoxin is a lipopolysaccharide (LPS) constituent of the outer membrane of most gram negative bacteria. Ubiquitous in the environment, it has been implicated as a cause or con-tributing factor in several disparate disorders from sepsis to heatstroke and Type II diabetes mellitus. Starting at birth, the innate immune system develops cellular defense mechanisms against environmen-tal microbes that are in part modulated through a series of receptors known as toll-like receptors. Endo-toxin, often referred to as LPS, binds to toll-like receptor 4 (TLR4)/ myeloid differentiation protein 2 (MD2) complexes on various tissues including cells of the innate immune system, smooth muscle and endothelial cells of blood vessels including coronary arteries, and adipose tissue. Entry of LPS into the systemic circulation ultimately leads to intracellular transcription of several inflammatory mediators. The subsequent inflammation has been implicated in the development and progression atherosclerosis and subsequent coronary artery disease and heart failure. Objective: The potential roles of endotoxin and TLR4 are reviewed regarding their role in the pathogen-esis of atherosclerotic heart disease. Conclusion: Atherosclerosis is initiated by inflammation in arterial endothelial and subendothelial cells, and inflammatory processes are implicated in its progression to clinical heart disease. Endotoxin and TLR4 play a central role in the inflammatory process, and represent potential targets for therapeutic intervention. Therapy with HMG-CoA inhibitors may reduce the expression of TLR4 on monocytes. Other therapeutic interventions targeting TLR4 expression or function may prove beneficial in athero-sclerotic disease prevention and treatment.

NO supplementation for transfusion medicine and cardiovascular applications.

PubMed

Cabrales, Pedro; Ortiz, Daniel; Friedman, Joel M

Blood transfusions are used to treat reduced O 2 -carrying capacity consequent to anemia. In many cases anemia is caused by a major blood loss, which also creates a state of hypovolemia. Whereas O 2 transport capacity is restored by increasing levels of circulating Hb, transfusion does not resolve the hypoperfusion, the hypoxia and the inflammatory cascades initiated during the anemia and hypovolemia. This explains why blood transfusion is not always an effective treatment and why transfusion of stored blood has been associated with increased morbidity and mortality, especially in patient populations receiving multiple transfusions. Epidemiologic data indicate that adverse events after transfusion are relatively common, having a great impact on the patients outcome and on the costs of public health. In this chapter, we explain why classical transfusion strategies target the reversal of hypoxia only, but do not address the inflammatory cascades initiated during anemic states and the importance of the flow and vascular endothelium interactions. We also establish the relation between red blood cells storage lesions, limited NO bioavailability and transfusion-associated adverse events. Lastly, we explain the potential use of long-lived sources of bioactive NO to reverse the hypoxic inflammatory cascades, promote a sustained increase in tissue perfusion and thereby allow transfusions to achieve their intended goal. The underlying premise is that adverse effects associated with transfusions are intimately linked to vascular dysfunction. Understanding of these mechanisms would lead to novel transfusion medicine strategies to preserve red cell function and to correct for functional changes induced by hemoglobinopathies that affect cell structure and function.

Korean Red Ginseng Saponin Fraction Rich in Ginsenoside-Rb1, Rc and Rb2 Attenuates the Severity of Mouse Collagen-Induced Arthritis

PubMed Central

Endale, Mehari; Im, Eun Ju; Lee, Joo Young; Kim, Sung Dae; Song, Yong-Bum; Kwak, Yi-Seong; Kim, Chaekyun; Kim, Seung-Hyung; Roh, Seong-Soo; Rhee, Man Hee

2014-01-01

Despite a multitude of reports on anti-inflammatory properties of ginseng extracts or individual ginsenosides, data on antiarthritic effect of ginseng saponin preparation with mixed ginsenosides is limited. On the other hand, a combined therapy of safe and inexpensive plant-derived natural products such as ginsenosides can be considered as an alternative to treat arthritis. Our previous in vitro data displayed a strong anti-inflammatory action of red ginseng saponin fraction-A (RGSF-A). We, herein, report a marked antiarthritic property of RGSF-A rich in ginsenoside Rb1, Rc, and Rb2. Collagen-induced arthritic (CIA) mice were treated with RGSF-A or methotrexate (MTX) for 5 weeks. Joint pathology, serum antibody production and leukocye activation, cytokine production in the circulation, lymph nodes, and joints were examined. RGSF-A markedly reduced severity of arthritis, cellular infiltration, and cartilage damage. It suppressed CD3+/CD69+, CD4+/CD25+, CD8+ T-cell, CD19+, B220/CD23+ B-cell, MHCII+/CD11c+, and Gr-1+/CD11b+ cell activations. It further suppressed anti-CII- or anti-RF-IgG/IgM, TNF-α, IL-1β, IL-17, and IL-6 secretions but stimulated IL-10 levels in the serum, joint, or splenocyte. RGSF-A attenuated arthritis severity, modified leukocyte activations, and restored cytokine imbalances, suggesting that it can be considered as an antiarthritic agent with the capacity to ameliorate the immune and inflammatory responses in CIA mice. PMID:24833816

Of Microbes and Meals: The Health Consequences of Dietary Endotoxemia

PubMed Central

Kelly, Caleb J.; Colgan, Sean P.; Frank, Daniel N.

2014-01-01

The human intestinal tract is comprised of a rich and complex microbial ecosystem. This intestinal microbota provides a large reservoir of potentially toxic molecules, including bacterial endotoxin (i.e., lipopolysaccharide). This potent inflammatory molecule is detectable in the circulation of healthy individuals and levels transiently increase following ingestion of energy rich meals. Chronic exposure to circulating endotoxin has been associated with obesity, diabetes, and cardiovascular disease. Western-style meals augment LPS translocation and by this mechanism may contribute to the pathogenesis of these diseases. By contrast, the gut and other organs have evolved mechanisms to detoxify endotoxin and to neutralize the potentially inflammatory qualities of circulating endotoxin. Of specific interest to clinicians is evidence that acute postprandial elevation of circulating endotoxin is dependent on meal composition. In this review we present an overview of the biochemical and cellular mechanisms that lead to endotoxemia, with emphasis on the interplay between microbial and nutritional determinants of this condition. The link between endotoxemia, diet, and changes in the intestinal microbiota raise the possibility that dietary interventions can, at least in part, ameliorate the detrimental outcomes of endotoxemia. PMID:22378797

Acute high-intensity interval exercise induces comparable levels of circulating cell-free DNA and Interleukin-6 in obese and normal-weight individuals.

PubMed

Ferrandi, Peter J; Fico, Brandon G; Whitehurst, Michael; Zourdos, Michael C; Bao, Fanchen; Dodge, Katelyn M; Rodriguez, Alexandra L; Pena, Gabriel; Huang, Chun-Jung

2018-06-01

Obesity is associated with lipid aggregation in adipocytes and macrophage infiltration, leading to increased oxidative stress and inflammation. Increased cell-free DNA (cfDNA) concentrations have been observed in clinical conditions of systemic inflammation. While the beneficial effects of regular physical activity on the release of circulating cfDNA still remain unknown, acute intense exercise has been shown to increase inflammatory cytokines and cfDNA concentrations in normal-weight individuals. Therefore, the primary purpose of this study was to examine the effect of acute high-intensity interval Exercise (HIIE) on plasma cfDNA and interleukin-6 (IL-6) responses in obese and normal-weight subjects. Fourteen male subjects (7 obese and 7 normal-weight) participated in an acute HIIE protocol (30 min, 4x4min @ 80% - 90% of VO 2max ) on a treadmill. Between HIIE intervals, subjects performed 3 min of active recovery at 50-60% VO 2max . Blood samples were collected prior to, immediately following exercise, and one hour into recovery for measurements of plasma cfDNA and IL-6. Our results demonstrated a significant elevation in plasma cfDNA immediately following acute HIIE in both obese and normal-weight subjects. A comparable elevation in the concentration of plasma IL-6 was also found between two groups in response to acute HIIE. Furthermore, the level of plasma cfDNA was not correlated with IL-6 either at baseline or in response to acute HIIE. These findings may support the utilization of HIIE as a time-efficient exercise protocol to understand the obesity-associated cfDNA and inflammatory responses. Published by Elsevier Inc.

Neutrophil Membrane Cholesterol Content is a Key Factor in Cystic Fibrosis Lung Disease.

PubMed

White, Michelle M; Geraghty, Patrick; Hayes, Elaine; Cox, Stephen; Leitch, William; Alfawaz, Bader; Lavelle, Gillian M; McElvaney, Oliver J; Flannery, Ryan; Keenan, Joanne; Meleady, Paula; Henry, Michael; Clynes, Martin; Gunaratnam, Cedric; McElvaney, Noel G; Reeves, Emer P

2017-09-01

Identification of mechanisms promoting neutrophil trafficking to the lungs of patients with cystic fibrosis (CF) is a challenge for next generation therapeutics. Cholesterol, a structural component of neutrophil plasma membranes influences cell adhesion, a key step in transmigration. The effect of chronic inflammation on neutrophil membrane cholesterol content in patients with CF (PWCF) remains unclear. To address this we examined neutrophils of PWCF to evaluate the cause and consequence of altered membrane cholesterol and identified the effects of lung transplantation and ion channel potentiator therapy on the cellular mechanisms responsible for perturbed membrane cholesterol and increased cell adhesion. PWCF homozygous for the ΔF508 mutation or heterozygous for the G551D mutation were recruited (n=48). Membrane protein expression was investigated by mass spectrometry. The effect of lung transplantation or ivacaftor therapy was assessed by ELISAs, and calcium fluorometric and μ-calpain assays. Membranes of CF neutrophils contain less cholesterol, yet increased integrin CD11b expression, and respond to inflammatory induced endoplasmic reticulum (ER) stress by activating μ-calpain. In vivo and in vitro, increased μ-calpain activity resulted in proteolysis of the membrane cholesterol trafficking protein caveolin-1. The critical role of caveolin-1 for adequate membrane cholesterol content was confirmed in caveolin-1 knock-out mice. Lung transplant therapy or treatment of PWCF with ivacaftor, reduced levels of circulating inflammatory mediators and actuated increased caveolin-1 and membrane cholesterol, with concurrent normalized neutrophil adhesion. Results demonstrate an auxiliary benefit of lung transplant and potentiator therapy, evident by a reduction in circulating inflammation and controlled neutrophil adhesion. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Prolonged sleep restriction induces changes in pathways involved in cholesterol metabolism and inflammatory responses.

PubMed

Aho, Vilma; Ollila, Hanna M; Kronholm, Erkki; Bondia-Pons, Isabel; Soininen, Pasi; Kangas, Antti J; Hilvo, Mika; Seppälä, Ilkka; Kettunen, Johannes; Oikonen, Mervi; Raitoharju, Emma; Hyötyläinen, Tuulia; Kähönen, Mika; Viikari, Jorma S A; Härmä, Mikko; Sallinen, Mikael; Olkkonen, Vesa M; Alenius, Harri; Jauhiainen, Matti; Paunio, Tiina; Lehtimäki, Terho; Salomaa, Veikko; Orešič, Matej; Raitakari, Olli T; Ala-Korpela, Mika; Porkka-Heiskanen, Tarja

2016-04-22

Sleep loss and insufficient sleep are risk factors for cardiometabolic diseases, but data on how insufficient sleep contributes to these diseases are scarce. These questions were addressed using two approaches: an experimental, partial sleep restriction study (14 cases and 7 control subjects) with objective verification of sleep amount, and two independent epidemiological cohorts (altogether 2739 individuals) with questions of sleep insufficiency. In both approaches, blood transcriptome and serum metabolome were analysed. Sleep loss decreased the expression of genes encoding cholesterol transporters and increased expression in pathways involved in inflammatory responses in both paradigms. Metabolomic analyses revealed lower circulating large HDL in the population cohorts among subjects reporting insufficient sleep, while circulating LDL decreased in the experimental sleep restriction study. These findings suggest that prolonged sleep deprivation modifies inflammatory and cholesterol pathways at the level of gene expression and serum lipoproteins, inducing changes toward potentially higher risk for cardiometabolic diseases.

Potential roles of cell-derived microparticles in ischemic brain disease.

PubMed

Horstman, Lawrence L; Jy, Wenche; Bidot, Carlos J; Nordberg, Mary L; Minagar, Alireza; Alexander, J Steven; Kelley, Roger E; Ahn, Yeon S

2009-10-01

The objective of this study is to review the role of cell-derived microparticles in ischemic cerebrovascular diseases. An extensive PubMed search of literature pertaining to this study was performed in April 2009 using specific keyword search terms related to cell-derived microparticles and ischemic stroke. Some references are not cited here as it is not possible to be all inclusive or due to space limitation. Cell-derived microparticles are small membranous vesicles released from the plasma membranes of platelets, leukocytes, red cells and endothelial cells in response to diverse biochemical agents or mechanical stresses. They are the main carriers of circulating tissue factor, the principal initiator of intravascular thrombosis, and are implicated in a variety of thrombotic and inflammatory disorders. This review outlines evidence suggesting that cell-derived microparticles are involved predominantly with microvascular, as opposed to macrovascular, thrombosis. More specifically, cell-derived microparticles may substantially contribute to ischemic brain disease in several settings, as well as to neuroinflammatory conditions. If further work confirms this hypothesis, novel therapeutic strategies for minimizing cell-derived microparticles-mediated ischemia are available or can be developed, as discussed.

Saturated fatty acids enhance TLR4 immune pathways in human trophoblasts.

PubMed

Yang, Xiaohua; Haghiac, Maricela; Glazebrook, Patricia; Minium, Judi; Catalano, Patrick M; Hauguel-de Mouzon, Sylvie

2015-09-01

What are the effects of fatty acids on placental inflammatory cytokine with respect to toll-like receptor-4/nuclear factor-kappa B (TLR4/NF-kB)? Exogenous fatty acids induce a pro-inflammatory cytokine response in human placental cells in vitro via activation of TLR4 signaling pathways. The placenta is exposed to changes in circulating maternal fatty acid concentrations throughout pregnancy. Fatty acids are master regulators of innate immune pathways through recruitment of toll-like receptors and activation of cytokine synthesis. Trophoblast cells isolated from 14 normal term human placentas were incubated with long chain fatty acids (FA) of different carbon length and degree of saturation. The expression and secretion of interleukin-6 (IL-6), IL-8 and tumor necrosis factor-alpha (TNF-α) were measured by reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay. Antibodies against TLR4 ligand binding domain, downstream signaling and anti-p65 NFkB-inhibitor were used to characterize the pathways of FA action. General approach used primary human term trophoblast cell culture. Methods and end-points used real-time quantitative PCR, cytokine measurements, immunohistochemistry, western blots. The long chain saturated fatty acids, stearic and palmitic (PA), stimulated the synthesis as well as the release of TNF-α, IL-6 and IL-8 by trophoblast cells (2- to 6-fold, P < 0.001). In contrast, the unsaturated (palmitoleic, oleic, linoleic) acids did not modify cytokine expression significantly. Palmitate-induced inflammatory effects were mediated via TLR4 activation, NF-kB phosphorylation and nuclear translocation. TNF-α protein level was close to the limit of detection in the culture medium even when cells were cultured with PA. These mechanisms open the way to a better understanding of how changes in maternal lipid homeostasis may regulate placental inflammatory status. X.Y. was recipient of fellowship award from West China Second University Hospital, Sichuan University (NIH HD 22965-19). The authors have nothing else to disclose. None. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US.

Pathophysiology and laboratory diagnosis of pernicious anemia.

PubMed

Toh, Ban-Hock

2017-02-01

Pernicious anemia is the hematologic manifestation of chronic atrophic gastritis affecting the corpus of the stomach that denudes the gastric mucosa of gastric parietal cells. Asymptomatic autoimmune gastritis, a chronic inflammatory disease of the gastric mucosa, precedes the onset of corpus atrophy by 10-20 years. The gastritis arises from activation of pathologic Th1 CD4 T cells to gastric H/K ATPase that is normally resident on gastric mucosal secretory membranes. The onset of autoimmune gastritis is marked by circulating parietal cell antibody to gastric H/K ATPase. Gastric parietal cells produce two essential biologics: intrinsic factor and HCl acid. Pernicious anemia is a consequence of intrinsic factor loss and neutralizing intrinsic factor antibody that impairs cobalamin absorption. Acid loss leads to iron deficiency anemia that precedes cobalamin-deficient pernicious anemia by 20 years. Laboratory diagnosis rests on parietal cell antibody with or without intrinsic factor antibody, cobalamin-deficient megaloblastic anemia and elevated serum gastrin from loss of acid secretion. Autoimmune gastritis is associated with autoimmune thyroiditis and type 1 diabetes mellitus.

Preliminary studies of the effects of psychological stress on circulating lymphocytes analyzed by synchrotron radiation based-Fourier transform infrared microspectroscopy

NASA Astrophysics Data System (ADS)

Vargas-Caraveo, Alejandra; Castillo-Michel, Hiram; Mejia-Carmona, Gloria Erika; Pérez-Ishiwara, David Guillermo; Cotte, Marine; Martínez-Martínez, Alejandro

2014-07-01

Psychological stress is a condition that not only generates behavioral disorders but also disrupts homeostasis and immune activity that can exacerbate or lead to inflammatory diseases. The aim of this work was to study biochemical changes in circulating immune cells from rats under psychological stress by using vibrational spectroscopy. A stress model was used, where exposure to a stressor was repeated for 5 days. Subsequently, circulating lymphocytes were examined for their biomolecular vibrational fingerprints with synchrotron radiation based-Fourier transform infrared microspectroscopy. The results showed an increased absorption at the ester lipid region (1720-1755 cm-1) in lymphocytes from stressed rats, suggesting lipid peroxidation. Statistical significant changes in wavenumber peak position and absorbance in the nucleic acid region were also observed (915-950 cm-1 Z-DNA, 1090-1150 cm-1 symmetric stretching of Psbnd Osbnd C, 1200-1260 cm-1 asymmetric PO2 and 1570-1510 cm-1 methylated nucleotides) which suggest a reduction of transcriptional activity in lymphocytes from stressed rat. These results unravel part of the mechanisms by which psychological stress may affect the immune system leading to systemic consequences.

Single-cell mRNA profiling reveals transcriptional heterogeneity among pancreatic circulating tumour cells.

PubMed

Lapin, Morten; Tjensvoll, Kjersti; Oltedal, Satu; Javle, Milind; Smaaland, Rune; Gilje, Bjørnar; Nordgård, Oddmund

2017-05-31

Single-cell mRNA profiling of circulating tumour cells may contribute to a better understanding of the biology of these cells and their role in the metastatic process. In addition, such analyses may reveal new knowledge about the mechanisms underlying chemotherapy resistance and tumour progression in patients with cancer. Single circulating tumour cells were isolated from patients with locally advanced or metastatic pancreatic cancer with immuno-magnetic depletion and immuno-fluorescence microscopy. mRNA expression was analysed with single-cell multiplex RT-qPCR. Hierarchical clustering and principal component analysis were performed to identify expression patterns. Circulating tumour cells were detected in 33 of 56 (59%) examined blood samples. Single-cell mRNA profiling of intact isolated circulating tumour cells revealed both epithelial-like and mesenchymal-like subpopulations, which were distinct from leucocytes. The profiled circulating tumour cells also expressed elevated levels of stem cell markers, and the extracellular matrix protein, SPARC. The expression of SPARC might correspond to an epithelial-mesenchymal transition in pancreatic circulating tumour cells. The analysis of single pancreatic circulating tumour cells identified distinct subpopulations and revealed elevated expression of transcripts relevant to the dissemination of circulating tumour cells to distant organ sites.

Effects of glucose ingestion on circulating inflammatory mediators: Influence of sex and weight excess.

PubMed

Escobar-Morreale, Héctor F; Martínez-García, M Ángeles; Montes-Nieto, Rafael; Fernández-Durán, Elena; Temprano-Carazo, Sara; Luque-Ramírez, Manuel

2017-04-01

Low-grade chronic inflammation is involved in the pathophysiology of obesity. However, little is known about the influence of sex and sex hormones on surrogate inflammatory markers and mediators, particularly after glucose ingestion. Observational study. We measured the circulating concentrations of interleukin-6, interleukin-18, macrophage migration inhibitory factor, matrix metallopeptidase-9, monocyte chemotactic protein-1 and pentraxin-3, in the fasting state and during a 75 g oral glucose tolerance test, in 24 women and 25 men. Eleven men and 11 women were lean whereas 14 men and 13 women had weight excess. Anti-inflammatory cytokines (interleukin-6 and interleukin-18) were increased in the fasting state and/or decreased in some women during the oral glucose tolerance test, as opposed to inflammatory mediators such as macrophage migration inhibitory factor and matrix metallopeptidase-9 that increased during the oral glucose tolerance test especially in subjects with weight excess. Body mass index and waist circumference were the main determinants of these changes. Fasting pentraxin-3 levels were especially increased in lean women in parallel to a decrease in free testosterone levels, and decreased during the oral glucose tolerance test as opposed to the increase in insulin concentrations. The circulating concentrations of markers of low-grade chronic inflammation in young healthy adults are not only influenced by obesity but also by abdominal adiposity, fasting and glucose ingestion and, in some cases, by sex and sex hormones. These influences should be considered when these markers are used as surrogate markers of the inflammatory milieu associated with obesity. Copyright © 2016 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

Oral nanotherapeutics: Redox nanoparticles attenuate ultraviolet B radiation-induced skin inflammatory disorders in Kud:Hr- hairless mice.

PubMed

Feliciano, Chitho P; Nagasaki, Yukio

2017-10-01

The active participation of an anti-inflammatory drug in the biological pathways of inflammation is crucial for the achievement of beneficial and therapeutic effects. This study demonstrated the development of redox nanoparticles that can circulate in the blood at significantly high levels, thus increasing their efficacy as an oral treatment against the deleterious effects of reactive oxygen species (ROS) in an in vivo inflammatory skin model. To confirm the blood bioavailability of the nanoparticles, mice were injected with the nanoparticles solution (RNP N ) via oral gavage. Using electron spin resonance and radioactive labeling techniques, the blood circulation of the redox polymer that forms the nanoparticles was confirmed 24 h after oral administration. This contrasted with its low molecular weight counterpart (NH 2 -TEMPO), which peaked 15 min post injection and was found to be cleared rapidly within minutes after the peak. We then tested its efficacy in the inflammatory skin model. Kud:Hr-hairless mice were irradiated with UVB (302 nm) to induce skin damage and inflammation. Throughout the entire period of UVB irradiation, RNP N was administered to mice by free drinking. NH 2 -TEMPO was used as the control. The results showed that oral supplementation of RNP N significantly improved the therapeutic effects of the core nitroxide radical compared with its low molecular weight counterpart. Furthermore, RNP N significantly reduced UVB-induced skin aging, epidermal thickening, edema, erythema, skin lesions, and various pathological skin inflammatory disorders in vivo. From the obtained data, we concluded that the use of long-circulating redox nanoparticles (RNP N ) provided an effective treatment against the damaging effects of excessive ROS in the body. Copyright © 2017 Elsevier Ltd. All rights reserved.

Circulating Angiogenic Cells can be Derived from Cryopreserved Peripheral Blood Mononuclear Cells

PubMed Central

Sofrenovic, Tanja; McEwan, Kimberly; Crowe, Suzanne; Marier, Jenelle; Davies, Robbie; Suuronen, Erik J.; Kuraitis, Drew

2012-01-01

Background Cell transplantation for regenerative medicine has become an appealing therapeutic method; however, stem and progenitor cells are not always freshly available. Cryopreservation offers a way to freeze cells as they are generated, for storage and transport until required for therapy. This study was performed to assess the feasibility of cryopreserving peripheral blood mononuclear cells (PBMCs) for the subsequent in vitro generation of their derived therapeutic population, circulating angiogenic cells (CACs). Methods PBMCs were isolated from healthy human donors. Freshly isolated cells were either analyzed immediately or cryopreserved in media containing 6% plasma serum and 5% dimethyl sulfoxide. PBMCs were thawed after being frozen for 1 (early thaw) or 28 (late thaw) days and analyzed, or cultured for 4 days to generate CACs. Analysis of the cells consisted of flow cytometry for viability and phenotype, as well as functional assays for their adhesion and migration potential, cytokine secretion, and in vivo angiogenic potential. Results The viability of PBMCs and CACs as well as their adhesion and migration properties did not differ greatly after cryopreservation. Phenotypic changes did occur in PBMCs and to a lesser extent in CACs after freezing; however the potent CD34+VEGFR2+CD133+ population remained unaffected. The derived CACs, while exhibiting changes in inflammatory cytokine secretion, showed no changes in the secretion of important regenerative and chemotactic cytokines, nor in their ability to restore perfusion in ischemic muscle. Conclusion Overall, it appears that changes do occur in cryopreserved PBMCs and their generated CACs; however, the CD34+VEGFR2+CD133+ progenitor population, the secretion of pro-vasculogenic factors, and the in vivo angiogenic potential of CACs remain unaffected by cryopreservation. PMID:23133548

Hepatocyte-specific PPARA expression exclusively promotes agonist-induced cell proliferation without influence from nonparenchymal cells

PubMed Central

Brocker, Chad N.; Yue, Jiang; Kim, Donghwan; Qu, Aijuan; Bonzo, Jessica A.

2017-01-01

Peroxisome proliferator-activated receptor-α (PPARA) is a nuclear transcription factor and key mediator of systemic lipid metabolism. Prolonged activation in rodents causes hepatocyte proliferation and hepatocellular carcinoma. Little is known about the contribution of nonparenchymal cells (NPCs) to PPARA-mediated cell proliferation. NPC contribution to PPARA agonist-induced hepatomegaly was assessed in hepatocyte (Ppara△Hep)- and macrophage (Ppara△Mac)-specific Ppara null mice. Mice were treated with the agonist Wy-14643 for 14 days, and response of conditional null mice was compared with conventional knockout mice (Ppara−/−). Wy-14643 treatment caused weight loss and severe hepatomegaly in wild-type and Ppara△Mac mice, and histological analysis revealed characteristic hepatocyte swelling; Ppara△Hep and Ppara−/− mice were protected from these effects. Ppara△Mac serum chemistries, as well as aspartate aminotransferase and alanine aminotransferase levels, matched wild-type mice. Agonist-treated Ppara△Hep mice had elevated serum cholesterol, phospholipids, and triglycerides when compared with Ppara−/− mice, indicating a possible role for extrahepatic PPARA in regulating circulating lipid levels. BrdU labeling confirmed increased cell proliferation only in wild-type and Ppara△Mac mice. Macrophage PPARA disruption did not impact agonist-induced upregulation of lipid metabolism, cell proliferation, or DNA damage and repair-related gene expression, whereas gene expression was repressed in Ppara△Hep mice. Interestingly, downregulation of inflammatory cytokines IL-15 and IL-18 was dependent on macrophage PPARA. Cell type-specific regulation of target genes was confirmed in primary hepatocytes and Kupffer cells. These studies conclusively show that cell proliferation is mediated exclusively by PPARA activation in hepatocytes and that Kupffer cell PPARA has an important role in mediating the anti-inflammatory effects of PPARA agonists. PMID:28082284

Role of Non-Neuronal Cells in Body Weight and Appetite Control

PubMed Central

Argente-Arizón, Pilar; Freire-Regatillo, Alejandra; Argente, Jesús; Chowen, Julie A.

2015-01-01

The brain is composed of neurons and non-neuronal cells, with the latter encompassing glial, ependymal and endothelial cells, as well as pericytes and progenitor cells. Studies aimed at understanding how the brain operates have traditionally focused on neurons, but the importance of non-neuronal cells has become increasingly evident. Once relegated to supporting roles, it is now indubitable that these diverse cell types are fundamental for brain development and function, including that of metabolic circuits, and they may play a significant role in obesity onset and complications. They participate in processes of neurogenesis, synaptogenesis, and synaptic plasticity of metabolic circuits both during development and in adulthood. Some glial cells, such as tanycytes and astrocytes, transport circulating nutrients and metabolic factors that are fundamental for neuronal viability and activity into and within the hypothalamus. All of these cell types express receptors for a variety of metabolic factors and hormones, suggesting that they participate in metabolic function. They are the first line of defense against any assault to neurons. Indeed, microglia and astrocytes participate in the hypothalamic inflammatory response to high fat diet (HFD)-induced obesity, with this process contributing to inflammatory-related insulin and leptin resistance. Moreover, HFD-induced obesity and hyperleptinemia modify hypothalamic astroglial morphology, which is associated with changes in the synaptic inputs to neuronal metabolic circuits. Astrocytic contact with the microvasculature is increased by HFD intake and this could modify nutrient/hormonal uptake into the brain. In addition, progenitor cells in the hypothalamus are now known to have the capacity to renew metabolic circuits, and this can be affected by HFD intake and obesity. Here, we discuss our current understanding of how non-neuronal cells participate in physiological and physiopathological metabolic control. PMID:25859240

Systemic and myocardial inflammatory response in coronary artery bypass graft surgery with miniaturized extracorporeal circulation: differences with a standard circuit and off-pump technique in a randomized clinical trial.

PubMed

Formica, Francesco; Mariani, Silvia; Broccolo, Francesco; Caruso, Rosa; Corti, Fabrizio; D'Alessandro, Stefano; Amigoni, Pietro; Sangalli, Fabio; Paolini, Giovanni

2013-01-01

Inflammatory response and hemodilution are the main drawbacks of extracorporeal circulation. We hypothesize that the use of miniaturized extracorporeal circulation (MECC) might lower the systemic and myocardial inflammatory patterns compared with a standard system (SECC) and off-pump coronary artery bypass grafting (OPCABG). Sixty-one patients undergoing isolated coronary artery bypass graft were prospectively randomized to MECC (n = 19), SECC (n = 20), or OPCABG (n = 22). Blood samples were collected from radial artery and coronary sinus to analyze blood lactate, hemodilution, and markers for inflammation and endothelial activation such as tumor necrosis factor (TNF)-α, interleukin-6, monocyte chemotactic protein-1, and E-selectin. No differences were observed in early clinical outcome. Interleukin -6 levels increased in every group during and after cardiac surgery, whereas TNF-α values grew in the SECC group (p = 0.05). E-selectin systemic values decreased during and after operation (p = 0.001) in every group. Monocyte chemotactic protein-1 systemic and cardiac levels raised only in SECC group (p = 0.014). In conclusion, MECC is comparable to SECC and OPCABG in the clinical outcome of low-risk patients, and it might be extensively used with no additional intraoperative risk. The analysis of the inflammatory patterns of endothelial activation shows MECC as effective as OPCABG, suggesting further studies to clarify MECC recommendation in high-risk patients.

Mechanisms of Endothelial Dysfunction in Hypertensive Pregnancy and Preeclampsia

PubMed Central

Possomato-Vieira, José S.; Khalil, Raouf A.

2016-01-01

Preeclampsia is a pregnancy-related disorder characterized by hypertension, and could lead to maternal and fetal morbidity and mortality. Although the causative factors and pathophysiological mechanisms are unclear, endothelial dysfunction is a major hallmark of preeclampsia. Clinical tests and experimental research have suggested that generalized endotheliosis in the systemic, renal, cerebral and hepatic circulation could decrease endothelium-derived vasodilators such as nitric oxide, prostacyclin and hyperpolarization factor and increase vasoconstrictors such as endothelin-1 and thromboxane A2, leading to increased vasoconstriction, hypertension and other manifestation of preeclampsia. In search for the upstream mechanisms that could cause endothelial dysfunction, certain genetic, demographic and environmental risk factors have been suggested to cause abnormal expression of uteroplacental integrins, cytokines and matrix metalloproteinases, leading to decreased maternal tolerance, apoptosis of invasive trophoblast cells, inadequate spiral arteries remodeling, reduced uterine perfusion pressure (RUPP), and placental ischemia/hypoxia. RUPP may cause imbalance between the anti-angiogenic factors soluble fms-like tyrosine kinase-1 and soluble endoglin and the pro-angiogenic factors vascular endothelial growth factor and placental growth factor, or stimulate the release of other circulating bioactive factors such as inflammatory cytokines, hypoxia-inducible factor-1, reactive oxygen species, and angiotensin AT1 receptor agonistic autoantibodies. These circulating factors could then target endothelial cells and cause generalized endothelial dysfunction. Therapeutic options are currently limited, but understanding the factors involved in endothelial dysfunction could help design new approaches for prediction and management of preeclampsia. PMID:27451103

Sex differences in the effects of adolescent stress on adult brain inflammatory markers in rats

PubMed Central

Pyter, Leah M.; Kelly, Sean D.; Harrell, Constance S.; Neigh, Gretchen N.

2013-01-01

Both basic and clinical research indicates that females are more susceptible to stress-related affective disorders than males. One of the mechanisms by which stress induces depression is via inflammatory signaling in the brain. Stress during adolescence, in particular, can also disrupt the activation and continued development of both the hypothalamic–pituitary–adrenal (HPA) and –gonadal (HPG) axes, both of which modulate inflammatory pathways and brain regions involved in affective behavior. Therefore, we tested the hypothesis that adolescent stress differentially alters brain inflammatory mechanisms associated with affective-like behavior into adulthood based on sex. Male and female Wistar rats underwent mixed-modality stress during adolescence (PND 37–48) and were challenged with lipopolysaccharide (LPS; 250 μg/kg, i.p.) or saline 4.5 weeks later (in adulthood). Hippocampal inflammatory marker gene expression and circulating HPA and HPG axes hormone concentrations were then determined. Despite previous studies indicating that adolescent stress induces affective-like behaviors in female rats only, this study demonstrated that adolescent stress increased hippocampal inflammatory responses to LPS in males only, suggesting that differences in neuroinflammatory signaling do not drive the divergent affective-like behaviors. The sex differences in inflammatory markers were not associated with differences in corticosterone. In females that experienced adolescent stress, LPS increased circulating estradiol. Estradiol positively correlated with hippocampal microglial gene expression in control female rats, whereas adolescent stress negated this relationship. Thus, estradiol in females may potentially protect against stress-induced increases in neuroinflammation. PMID:23348027

Circulating milk fat globule-epidermal growth factor 8 levels are increased in pregnancy and gestational diabetes mellitus.

PubMed

Li, Yuanyuan; Ran, Wenzhuo; Zhang, Jiaqiang; Chen, Shi; Li, Yihang; Luo, Deng; Wang, Chen; Jia, Weiping

2017-07-01

Milk fat globule-epidermal growth factor 8 (MFG-E8) is the key mediator in anti-inflammatory responses that facilitate phagocytosis of apoptotic cells, and play an essential role in type 2 diabetes and pregnancy, both of which are under a low-grade inflammatory state. However, the action of MFG-E8 in gestational diabetes mellitus (GDM) is unclear. We measured plasma MFG-E8 levels in pregnancy and GDM for the first time, and elucidated possible relationships between its plasma levels and various metabolic parameters. Plasma MFG-E8 levels were quantified by enzyme-linked immunosorbent assay in 66 women with GDM, 70 with normal pregnancy (p-NGT) and 44 healthy non-pregnant controls (CON), who were matched for age and body mass index. Inflammatory factors tumor necrosis factor-α (TNF-α) and C-reactive protein levels were measured, oral glucose tolerance test was carried out and β-cell function was evaluated. Plasma MFG-E8 levels were remarkably higher in p-NGT than in CON (P = 0.024), and were further elevated in GDM vs p-NGT (P = 0.016). MFG-E8 concentrations correlated positively with hemoglobin A1c, glucose levels and insulin resistance (homeostasis model assessment for insulin resistance), and correlated inversely with TNF-α and insulin secretion evaluated by disposition indices in pregnancies. Fasting glucose levels, disposition index of first phase insulin secretion and TNF-α were independent predictors of MFG-E8 levels in pregnancies. Logistic regression analyses showed that women in the third tertile of MFG-E8 levels had a markedly elevated risk of GDM. Circulating MFG-E8 levels are dramatically elevated in pregnancy, and are significantly higher in GDM vs p-NGT. MFG-E8 concentrations are significantly associated with TNF-α, fasting glucose levels, homeostasis model assessment for insulin resistance and disposition indices. However, further studies are required to elucidate the regulation mechanism of MFG-E8 during pregnancy and GDM. © 2016 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.

Circulating interleukin-6 and high-sensitivity C-reactive protein decrease after periodontal therapy in otherwise healthy subjects.

PubMed

Marcaccini, Andrea M; Meschiari, César A; Sorgi, Carlos A; Saraiva, Maria C P; de Souza, Ana M; Faccioli, Lúcia H; Tanus-Santos, José E; Novaes, Arthur B; Gerlach, Raquel F

2009-04-01

Periodontal disease has been associated with many chronic inflammatory systemic diseases, and a common chronic inflammation pathway has been suggested for these conditions. However, few studies have evaluated whether periodontal disease, in the absence of other known inflammatory conditions and smoking, affects circulating markers of chronic inflammation. This study compared chronic inflammation markers in control individuals and patients with periodontal disease and observed whether non-surgical periodontal therapy affected inflammatory disease markers after 3 months. Plasma and serum of 20 controls and 25 patients with periodontal disease were obtained prior to and 3 months after non-surgical periodontal therapy. All patients were non-smokers, they did not use any medication, and they had no history or detectable signs and symptoms of systemic diseases. Periodontal and systemic parameters included probing depth, bleeding on probing, clinical attachment level, hematologic parameters, as well as the following inflammatory markers: interleukin (IL)-6, high-sensitivity C-reactive protein (hs-CRP), CD40 ligand, monocyte chemoattractant protein (MCP)-1, soluble P-selectin (sP-selectin), soluble vascular adhesion molecule (sVCAM)-1, and soluble intercellular adhesion molecule (sICAM)-1. There were no differences in the hematologic parameters of the patients in the control and periodontal disease groups. Among the tested inflammatory markers, IL-6 concentrations were higher in the periodontal disease group at baseline compared to the controls (P = 0.006). Therapy was highly effective (P <0.001 for all the analyzed clinical parameters), and a decrease in circulating IL-6 and hs-CRP concentrations was observed 3 months after therapy (P = 0.001 and P = 0.006, respectively). Our results also suggest that the CD40 ligand marker may have been different in the control and periodontal disease groups prior to the therapy (P = 0.009). In apparently otherwise healthy patients, periodontal disease is associated with increased circulating concentrations of IL-6 and hs-CRP, which decreased 3 months after non-surgical periodontal therapy. With regard to the CD40 ligand, MCP-1, sP-selectin, sVCAM-1, and sICAM-1, no changes were seen in the periodontal disease group between baseline and 3 months after therapy.

Systemic influences contribute to prolonged microvascular rarefaction after brain irradiation: a role for endothelial progenitor cells

PubMed Central

Ashpole, Nicole M.; Warrington, Junie P.; Mitschelen, Matthew C.; Yan, Han; Sosnowska, Danuta; Gautam, Tripti; Farley, Julie A.; Csiszar, Anna; Ungvari, Zoltan

2014-01-01

Whole brain radiation therapy (WBRT) induces profound cerebral microvascular rarefaction throughout the hippocampus. Despite the vascular loss and localized cerebral hypoxia, angiogenesis fails to occur, which subsequently induces long-term deficits in learning and memory. The mechanisms underlying the absence of vessel recovery after WBRT are unknown. We tested the hypotheses that vascular recovery fails to occur under control conditions as a result of loss of angiogenic drive in the circulation, chronic tissue inflammation, and/or impaired endothelial cell production/recruitment. We also tested whether systemic hypoxia, which is known to promote vascular recovery, reverses these chronic changes in inflammation and endothelial cell production/recruitment. Ten-week-old C57BL/6 mice were subjected to a clinical series of fractionated WBRT: 4.5-Gy fractions 2 times/wk for 4 wk. Plasma from radiated mice increased in vitro endothelial cell proliferation and adhesion compared with plasma from control mice, indicating that WBRT did not suppress the proangiogenic drive. Analysis of cytokine levels within the hippocampus revealed that IL-10 and IL-12(p40) were significantly increased 1 mo after WBRT; however, systemic hypoxia did not reduce these inflammatory markers. Enumeration of endothelial progenitor cells (EPCs) in the bone marrow and circulation indicated that WBRT reduced EPC production, which was restored with systemic hypoxia. Furthermore, using a bone marrow transplantation model, we determined that bone marrow-derived endothelial-like cells home to the hippocampus after systemic hypoxia. Thus, the loss of production and homing of EPCs have an important role in the prolonged vascular rarefaction after WBRT. PMID:25038144

Receptors, mediators, and mechanisms involved in bacterial sepsis and septic shock.

PubMed

Van Amersfoort, Edwin S; Van Berkel, Theo J C; Kuiper, Johan

2003-07-01

Bacterial sepsis and septic shock result from the overproduction of inflammatory mediators as a consequence of the interaction of the immune system with bacteria and bacterial wall constituents in the body. Bacterial cell wall constituents such as lipopolysaccharide, peptidoglycans, and lipoteichoic acid are particularly responsible for the deleterious effects of bacteria. These constituents interact in the body with a large number of proteins and receptors, and this interaction determines the eventual inflammatory effect of the compounds. Within the circulation bacterial constituents interact with proteins such as plasma lipoproteins and lipopolysaccharide binding protein. The interaction of the bacterial constituents with receptors on the surface of mononuclear cells is mainly responsible for the induction of proinflammatory mediators by the bacterial constituents. The role of individual receptors such as the toll-like receptors and CD14 in the induction of proinflammatory cytokines and adhesion molecules is discussed in detail. In addition, the roles of a number of other receptors that bind bacterial compounds such as scavenger receptors and their modulating role in inflammation are described. Finally, the therapies for the treatment of bacterial sepsis and septic shock are discussed in relation to the action of the aforementioned receptors and proteins.

Circulating exosomes from patients with systemic lupus erythematosus induce an proinflammatory immune response.

PubMed

Lee, Joo Youn; Park, Jin Kyun; Lee, Eun Young; Lee, Eun Bong; Song, Yeong Wook

2016-11-16

Exosomes are involved in intercellular communication. The aim of this study was to investigate whether circulating exosomes effectively contribute to the inflammatory response in systemic lupus erythematosus (SLE). Exosomes were purified from SLE patients and healthy controls (HCs). Healthy peripheral blood mononuclear cells (PBMCs) were stimulated with exosomes isolated from SLE patients and HCs in the presence or absence of Toll-like receptor (TLR) inhibitors. Production of interferon (IFN)-α, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 were measured. Correlation between exosome levels and SLE disease activity was examined. The serum exosomes levels were significantly higher in SLE patients than in HCs. SLE exosomes induced a higher production of IFN-α, TNF-α, IL-1β, and IL-6 compared to healthy exosomes. SLE serum that was depleted of exosomes and SLE exosomes that were mechanically disrupted failed to induce any significant cytokine production. Exosome-mediated production of TNF-α, IL-1β, and IL-6 was decreased by the TLR4 antagonist, whereas that of IFN-α was suppressed by the TLR1/2, TLR7, and TLR9 antagonists. Exosome levels correlated with disease activity in SLE patients (rho = 0.846, p = 0.008). The circulating exosomes are immunologically active and their levels correlate with disease activity in SLE patients. The circulating exosomes might serve as novel biomarkers of SLE disease activity.

Preferential Elimination of Older Erythrocytes in Circulation and Depressed Bone Marrow Erythropoietic Activity Contribute to Cadmium Induced Anemia in Mice

PubMed Central

Chatterjee, Sreoshi; Saxena, Rajiv K.

2015-01-01

Feeding cadmium chloride (50 or 1000 ppm CdCl2 in drinking water, ad libitum) to C57BL/6 mice resulted in a significant and sustained fall in blood erythrocyte count and hemoglobin levels that started 4 and 3 weeks after the start of 50 and 1000 ppm cadmium doses respectively. A transient yet significant reticulocytosis occurred during the first 4 weeks of cadmium treatment. Using the recently developed double in vivo biotinylation (DIB) technique, turnover of erythrocyte cohorts of different age groups was simultaneously monitored in control and cadmium treated mice. A significant accumulation of younger erythrocytes and a concomitant decline in the relative proportions of older erythrocytes in circulation was observed in both 50 and 1000 ppm cadmium groups indicating that older erythrocytes were preferentially eliminated in cadmium induced anemia. A significant increase in the erythropoietin levels in plasma was seen in mice exposed to 1000 ppm cadmium. Levels of inflammatory cytokines (IL1A, IL6, TNFα, IFNγ) were however not significantly altered in cadmium treated mice. A significant increase in cellular levels of reactive oxygen species (ROS) was observed in older erythrocytes in circulation but not in younger erythrocytes. Erythropoietic activity in the bone marrows and spleens of cadmium treated mice was examined by monitoring the relative proportion of cells belonging to the erythroid line of differentiation in these organs. Erythroid cells in bone marrow declined markedly (about 30%) in mice in the 1000 ppm cadmium group but the decline was not significant in the 50 ppm cadmium group. Cells representing various stages of erythroid differentiation in bone marrow and spleen were enumerated flow cytometrically by double staining with anti-Ter119 and anti-transferrin receptor (CD71) monoclonal antibodies. Decline of erythroid cells was essentially confined to pro-erythroblast and erythroblast-A, along with a concurrent increase in the splenic erythroid population indicating a stress response. In short cadmium exposure causes preferential clearance of older erythrocytes from circulation along with a depressed erythropoietic activity at higher doses. PMID:26161863

Inflammatory and bone turnover markers in relation to PTH and vitamin D status among saudi postmenopausal women with and without osteoporosis

PubMed Central

Al-Daghri, Nasser M; Yakout, Sobhy; Al-Shehri, Eman; Al-Fawaz, Hanan A; Aljohani, Naji; Al-Saleh, Yousef

2014-01-01

Postmenopausal osteoporosis is characterized by rapid bone loss occurring in the post-menopausal period. The bone loss predominantly involves the trabecular bone and is brought about by an imbalance between the bone remodeling process which can be influenced by factors that could cause or contribute to osteoporosis. Pro-inflammatory cytokines (Il-1β, Il-6, IL-8 and TNF-α) have been implicated in the regulation of bone cells and play a critical role in bone remodeling. They act both directly and indirectly to increase bone resorption, and/or inhibit bone formation. The aim of the study is to determine whether pro-inflammatory cytokines correlate with bone turnover markers (BTM) in a cohort of Saudi post-menopausal women with or without osteoporosis and which BTMs will correlate with PTH and Vitamin D for use in osteoporosis diagnosis. The study is composed of 100 post-menopausal patients and 100 controls aged around 50 years. Serum concentrations of pro-inflammatory and BTMs as well as PTH and vitamin D were determined by ELISA, Luminex and electrochemiluminescence. Serum calcium, phosphorus, glucose, and lipid profile were measured by using a chemical analyzer. There was a significant increase in the levels of pro-inflammatory cytokines, PTH, CTx, and glucose. A significantly lower vitamin D and osteocalcin levels were observed in subjects with osteoporosis than those without. No significant differences were recorded in the circulating lipid profile between groups. The present study proved that the pro-inflammatory cytokines accelerate the bone loss in postmenopausal women. PMID:25419393

Inflammatory and bone turnover markers in relation to PTH and vitamin D status among Saudi postmenopausal women with and without osteoporosis

PubMed Central

Al-Daghri, Nasser M; Yakout, Sobhy; Al-Shehri, Eman; Al-Fawaz, Hanan; Aljohani, Naji; Al-Saleh, Yousef

2014-01-01

Postmenopausal osteoporosis is characterized by rapid bone loss occurring in the post-menopausal period. The bone loss predominantly involves the trabecular bone and is brought about by an imbalance between the bone remodeling process which can be influenced by factors that could cause or contribute to osteoporosis. Pro-inflammatory cytokines (Il-1β, Il-6, IL-8 and TNF-α) have been implicated in the regulation of bone cells and play a critical role in bone remodeling. They act both directly and indirectly to increase bone resorption, and/or inhibit bone formation. The aim of the study is to determine whether pro-inflammatory cytokines correlate with bone turnover markers (BTM) in a cohort of Saudi post-menopausal women with or without osteoporosis and which BTMs will correlate with PTH and Vitamin D for use in osteoporosis diagnosis. The study is composed of 100 post-menopausal patients and 100 controls aged 50 years and above. Serum concentrations of pro-inflammatory and BTMs as well as PTH and vitamin D were determined by ELISA, Luminex and electrochemiluminescence. Serum calcium, phosphorus, glucose, and lipid profile were measured by using a chemical analyzer. There was a significant increase in the levels of pro-inflammatory cytokines, PTH, CTx, and glucose. A significantly lower vitamin D and osteocalcin levels were observed in subjects with osteoporosis than those without. No significant differences were recorded in the circulating lipid profile between groups. The present study proved that the pro-inflammatory cytokines accelerate the bone loss in postmenopausal women. PMID:25356143

Mesenteric Th1 polarization and monocyte TNF-alpha production: first steps to systemic inflammation in rats with cirrhosis.

PubMed

Muñoz, Leticia; Albillos, Agustín; Nieto, Mónica; Reyes, Eduardo; Lledó, Lourdes; Monserrat, Jorge; Sanz, Eva; de la Hera, Antonio; Alvarez-Mon, Melchor

2005-08-01

A systemic inflammatory state with increased circulating tumor necrosis factor alpha (TNF-alpha) has been related to the bacterial infection susceptibility and hemodynamic derangement of patients with cirrhosis. We compared the activation status of immune cell subpopulations defined by 4-color cytometry in mesenteric and peripheral lymph nodes and blood of rats with CCl(4)-cirrhosis to define the immune response initiation site, the T-cell and monocyte contribution to pro-inflammatory cytokine production, as well as the pathogenic role of enteric bacteria in the cirrhosis immune response. Th1 cells and monocytes were expanded in the mesenteric nodes (P < .001) and blood (P < .001) of rats with cirrhosis, and activated to produce interferon gamma (P < .0001) and TNF-alpha (P < .0001), respectively. The greater numbers of recently activated CD134(+) Th cells in mesenteric nodes compared with blood, the correlation between their numbers in mesenteric nodes and blood (r = 0.66, P < .001), and the expansion of activated CD45RC(-) Th cells, which are unable to re-enter lymph nodes, in mesenteric nodes but not in blood or axillary nodes points to mesenteric nodes as the origin site of activated Th cells. Abrogation of bacterial translocation by bowel decontamination reduced the number of activated Th cells and monocytes, and normalized interferon gamma production by Th cells and TNF-alpha production by monocytes in mesenteric nodes and blood, respectively. In conclusion, in cirrhosis, enteric bacteria start off an orchestrated immune response cascade in mesenteric nodes involving Th1 polarization and monocyte activation to TNF-alpha production. Later, the recirculation of these activated effector immune cells into blood promotes systemic inflammation.

Evidence of functional cell-mediated immune responses to nontypeable Haemophilus influenzae in otitis-prone children

PubMed Central

Seppanen, Elke; Tan, Dino; Corscadden, Karli J.; Currie, Andrew J.; Richmond, Peter C.; Thornton, Ruth B.

2018-01-01

Otitis media (OM) remains a common paediatric disease, despite advances in vaccinology. Susceptibility to recurrent acute OM (rAOM) has been postulated to involve defective cell-mediated immune responses to common otopathogenic bacteria. We compared the composition of peripheral blood mononuclear cells (PBMC) from 20 children with a history of rAOM (otitis-prone) and 20 healthy non-otitis-prone controls, and assessed innate and cell-mediated immune responses to the major otopathogen nontypeable Haemophilus influenzae (NTHi). NTHi was a potent stimulator of inflammatory cytokine secretion from PBMC within 4 hours, with no difference in cytokine levels produced between PBMC from cases or controls. In the absence of antigen stimulation, otitis-prone children had more circulating Natural Killer (NK) cells (p<0.01), particularly NKdim (CD56lo) cells (p<0.01), but fewer CD4+ T cells (p<0.01) than healthy controls. NTHi challenge significantly increased the proportion of activated (CD107a+) NK cells in otitis-prone and non-otitis-prone children (p<0.01), suggesting that NK cells from otitis-prone children are functional and respond to NTHi. CD8+ T cells and NK cells from both cases and controls produced IFNγ in response to polyclonal stimulus (Staphylococcal enterotoxin B; SEB), with more IFNγ+ CD8+ T cells present in cases than controls (p<0.05) but similar proportions of IFNγ+ NK cells. Otitis-prone children had more circulating IFNγ-producing NK cells (p<0.05) and more IFNγ-producing CD4+ (p<0.01) or CD8+ T-cells (p<0.05) than healthy controls. In response to SEB, more CD107a-expressing CD8+ T cells were present in cases than controls (p<0.01). Despite differences in PBMC composition, PBMC from otitis-prone children mounted innate and T cell-mediated responses to NTHi challenge that were comparable to healthy children. These data provide evidence that otitis-prone children do not have impaired functional cell mediated immunity. PMID:29621281

Preferential Reduction of Circulating Innate Lymphoid Cells Type 2 in Patients with Common Variable Immunodeficiency with Secondary Complications Is Part of a Broader Immune Dysregulation.

PubMed

Friedmann, David; Keller, Baerbel; Harder, Ina; Schupp, Jonas; Tanriver, Yakup; Unger, Susanne; Warnatz, Klaus

2017-11-01

Over a third of patients with common variable immunodeficiency (CVID) suffer from secondary complications like inflammatory organ disease, autoimmune manifestations, or lymphoproliferation contributing to increased morbidity and mortality in affected patients. Innate lymphoid cells (ILCs) have emerging roles in setting the milieu for physiological, but also pathological, immune responses and inflammation. We therefore sought to correlate the recently identified disturbed homeostasis of ILCs with alterations of the adaptive immune system in complex CVID patients (CVIDc). We quantified peripheral blood ILC and T helper cell subsets of 58 CVID patients by flow cytometry and compared the results to the clinical and immunological phenotype. Total ILCs were significantly reduced in peripheral blood of CVIDc patients compared to healthy individuals, but not to CVID patients who suffered only from infections (CVIDio). This reduction was mainly due to a decrease in ILC2s, while ILC3s were relatively increased in CVIDc compared to CVIDio patients. This alteration in ILC phenotype was more prominent in patients with an expansion of CD21 low B cells, but we could not detect an association of the altered ILC phenotype with a T H 1-shift among circulating CD4 T cells, which was also prominent in CVIDc patients. We confirm a relative shift in ILCs of CVIDc patients towards ILC3s which was associated with the expansion of CD21 low B cells, but not overtly with the relative expansion of T H 1-like T cells. Given the relative abundance of T H 1-like T cells compared to ILCs, these probably represent a more prominent source of the observed IFNγ-signature in CVIDc patients.

Evidence for Anti-Inflammatory Effects of Exercise in CKD

PubMed Central

Kosmadakis, George C.; Watson, Emma L.; Bevington, Alan; Feehally, John; Bishop, Nicolette C.; Smith, Alice C.

2014-01-01

CKD is associated with a complex state of immune dysfunction characterized by immune depression, predisposing patients to infections, and immune activation, resulting in inflammation that associates with higher risk of cardiovascular disease. Physical exercise may enhance immune function and exert anti-inflammatory effects, but such effects are unclear in CKD. We investigated the separate effects of acute and regular moderate-intensity aerobic exercise on neutrophil degranulation (elastase release), activation of T lymphocytes (CD69 expression) and monocytes (CD86 and HLA-DR expression), and plasma inflammatory markers (IL-6, IL-10, soluble TNF-receptors, and C-reactive protein) in patients with predialysis CKD. A single 30-minute (acute) bout of walking induced a normal pattern of leukocyte mobilization and had no effect on T-lymphocyte and monocyte activation but improved neutrophil responsiveness to a bacterial challenge in the postexercise period. Furthermore, acute exercise induced a systemic anti-inflammatory environment, evidenced by a marked increase in plasma IL-10 levels (peaked at 1 hour postexercise), that was most likely mediated by increased plasma IL-6 levels (peaked immediately postexercise). Six months of regular walking exercise (30 min/d for 5 times/wk) exerted anti-inflammatory effects (reduction in the ratio of plasma IL-6 to IL-10 levels) and a downregulation of T-lymphocyte and monocyte activation, but it had no effect on circulating immune cell numbers or neutrophil degranulation responses. Renal function, proteinuria, and BP were also unaffected. These findings provide compelling evidence that walking exercise is safe with regard to immune and inflammatory responses and has the potential to be an effective anti-inflammatory therapy in predialysis CKD. PMID:24700875

Yoga and immune system functioning: a systematic review of randomized controlled trials.

PubMed

Falkenberg, R I; Eising, C; Peters, M L

2018-02-10

Yoga is an ancient mind-body practice that is increasingly recognized to have health benefits in a variety of clinical and non-clinical conditions. This systematic review summarizes the findings of randomized controlled trials examining the effects of yoga on immune system functioning which is imperative to justify its application in the clinic. Fifteen RCTs were eligible for the review. Even though the existing evidence is not entirely consistent, a general pattern emerged suggesting that yoga can downregulate pro-inflammatory markers. In particular, the qualitative evaluation of RCTs revealed decreases in IL-1beta, as well as indications for reductions in IL-6 and TNF-alpha. These results imply that yoga may be implemented as a complementary intervention for populations at risk or already suffering from diseases with an inflammatory component. Beyond this, yoga practice may exert further beneficial effects by enhancing cell-mediated and mucosal immunity. It is hypothesized that longer time spans of yoga practice are required to achieve consistent effects especially on circulating inflammatory markers. Overall, this field of investigation is still young, hence the current body of evidence is small and for most immune parameters, more research is required to draw distinct conclusions.

Immune and Neuroendocrine Mechanisms of Stress Vulnerability and Resilience

PubMed Central

Ménard, Caroline; Pfau, Madeline L; Hodes, Georgia E; Russo, Scott J

2017-01-01

Diagnostic criteria for mood disorders including major depressive disorder (MDD) largely ignore biological factors in favor of behavioral symptoms. Compounding this paucity of psychiatric biomarkers is a need for therapeutics to adequately treat the 30–50% of MDD patients who are unresponsive to traditional antidepressant medications. Interestingly, MDD is highly prevalent in patients suffering from chronic inflammatory conditions, and MDD patients exhibit higher levels of circulating pro-inflammatory cytokines. Together, these clinical findings suggest a role for the immune system in vulnerability to stress-related psychiatric illness. A growing body of literature also implicates the immune system in stress resilience and coping. In this review, we discuss the mechanisms by which peripheral and central immune cells act on the brain to affect stress-related neurobiological and neuroendocrine responses. We specifically focus on the roles of pro-inflammatory cytokine signaling, peripheral monocyte infiltration, microglial activation, and hypothalamic-pituitary-adrenal axis hyperactivity in stress vulnerability. We also highlight recent evidence suggesting that adaptive immune responses and treatment with immune modulators (exogenous glucocorticoids, humanized antibodies against cytokines) may decrease depressive symptoms and thus represent an attractive alternative to the current antidepressant treatments. PMID:27291462

Hepatic JAK2 protects against atherosclerosis through circulating IGF-1

PubMed Central

Sivasubramaniyam, Tharini; Schroer, Stephanie A.; Li, Angela; Luk, Cynthia T.; Shi, Sally Yu; Besla, Rickvinder; Metherel, Adam H.; Kitson, Alex P.; Brunt, Jara J.; Lopes, Joshua; Wagner, Kay-Uwe; Bazinet, Richard P.; Bendeck, Michelle P.; Robbins, Clinton S.

2017-01-01

Atherosclerosis is considered both a metabolic and inflammatory disease; however, the specific tissue and signaling molecules that instigate and propagate this disease remain unclear. The liver is a central site of inflammation and lipid metabolism that is critical for atherosclerosis, and JAK2 is a key mediator of inflammation and, more recently, of hepatic lipid metabolism. However, precise effects of hepatic Jak2 on atherosclerosis remain unknown. We show here that hepatic Jak2 deficiency in atherosclerosis-prone mouse models exhibited accelerated atherosclerosis with increased plaque macrophages and decreased plaque smooth muscle cell content. JAK2’s essential role in growth hormone signalling in liver that resulted in reduced IGF-1 with hepatic Jak2 deficiency played a causal role in exacerbating atherosclerosis. As such, restoring IGF-1 either pharmacologically or genetically attenuated atherosclerotic burden. Together, our data show hepatic Jak2 to play a protective role in atherogenesis through actions mediated by circulating IGF-1 and, to our knowledge, provide a novel liver-centric mechanism in atheroprotection. PMID:28724798

Shear Stress Enhances Chemokine Secretion from Chlamydia pneumoniae-infected Monocytes.

PubMed

Evani, Shankar J; Dallo, Shatha F; Murthy, Ashlesh K; Ramasubramanian, Anand K

2013-09-01

Chlamydia pneumoniae is a common respiratory pathogen that is considered a highly likely risk factor for atherosclerosis. C. pneumoniae is disseminated from the lung into systemic circulation via infected monocytes and lodges at the atherosclerotic sites. During transit, C. pneumoniae -infected monocytes in circulation are subjected to shear stress due to blood flow. The effect of mechanical stimuli on infected monocytes is largely understudied in the context of C. pneumoniae infection and inflammation. We hypothesized that fluid shear stress alters the inflammatory response of C. pneumoniae -infected monocytes and contributes to immune cell recruitment to the site of tissue damage. Using an in vitro model of blood flow, we determined that a physiological shear stress of 7.5 dyn/cm 2 for 1 h on C. pneumoniae -infected monocytes enhances the production of several chemokines, which in turn is correlated with the recruitment of significantly large number of monocytes. Taken together, these results suggest synergistic interaction between mechanical and chemical factors in C. pneumoniae infection and associated inflammation.

CD47 Promotes Protective Innate and Adaptive Immunity in a Mouse Model of Disseminated Candidiasis

PubMed Central

Navarathna, Dhammika H. M. L. P.; Stein, Erica V.; Lessey-Morillon, Elizabeth C.; Nayak, Debasis; Martin-Manso, Gema; Roberts, David D.

2015-01-01

CD47 is a widely expressed receptor that regulates immunity by engaging its counter-receptor SIRPα on phagocytes and its secreted ligand thrombospondin-1. Mice lacking CD47 can exhibit enhanced or impaired host responses to bacterial pathogens, but its role in fungal immunity has not been examined. cd47 -/- mice on a C57BL/6 background showed significantly increased morbidity and mortality following Candida albicans infection when compared with wild-type mice. Despite normal fungal colonization at earlier times, cd47 -/- mice at four days post-infection had increased colonization of brain and kidneys accompanied by stronger inflammatory reactions. Neutrophil and macrophage numbers were significantly elevated in kidneys and neutrophils in the brains of infected cd47 -/- mice. However, no defect in phagocytic activity towards C. albicans was observed in cd47 -/- bone-marrow-derived macrophages, and neutrophil and macrophage killing of C. albicans was not impaired. CD47-deficiency did not alter the early humoral immune response to C. albicans. Th1, Th2, and Th17 population of CD4+ T cells were expanded in the spleen, and gene expression profiles of spleen and kidney showed stronger pro-inflammatory signaling in infected cd47 -/- mice. The chemoattractant chemokines MIP-2α and MIP-2β were highly expressed in infected spleens of cd47 -/- mice. G-CSF, GM-CSF, and the inflammasome component NLRP3 were more highly expressed in infected cd47 -/- kidneys than in infected wild-type controls. Circulating pro- (TNF-α, IL-6) and anti-inflammatory cytokines (IL-10) were significantly elevated, but IL-17 was decreased. These data indicate that CD47 plays protective roles against disseminated candidiasis and alters pro-inflammatory and immunosuppressive pathways known to regulate innate and T cell immunity. PMID:26010544

Modulating the Biologic Activity of Mesenteric Lymph after Traumatic Shock Decreases Systemic Inflammation and End Organ Injury.

PubMed

Langness, Simone; Costantini, Todd W; Morishita, Koji; Eliceiri, Brian P; Coimbra, Raul

2016-01-01

Trauma/hemorrhagic shock (T/HS) causes the release of pro-inflammatory mediators into the mesenteric lymph (ML), triggering a systemic inflammatory response and acute lung injury (ALI). Direct and pharmacologic vagal nerve stimulation prevents gut barrier failure and alters the biologic activity of ML after injury. We hypothesize that treatment with a pharmacologic vagal agonist after T/HS would attenuate the biologic activity of ML and prevent ALI. ML was collected from male Sprague-Dawley rats after T/HS, trauma-sham shock (T/SS) or T/HS with administration of the pharmacologic vagal agonist CPSI-121. ML samples from each experimental group were injected into naïve mice to assess biologic activity. Blood samples were analyzed for changes in STAT3 phosphorylation (pSTAT3). Lung injury was characterized by histology, permeability and immune cell recruitment. T/HS lymph injected in naïve mice caused a systemic inflammatory response characterized by hypotension and increased circulating monocyte pSTAT3 activity. Injection of T/HS lymph also resulted in ALI, confirmed by histology, lung permeability and increased recruitment of pulmonary macrophages and neutrophils to lung parenchyma. CPSI-121 attenuated T/HS lymph-induced systemic inflammatory response and ALI with stable hemodynamics and similar monocyte pSTAT3 levels, lung histology, lung permeability and lung immune cell recruitment compared to animals injected with lymph from T/SS. Treatment with CPSI-121 after T/HS attenuated the biologic activity of the ML and decreased ALI. Given the superior clinical feasibility of utilizing a pharmacologic approach to vagal nerve stimulation, CPSI-121 is a potential treatment strategy to limit end organ dysfunction after injury.

A Critical Role for Monocytes/Macrophages During Intestinal Inflammation-associated Lymphangiogenesis

PubMed Central

Becker, Felix; Kurmaeva, Elvira; Gavins, Felicity N. E.; Stevenson, Emily V.; Navratil, Aaron R.; Jin, Long; Tsunoda, Ikuo; Orr, A. Wayne; Alexander, Jonathan S.; Ostanin, Dmitry V.

2016-01-01

Background Inflammation-associated lymphangiogenesis (IAL) is frequently observed in inflammatory bowel diseases. IAL is believed to limit inflammation by enhancing fluid and immune cell clearance. Although monocytes/macrophages (MΦ) are known to contribute to intestinal pathology in inflammatory bowel disease, their role in intestinal IAL has never been studied mechanistically. We investigated contributions of monocytes/MΦ to the development of intestinal inflammation and IAL. Methods Because inflammatory monocytes express CC chemokine receptor 2 (CCR2), we used CCR2 diphtheria toxin receptor transgenic (CCR2.DTR) mice, in which monocytes can be depleted by diphtheria toxin injection, and CCR2−/− mice, which have reduced circulating monocytes. Acute or chronic colitis was induced by dextran sodium sulfate or adoptive transfer of CD4+CD45RBhigh T cells, respectively. Intestinal inflammation was assessed by flow cytometry, immunofluorescence, disease activity, and histopathology, whereas IAL was assessed by lymphatic vessel morphology and density. Results We demonstrated that intestinal MΦ expressed vascular endothelial growth factor-C/D. In acute colitis, monocyte-depleted mice were protected from intestinal injury and showed reduced IAL, which was reversed after transfer of wild-type monocytes into CCR2−/− mice. In chronic colitis, CCR2 deficiency did not attenuate inflammation but reduced IAL. Conclusions We propose a dual role of MΦ in (1) promoting acute inflammation and (2) contributing to IAL. Our data suggest that intestinal inflammation and IAL could occur independently, because IAL was reduced in the absence of monocytes/MΦ, even when inflammation was present. Future inflammatory bowel disease therapies might exploit promotion of IAL and suppression of MΦ independently, to restore lymphatic clearance and reduce inflammation. PMID:26950310

S100A8/A9 increases the mobilization of pro-inflammatory Ly6Chigh monocytes to the synovium during experimental osteoarthritis.

PubMed

Cremers, Niels A J; van den Bosch, Martijn H J; van Dalen, Stephanie; Di Ceglie, Irene; Ascone, Giuliana; van de Loo, Fons; Koenders, Marije; van der Kraan, Peter; Sloetjes, Annet; Vogl, Thomas; Roth, Johannes; Geven, Edwin J W; Blom, Arjen B; van Lent, Peter L E M

2017-09-29

Monocytes are dominant cells present within the inflamed synovium during osteoarthritis (OA). In mice, two functionally distinct monocyte subsets are described: pro-inflammatory Ly6C high and patrolling Ly6C low monocytes. Alarmins S100A8/A9 locally released by the synovium during inflammatory OA for prolonged periods may be dominant proteins involved in stimulating recruitment of Ly6C high monocytes from the circulation to the joint. Our objective was to investigate the role of S100A8/A9 in the mobilization of Ly6C high and Ly6C low monocytic populations to the inflamed joint in collagenase-induced OA (CiOA). S100A8 was injected intra-articularly to investigate monocyte influx. CiOA was induced by injection of collagenase into knee joints of wild-type C57BL/6 (WT), and S100a9 -/- mice. Mice were sacrificed together with age-matched saline-injected control mice (n = 6/group), and expression of monocyte markers, pro-inflammatory cytokines, and chemokines was determined in the synovium using ELISA and RT-qPCR. Cells were isolated from the bone marrow (BM), spleen, blood, and synovium and monocytes were identified using FACS. S100A8/A9 was highly expressed during CiOA. Intra-articular injection of S100A8 leads to elevated expression of monocyte markers and the monocyte-attracting chemokines CCL2 and CX3CL1 in the synovium. At day 7 (d7) after CiOA induction in WT mice, numbers of Ly6C high , but not Ly6C low monocytes, were strongly increased (7.6-fold) in the synovium compared to saline-injected controls. This coincided with strong upregulation of CCL2, which preferentially attracts Ly6C high monocytes. In contrast, S100a9 -/- mice showed a significant increase in Ly6C low monocytes (twofold) within the synovium at CiOA d7, whereas the number of Ly6C high monocytes remained unaffected. In agreement with this finding, the Ly6C low mobilization marker CX3CL1 was significantly higher within the synovium of S100a9 -/- mice. Next, we studied the effect of S100A8/A9 on release of Ly6C high monocytes from the BM into the circulation. A 14% decrease in myeloid cells was found in WT BM at CiOA d7. No decrease in myeloid cells in S100a9 -/- BM was found, suggesting that S100A8/A9 promotes the release of myeloid populations from the BM. Induction of OA locally leads to strongly elevated S100A8/A9 expression and an elevated influx of Ly6C high monocytes from the BM to the synovium.

Label-free counting of circulating cells by in vivo photoacoustic flow cytometry

NASA Astrophysics Data System (ADS)

Zhou, Quanyu; Yang, Ping; Wang, Qiyan; Pang, Kai; Zhou, Hui; He, Hao; Wei, Xunbin

2018-02-01

Melanoma, developing from melanocytes, is the most serious type of skin cancer. Circulating melanoma cells, the prognosis marker for metastasis, are present in the circulation at the early stage. Thus, quantitative detection of rare circulating melanoma cells is essential for monitoring tumor metastasis and prognosis evaluation. Compared with in vitro assays, in vivo flow cytometry is able to identify circulating tumor cells without drawing blood. Here, we built in vivo photoacoustic flow cytometry based on the high absorption coefficient of melanoma cells, which is applied to labelfree counting of circulating melanoma cells in tumor-bearing mice.

Inflammatory reactions in placental blood of Plasmodium falciparum-infected women and high concentrations of soluble E-selectin and a circulating P. falciparum protein in the cord sera.

PubMed Central

Jakobsen, P H; Rasheed, F N; Bulmer, J N; Theisen, M; Ridley, R G; Greenwood, B M

1998-01-01

To better understand reasons for increased susceptibility to malaria in pregnancy; and the interrelationships between maternal malaria, local immune reactions and the development of the fetus, concentrations of soluble interleukin-10 (IL-10), cytokine receptors, adhesion molecules, a Plasmodium falciparum protein, glutamate-rich protein (GLURP) and antibodies to P. falciparum rhoptry-associated protein-1 were measured among 105 Gambian women and their neonates. Peripheral blood concentrations of IL-10, soluble cytokine receptors and soluble adhesion molecules were found to be different from those concentrations measured in the placenta. Markers of inflammatory reactions: IL-10, sIL-2R, sIL-4R, and soluble tumour necrosis factor receptor I (sTNF-RI) were found in high concentrations in the placenta, indicating that inflammatory reactions take place in the placenta which has been regarded as an immunoprivileged site. Concentrations of soluble vascular cell adhesion molecule-1 (sVCAM-1) and soluble intracellular adhesion molecule-1 (sICAM-1), potential adhesion receptors for malaria parasites, were associated with an active P. falciparum infection in the placenta although the associations did not reach significance. P. falciparum exoantigen, GLURP, was detected in cord blood indicating transplacental passage of malarial antigens. Concentrations of E-selectin were higher in cord blood samples compared with peripheral blood samples. This appeared to be associated with development of cord endothelial cells and not with P. falciparum infection. PMID:9616377

Thiopurine use associated with reduced B and natural killer cells in inflammatory bowel disease

PubMed Central

Lord, James D; Shows, Donna M

2017-01-01

AIM To identify which blood and mucosal lymphocyte populations are specifically depleted by thiopurine use in vivo. METHODS The thiopurines azathioprine and 6-mercaptopurine have been a mainstay of inflammatory bowel disease (IBD) therapy for decades, but their mechanism of action in vivo remains obscure. Although thiopurines are lymphotoxic at high doses, and have been reported to cause T cell apoptosis in vitro, their ability to control IBD at lower doses suggests that they may selectively deplete particular lymphocyte populations. Blood cells from 19 IBD patients on a thiopurine, 19 IBD patients not on a thiopurine, and 38 matched healthy control subjects were analyzed by multiple multi-color flow cytometry panels to quantify the immune cell subsets contained therein, both as a percent of cells, and as an absolute cell count. Similar analyses were performed on colon biopsies from 17 IBD patients on a thiopurine, 17 IBD patients not on a thiopurine, and 49 healthy screening colonoscopy recipients. RESULTS Complete blood counts revealed lower lymphocyte, but not monocyte or granulocyte, counts in IBD patients who were taking thiopurines at the time of sampling. This reduction was restricted to CD3-negative lymphocytes, wherein both natural killer (NK) and B cells were significantly reduced among thiopurine recipients. Among CD19+ B cells, the transitional B cells were particularly depleted, being nearly absent in both blood and colon biopsies of thiopurine recipients. No differences were associated with thiopurine use in CD8+ T cells, mucosa-associated invariant T (MAIT) cells, invariant natural killer T (iNKT) cells, gamma/delta T cells, Th1, Th17, regulatory T cells (Tregs) or naïve CD4+ T cells. However, patients with IBD had significantly more circulating FOXP3+, Helios+ Tregs and fewer iNKT and MAIT cells than healthy controls. CONCLUSION Thiopurine use is associated with reduced B and NK cell, but not T cell, subpopulations in the blood of IBD patients. PMID:28566883

Quantification of Mesenchymal Stem Cells (MSCs) at sites of human prostate cancer.

PubMed

Brennen, W Nathaniel; Chen, Shuangling; Denmeade, Samuel R; Isaacs, John T

2013-01-01

Circulating bone marrow-derived Mesenchymal Stem Cells (BM-MSCs) have an innate tropism for tumor tissue in response to the inflammatory microenvironment present in malignant lesions. The prostate is bombarded by numerous infectious and inflammatory insults over a lifetime. Chronic inflammation is associated with CXCL12, CCL5, and CCL2, which are highly overexpressed in prostate cancer. Among other cell types, these chemoattractant stimuli recruit BM-MSCs to the tumor. MSCs are minimally defined as plastic-adhering cells characterized by the expression of CD90, CD73, and CD105 in the absence of hematopoietic markers, which can differentiate into osteoblasts, chondrocytes, and adipocytes. MSCs are immunoprivileged and have been implicated in tumorigenesis through multiple mechanisms, including promoting proliferation, angiogenesis, and metastasis, in addition to the generation of an immunosuppressive microenvironment. We have demonstrated that MSCs represent 0.01-1.1% of the total cells present in core biopsies from primary human prostatectomies. Importantly, these analyses were performed on samples prior to expansion in tissue culture. MSCs in these prostatectomy samples are FAP-, CD90-, CD73-, and CD105-positive, and CD14-, CD20-, CD34-, CD45-, and HLA-DR-negative. Additionally, like BM-MSCs, these prostate cancer-derived stromal cells (PrCSCs) were shown to differentiate into osteoblasts, adipocytes and chondrocytes. In contrast to primary prostate cancer-derived epithelial cells, fluorescently-labeled PrCSCs and BM-MSCs were both shown to home to CWR22RH prostate cancer xenografts following IV injection. These studies demonstrate that not only are MSCs present in sites of prostate cancer where they may contribute to carcinogenesis, but these cells may also potentially be used to deliver cytotoxic or imaging agents for therapeutic and/or diagnostic purposes.

HER2 expression identifies dynamic functional states within circulating breast cancer cells.

PubMed

Jordan, Nicole Vincent; Bardia, Aditya; Wittner, Ben S; Benes, Cyril; Ligorio, Matteo; Zheng, Yu; Yu, Min; Sundaresan, Tilak K; Licausi, Joseph A; Desai, Rushil; O'Keefe, Ryan M; Ebright, Richard Y; Boukhali, Myriam; Sil, Srinjoy; Onozato, Maristela L; Iafrate, Anthony J; Kapur, Ravi; Sgroi, Dennis; Ting, David T; Toner, Mehmet; Ramaswamy, Sridhar; Haas, Wilhelm; Maheswaran, Shyamala; Haber, Daniel A

2016-09-01

Circulating tumour cells in women with advanced oestrogen-receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer acquire a HER2-positive subpopulation after multiple courses of therapy. In contrast to HER2-amplified primary breast cancer, which is highly sensitive to HER2-targeted therapy, the clinical significance of acquired HER2 heterogeneity during the evolution of metastatic breast cancer is unknown. Here we analyse circulating tumour cells from 19 women with ER + /HER2 - primary tumours, 84% of whom had acquired circulating tumour cells expressing HER2. Cultured circulating tumour cells maintain discrete HER2 + and HER2 - subpopulations: HER2 + circulating tumour cells are more proliferative but not addicted to HER2, consistent with activation of multiple signalling pathways; HER2 - circulating tumour cells show activation of Notch and DNA damage pathways, exhibiting resistance to cytotoxic chemotherapy, but sensitivity to Notch inhibition. HER2 + and HER2 - circulating tumour cells interconvert spontaneously, with cells of one phenotype producing daughters of the opposite within four cell doublings. Although HER2 + and HER2 - circulating tumour cells have comparable tumour initiating potential, differential proliferation favours the HER2 + state, while oxidative stress or cytotoxic chemotherapy enhances transition to the HER2 - phenotype. Simultaneous treatment with paclitaxel and Notch inhibitors achieves sustained suppression of tumorigenesis in orthotopic circulating tumour cell-derived tumour models. Together, these results point to distinct yet interconverting phenotypes within patient-derived circulating tumour cells, contributing to progression of breast cancer and acquisition of drug resistance.

Characterization of Microparticles after Hepatic Ischemia-Reperfusion Injury

PubMed Central

Freeman, Christopher M.; Quillin, Ralph C.; Wilson, Gregory C.; Nojima, Hiroyuki; Johnson, Bobby L.; Sutton, Jeffrey M.; Schuster, Rebecca M.; Blanchard, John; Edwards, Michael J.; Caldwell, Charles C.; Lentsch, Alex B.

2014-01-01

Background Hepatic ischemia-reperfusion (I/R) is a well-studied model of liver injury and has demonstrated a biphasic injury followed by recovery and regeneration. Microparticles (MPs) are a developing field of study and these small membrane bound vesicles have been shown to have effector function in other physiologic and pathologic states. This study was designed to quantify the levels of MPs from various cell origins–platelets, neutrophils, and endolethial cells–following hepatic ischemia-reperfusion injury. Methods A murine model was used with mice undergoing 90 minutes of partial hepatic ischemia followed by various times of reperfusion. Following reperfusion, plasma samples were taken and MPs of various cell origins were labeled and levels were measured using flow cytometry. Additionally, cell specific MPs were further assessed by Annexin V, which stains for the presence of phosphatidylserine, a cell surface marker linked to apoptosis. Statistical analysis was performed using one-way analysis of variance with subsequent Student-Newman-Keuls test with data presented as the mean and standard error of the mean. Results MPs from varying sources show an increase in circulating levels following hepatic I/R injury. However, the timing of the appearance of different MP subtypes differs for each cell type. Platelet and neutrophil-derived MP levels demonstrated an acute elevation following injury whereas endothelial-derived MP levels demonstrated a delayed elevation. Conclusion This is the first study to characterize circulating levels of cell-specific MPs after hepatic I/R injury and suggests that MPs derived from platelets and neutrophils serve as markers of inflammatory injury and may be active participants in this process. In contrast, MPs derived from endothelial cells increase after the injury response during the reparative phase and may be important in angiogenesis that occurs in the regenerating liver. PMID:24879335

Quantifying oral inflammatory load: oral neutrophil counts in periodontal health and disease.

PubMed

Landzberg, M; Doering, H; Aboodi, G M; Tenenbaum, H C; Glogauer, M

2015-06-01

Neutrophils are the primary white blood cells that are recruited to fight the initial phases of microbial infections. While healthy norms have been determined for circulating blood neutrophil counts in order to identify patients with suspected systemic infections, the levels of oral neutrophils (oPMNs) in oral health and in the presence of periodontal diseases have not been described. It is important to address this deficiency in our knowledge as neutrophils are the primary immune cell present in the crevicular fluid and oral environment and previous work has suggested that they may be good indicators of overall oral inflammation and periodontal disease severity. The objective of this study was to measure oPMN counts obtained in a standardized oral rinse from healthy patients and from those with chronic periodontal disease in order to determine if oPMN levels have clinical relevance as markers of periodontal inflammation. A parallel goal of this investigation was to introduce the concept of 'oral inflammatory load', which constitutes the inflammatory burden experienced by the body as a consequence of oral inflammatory disease. Periodontal examinations of patients with a healthy periodontium and chronic periodontal disease were performed (n = 124). Two standardized consecutive saline rinses of 30 s each were collected before patient examination and instrumentation. Neutrophils were quantified in the rinse samples and correlated with the clinical parameters and periodontal diagnosis. Average oPMN counts were determined for healthy patients and for those with mild, moderate and severe chronic periodontal diseases. A statistically significant correlation was found between oPMN counts and deep periodontal probing, sites with bleeding on probing and overall severity of periodontal disease. oPMN counts obtained through a 30-s oral rinse are a good marker of oral inflammatory load and correlate with measures of periodontal disease severity. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Progesterone Is Essential for Protecting against LPS-Induced Pregnancy Loss. LIF as a Potential Mediator of the Anti-inflammatory Effect of Progesterone

PubMed Central

Aisemberg, Julieta; Vercelli, Claudia A.; Bariani, María V.; Billi, Silvia C.; Wolfson, Manuel L.; Franchi, Ana M.

2013-01-01

Lipopolysaccharide (LPS) administration to mice on day 7 of gestation led to 100% embryonic resorption after 24 h. In this model, nitric oxide is fundamental for the resorption process. Progesterone may be responsible, at least in part, for a Th2 switch in the feto-maternal interface, inducing active immune tolerance against fetal antigens. Th2 cells promote the development of T cells, producing leukemia inhibitory factor (LIF), which seems to be important due to its immunomodulatory action during early pregnancy. Our aim was to evaluate the involvement of progesterone in the mechanism of LPS-induced embryonic resorption, and whether LIF can mediate hormonal action. Using in vivo and in vitro models, we provide evidence that circulating progesterone is an important component of the process by which infection causes embryonic resorption in mice. Also, LIF seems to be a mediator of the progesterone effect under inflammatory conditions. We found that serum progesterone fell to very low levels after 24 h of LPS exposure. Moreover, progesterone supplementation prevented embryonic resorption and LPS-induced increase of uterine nitric oxide levels in vivo. Results show that LPS diminished the expression of the nuclear progesterone receptor in the uterus after 6 and 12 h of treatment. We investigated the expression of LIF in uterine tissue from pregnant mice and found that progesterone up-regulates LIF mRNA expression in vitro. We observed that LIF was able to modulate the levels of nitric oxide induced by LPS in vitro, suggesting that it could be a potential mediator of the inflammatory action of progesterone. Our observations support the view that progesterone plays a critical role in a successful pregnancy as an anti-inflammatory agent, and that it could have possible therapeutic applications in the prevention of early reproductive failure associated with inflammatory disorders. PMID:23409146

Complement factor H is expressed in adipose tissue in association with insulin resistance.

PubMed

Moreno-Navarrete, José María; Martínez-Barricarte, Rubén; Catalán, Victoria; Sabater, Mònica; Gómez-Ambrosi, Javier; Ortega, Francisco José; Ricart, Wifredo; Blüher, Mathias; Frühbeck, Gema; Rodríguez de Cordoba, Santiago; Fernández-Real, José Manuel

2010-01-01

Activation of the alternative pathway of the complement system, in which factor H (fH; complement fH [CFH]) is a key regulatory component, has been suggested as a link between obesity and metabolic disorders. Our objective was to study the associations between circulating and adipose tissue gene expressions of CFH and complement factor B (fB; CFB) with obesity and insulin resistance. Circulating fH and fB were determined by enzyme-linked immunosorbent assay in 398 subjects. CFH and CFB gene expressions were evaluated in 76 adipose tissue samples, in isolated adipocytes, and in stromovascular cells (SVC) (n = 13). The effects of weight loss and rosiglitazone were investigated in independent cohorts. Both circulating fH and fB were associated positively with BMI, waist circumference, triglycerides, and inflammatory parameters and negatively with insulin sensitivity and HDL cholesterol. For the first time, CFH gene expression was detected in human adipose tissue (significantly increased in subcutaneous compared with omental fat). CFH gene expression in omental fat was significantly associated with insulin resistance. In contrast, CFB gene expression was significantly increased in omental fat but also in association with fasting glucose and triglycerides. The SVC fraction was responsible for these differences, although isolated adipocytes also expressed fB and fH at low levels. Both weight loss and rosiglitazone led to significantly decreased circulating fB and fH levels. Increased circulating fH and fB concentrations in subjects with altered glucose tolerance could reflect increased SVC-induced activation of the alternative pathway of complement in omental adipose tissue linked to insulin resistance and metabolic disturbances.

A Multiscale Agent-Based in silico Model of Liver Fibrosis Progression

PubMed Central

Dutta-Moscato, Joyeeta; Solovyev, Alexey; Mi, Qi; Nishikawa, Taichiro; Soto-Gutierrez, Alejandro; Fox, Ira J.; Vodovotz, Yoram

2014-01-01

Chronic hepatic inflammation involves a complex interplay of inflammatory and mechanical influences, ultimately manifesting in a characteristic histopathology of liver fibrosis. We created an agent-based model (ABM) of liver tissue in order to computationally examine the consequence of liver inflammation. Our liver fibrosis ABM (LFABM) is comprised of literature-derived rules describing molecular and histopathological aspects of inflammation and fibrosis in a section of chemically injured liver. Hepatocytes are modeled as agents within hexagonal lobules. Injury triggers an inflammatory reaction, which leads to activation of local Kupffer cells and recruitment of monocytes from circulation. Portal fibroblasts and hepatic stellate cells are activated locally by the products of inflammation. The various agents in the simulation are regulated by above-threshold concentrations of pro- and anti-inflammatory cytokines and damage-associated molecular pattern molecules. The simulation progresses from chronic inflammation to collagen deposition, exhibiting periportal fibrosis followed by bridging fibrosis, and culminating in disruption of the regular lobular structure. The ABM exhibited key histopathological features observed in liver sections from rats treated with carbon tetrachloride (CCl4). An in silico “tension test” for the hepatic lobules predicted an overall increase in tissue stiffness, in line with clinical elastography literature and published studies in CCl4-treated rats. Therapy simulations suggested differential anti-fibrotic effects of neutralizing tumor necrosis factor alpha vs. enhancing M2 Kupffer cells. We conclude that a computational model of liver inflammation on a structural skeleton of physical forces can recapitulate key histopathological and macroscopic properties of CCl4-injured liver. This multiscale approach linking molecular and chemomechanical stimuli enables a model that could be used to gain translationally relevant insights into liver fibrosis. PMID:25152891

Heart-rate reduction by If-channel inhibition with ivabradine restores collateral artery growth in hypercholesterolemic atherosclerosis.

PubMed

Schirmer, Stephan H; Degen, Achim; Baumhäkel, Magnus; Custodis, Florian; Schuh, Lisa; Kohlhaas, Michael; Friedrich, Erik; Bahlmann, Ferdinand; Kappl, Reinhard; Maack, Christoph; Böhm, Michael; Laufs, Ulrich

2012-05-01

Collateral arteries protect tissue from ischaemia. Heart rate correlates with vascular events in patients with arterial obstructive disease. Here, we tested the effect of heart-rate reduction (HRR) on collateral artery growth. The I(f)-channel inhibitor ivabradine reduced heart rate by 11% in wild-type and 15% in apolipoprotein E (ApoE)(-/-) mice and restored endothelium-dependent relaxation in aortic rings of ApoE(-/-) mice. Microsphere perfusion and angiographies demonstrated that ivabradine did not change hindlimb perfusion in wild-type mice but improved perfusion in ApoE(-/-) mice from 40.5 ± 15.8-60.2 ± 18.5% ligated/unligated hindlimb. Heart rate reduction (13%) with metoprolol failed to improve endothelial function and perfusion. Protein expression of endothelial nitric oxide synthase (eNOS), phosphorylated eNOS, and eNOS activity were increased in collateral tissue following ivabradine treatment of ApoE(-/-) mice. Co-treatment with nitric oxide-inhibitor N (G)-nitro-L-arginine methyl ester abolished the effects of ivabradine on arteriogenesis. Following ivabradine, classical inflammatory cytokine expression was lowered in ApoE(-/-) circulating mononuclear cells and in plasma, but unaltered in collateral-containing hindlimb tissue, where numbers of perivascular macrophages also remained unchanged. However, ivabradine reduced expression of anti-arteriogenic cytokines CXCL10and CXCL11 and of smooth muscle cell markers smoothelin and desmin in ApoE(-/-) hindlimb tissue. Endothelial nitric oxide synthase and inflammatory cytokine expression were unchanged in wild-type mice. Ivabradine did not affect cytokine production in HUVECs and THP1 mononuclear cells and had no effect on the membrane potential of HUVECs in patch-clamp experiments. Ivabradine-induced HRR stimulates adaptive collateral artery growth. Important contributing mechanisms include improved endothelial function, eNOS activity, and modulation of inflammatory cytokine gene expression.

Endothelial microparticles reduce ICAM-1 expression in a microRNA-222-dependent mechanism

PubMed Central

Jansen, Felix; Yang, Xiaoyan; Baumann, Katharina; Przybilla, David; Schmitz, Theresa; Flender, Anna; Paul, Kathrin; Alhusseiny, Adil; Nickenig, Georg; Werner, Nikos

2015-01-01

Endothelial microparticles (EMP) are released from activated or apoptotic endothelial cells (ECs) and can be taken up by adjacent ECs, but their effect on vascular inflammation after engulfment is largely unknown. We sought to determine the role of EMP in EC inflammation. In vitro, EMP treatment significantly reduced tumour necrosis factor-α-induced endothelial intercellular adhesion molecule (ICAM)-1 expression on mRNA and protein level, whereas there was no effect on vascular cell adhesion molecule-1 expression. Reduced ICAM-1 expression after EMP treatment resulted in diminished monocyte adhesion in vitro. In vivo, systemic treatment of ApoE−/− mice with EMP significantly reduced murine endothelial ICAM-1 expression. To explore the underlying mechanisms, Taqman microRNA array was performed and microRNA (miR)-222 was identified as the strongest regulated miR between EMP and ECs. Following experiments demonstrated that miR-222 was transported into recipient ECs by EMP and functionally regulated expression of its target protein ICAM-1 in vitro and in vivo. After simulating diabetic conditions, EMP derived from glucose-treated ECs contained significantly lower amounts of miR-222 and showed reduced anti-inflammatory capacity in vitro and in vivo. Finally, circulating miR-222 level was diminished in patients with coronary artery disease (CAD) compared to patients without CAD. EMPs promote anti-inflammatory effects in vitro and in vivo by reducing endothelial ICAM-1 expression via the transfer of functional miR-222 into recipient cells. In pathological hyperglycaemic conditions, EMP-mediated miR-222-dependent anti-inflammatory effects are reduced. PMID:26081516

Endothelial microparticles reduce ICAM-1 expression in a microRNA-222-dependent mechanism.

PubMed

Jansen, Felix; Yang, Xiaoyan; Baumann, Katharina; Przybilla, David; Schmitz, Theresa; Flender, Anna; Paul, Kathrin; Alhusseiny, Adil; Nickenig, Georg; Werner, Nikos

2015-09-01

Endothelial microparticles (EMP) are released from activated or apoptotic endothelial cells (ECs) and can be taken up by adjacent ECs, but their effect on vascular inflammation after engulfment is largely unknown. We sought to determine the role of EMP in EC inflammation. In vitro, EMP treatment significantly reduced tumour necrosis factor-α-induced endothelial intercellular adhesion molecule (ICAM)-1 expression on mRNA and protein level, whereas there was no effect on vascular cell adhesion molecule-1 expression. Reduced ICAM-1 expression after EMP treatment resulted in diminished monocyte adhesion in vitro. In vivo, systemic treatment of ApoE-/- mice with EMP significantly reduced murine endothelial ICAM-1 expression. To explore the underlying mechanisms, Taqman microRNA array was performed and microRNA (miR)-222 was identified as the strongest regulated miR between EMP and ECs. Following experiments demonstrated that miR-222 was transported into recipient ECs by EMP and functionally regulated expression of its target protein ICAM-1 in vitro and in vivo. After simulating diabetic conditions, EMP derived from glucose-treated ECs contained significantly lower amounts of miR-222 and showed reduced anti-inflammatory capacity in vitro and in vivo. Finally, circulating miR-222 level was diminished in patients with coronary artery disease (CAD) compared to patients without CAD. EMPs promote anti-inflammatory effects in vitro and in vivo by reducing endothelial ICAM-1 expression via the transfer of functional miR-222 into recipient cells. In pathological hyperglycaemic conditions, EMP-mediated miR-222-dependent anti-inflammatory effects are reduced. © 2015 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Antioxidant, anti-inflammatory, anti-apoptotic, and skin regenerative properties of an Aloe vera-based extract of Nerium oleander leaves (nae-8(®)).

PubMed

Benson, Kathleen F; Newman, Robert A; Jensen, Gitte S

2015-01-01

The goal for this study was to evaluate the effects of an Aloe vera-based Nerium oleander extract (NAE-8(®)), compared to an extract of A. vera gel alone (ALOE), and to an aqueous extract of N. oleander (AQ-NOE) in bioassays pertaining to dermatologic potential with respect to antioxidant protection, anti-inflammatory effects, and cytokine profiles in vitro. Cellular antioxidant protection was evaluated in three separate bioassays: The cellular antioxidant protection of erythrocytes (CAP-e) assay, protection of cellular viability and prevention of apoptosis, and protection of intracellular reduced glutathione levels, where the last two assays were performed using human primary dermal fibroblasts. Reduction of intracellular formation of reactive oxygen species (ROS) was tested using polymorphonuclear cells in the absence and presence of oxidative stress. Changes to cytokine and chemokine profiles when whole blood cells and human primary dermal fibroblasts were exposed to test products were determined using a 40-plex Luminex array as a method for exploring the potential cross-talk between circulating and skin-resident cells. The NAE-8(®) provided significantly better antioxidant protection in the CAP-e bioassay than AQ-NOE. NAE-8(®) and AQ-NOE both protected cellular viability and intracellular reduced glutathione, and reduced the ROS formation significantly when compared to control cells, both under inflamed and neutral culture conditions. ALOE showed minimal effect in these bioassays. In contrast to the NAE-8(®), the AQ-NOE showed induction of inflammation in the whole blood cultures, as evidenced by the high induction of CD69 expression and secretion of a number of inflammatory cytokines. The treatment of dermal fibroblasts with NAE-8(®) resulted in selective secretion of cytokines involved in collagen and hyaluronan production as well as re-epithelialization during wound healing. NAE-8(®), a novel component of a commercial cosmetic product, showed beneficial antioxidant protection in several cellular models, without the induction of leukocyte activation and secretion of inflammatory cytokines. The biological efficacy of NAE-8(®) was unique from both ALOE and AQ-NOE.

Leptin–cytokine crosstalk in breast cancer

PubMed Central

Newman, Gale; Gonzalez-Perez, Ruben Rene

2013-01-01

Despite accumulating evidence suggesting a positive correlation between leptin levels, obesity, post-menopause and breast cancer incidence, our current knowledge on the mechanisms involved in these relationships is still incomplete. Since the cloning of leptin in 1994 and its receptor (OB-R) 1 year later by Friedman’s laboratory (Zhang et al., 1994) and Tartaglia et al. (Tartaglia et al., 1995), respectively, more than 22,000 papers related to leptin functions in several biological systems have been published (Pubmed, 2012). The ob gene product, leptin, is an important circulating signal for the regulation of body weight. Additionally, leptin plays critical roles in the regulation of glucose homeostasis, reproduction, growth and the immune response. Supporting evidence for leptin roles in cancer has been shown in more than 1000 published papers, with almost 300 papers related to breast cancer (Pubmed, 2012). Specific leptin-induced signaling pathways are involved in the increased levels of inflammatory, mitogenic and pro-angiogenic factors in breast cancer. In obesity, a mild inflammatory condition, deregulated secretion of proinflammatory cytokines and adipokines such as IL-1, IL-6, TNF-α and leptin from adipose tissue, inflammatory and cancer cells could contribute to the onset and progression of cancer. We used an in silico software program, Pathway Studio 9, and found 4587 references citing these various interactions. Functional crosstalk between leptin, IL-1 and Notch signaling (NILCO) found in breast cancer cells could represent the integration of developmental, proinflammatory and pro-angiogenic signals critical for leptin-induced breast cancer cell proliferation/migration, tumor angiogenesis and breast cancer stem cells (BCSCs). Remarkably, the inhibition of leptin signaling via leptin peptide receptor antagonists (LPrAs) significantly reduced the establishment and growth of syngeneic, xenograft and carcinogen-induced breast cancer and, simultaneously decreased the levels of VEGF/VEGFR2, IL-1 and Notch. Inhibition of leptin–cytokine crosstalk might serve as a preventative or adjuvant measure to target breast cancer, particularly in obese women. This review is intended to present an update analysis of leptin actions in breast cancer, highlighting its crosstalk to inflammatory cytokines and growth fact ors essential for tumor development, angiogenesis and potential role in BCSC. PMID:23562747

Circulatory shear flow alters the viability and proliferation of circulating colon cancer cells

NASA Astrophysics Data System (ADS)

Fan, Rong; Emery, Travis; Zhang, Yongguo; Xia, Yuxuan; Sun, Jun; Wan, Jiandi

2016-06-01

During cancer metastasis, circulating tumor cells constantly experience hemodynamic shear stress in the circulation. Cellular responses to shear stress including cell viability and proliferation thus play critical roles in cancer metastasis. Here, we developed a microfluidic approach to establish a circulatory microenvironment and studied circulating human colon cancer HCT116 cells in response to a variety of magnitude of shear stress and circulating time. Our results showed that cell viability decreased with the increase of circulating time, but increased with the magnitude of wall shear stress. Proliferation of cells survived from circulation could be maintained when physiologically relevant wall shear stresses were applied. High wall shear stress (60.5 dyne/cm2), however, led to decreased cell proliferation at long circulating time (1 h). We further showed that the expression levels of β-catenin and c-myc, proliferation regulators, were significantly enhanced by increasing wall shear stress. The presented study provides a new insight to the roles of circulatory shear stress in cellular responses of circulating tumor cells in a physiologically relevant model, and thus will be of interest for the study of cancer cell mechanosensing and cancer metastasis.

[Advances in the research of effects of glutamine on immune function of burn patients].

PubMed

Liu, Y H; Guo, P F; Chen, G Y; Bo, Y C; Ma, Y; Cui, Z J

2018-04-20

Glutamine is the most abundant amino acid found in plasma and cells. It is the preferred fuel for enterocytes in the small intestine, macrophages, and lymphocytes. After serious burn, increased requirement of glutamine by the gastrointestinal tract, kidney and lymphocytes, and relatively insufficient self synthesis likely contribute to the rapid decline of glutamine in circulation and cells. Glutamine supplementation can not only protect intestinal mucosa, maintain normal intestinal barrier function, reduce bacterial translocation, and enhance the intestinal immune function, but also increase the number of lymphocytes, enhance the phagocytic function of macrophage, promote the synthesis of immunoglobulin, and reduce the body's inflammatory response, so as to enhance the immune function. Therefore, glutamine supplementation can improve and enhance the immune function, reduce complications and promote the prognosis of severely burned patients.

The Absence of Platelet-Derived Growth Factor-B in Circulating Cells Promotes Immune and Inflammatory Responses in Atherosclerosis-Prone ApoE−/− Mice

PubMed Central

Tang, Jingjing; Kozaki, Koichi; Farr, Andrew G.; Martin, Paul J.; Lindahl, Per; Betsholtz, Christer; Raines, Elaine W.

2005-01-01

Both innate and adaptive immunity contribute to the progression of inflammatory-fibrotic lesions of atherosclerosis. Although platelet-derived growth factor (PDGF)-B has been investigated as a stimulant of smooth muscle cells in vascular diseases, its effects on the immune response during disease have not been evaluated in vivo. We used hematopoietic chimeras generated after lethal irradiation of ApoE−/− recipients to test the role of PDGF in atherosclerosis. Monocyte accumulation in early atherosclerotic lesions increased 1.9-fold in ApoE−/−/PDGF-B−/− chimeras. Lymphocytes from null chimeras showed a 1.6- to 2.0-fold increase in the number of activated CD4+ T cells and a 2.5-fold elevation of interferon-γ-secreting CD4+ T cells on ex vivo challenge with modified low-density lipoprotein. Splenocyte transcript levels were also altered with a twofold decrease in interleukin-10 and 1.7- and 3.0-fold increases in interleukin-18 and CCR5, respectively. These cellular and molecular changes were consistent with a shift to a proinflammatory phenotype in null chimeras. Our data also demonstrated for the first time the presence of a recently discovered family of negative regulators of innate and adaptive immunity, the suppressors of cytokine signaling (SOCS), in developing atherosclerotic lesions. Thus, our studies identify two independent negative immune regulatory pathways—PDGF-B and SOCS—that may help limit lesion expansion. PMID:16127167

The absence of platelet-derived growth factor-B in circulating cells promotes immune and inflammatory responses in atherosclerosis-prone ApoE-/- mice.

PubMed

Tang, Jingjing; Kozaki, Koichi; Farr, Andrew G; Martin, Paul J; Lindahl, Per; Betsholtz, Christer; Raines, Elaine W

2005-09-01

Both innate and adaptive immunity contribute to the progression of inflammatory-fibrotic lesions of atherosclerosis. Although platelet-derived growth factor (PDGF)-B has been investigated as a stimulant of smooth muscle cells in vascular diseases, its effects on the immune response during disease have not been evaluated in vivo. We used hematopoietic chimeras generated after lethal irradiation of ApoE-/- recipients to test the role of PDGF in atherosclerosis. Monocyte accumulation in early atherosclerotic lesions increased 1.9-fold in ApoE-/-/PDGF-B-/- chimeras. Lymphocytes from null chimeras showed a 1.6- to 2.0-fold increase in the number of activated CD4(+) T cells and a 2.5-fold elevation of interferon-gamma-secreting CD4(+) T cells on ex vivo challenge with modified low-density lipoprotein. Splenocyte transcript levels were also altered with a twofold decrease in interleukin-10 and 1.7- and 3.0-fold increases in interleukin-18 and CCR 5, respectively. These cellular and molecular changes were consistent with a shift to a proinflammatory phenotype in null chimeras. Our data also demonstrated for the first time the presence of a recently discovered family of negative regulators of innate and adaptive immunity, the suppressors of cytokine signaling (SOCS), in developing atherosclerotic lesions. Thus, our studies identify two independent negative immune regulatory pathways-PDGF-B and SOCS-that may help limit lesion expansion.

Curcumin ameliorates cardiac dysfunction induced by mechanical trauma.

PubMed

Li, Xintao; Cao, Tingting; Ma, Shuo; Jing, Zehao; Bi, Yue; Zhou, Jicheng; Chen, Chong; Yu, Deqin; Zhu, Liang; Li, Shuzhuang

2017-11-05

Curcumin, a phytochemical component derived from turmeric (Carcuma longa), has been extensively investigated because of its anti-inflammatory and anti-oxidative properties. Inflammation and oxidative stress play critical roles in posttraumatic cardiomyocyte apoptosis, which contributes to secondary cardiac dysfunction. This research was designed to identify the protective effect of curcumin on posttraumatic cardiac dysfunction and investigate its underlying mechanism. Noble-Collip drum was used to prepare a mechanical trauma (MT) model of rats, and the hemodynamic responses of traumatized rats were observed by ventricular intubation 12h after trauma. Myocardial apoptosis was determined through terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining and caspase-3 activity assay. Tumor necrosis factor-α (TNF-α) and reactive oxygen species (ROS) generated by monocytes and myocardial cells were identified through enzyme-linked immunosorbent assay (ELISA), and the intracellular alteration of Ca 2+ in cardiomyocytes was examined through confocal microscopy. In vivo, curcumin effectively ameliorated MT-induced secondary cardiac dysfunction and significantly decreased the apoptotic indices of the traumatized myocardial cells. In vitro, curcumin inhibited TNF-α production by monocytes and reduced the circulating TNF-α levels. With curcumin pretreatment, ROS production and Ca 2+ overload in H9c2 cells were attenuated when these cells were incubated with traumatic plasma. Therefore, curcumin can effectively ameliorate MT-induced cardiac dysfunction mainly by inhibiting systemic inflammatory responses and by weakening oxidative stress reaction and Ca 2+ overload in cardiomyocytes. Copyright © 2017 Elsevier B.V. All rights reserved.

Culture and Characterization of Circulating Endothelial Progenitor Cells in Patients with Renal Cell Carcinoma.

PubMed

Gu, Wenyu; Sun, Wei; Guo, Changcheng; Yan, Yang; Liu, Min; Yao, Xudong; Yang, Bin; Zheng, Junhua

2015-07-01

Although emerging evidence demonstrates increased circulating endothelial progenitor cells in patients with solid tumors, to our knowledge it is still unknown whether such cells can be cultured from patients with highly angiogenic renal cell carcinoma. We cultured and characterized circulating endothelial progenitor cells from patients with renal cell carcinoma. The circulating endothelial progenitor cell level (percent of CD45(-)CD34(+) VEGF-R2(+) cells in total peripheral blood mononuclear cells) was quantified in 47 patients with renal cell carcinoma and 40 healthy controls. Peripheral blood mononuclear cells were then isolated from 33 patients with renal cell carcinoma and 30 healthy controls to culture and characterize circulating endothelial progenitor cells. The circulating endothelial progenitor cell level was significantly higher in patients with renal cell carcinoma than in healthy controls (0.276% vs 0.086%, p <0.001). A colony of circulating endothelial progenitor cells first emerged significantly earlier in patient than in control preparations (6.72 vs 14.67 days, p <0.001). The culture success rate (87.8% vs 40.0% of participants) and the number of colonies (10.06 vs 1.83) were significantly greater for patients than for controls (each p <0.001). The circulating endothelial progenitor cell level correlated positively with the number of patient colonies (r = 0.762, p <0.001). Cells cultured from patients and controls showed a similar growth pattern, immunophenotype, ability to uptake Ac-LDL and bind lectin, and form capillary tubes in vitro. However, significantly more VEGF-R2(+) circulating endothelial progenitor cells were found in preparations from patients with renal cell carcinoma than from healthy controls (21.1% vs 13.4%, p <0.001). Earlier emergence of circulating endothelial progenitor cell colonies, a higher cell culture success rate and more colonies were found for patients with renal cell carcinoma than for healthy controls. Results indicate the important significance of VEGF-R2(+) circulating endothelial progenitors in patients with renal cell carcinoma. Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

21 CFR 866.6020 - Immunomagnetic circulating cancer cell selection and enumeration system.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Immunomagnetic circulating cancer cell selection... Associated Antigen immunological Test Systems § 866.6020 Immunomagnetic circulating cancer cell selection and enumeration system. (a) Identification. An immunomagnetic circulating cancer cell selection and enumeration...

21 CFR 866.6020 - Immunomagnetic circulating cancer cell selection and enumeration system.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Immunomagnetic circulating cancer cell selection... Associated Antigen immunological Test Systems § 866.6020 Immunomagnetic circulating cancer cell selection and enumeration system. (a) Identification. An immunomagnetic circulating cancer cell selection and enumeration...

21 CFR 866.6020 - Immunomagnetic circulating cancer cell selection and enumeration system.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Immunomagnetic circulating cancer cell selection... Associated Antigen immunological Test Systems § 866.6020 Immunomagnetic circulating cancer cell selection and enumeration system. (a) Identification. An immunomagnetic circulating cancer cell selection and enumeration...

21 CFR 866.6020 - Immunomagnetic circulating cancer cell selection and enumeration system.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Immunomagnetic circulating cancer cell selection... Associated Antigen immunological Test Systems § 866.6020 Immunomagnetic circulating cancer cell selection and enumeration system. (a) Identification. An immunomagnetic circulating cancer cell selection and enumeration...

21 CFR 866.6020 - Immunomagnetic circulating cancer cell selection and enumeration system.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Immunomagnetic circulating cancer cell selection... Associated Antigen immunological Test Systems § 866.6020 Immunomagnetic circulating cancer cell selection and enumeration system. (a) Identification. An immunomagnetic circulating cancer cell selection and enumeration...

Advanced drug delivery systems of curcumin for cancer chemoprevention.

PubMed

Bansal, Shyam S; Goel, Mehak; Aqil, Farrukh; Vadhanam, Manicka V; Gupta, Ramesh C

2011-08-01

Since ancient times, chemopreventive agents have been used to treat/prevent several diseases including cancer. They are found to elicit a spectrum of potent responses including anti-inflammatory, antioxidant, antiproliferative, anticarcinogenic, and antiangiogenic activity in various cell cultures and some animal studies. Research over the past 4 decades has shown that chemopreventives affect a number of proteins involved in various molecular pathways that regulate inflammatory and carcinogenic responses in a cell. Various enzymes, transcription factors, receptors, and adhesion proteins are also affected by chemopreventives. Although, these natural compounds have shown significant efficacy in cell culture studies, they elicited limited efficacy in various clinical studies. Their introduction into the clinical setting is hindered largely by their poor solubility, rapid metabolism, or a combination of both, ultimately resulting in poor bioavailability upon oral administration. Therefore, to circumvent these limitations and to ease their transition to clinics, alternate strategies should be explored. Drug delivery systems such as nanoparticles, liposomes, microemulsions, and polymeric implantable devices are emerging as one of the viable alternatives that have been shown to deliver therapeutic concentrations of various potent chemopreventives such as curcumin, ellagic acid, green tea polyphenols, and resveratrol into the systemic circulation. In this review article, we have attempted to provide a comprehensive outlook for these delivery approaches, using curcumin as a model agent, and discussed future strategies to enable the introduction of these highly potent chemopreventives into a physician's armamentarium.

The macrophage as a Trojan horse for antisense oligonucleotide delivery.

PubMed

Novak, James S; Jaiswal, Jyoti K; Partridge, Terence A

2018-06-04

The gateway to the promised land of gene therapy has been obstructed by the problem of accurate and efficient delivery of therapeutic agents to their target sites. This is true both of constructs designed to directly express proteins of interest, and of constructs or agents aimed at modifying the expression of endogenous genes. It is recognized as a major impediment to the effective application of genetic therapies currently or incipiently in clinical trial. Our recent study has examined the mechanism underlying delivery of therapeutic antisense oligonucleotides (ASO) for treating the devastating muscle disease Duchenne muscular dystrophy [1]. Working to understand the mode of ASO delivery in DMD, we discovered that inflammatory cells act as a depot that locally stores the intravenously administered ASO. This local depot of ASO then becomes available to the muscle fibres by way of satellite cells that deliver their cargo by fusion with damaged fibres during muscle repair. This finding points to a potentially novel strategy for systemic ASO delivery, involving the use of the inflammatory cell as a Trojan horse. Such an approach would have the benefit not only of enhancing tissue-specific delivery of ASO, but also of reducing the impact of their rapid clearance from the circulation. Here, we discuss the issues surrounding ASO-mediated exon skipping efficacy for DMD, and outline research aimed at improving targeted ASO delivery.

Polytrauma Increases Susceptibility to Pseudomonas Pneumonia in Mature Mice.

PubMed

Turnbull, Isaiah R; Ghosh, Sarbani; Fuchs, Anja; Hilliard, Julia; Davis, Christopher G; Bochicchio, Grant V; Southard, Robert E

2016-05-01

Pneumonia is the most common complication observed in patients with severe injuries. Although the average age of injured patients is 47 years, existing studies of the effect of injury on the susceptibility to infectious complications have focused on young animals, equivalent to a late adolescent human. We hypothesized that mature adult animals are more susceptible to infection after injury than younger counterparts. To test this hypothesis, we challenged 6 to 8-month-old mature mice to a polytrauma injury followed by Pseudomonas aeruginosa pneumonia and compared them to young (8-10-week-old) animals. We demonstrate that polytrauma injury increases mortality from pneumonia in mature animals (sham-pneumonia 21% vs. polytrauma-pneumonia 62%) but not younger counterparts. After polytrauma, pneumonia in mature mice is associated with higher bacterial burden in lung, increased incidence of bacteremia, and elevated levels of bacteria in the blood, demonstrating that injury decreases the ability to control the infectious challenge. We further find that polytrauma did not induce elevations in circulating cytokine levels (TNF-alpha, IL-6, KC, and IL-10) 24  h after injury. However, mature mice subjected to polytrauma demonstrated an exaggerated circulating inflammatory cytokine response to subsequent Pseudomonas pneumonia. Additionally, whereas prior injury increases LPS-stimulated IL-6 production by peripheral blood leukocytes from young (8-10-week-old) mice, injury does not prime IL-6 production by cell from mature adult mice. We conclude that in mature mice polytrauma results in increased susceptibility to Pseudomonas pneumonia while priming an exaggerated but ineffective inflammatory response.

Advances in the mechanisms and early warning indicators of the postoperative cognitive dysfunction after the extracorporeal circulation.

PubMed

Liu, Chao; Han, Jian-ge

2015-02-01

The high incidence of postoperative cognitive dysfunction (POCD) after extracorporeal circulation has seriously affected the prognosis and quality of life. Its mechanism may involve the inflammatory response and oxidative stress,the excessive phosphorylation of tau protein, the decreased blood volume and oxygen in the cerebral cortex. Appropriate early warning indicators of POCD after the extracorporeal circulation should be chosen to facilitate the cross validation of the results obtained different technical approaches and thus promote the early diagnosis and treatment of POCD.

The effect of red ginseng extract on inflammatory cytokines after chemotherapy in children.

PubMed

Lee, Jae Min; Hah, Jeong Ok; Kim, Hee Sun

2012-10-01

Ginseng has been used as an herbal medicine, widely used in Asian countries, for long time. Recently, beneficial effects for immune functions of Korean red ginseng (KRG) have been reported in adults. This study was performed to investigate the effects of ginseng on immune functions in children after cessation of chemotherapy or stem cell transplantation for advanced cancer. Thirty patients, who were diagnosed and treated for leukemia and solid cancer at the department of pediatrics and adolescence of the Yeungnam University Hospital from June 2004 to June 2009, were enrolled for the study. The study group consisted of 19 patients who received KRG extract (60 mg/kg/d) for 1 yr and 11 patients who did not receive KRG extract were the control group. Blood samples were collected every 6 mo. Immune assays included circulating lymphocyte subpopulation, serum cytokines (IL- 2, IL-10, IL-12, TNF-alpha, and IFN-gamma), and total concentrations of serum IgG, IgA, and IgM subclasses. Age at diagnosis ranged from 2 mo to 15 yr (median 5 yr). Nine patients received stem cell transplantation. The cytokines of the KRG treated group were decreasing more rapidly than that of the control group. Lymphocyte subpopulations (T cell, B cell, NK cell, T4, T8, and T4/ T8 ratio) and serum immunoglobulin subclasses (IgG, IgA, and IgM) did not show significant differences between the study and the control groups. This study suggests that KRG extract might have a stabilizing effect on the inflammatory cytokines in children with cancer after chemotherapy.

Increases in reactive oxygen species enhance vascular endothelial cell migration through a mechanism dependent on the transient receptor potential melastatin 4 ion channel.

PubMed

Sarmiento, Daniela; Montorfano, Ignacio; Cerda, Oscar; Cáceres, Mónica; Becerra, Alvaro; Cabello-Verrugio, Claudio; Elorza, Alvaro A; Riedel, Claudia; Tapia, Pablo; Velásquez, Luis A; Varela, Diego; Simon, Felipe

2015-03-01

A hallmark of severe inflammation is reactive oxygen species (ROS) overproduction induced by increased inflammatory mediators secretion. During systemic inflammation, inflammation mediators circulating in the bloodstream interact with endothelial cells (ECs) raising intracellular oxidative stress at the endothelial monolayer. Oxidative stress mediates several pathological functions, including an exacerbated EC migration. Because cell migration critically depends on calcium channel-mediated Ca(2+) influx, the molecular identification of the calcium channel involved in oxidative stress-modulated EC migration has been the subject of intense investigation. The transient receptor potential melastatin 4 (TRPM4) protein is a ROS-modulated non-selective cationic channel that performs several cell functions, including regulating intracellular Ca(2+) overload and Ca(2+) oscillation. This channel is expressed in multiple tissues, including ECs, and contributes to the migration of certain immune cells. However, whether the TRPM4 ion channel participates in oxidative stress-mediated EC migration is not known. Herein, we investigate whether oxidative stress initiates or enhances EC migration and study the role played by the ROS-modulated TRPM4 ion channel in oxidative stress-mediated EC migration. We demonstrate that oxidative stress enhances, but does not initiate, EC migration in a dose-dependent manner. Notably, we demonstrate that the TRPM4 ion channel is critical in promoting H2O2-enhanced EC migration. These results show that TRPM4 is a novel pharmacological target for the possible treatment of severe inflammation and other oxidative stress-mediated inflammatory diseases. Copyright © 2014 Elsevier Inc. All rights reserved.

Canines as sentinel species for assessing chronic exposures to air pollutants: part 1. Respiratory pathology.

PubMed

Calderón-Garcidueñas, L; Mora-Tiscareño, A; Fordham, L A; Chung, C J; García, R; Osnaya, N; Hernández, J; Acuña, H; Gambling, T M; Villarreal-Calderón, A; Carson, J; Koren, H S; Devlin, R B

2001-06-01

A complex mixture of air pollutants is present in the ambient air in urban areas. People, animals, and vegetation are chronically and sequentially exposed to outdoor pollutants. The objective of this first of 2 studies is to evaluate by light and electron microscopy the lungs of Mexico City dogs and compare the results to those of 3 less polluted cities in MEXICO: One hundred fifty-two clinically healthy stray mongrel dogs (91 males/61 females), including 43 dogs from 3 less polluted cities, and 109 from southwest and northeast metropolitian Mexico City (SWMMC, NEMMC) were studied. Lungs of dogs living in Mexico City and Cuernavaca exhibited patchy chronic mononuclear cell infiltrates along with macrophages loaded with particulate matter (PM) surrounding the bronchiolar walls and extending into adjacent vascular structures; bronchiolar epithelial and smooth muscle hyperplasia, peribronchiolar fibrosis, microthrombi, and capillary and venule polymorphonuclear leukocytes (PMN) margination. Ultrafine PM was seen in alveolar type I and II cells, endothelial cells, interstitial macrophages (Mtheta), and intravascular Mtheta-like cells. Bronchoalveolar lavage showed significant numbers of alveolar macrophages undergoing proliferation. Exposure to complex mixtures of pollutants-predominantly particulate matter and ozone-is causing lung structural changes induced by the sustained inflammatory process and resulting in airway and vascular remodeling and altered repair. Cytokines released from both, circulating inflammatory and resident lung cells in response to endothelial and epithelial injury may be playing a role in the pathology described here. Deep concern exists for the potential of an increasing rise in lung diseases in child populations exposed to Mexico City's environment.

Circulating Inflammatory Mediators in Patients with Fever: Predicting Bloodstream Infection

PubMed Central

Groeneveld, A. B. Johan; Bossink, Ailko W. J.; van Mierlo, Gerard J.; Hack, C. Erik

2001-01-01

The systemic host response to microbial infection involves clinical signs and symptoms of infection, including fever and elevated white blood cell (WBC) counts. In addition, inflammatory mediators are released, including activated complement product C3a, interleukin 6 (IL-6), and the acute-phase reactant secretory phospholipase A2 (sPLA2). To compare the value of the latter with the former in predicting (the degree of) microbial infection at the bedside, we determined clinical variables and took blood samples daily for 3 consecutive days in 300 patients with a new fever (>38.0°C rectally or >38.3°C axillary). Microbiological culture results for 7 days after inclusion were collected. Patients were divided into clinical and microbial categories: those without and with a clinical focus of infection and those with negative cultures, with positive local cultures or specific stains for fungal (n = 13) or tuberculous infections (n = 1), and with positive blood cultures, including one patient with malaria parasitemia. The area under the curve (AUC) of the receiver operating characteristic (ROC) for prediction of positive cultures was 0.60 (P < 0.005) for peak temperature and 0.59 (P < 0.01) for peak WBC count, 0.60 (P < 0.005) for peak C3a, 0.63 (P < 0.001) for peak IL-6, and 0.61 (P < 0.001) for peak sPLA2. The AUC under the ROC curve for prediction of positive blood cultures was 0.68 (P < 0.001) for peak temperature and 0.56 for peak WBC count (P < 0.05). The AUC for peak C3a was 0.69, that for peak IL-6 was 0.70, and that for sPLA2 was 0.67 (for all, P < 0.001). The degree of microbial invasion is thus a major determinant of the clinical and inflammatory host response in patients with fever. Moreover, circulating inflammatory mediators such as C3a and IL-6 may help to predict positive blood cultures, together with clinical signs and symptoms of the host response to microbial infection, even before culture results are available. This may help in the designing of entry criteria for therapeutic intervention studies. PMID:11687462

From lymphopoiesis to plasma cells differentiation, the age-related modifications of B cell compartment are influenced by "inflamm-ageing".

PubMed

Bulati, Matteo; Caruso, Calogero; Colonna-Romano, Giuseppina

2017-07-01

Ageing is a complex process characterized by a general decline in physiological functions with increasing morbidity and mortality. The most important aspect of ageing is the chronic inflammatory status, named "inflamm-ageing", strictly associated with the deterioration of the immune function, termed "immunosenescence". Both are causes of increased susceptibility of elderly to infectious diseases, cancer, dementia, cardiovascular diseases and autoimmunity, and of a decreased response to vaccination. It has been widely demonstrated that ageing has a strong impact on the remodelling of the B cell branch of immune system. The first evident effect is the significant decrease in circulating B cells, primarily due to the reduction of new B cell coming from bone marrow (BM) progenitors, as inflammation directly impacts on B lymphopoiesis. Besides, in aged individuals, there is a shift from naïve to memory immunoglobulins production, accompanied by the impaired ability to produce high affinity protective antibodies against newly encountered antigens. This is accompanied by the increase of expanded clones of B cells, which correlates with poor health status. Age-related modifications also occur in naïve/memory B cells subsets. Indeed, in the elderly, there is a reduction of naïve B cells, accompanied by the expansion of memory B cells that show a senescence-associated phenotype. Finally, elderly show the impaired ability of memory B cells to differentiate into plasma cells. It can be concluded that inflammation is the leading cause of the age-related impairment of B cell compartment, which play certainly a key role in the development of age-related diseases. This makes study of B cells in the aged an important tool for monitoring immunosenescence, chronic inflammatory disorders and the effectiveness of vaccines or pharmacological therapies. Copyright © 2017 Elsevier B.V. All rights reserved.

Intestinal epithelial apoptosis initiates gut mucosal injury during extracorporeal membrane oxygenation in the newborn piglet.

PubMed

MohanKumar, Krishnan; Killingsworth, Cheryl R; McIlwain, R Britt; Timpa, Joseph G; Jagadeeswaran, Ramasamy; Namachivayam, Kopperuncholan; Kurundkar, Ashish R; Kelly, David R; Garzon, Steven A; Maheshwari, Akhil

2014-02-01

Neonates and young infants exposed to extracorporeal circulation during extracorporeal membrane oxygenation (ECMO) and cardiopulmonary bypass are at risk of developing a systemic inflammatory response syndrome with multi-organ dysfunction. We used a piglet model of ECMO to investigate the hypothesis that epithelial apoptosis is an early event that precedes villous damage during ECMO-related bowel injury. Healthy 3-week-old piglets were subjected to ECMO for up to 8 h. Epithelial apoptosis was measured in histopathological analysis, nuclear imaging, and terminal deoxynucleotidyl transferase dUTP nick end labeling. Plasma intestinal fatty acid-binding protein (I-FABP) levels were measured by enzyme immunoassay. Intestinal mast cells were isolated by fluorescence-assisted cell sorting. Cleaved caspase-8, caspase-9, phospho-p38 MAPK, and fas ligand expression were investigated by immunohistochemistry, western blots, and reverse transcriptase-quantitative PCR. Piglet ECMO was associated with increased gut epithelial apoptosis. Extensive apoptotic changes were noted on villus tips and in scattered crypt cells after 2 h of ECMO. After 8 h, the villi were denuded and apoptotic changes were evident in a majority of crypt cells. Increased circulating I-FABP levels, a marker of gut epithelial injury, showed that epithelial injury occurred during ECMO. We detected increased cleaved caspase-8, but not cleaved caspase-9, in epithelial cells indicating that the extrinsic apoptotic pathway was active. ECMO was associated with increased fas ligand expression in intestinal mast cells, which was induced through activation of the p38 mitogen-activated protein kinase. We conclude that epithelial apoptosis is an early event that initiates gut mucosal injury in a piglet model of ECMO.

Intestinal Epithelial Apoptosis initiates Gut Mucosal Injury during Extracorporeal Membrane Oxygenation in the Newborn Piglet

PubMed Central

MohanKumar, Krishnan; Killingsworth, Cheryl R.; McILwain, R. Britt; Timpa, Joseph G.; Jagadeeswaran, Ramasamy; Namachivayam, Kopperuncholan; Kurundkar, Ashish R.; Kelly, David R.; Garzon, Steven A.; Maheshwari, Akhil

2013-01-01

Background Neonates and young infants exposed to extracorporeal circulation during extracorporeal membrane oxygenation (ECMO) and cardiopulmonary bypass (CPB) are at risk of developing a systemic inflammatory response syndrome (SIRS) with multi-organ dysfunction. We used a piglet model of ECMO to investigate the hypothesis that epithelial apoptosis is an early event that precedes villous damage during ECMO-related bowel injury. Methods Healthy 3-week-old piglets were subjected to ECMO for up to 8h. Epithelial apoptosis was measured in histopathological analysis, nuclear imaging, and terminal deoxynucleotidyl transferase dUTP nick end labeling. Plasma intestinal-fatty acid-binding protein (I-FABP) levels were measured by enzyme immunoassay. Intestinal mast cells were isolated by fluorescence-assisted cell sorting. Cleaved caspase-8, caspase-9, phospho-p38 MAPK, and fas ligand expression was investigated by immunohistochemistry, Western blots, and reverse transcriptase-quantitative polymerase chain reaction. Results Piglet ECMO was associated with increased gut epithelial apoptosis. Extensive apoptotic changes were noted on villus tips and in scattered crypt cells after 2h of ECMO. After 8h, the villi were denuded and apoptotic changes were evident in a majority of crypt cells. Increased circulating I-FABP levels, a marker of gut epithelial injury, showed that epithelial injury occurred during ECMO. We detected increased cleaved caspase-8, but not cleaved caspase-9, in epithelial cells indicating that the extrinsic apoptotic pathway was active. ECMO was associated with increased fas ligand expression in intestinal mast cells, which was induced through activation of the p38 mitogen-activated protein kinase. Conclusions Epithelial apoptosis is an early event that initiates gut mucosal injury in a piglet model of ECMO. PMID:24365747

Cytokine profiling of docetaxel-resistant castration-resistant prostate cancer.

PubMed

Mahon, K L; Lin, H-M; Castillo, L; Lee, B Y; Lee-Ng, M; Chatfield, M D; Chiam, K; Breit, S N; Brown, D A; Molloy, M P; Marx, G M; Pavlakis, N; Boyer, M J; Stockler, M R; Daly, R J; Henshall, S M; Horvath, L G

2015-04-14

Docetaxel improves symptoms and survival in metastatic castration-resistant prostate cancer (CRPC). However, ∼50% of patients are chemoresistant. This study examined whether changes in cytokine levels predict for docetaxel resistance in vitro and in a clinical cohort. PC3 cells or their docetaxel-resistant subline (PC3Rx) were co-cultured with U937 monocytes, with and without docetaxel treatment, and cytokine levels were measured. The circulating levels of 28 cytokines were measured pre-/post cycle 1 of docetaxel from 55 men with CRPC, and compared with prostate-specific antigen (PSA) response. PC3Rx-U937 co-culture expressed more cytokines, chiefly markers of alternative macrophage differentiation, compared with PC3-U937 co-culture. Docetaxel treatment enhanced cytokine production by PC3Rx-U937 co-culture, while reducing cytokine levels in PC3-U937. In patients, changes in the levels of seven circulating cytokines (macrophage inhibitory cytokine 1 (MIC1), interleukin (IL)-1ra, IL-1β, IL-4, IL-6, IL-12 and IFNγ) after cycle 1 of docetaxel were associated with progressive disease (all P<0.05). The combination of changes in MIC1, IL-4 and IL-6 most strongly predicted PSA response (P=0.002). In vitro studies suggest docetaxel resistance is mediated, at least in part, by cytokines induced by the interaction between the docetaxel-resistant tumour cells and macrophages. Early changes in circulating cytokine levels were associated with docetaxel resistance in CRPC patients. When considered together, these data suggest a significant role for the inflammatory response and macrophages in the development of docetaxel resistance in CRPC.

Avian Influenza Viruses, Inflammation, and CD8+ T Cell Immunity

PubMed Central

Wang, Zhongfang; Loh, Liyen; Kedzierski, Lukasz; Kedzierska, Katherine

2016-01-01

Avian influenza viruses (AIVs) circulate naturally in wild aquatic birds, infect domestic poultry, and are capable of causing sporadic bird-to-human transmissions. AIVs capable of infecting humans include a highly pathogenic AIV H5N1, first detected in humans in 1997, and a low pathogenic AIV H7N9, reported in humans in 2013. Both H5N1 and H7N9 cause severe influenza disease in humans, manifested by acute respiratory distress syndrome, multi-organ failure, and high mortality rates of 60% and 35%, respectively. Ongoing circulation of H5N1 and H7N9 viruses in wild birds and poultry, and their ability to infect humans emphasizes their epidemic and pandemic potential and poses a public health threat. It is, thus, imperative to understand the host immune responses to the AIVs so we can control severe influenza disease caused by H5N1 or H7N9 and rationally design new immunotherapies and vaccines. This review summarizes our current knowledge on AIV epidemiology, disease symptoms, inflammatory processes underlying the AIV infection in humans, and recent studies on universal pre-existing CD8+ T cell immunity to AIVs. Immune responses driving the host recovery from AIV infection in patients hospitalized with severe influenza disease are also discussed. PMID:26973644

Influence of irradiation on release of endothelial microparticles (EMP) in vitro.

PubMed

Neuber, Christin; Pufe, Johanna; Pietzsch, Jens

2015-01-01

Survivors of Hodgkin's disease as well as of breast and lung cancer are at risk of radiation-associated cardiovascular disease. Recent studies demonstrated a correlation between cardiovascular risk factors and circulating endothelial microparticles (EMP) and thereby suggest increased EMP levels in circulation to be an early biomarker of endothelial dysfunction and cardiovascular risk. This prompted us to analyze the amount of EMP released by human aortic endothelial cells (HAEC) after exposure to different doses of X-ray (0.4, 2, 4, 6, and 20 Gy) using antibodies against the endothelial cell markers CD31, CD144, and CD146 by flow cytometry. In this pilot experiment only CD146 proved appropriate for quantification of HAEC-derived EMP. Exposure of HAEC to different doses of X-ray did not significantly influence formation of CD146-positive EMP. However, low doses (0.4 Gy) tended to decrease EMP formation, whereas higher doses (2 or 4 Gy) slightly increased release of CD146-positive EMP. By contrast, inflammatory activation of HAEC by TPA significantly increased EMP release about 15-fold (P <  0.01). In conclusion, under the present experimental conditions EMP did not prove a suitable biomarker for radiation-induced endothelial dysfunction in vitro.

Why is coronary collateral growth impaired in type II diabetes and the metabolic syndrome?

PubMed Central

Rocic, Petra

2012-01-01

Type II diabetes and the metabolic syndrome are strong predictors of severity of occlusive coronary disease and poorer outcomes of coronary revascularization therapies. Coronary collateral growth can provide an alternative or accessory pathway of revascularization. However, collateral growth is impaired in type II diabetes and the metabolic syndrome. Although many factors necessary for collateral growth are known and many interventions have shown promising results in animal studies, not a single attempt to induce coronary collateral growth in human clinical trials has led to satisfactory results. Accordingly, the first part of this review outlines the known deleterious effects of diabetes and the metabolic syndrome on factors necessary for collateral growth, including pro-angiogenic growth factors, endothelial function, the redox state of the coronary circulation, intracellular signaling, leukocytes and bone marrow-derived progenitors cells. The second section highlights the gaps in our current knowledge of how these factors interact with the radically altered environment of the coronary circulation in diabetes and the metabolic syndrome. The interplay between these pathologies and inadequately explored areas related to the temporal regulation of collateral remodeling and the roles of the extracellular matrix, vascular cell phenotype and pro-inflammatory cytokines are emphasized with implications to development of efficient therapies. PMID:22342811

Deep hypothermia therapy attenuates LPS-induced microglia neuroinflammation via the STAT3 pathway.

PubMed

Tong, G; Krauss, A; Mochner, J; Wollersheim, S; Soltani, P; Berger, F; Schmitt, K R L

2017-09-01

Deep hypothermia therapy (HT) is a standard method for neuroprotection during complex pediatric cardiac surgery involving extracorporeal circulation and deep hypothermic cardiac arrest. The procedure, however, can provoke systemic inflammatory response syndrome (SIRS), one of the most severe side effects associated with pediatric cardiac surgery. To date, the cellular inflammatory mechanisms induced by deep HT remain to be elucidated. Therefore, we investigated the effects of deep HT (17°C) and rewarming on the inflammatory response in lipopolysaccharide (LPS) stimulated BV-2 murine microglia. Additionally, we also investigated the application of Stattic, a signal transducer and activator of transcription 3 (STAT3) activation inhibitor, as an alternative to physical cooling to attenuate the LPS-induced inflammatory response. Deep HT had no cytotoxic effect but attenuated microglia migration. IκBα degradation was delayed by deep HT resulting in the attenuation of pNF-κB p65 migration into the nucleus and significant decreases in pro-inflammatory IL-6, TNF-α, and MCP-1 expressions and secretions, as well as decreased anti-inflammatory IL-10 and SOCS3 expressions. Additionally, pStat3 was significantly down regulated under deep hypothermic conditions, also corresponding with the significant reduction in IL-6 and TNF-α expressions. Similar to the effects of HT, the application of Stattic under normothermic conditions resulted in significantly reduced IL-6 and TNF-α expressions. Moreover, attenuation of the inflammatory response resulted in decreased apoptosis in a direct co-culture of microglia and neurons. HT reduces the inflammatory response in LPS-stimulated BV-2 microglial cells, alluding to a possible mechanism of therapeutic hypothermia-induced neuroprotection. In the future, attenuating the phospho-STAT3 pathway may lead to the development of a neuroprotectant with greater clinical efficacy. Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

Evaluation of Chitotriosidase as a Marker of Inflammatory Status in Critical Limb Ischemia.

PubMed

Ciocan, Răzvan A; Drugan, Cristina; Gherman, Claudia D; Cătană, Cristina-Sorina; Ciocan, Andra; Drugan, Tudor C; Bolboacă, Sorana D

2017-11-01

Chitotriosidase is an enzyme secreted by activated macrophages. This study aims to investigate the usefulness of circulating chitotriosidase activity as a marker of inflammatory status in patients with critical limb ischemia (CLI). An observational gender-matched case-control study was conducted on patients hospitalized with the primary diagnosis of CLI, as well as a control group. The control group consisted of healthy volunteers. Forty-three patients were included in each group. Similar demographic characteristics (median age of 60-62 years and overweight) were observed in both groups. Chitotriosidase activity ranged from 110 nmol/ml/hr to 1530 nmol/ml/hr in the CLI group and from 30 nmol/ml/hr to 440 nmol/ml/hr in the control group; demonstrating significantly elevated values in the CLI group ( p <0.001). Median plasma chitotriosidase activity was significantly elevated in smokers compared with non-smokers in both groups ( p <0.05). However, this activity had higher values in CLI than in control subjects. Receiver operating characteristic (ROC) analysis was then performed in order to verify the diagnostic accuracy of chitotriosidase as an inflammatory biomarker in CLI. Circulating chitotriosidase is a test which can potentially be used for the monitoring of CLI patients without other inflammatory conditions. However, the interpretation of elevated values must take into account the inflammatory response induced by tobacco exposure. © 2017 by the Association of Clinical Scientists, Inc.

MIP-2 causes differential activation of RhoA in mouse aortic versus pulmonary artery endothelial cells

PubMed Central

Moldobaeva, Aigul; Baek, Amy; Wagner, Elizabeth M.

2008-01-01

Previously, we have shown that endothelial cell chemotaxis to the proangiogenic chemokine MIP-2 (macrophage inflammatory protein-2), is much greater in mouse aortic endothelial cells (EC) than pulmonary arterial endothelial cells (PA EC). This was true despite the observation that both cell types display comparable levels of the ligand receptor, CXCR2 (8). Since the systemic arterial circulation is proangiogenic in the adult lung and the pulmonary circulation is relatively resistant to neovascularization, we questioned whether the observed functional heterogeneity is related to inherent differences in cell signaling cascades of the two EC subtypes. Specifically, we measured activation of Rac1 and RhoA, both thought to be involved in EC cell migration. Rac1 showed inconsistent and minimal changes in both cell types after MIP-2 treatment (p>0.05). However, activated RhoA was increased upon exposure to MIP-2 only in aortic EC (61% increase; p<0.05). Decreased RhoA activation after treatment of aortic EC with specific siRNA for RhoA resulted in a functional decrease in EC chemotaxis to MIP-2 (17% increase; p<0.05). Additionally, increased RhoA activation in PA EC with adenoviral infection of RhoA caused an increase in PA EC chemotaxis to MIP-2 (46% increase; p<0.05). Inhibition of RhoA activity with the Rho kinase inhibitor, Y27632 blocked aortic EC chemotaxis and stress fiber formation. Thus, RhoA activation is increased after MIP-2 treatment in mouse aortic endothelial cells but not in pulmonary artery endothelial cells. We conclude that RhoA is part of a signaling pathway essential for aortic cell migration after CXCR2 ligation. This result provides one explanation for the difference in chemotaxis observed in these two endothelial subtypes that express similar levels of CXCR2. PMID:17662312

Higher Circulating Leukocytes in Women with PCOS is Reversed by Aerobic Exercise

PubMed Central

Covington, Jeffrey D.; Tam, Charmaine S.; Pasarica, Magdalena; Redman, Leanne M.

2014-01-01

Polycystic ovary syndrome (PCOS) is characterized by insulin resistance, elevated circulating leukocytes, and hypothesized to have higher adipose tissue inflammation. Aerobic exercise reduces circulating leukocytes and improves insulin sensitivity in obese individuals, but the effect of exercise on inflammation in PCOS is not known. We investigated circulating leukocytes, insulin sensitivity by euglycemic-hyperinsulinemic clamp, serum pro- and anti-inflammatory markers (hsCRP, TNF-α, total and high molecular weight adiponectin), and abdominal subcutaneous adipose tissue (SAT) gene expression of proinflammatory markers in 8 PCOS women and 8 obese control females matched for BMI. Additionally, in a prospective study, the 8 women with PCOS underwent a 16-week aerobic exercise regimen with the same measures performed post-intervention. Compared to controls, white blood cell counts (WBC) were 30% higher (p = 0.04) and circulating total adiponectin levels were 150% lower (p = 0.03) in women with PCOS at baseline/pre-exercise conditions. SAT gene expression of macrophage migration inhibitory factor (MIF, p < 0.01) and interleukin-6 (IL-6, p < 0.05) were also lower in women with PCOS. In response to 16 weeks of aerobic exercise, insulin sensitivity improved (p < 0.01) and WBC counts decreased (p = 0.02). The exercise-induced change in WBC and circulating neutrophils correlated inversely with changes in glucose disposal rate (r= -0.73, p=0.03; and r= -0.82, p=0.01, respectively). Aerobic exercise reduced serum leptin (p < 0.05) after 4 weeks, trended to reduce the ratio of leptin-to-high molecular weight adiponectin (p < 0.1) by the 8th week, and significantly increased serum dehydroepiandrosterone sulfate (DHEA-S, p < 0.001) after 16 weeks. In conclusion, women with PCOS have higher circulating leukocytes compared to controls, which can be reversed by aerobic exercise and is associated with improvements in insulin sensitivity. PMID:25446648

Tracking flow of leukocytes in blood for drug analysis

NASA Astrophysics Data System (ADS)

Basharat, Arslan; Turner, Wesley; Stephens, Gillian; Badillo, Benjamin; Lumpkin, Rick; Andre, Patrick; Perera, Amitha

2011-03-01

Modern microscopy techniques allow imaging of circulating blood components under vascular flow conditions. The resulting video sequences provide unique insights into the behavior of blood cells within the vasculature and can be used as a method to monitor and quantitate the recruitment of inflammatory cells at sites of vascular injury/ inflammation and potentially serve as a pharmacodynamic biomarker, helping screen new therapies and individualize dose and combinations of drugs. However, manual analysis of these video sequences is intractable, requiring hours per 400 second video clip. In this paper, we present an automated technique to analyze the behavior and recruitment of human leukocytes in whole blood under physiological conditions of shear through a simple multi-channel fluorescence microscope in real-time. This technique detects and tracks the recruitment of leukocytes to a bioactive surface coated on a flow chamber. Rolling cells (cells which partially bind to the bioactive matrix) are detected counted, and have their velocity measured and graphed. The challenges here include: high cell density, appearance similarity, and low (1Hz) frame rate. Our approach performs frame differencing based motion segmentation, track initialization and online tracking of individual leukocytes.

Oxidative stress and reduced responsiveness of challenged circulating leukocytes following pulmonary instillation of metal-rich particulate matter in rats

PubMed Central

2014-01-01

Welding fume is an exposure that consists of a mixture of metal-rich particulate matter with gases (ozone, carbon monoxide) and/or vapors (VOCs). Data suggests that welders are immune compromised. Given the inability of pulmonary leukocytes to properly respond to a secondary infection in animal models, the question arose whether the dysfunction persisted systemically. Our aim was to evaluate the circulating leukocyte population in terms of cellular activation, presence of oxidative stress, and functionality after a secondary challenge, following welding fume exposure. Rats were intratracheally instilled (ITI) with PBS or 2 mg of welding fume collected from a stainless steel weld. Rats were sacrificed 4 and 24 h post-exposure and whole blood was collected. Whole blood was used for cellular differential counts, RNA isolation with subsequent microarray and Ingenuity Pathway Analysis, and secondary stimulation with LPS utilizing TruCulture technology. In addition, mononuclear cells were isolated 24 h post-exposure to measure oxidative stress by flow cytometry and confocal microscopy. Welding fume exposure had rapid effects on the circulating leukocyte population as identified by relative mRNA expression changes. Instillation of welding fume reduced inflammatory protein production of circulating leukocytes when challenged with the secondary stimulus LPS. The effects were not related to transcription, but were observed in conjunction with oxidative stress. These findings support previous studies of an inadequate pulmonary immune response following a metal-rich exposure and extend those findings showing leukocyte dysfunction occurs systemically. PMID:25123171

Oxidative stress and reduced responsiveness of challenged circulating leukocytes following pulmonary instillation of metal-rich particulate matter in rats.

PubMed

Erdely, Aaron; Antonini, James M; Young, Shih-Houng; Kashon, Michael L; Gu, Ja K; Hulderman, Tracy; Salmen, Rebecca; Meighan, Terence; Roberts, Jenny R; Zeidler-Erdely, Patti C

2014-08-15

Welding fume is an exposure that consists of a mixture of metal-rich particulate matter with gases (ozone, carbon monoxide) and/or vapors (VOCs). Data suggests that welders are immune compromised. Given the inability of pulmonary leukocytes to properly respond to a secondary infection in animal models, the question arose whether the dysfunction persisted systemically. Our aim was to evaluate the circulating leukocyte population in terms of cellular activation, presence of oxidative stress, and functionality after a secondary challenge, following welding fume exposure. Rats were intratracheally instilled (ITI) with PBS or 2 mg of welding fume collected from a stainless steel weld. Rats were sacrificed 4 and 24 h post-exposure and whole blood was collected. Whole blood was used for cellular differential counts, RNA isolation with subsequent microarray and Ingenuity Pathway Analysis, and secondary stimulation with LPS utilizing TruCulture technology. In addition, mononuclear cells were isolated 24 h post-exposure to measure oxidative stress by flow cytometry and confocal microscopy. Welding fume exposure had rapid effects on the circulating leukocyte population as identified by relative mRNA expression changes. Instillation of welding fume reduced inflammatory protein production of circulating leukocytes when challenged with the secondary stimulus LPS. The effects were not related to transcription, but were observed in conjunction with oxidative stress. These findings support previous studies of an inadequate pulmonary immune response following a metal-rich exposure and extend those findings showing leukocyte dysfunction occurs systemically.

Circulating nucleic acids as possible damage-associated molecular patterns in different stages of renal failure.

PubMed

Kocić, Gordana; Radenkovic, Sonja; Cvetkovic, Tatjana; Cencic, Avrelija; Carluccio, Francesco; Musovic, Dijana; Nikolić, Goran; Jevtović-Stoimenov, Tatjana; Sokolović, Dusan; Milojkovic, Boban; Basic, Jelena; Veljkovic, Andrej; Stojanović, Svetlana

2010-05-01

Chronic renal failure (CRF) is a condition associated with the risk of cardiovascular complications. Systemic inflammatory response, initiated by the pathogen-associated molecular-pattern (PAMP) molecules, exerts many similarities with the damage-associated molecular-pattern (DAMP) molecule-induced systemic response. Up to now, a number of DAMP molecules were identified. We hypothesized that the available circulating nucleic acids, acting as DAMPs, may modulate immunoinflammatory reaction in CRF. Patients with the different stages of chronic kidney disease, kidney transplantation, and patients on dialysis were included in the study. Obtained results about higher concentration of circulating ribonucleic acid (RNA), according to the stages of kidney diseases, may contribute to the hypothesis that damaged kidney tissue releases nucleic acids. Circulating RNAs expressed maximal absorbance peak at 270 nm in spectrophotometric scan analysis, which corresponded to polyC, compared to different standard samples. During in vitro conditions, by using the culture of human residential macrophages, circulating RNA isolated from patients with IV-V-stage renal diseases, patients on hemodialysis, and patients who underwent renal transplantation were able to significantly change signal transduction proteins related to inflammation and antiviral response. They significantly increased the intracellular concentration of active nuclear transcription factor nuclear factor kappa B (NF-kappaB), interferon regulatory factors (IRF)-3, and IRF-7 and significantly decreased melanoma differentiation-associated protein-5 (MDA-5) and p38. In this way, it seems that circulating RNA, acting as DAMP, may contribute to the mechanisms of additional inflammatory reaction, possible immune destruction, and decreased antiviral response, related to complications in kidney diseases.

Prognostic impact of circulating plasma cells in patients with multiple myeloma: implications for plasma cell leukemia definition

PubMed Central

Granell, Miquel; Calvo, Xavier; Garcia-Guiñón, Antoni; Escoda, Lourdes; Abella, Eugènia; Martínez, Clara Mª; Teixidó, Montserrat; Gimenez, Mª Teresa; Senín, Alicia; Sanz, Patricia; Campoy, Desirée; Vicent, Ana; Arenillas, Leonor; Rosiñol, Laura; Sierra, Jorge; Bladé, Joan; de Larrea, Carlos Fernández

2017-01-01

The presence of circulating plasma cells in patients with multiple myeloma is considered a marker for highly proliferative disease. In the study herein, the impact of circulating plasma cells assessed by cytology on survival of patients with multiple myeloma was analyzed. Wright-Giemsa stained peripheral blood smears of 482 patients with newly diagnosed myeloma or plasma cell leukemia were reviewed and patients were classified into 4 categories according to the percentage of circulating plasma cells: 0%, 1–4%, 5–20%, and plasma cell leukemia with the following frequencies: 382 (79.2%), 83 (17.2%), 12 (2.5%) and 5 (1.0%), respectively. Median overall survival according to the circulating plasma cells group was 47, 50, 6 and 14 months, respectively. At multivariate analysis, the presence of 5 to 20% circulating plasma cells was associated with a worse overall survival (relative risk 4.9, 95% CI 2.6–9.3) independently of age, creatinine, the Durie-Salmon system stage and the International Staging System (ISS) stage. Patients with ≥5% circulating plasma cells had lower platelet counts (median 86×109/L vs. 214×109/L, P<0.0001) and higher bone marrow plasma cells (median 53% vs. 36%, P=0.004). The presence of ≥5% circulating plasma cells in patients with multiple myeloma has a similar adverse prognostic impact as plasma cell leukemia. PMID:28255016

Two C-C Family Chemokines, Eotaxin and RANTES, Are Novel Independent Plasma Biomarkers for Abdominal Aortic Aneurysm.

PubMed

Jones, Gregory T; Phillips, L Victoria; Williams, Michael J A; van Rij, Andre M; Kabir, Tasnuva D

2016-04-28

Inflammation of the aortic wall is recognised as a key pathogenesis of abdominal aortic aneurysm (AAA). This study was undertaken to determine whether inflammatory cytokines could be used as biomarkers for the presence of AAA. Tissue profiles of 27 inflammatory cytokine were examined in AAA (n=14) and nonaneurysmal (n=14) aortic tissues. Three cytokines, regulated upon activation normally T-cell expressed and secreted (RANTES), eotaxin, and macrophage inflammatory protein 1 beta (MIP-1b), had increased expression in AAA, particularly within the adventitial layer of the aortic wall. Basic fibroblast growth factor (bFGF) had reduced expression in all layers of the AAA wall. Examination of the circulating plasma profiles of AAA (n=442) and AAA-free controls (n=970) suggested a (risk factor adjusted) AAA-association with eotaxin, RANTES, and high sensitivity C-reactive protein (hsCRP). A plasma inflammatory cytokine score, calculated using these three markers, suggested a strong risk association with AAA (odds ratio, 4.8; 95% CI, 3.5-6.7; P<0.0001), independent of age, sex, history of ischemic heart disease, and smoking. Contrary to reports suggesting a distinct T helper 2-associated inflammatory profile in AAA, this current study suggests a more-generalized pattern of inflammation, albeit with some potentially distinct features, including elevated plasma eotaxin and decreased plasma RANTES. In combination with hsCRP, these markers may have potential utility as AAA biomarkers. © 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Whey and Casein Proteins and Medium-Chain Saturated Fatty Acids from Milk Do Not Increase Low-Grade Inflammation in Abdominally Obese Adults.

PubMed

Bohl, Mette; Bjørnshave, Ann; Gregersen, Søren; Hermansen, Kjeld

2016-01-01

Low-grade inflammation is involved in the development of diabetes and cardiovascular disease (CVD). Inflammation can be modulated by dietary factors. Dairy products are rich in saturated fatty acids (SFA), which are known to possess pro-inflammatory properties. However, different fatty acid compositions may exert different effects. Other components such as milk proteins may exert anti-inflammatory properties which may compensate for the potential negative effects of SFAs. Generally, the available data suggest a neutral role of dairy product consumption on inflammation. To investigate the effects of, and potential interaction between, a dietary supplementation with whey protein and milk fat, naturally enriched in medium-chain SFA (MC-SFA), on inflammatory markers in abdominal obese adults. The study was a 12-week, randomized, double-blinded, intervention study. Sixty-three adults were equally allocated to one of four groups which received a supplement of either 60 g/day whey or 60 g/day casein plus 63 g/day milk fat either high or low in MC-SFA content. Fifty-two subjects completed the study. Before and after the intervention, changes in plasma interleukin-6 (IL-6), interleukin-1 receptor antagonist (IL-1RA), high-sensitive C-reactive protein (hsCRP), adiponectin, and monocyte chemoattractant protein-1 (MCP-1) were measured. Changes in inflammatory genes in the subcutaneous adipose tissue were also documented. There were no differences in circulating inflammatory markers between protein types or fatty acid compositions in abdominally obese subjects, with the exception of an increase in adiponectin in response to high compared to low MC-SFA consumption in women. We found that combined dairy proteins and MC-SFAs influenced inflammatory gene expression in adipose tissue, while no effect was detected by dairy proteins or MC-SFA per se. Whey protein compared with casein and MC-SFA-enriched milk fat did not alter circulating markers of low-grade inflammation in abdominally obese subjects, except for an increase in circulating adiponectin in response to high MC-SFA in abdominally obese women.

Myeloid-cell protein tyrosine phosphatase-1B deficiency in mice protects against high-fat diet and lipopolysaccharide-induced inflammation, hyperinsulinemia, and endotoxemia through an IL-10 STAT3-dependent mechanism.

PubMed

Grant, Louise; Shearer, Kirsty D; Czopek, Alicja; Lees, Emma K; Owen, Carl; Agouni, Abdelali; Workman, James; Martin-Granados, Cristina; Forrester, John V; Wilson, Heather M; Mody, Nimesh; Delibegovic, Mirela

2014-02-01

Protein tyrosine phosphatase-1B (PTP1B) negatively regulates insulin and leptin signaling, rendering it an attractive drug target for treatment of obesity-induced insulin resistance. However, some studies suggest caution when targeting macrophage PTP1B, due to its potential anti-inflammatory role. We assessed the role of macrophage PTP1B in inflammation and whole-body metabolism using myeloid-cell (LysM) PTP1B knockout mice (LysM PTP1B). LysM PTP1B mice were protected against lipopolysaccharide (LPS)-induced endotoxemia and hepatic damage associated with decreased proinflammatory cytokine secretion in vivo. In vitro, LPS-treated LysM PTP1B bone marrow-derived macrophages (BMDMs) displayed increased interleukin (IL)-10 mRNA expression, with a concomitant decrease in TNF-α mRNA levels. These anti-inflammatory effects were associated with increased LPS- and IL-10-induced STAT3 phosphorylation in LysM PTP1B BMDMs. Chronic inflammation induced by high-fat (HF) feeding led to equally beneficial effects of macrophage PTP1B deficiency; LysM PTP1B mice exhibited improved glucose and insulin tolerance, protection against LPS-induced hyperinsulinemia, decreased macrophage infiltration into adipose tissue, and decreased liver damage. HF-fed LysM PTP1B mice had increased basal and LPS-induced IL-10 levels, associated with elevated STAT3 phosphorylation in splenic cells, IL-10 mRNA expression, and expansion of cells expressing myeloid markers. These increased IL-10 levels negatively correlated with circulating insulin and alanine transferase levels. Our studies implicate myeloid PTP1B in negative regulation of STAT3/IL-10-mediated signaling, highlighting its inhibition as a potential anti-inflammatory and antidiabetic target in obesity.

Perinatal stress, brain inflammation and risk of autism-Review and proposal

PubMed Central

2012-01-01

Background Autism Spectrum Disorders (ASD) are neurodevelopmental disorders characterized by varying deficits in social interactions, communication, and learning, as well as stereotypic behaviors. Despite the significant increase in ASD, there are few if any clues for its pathogenesis, hampering early detection or treatment. Premature babies are also more vulnerable to infections and inflammation leading to neurodevelopmental problems and higher risk of developing ASD. Many autism “susceptibility” genes have been identified, but “environmental” factors appear to play a significant role. Increasing evidence suggests that there are different ASD endophenotypes. Discussion We review relevant literature suggesting in utero inflammation can lead to preterm labor, while insufficient development of the gut-blood–brain barriers could permit exposure to potential neurotoxins. This risk apparently may increase in parents with “allergic” or autoimmune problems during gestation, or if they had been exposed to stressors. The presence of circulating auto-antibodies against fetal brain proteins in mothers is associated with higher risk of autism and suggests disruption of the blood–brain-barrier (BBB). A number of papers have reported increased brain expression or cerebrospinal fluid (CSF) levels of pro-inflammatory cytokines, especially TNF, which is preformed in mast cells. Recent evidence also indicates increased serum levels of the pro-inflammatory mast cell trigger neurotensin (NT), and of extracellular mitochondrial DNA (mtDNA), which is immunogenic. Gene mutations of phosphatase and tensin homolog (PTEN), the negative regulator of the mammalian target of rapamycin (mTOR), have been linked to higher risk of autism, but also to increased proliferation and function of mast cells. Summary Premature birth and susceptibility genes may make infants more vulnerable to allergic, environmental, infectious, or stress-related triggers that could stimulate mast cell release of pro-inflammatory and neurotoxic molecules, thus contributing to brain inflammation and ASD pathogenesis, at least in an endophenotype of ASD patients. PMID:22747567

Dysregulation of miR-31 and miR-21 induced by zinc deficiency promotes esophageal cancer

PubMed Central

Croce, Carlo M; Fong, Louise Y.Y

2012-01-01

Zinc deficiency (ZD) increases the risk of esophageal squamous cell carcinoma (ESCC). In a rat model, chronic ZD induces an inflammatory gene signature that fuels ESCC development. microRNAs regulate gene expression and are aberrantly expressed in cancers. Here we investigated whether chronic ZD (23 weeks) also induces a protumorigenic microRNA signature. Using the nanoString technology, we evaluated microRNA profiles in ZD esophagus and six additional tissues (skin, lung, pancreas, liver, prostate and peripheral blood mononuclear cells [PBMC]). ZD caused overexpression of inflammation genes and altered microRNA expression across all tissues analyzed, predictive of disease development. Importantly, the inflammatory ZD esophagus had a distinct microRNA signature resembling human ESCC or tongue SCC miRNAomes with miR-31 and miR-21 as the top-up-regulated species. Circulating miR-31 was also the top-up-regulated species in PBMCs. In ZD esophagus and tongue, oncogenic miR-31 and miR-21 overexpression was accompanied by down-regulation of their respective tumor-suppressor targets PPP2R2A and PDCD4. Importantly, esophageal miR-31 and miR-21 levels were directly associated with the appearance of ESCC in ZD rats, as compared with their cancer-free Zn-sufficient or Zn-replenished counterparts. In situ hybridization analysis in rat and human tongue SCCs localized miR-31 to tumor cells and miR-21 to stromal cells. In regressing tongue SCCs from Zn-supplemented rats, miR-31 and miR-21 expression was concomitantly reduced, establishing their responsiveness to Zn therapy. A search for putative microRNA targets revealed a bias toward genes in inflammatory pathways. Our finding that ZD causes miR-31 and miR-21 dysregulation associated with inflammation provides insight into mechanisms whereby ZD promotes ESCC. PMID:22689922

Mesenchymal Stromal Cells Modulate Monocytes Trafficking in Coxsackievirus B3‐Induced Myocarditis

PubMed Central

Miteva, Kapka; Pappritz, Kathleen; El‐Shafeey, Muhammad; Dong, Fengquan; Ringe, Jochen; Tschöpe, Carsten

2017-01-01

Abstract Mesenchymal stromal cell (MSC) application in Coxsackievirus B3 (CVB3)‐induced myocarditis reduces myocardial inflammation and fibrosis, exerts prominent extra‐cardiac immunomodulation, and improves heart function. Although the abovementioned findings demonstrate the benefit of MSC application, the mechanism of the MSC immunomodulatory effects leading to a final cardioprotective outcome in viral myocarditis remains poorly understood. Monocytes are known to be a trigger of myocardial tissue inflammation. The present study aims at investigating the direct effect of MSC on the mobilization and trafficking of monocytes to the heart in CVB3‐induced myocarditis. One day post CVB3 infection, C57BL/6 mice were intravenously injected with 1 x 106 MSC and sacrificed 6 days later for molecular biology and flow cytometry analysis. MSC application reduced the severity of myocarditis, and heart and blood pro‐inflammatory Ly6Chigh and Ly6Cmiddle monocytes, while those were retained in the spleen. Anti‐inflammatory Ly6Clow monocytes increased in the blood, heart, and spleen of MSC‐treated CVB3 mice. CVB3 infection induced splenic myelopoiesis, while MSC application slightly diminished the spleen myelopoietic activity in CVB3 mice. Left ventricular (LV) mRNA expression of the chemokines monocyte chemotactic protein‐1 (MCP)−1, MCP‐3, CCL5, the adhesion molecules intercellular adhesion molecule‐1, vascular cell adhesion molecule‐1, the pro‐inflammatory cytokines interleukin‐6, interleukin‐12, tumor necrosis factor‐α, the pro‐fibrotic transforming growth factorβ1, and circulating MCP‐1 and MCP‐3 levels decreased in CVB3 MSC mice, while LV stromal cell‐derived factor‐1α RNA expression and systemic levels of fractalkine were increased in CVB3 MSC mice. MSC application in CVB3‐induced myocarditis modulates monocytes trafficking to the heart and could be a promising strategy for the resolution of cardiac inflammation and prevention of the disease progression. Stem Cells Translational Medicine 2017;6:1249–1261 PMID:28186704

Evidence for circulating cancer stem-like cells and epithelial-mesenchymal transition phenotype in the pleurospheres derived from lung adenocarcinoma using liquid biopsy.

PubMed

Mirza, Sheefa; Jain, Nayan; Rawal, Rakesh

2017-03-01

Lung cancer stem cells are supposed to be the main drivers of tumor initiation, maintenance, drug resistance, and relapse of the disease. Hence, identification of the cellular and molecular aspects of these cells is a prerequisite for targeted therapy of lung cancer. Currently, analysis of circulating tumor cells has the potential to become the main diagnostic technique to monitor disease progression or therapeutic response as it is non-invasive. However, accurate detection of circulating tumor cells has remained a challenge, as epithelial cell markers used so far are not always trustworthy for detecting circulating tumor cells, especially during epithelial-mesenchymal transition. As cancer stem cells are the only culprit to initiate metastatic tumors, our aim was to isolate and characterize circulating tumor stem cells rather than circulating tumor cells from the peripheral blood of NSCLC adenocarcinoma as limited data are available addressing the gene expression profiling of lung cancer stem cells. Here, we reveal that CD44(+)/CD24(-) population in circulation not only exhibit stem cell-related genes but also possess epithelial-mesenchymal transition characteristics. In conclusion, the use of one or more cancer stem cell markers along with epithelial, mesenchymal and epithelial mesenchymal transition markers will prospectively provide the most precise assessment of the threat for recurrence and metastatic disease and has a great potential for forthcoming applications in harvesting circulating tumor stem cells and their downstream applications. Our results will aid in developing diagnostic and prognostic modalities and personalized treatment regimens like dendritic cell-based immunotherapy that can be utilized for targeting and eliminating circulating tumor stem cells, to significantly reduce the possibility of relapse and improve clinical outcomes.

The Synthetic Antimicrobial Peptide 19-2.5 Interacts with Heparanase and Heparan Sulfate in Murine and Human Sepsis.

PubMed

Martin, Lukas; De Santis, Rebecca; Koczera, Patrick; Simons, Nadine; Haase, Hajo; Heinbockel, Lena; Brandenburg, Klaus; Marx, Gernot; Schuerholz, Tobias

2015-01-01

Heparanase is an endo-β-glucuronidase that cleaves heparan sulfate side chains from their proteoglycans. Thereby, heparanase liberates highly potent circulating heparan sulfate-fragments (HS-fragments) and triggers the fatal and excessive inflammatory response in sepsis. As a potential anti-inflammatory agent for sepsis therapy, peptide 19-2.5 belongs to the class of synthetic anti-lipopolysaccharide peptides; however, its activity is not restricted to Gram-negative bacterial infection. We hypothesized that peptide 19-2.5 interacts with heparanase and/or HS, thereby reducing the levels of circulating HS-fragments in murine and human sepsis. Our data indicate that the treatment of septic mice with peptide 19-2.5 compared to untreated control animals lowers levels of plasma heparanase and circulating HS-fragments and reduces heparanase activity. Additionally, mRNA levels of heparanase in heart, liver, lung, kidney and spleen are downregulated in septic mice treated with peptide 19-2.5 compared to untreated control animals. In humans, plasma heparanase level and activity are elevated in septic shock. The ex vivo addition of peptide 19-2.5 to plasma of septic shock patients decreases heparanase activity but not heparanase level. Isothermal titration calorimetry revealed a strong exothermic reaction between peptide 19-2.5 and heparanase and HS-fragments. However, a saturation character has been identified only in the peptide 19-2.5 and HS interaction. In conclusion, the findings of our current study indicate that peptide 19-2.5 interacts with heparanase, which is elevated in murine and human sepsis and consecutively attenuates the generation of circulating HS-fragments in systemic inflammation. Thus, peptide 19-2.5 seems to be a potential anti-inflammatory agent in sepsis.

High levels of circulating TNFR1 increase the risk of all-cause mortality and progression of renal disease in type 2 diabetic nephropathy.

PubMed

Fernández-Juárez, Gema; Villacorta Perez, Javier; Luño Fernández, José Luis; Martinez-Martinez, Ernesto; Cachofeiro, Victoria; Barrio Lucia, Vicente; Tato Ribera, Ana M; Mendez Abreu, Angel; Cordon, Alfredo; Oliva Dominguez, Jesus Angel; Praga Terente, Manuel

2017-05-01

Several studies have demonstrated that levels of circulating inflammatory markers such as tumour necrosis factorα (TNFα), are associated with early progression of diabetic nephropathy (DN). The aim of this study was to investigate whether there is an association between circulating TNFα receptor and disease progression in patients with advanced type 2 DN and severe proteinuria. Between 2006 and 2011, we measured levels of circulating soluble TNFα receptor 1 (TNFR1) and soluble TNFα receptor 2 (TNFR2) at baseline and 4 and 12 months in 101 patients included in a multicenter randomized controlled trial to compare the effect of optimal doses of renin-angiotensin system blockers in monotherapy or in combination (dual blockade) to slow progression of established type 2 DN. The primary composite endpoint was a >50% increase in baseline serum creatinine, end-stage renal disease, or death. The median follow-up was 32 months (IQR, 18-48), during which time 28 patients (22.7%) achieved the primary endpoint. The TNFR1 level, but not the TNFR2 level, was correlated with other inflammatory markers. Cox regression analysis showed that the highest TNFR1 levels (HR, 2.60; 95%CI, 1.11-86.34) and baseline proteinuria (HR 1.32; 95%CI 1.15-1.52) were associated with the primary endpoint. The mixed model analysis revealed that TNFR1 and the TNFR2 levels did not change after starting treatment with renin-angiotensin system blockers. Our results show that the highest levels of TNFR1 are independently associated with progression of renal disease and death in type 2 DN. The renin angiotensin blockers have no effect on these inflammatory markers. © 2016 Asian Pacific Society of Nephrology.

Intrauterine growth restriction increases circulating mitochondrial DNA and Toll-like receptor 9 expression in adult offspring: could aerobic training counteract these adaptations?

PubMed

Oliveira, V; Silva Junior, S D; de Carvalho, M H C; Akamine, E H; Michelini, L C; Franco, M C

2017-04-01

It has been demonstrated that intrauterine growth restriction (IUGR) can program increase cardiometabolic risk. There are also evidences of the correlation between IUGR with low-grade inflammation and, thus can contribute to development of several cardiometabolic comorbidities. Therefore, we investigated the influence of IUGR on circulating mitochondrial DNA (mtDNA)/Toll-like receptor 9 (TLR9) and TNF-α expression in adult offspring. Considering that the aerobic training has anti-inflammatory actions, we also investigated whether aerobic training would improve these inflammatory factors. Pregnant Wistar rats received ad libitum or 50% of ad libitum diet throughout gestation. At 8 weeks of age, male offspring from both groups were randomly assigned to control, trained control, restricted and trained restricted. Aerobic training protocol was performed on a treadmill and after that, we evaluated circulating mtDNA, cardiac protein expression of TLR9, plasma and cardiac TNF-α levels, and left ventricle (LV) mass. We found that IUGR promoted an increase in the circulating mtDNA, TLR9 expression and plasma TNF-α levels. Further, our results revealed that aerobic training can restore mtDNA/TLR9 content and plasma levels of TNF-α among restricted rats. The cardiac TNF-α content and LV mass were not influenced either by IUGR or aerobic training. In conclusion, IUGR can program mtDNA/TLR9 content, which may lead to high levels of TNF-α. However, aerobic training was able to normalize these alterations. These findings evidenced that the association of IUGR and aerobic training seems to exert an important interaction effect regarding pro-inflammatory condition and, aerobic training may be used as a strategy to reduce deleterious adaptations in IUGR offspring.

Facilitatory effects of fetuin-A on atherosclerosis.

PubMed

Naito, Chisato; Hashimoto, Mio; Watanabe, Kaho; Shirai, Remina; Takahashi, Yui; Kojima, Miho; Watanabe, Rena; Sato, Kengo; Iso, Yoshitaka; Matsuyama, Taka-Aki; Suzuki, Hiroshi; Ishibashi-Ueda, Hatsue; Watanabe, Takuya

2016-03-01

Fetuin-A is a circulating glycoprotein that is produced by liver and adipose tissue. Fetuin-A is known to induce insulin resistance and suppress vascular calcification. There are conflicting reports that show increased or decreased serum fetuin-A levels in patients with coronary artery disease (CAD). Since the role of fetuin-A in atherosclerosis remains still controversial, we aimed to clarify it in this study. We investigated the expression of fetuin-A in atheromatous plaques in CAD patients and restenosis lesions in balloon-injured rat carotid arteries in vivo. We also assessed in vitro effects of fetuin-A on inflammatory molecules in human umbilical vein endothelial cells (HUVECs), oxidized low-density lipoprotein-induced foam cell formation in human monocyte-derived macrophages, and the migration, proliferation, and extracellular matrix expression in human aortic smooth muscle cells (HASMCs) in a serum-free culture system. Fetuin-A was abundantly expressed in cultured human monocytes, macrophages, fibroblasts, HASMCs, and human coronary artery SMCs, atheromatous plaques in human coronary arteries, and restenosis lesions in rat carotid arteries. In vitro experiments showed that fetuin-A stimulated interleukin-6, monocyte chemotactic protein-1, intercellular adhesion molecule-1, and E-selectin expression in HUVECs. Fetuin-A enhanced macrophage foam cell formation associated with scavenger receptors (CD36 and SR-A) and acyl-CoA:cholesterol acyltransferase-1 down-regulation and ATP-binding cassette transporter A1 up-regulation, and increased cell proliferation and collagen-1 and -3 expression via PI3K/AKT/c-Src/NF-κB/ERK1/2 pathways in HASMCs. Our results indicate that fetuin-A exerts the stimulatory effects on inflammatory responses in HUVECs, macrophage foam cell formation, and proliferation and collagen production in HASMCs, leading to the development of atherosclerosis. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Ageing and the telomere connection: An intimate relationship with inflammation.

PubMed

Zhang, Jingwen; Rane, Grishma; Dai, Xiaoyun; Shanmugam, Muthu K; Arfuso, Frank; Samy, Ramar Perumal; Lai, Mitchell Kim Peng; Kappei, Dennis; Kumar, Alan Prem; Sethi, Gautam

2016-01-01

Telomeres are the heterochromatic repeat regions at the ends of eukaryotic chromosomes, whose length is considered to be a determinant of biological ageing. Normal ageing itself is associated with telomere shortening. Here, critically short telomeres trigger senescence and eventually cell death. This shortening rate may be further increased by inflammation and oxidative stress and thus affect the ageing process. Apart from shortened or dysfunctional telomeres, cells undergoing senescence are also associated with hyperactivity of the transcription factor NF-κB and overexpression of inflammatory cytokines such as TNF-α, IL-6, and IFN-γ in circulating macrophages. Interestingly, telomerase, a reverse transcriptase that elongates telomeres, is involved in modulating NF-κB activity. Furthermore, inflammation and oxidative stress are implicated as pre-disease mechanisms for chronic diseases of ageing such as neurodegenerative diseases, cardiovascular disease, and cancer. To date, inflammation and telomere shortening have mostly been studied individually in terms of ageing and the associated disease phenotype. However, the interdependent nature of the two demands a more synergistic approach in understanding the ageing process itself and for developing new therapeutic approaches. In this review, we aim to summarize the intricate association between the various inflammatory molecules and telomeres that together contribute to the ageing process and related diseases. Copyright © 2015 Elsevier B.V. All rights reserved.

The possible impact of advanced glycation end products on pregnancy outcome in women with diabetes mellitus type 1.

PubMed

Pertynska-Marczewska, Magdalena; Cypryk, Katarzyna

2017-09-01

Diabetes mellitus (DM) is a group of metabolic disorders of carbohydrate metabolism in which glucose is underutilized, resulting in hyperglycemia. Reproductive impairment in poorly controlled diabetes mellitus type 1 (T1DM) results from a combined effect of insulin deficiency and hyperglycemia that disrupt the functioning of metabolic signals participating in the regulation of the reproductive system. Good metabolic control as a result of intensive insulin therapy has a great impact on the fertility and childbearing possibilities in the T1DM females. Advanced glycation end products (AGEs) are formed by nonenzymatic modification of proteins, lipids, and nucleic acids by glucose. The formation and accumulation of AGEs are known to progress at an accelerated rate in diabetes. AGEs either act on the pro-inflammatory cell surface receptors called RAGE or bind to the circulating anti-inflammatory sRAGE that prevents activation of cell-surface RAGE by AGEs and other proinflammatory ligands. Pregnancy has been found to induce a significant increase in RAGE protein levels in both myometrium and omental vasculature. This review will focus on the role of AGEs and RAGE in pregnancy complicated by DM type 1 as well as ways to reduce the rate of congenital malformations in the offspring of diabetic type 1 women.

Microwave & Magnetic (M2) Proteomics Reveals CNS-Specific Protein Expression Waves that Precede Clinical Symptoms of Experimental Autoimmune Encephalomyelitis

NASA Astrophysics Data System (ADS)

Raphael, Itay; Mahesula, Swetha; Purkar, Anjali; Black, David; Catala, Alexis; Gelfond, Jonathon A. L.; Forsthuber, Thomas G.; Haskins, William E.

2014-09-01

Central nervous system-specific proteins (CSPs), transported across the damaged blood-brain-barrier (BBB) to cerebrospinal fluid (CSF) and blood (serum), might be promising diagnostic, prognostic and predictive protein biomarkers of disease in individual multiple sclerosis (MS) patients because they are not expected to be present at appreciable levels in the circulation of healthy subjects. We hypothesized that microwave & magnetic (M2) proteomics of CSPs in brain tissue might be an effective means to prioritize putative CSP biomarkers for future immunoassays in serum. To test this hypothesis, we used M2 proteomics to longitudinally assess CSP expression in brain tissue from mice during experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. Confirmation of central nervous system (CNS)-infiltrating inflammatory cell response and CSP expression in serum was achieved with cytokine ELISPOT and ELISA immunoassays, respectively, for selected CSPs. M2 proteomics (and ELISA) revealed characteristic CSP expression waves, including synapsin-1 and α-II-spectrin, which peaked at day 7 in brain tissue (and serum) and preceded clinical EAE symptoms that began at day 10 and peaked at day 20. Moreover, M2 proteomics supports the concept that relatively few CNS-infiltrating inflammatory cells can have a disproportionally large impact on CSP expression prior to clinical manifestation of EAE.

C1q Deficiency Promotes Pulmonary Vascular Inflammation and Enhances the Susceptibility of the Lung Endothelium to Injury.

PubMed

Shah, Dilip; Romero, Freddy; Zhu, Ying; Duong, Michelle; Sun, Jianxin; Walsh, Kenneth; Summer, Ross

2015-12-04

The collectin proteins are innate immune molecules found in high concentrations on the epithelial and endothelial surfaces of the lung. While these proteins are known to have important anti-inflammatory actions in the airways of the lung little is known of their functional importance in the pulmonary circulation. We recently demonstrated that the circulating collectin protein adiponectin has potent anti-inflammatory effects on the lung endothelium, leading us to reason that other structurally related proteins might have similar effects. To test this hypothesis, we investigated the anti-inflammatory actions of C1q in lung endothelial homeostasis and the pulmonary vascular response to LPS or HCl injury. We show that lung endothelium from C1q-deficient (C1q(-/-)) mice expresses higher baseline levels of the vascular adhesion markers ICAM-1, VCAM-1, and E-selectin when compared with wild-type mice. Further, we demonstrate that these changes are associated with enhanced susceptibility of the lung to injury as evident by increased expression of adhesion markers, enhanced production of pro-inflammatory cytokines, and augmented neutrophil recruitment. Additionally, we found that C1q(-/-) mice also exhibited enhanced endothelial barrier dysfunction after injury as manifested by decreased expression of junctional adherens proteins and enhanced vascular leakage. Mechanistically, C1q appears to mediate its effects by inhibiting phosphorylation of p38 mitogen-activated protein kinase (MAPK) and blocking nuclear translocation of the P65 subunit of nuclear factor (NF)-κB. In summary, our findings indicate a previously unrecognized role for C1q in pulmonary vascular homeostasis and provide added support for the hypothesis that circulating collectin proteins have protective effects on the lung endothelium. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

C1q Deficiency Promotes Pulmonary Vascular Inflammation and Enhances the Susceptibility of the Lung Endothelium to Injury*

PubMed Central

Shah, Dilip; Romero, Freddy; Zhu, Ying; Duong, Michelle; Sun, Jianxin; Walsh, Kenneth; Summer, Ross

2015-01-01

The collectin proteins are innate immune molecules found in high concentrations on the epithelial and endothelial surfaces of the lung. While these proteins are known to have important anti-inflammatory actions in the airways of the lung little is known of their functional importance in the pulmonary circulation. We recently demonstrated that the circulating collectin protein adiponectin has potent anti-inflammatory effects on the lung endothelium, leading us to reason that other structurally related proteins might have similar effects. To test this hypothesis, we investigated the anti-inflammatory actions of C1q in lung endothelial homeostasis and the pulmonary vascular response to LPS or HCl injury. We show that lung endothelium from C1q-deficient (C1q−/−) mice expresses higher baseline levels of the vascular adhesion markers ICAM-1, VCAM-1, and E-selectin when compared with wild-type mice. Further, we demonstrate that these changes are associated with enhanced susceptibility of the lung to injury as evident by increased expression of adhesion markers, enhanced production of pro-inflammatory cytokines, and augmented neutrophil recruitment. Additionally, we found that C1q−/− mice also exhibited enhanced endothelial barrier dysfunction after injury as manifested by decreased expression of junctional adherens proteins and enhanced vascular leakage. Mechanistically, C1q appears to mediate its effects by inhibiting phosphorylation of p38 mitogen-activated protein kinase (MAPK) and blocking nuclear translocation of the P65 subunit of nuclear factor (NF)-κB. In summary, our findings indicate a previously unrecognized role for C1q in pulmonary vascular homeostasis and provide added support for the hypothesis that circulating collectin proteins have protective effects on the lung endothelium. PMID:26487714

Development of an ex vivo cellular model of rheumatoid arthritis: critical role of CD14-positive monocyte/macrophages in the development of pannus tissue.

PubMed

Nozaki, Toshiko; Takahashi, Kyoko; Ishii, Osamu; Endo, Sachio; Hioki, Kyoji; Mori, Toshihito; Kikukawa, Tadahiro; Boumpas, Dimitrios T; Ozaki, Shoichi; Yamada, Hidehiro

2007-09-01

To establish an ex vivo cellular model of pannus, the aberrant overgrowth of human synovial tissue (ST). Inflammatory cells that infiltrated pannus tissue from patients with rheumatoid arthritis (RA) were collected without enzyme digestion, and designated as ST-derived inflammatory cells. Single-cell suspensions of ST-derived inflammatory cells were cultured in medium alone. Levels of cytokines produced in culture supernatants were measured using enzyme-linked immunosorbent assay kits. ST-derived inflammatory cells were transferred into the joints of immunodeficient mice to explore whether these cells could develop pannus. CD14 and CD2 cells were depleted by negative selection. Culture of ST-derived inflammatory cells from 92 of 111 patients with RA resulted in spontaneous reconstruction of inflammatory tissue in vitro within 4 weeks. Ex vivo tissue contained fibroblasts, macrophages, T cells, and tartrate-resistant acid phosphatase-positive multinucleated cells. On calcium phosphate-coated slides, ST-derived inflammatory cell cultures showed numerous resorption pits. ST-derived inflammatory cell cultures continuously produced matrix metalloproteinase 9 and proinflammatory cytokines associated with osteoclastogenesis, such as tumor necrosis factor alpha, interleukin-8, and macrophage colony-stimulating factor. More importantly, transferring ST-derived inflammatory cells into the joints of immunodeficient mice resulted in the development of pannus tissue and erosive joint lesions. Both in vitro development and in vivo development of pannus tissue by ST-derived inflammatory cells were inhibited by depleting CD14-positive, but not CD2-positive, cells from ST-derived inflammatory cells. These findings suggest that overgrowth of inflammatory cells from human rheumatoid synovium simulates the development of pannus. This may prove informative in the screening of potential antirheumatic drugs.

Enhanced Chemokine Receptor Expression on Leukocytes of Patients with Alzheimer's Disease.

PubMed

Goldeck, David; Larbi, Anis; Pellicanó, Mariavaleria; Alam, Iftikhar; Zerr, Inga; Schmidt, Christian; Fulop, Tamas; Pawelec, Graham

2013-01-01

Although primarily a neurological complaint, systemic inflammation is present in Alzheimer's Disease, with higher than normal levels of proinflammatory cytokines and chemokines in the periphery as well as the brain. A gradient of these factors may enhance recruitment of activated immune cells into the brain via chemotaxis. Here, we investigated the phenotypes of circulating immune cells in AD patients with multi-colour flow cytometry to determine whether their expression of chemokine receptors is consistent with this hypothesis. In this study, we confirmed our previously reported data on the shift of early- to late-differentiated CD4+ T-cells in AD patients. The percentage of cells expressing CD25, a marker of acute T-cell activation, was higher in patients than in age-matched controls, and percentages of CCR6+ cells were elevated. This chemokine receptor is primarily expressed on pro-inflammatory memory cells and Th17 cells. The proportion of cells expressing CCR4 (expressed on Th2 cells) and CCR5 (Th1 cells and dendritic cells) was also greater in patients, and was more pronounced on CD4+ than CD8+ T-cells. These findings allow a more detailed insight into the systemic immune status of patients with Alzheimer's disease and suggest possible novel targets for immune therapy.

Cytokine-associated neutrophil extracellular traps and antinuclear antibodies in Plasmodium falciparum infected children under six years of age

PubMed Central

Baker, Virginia S; Imade, Godwin E; Molta, Norman B; Tawde, Pallavi; Pam, Sunday D; Obadofin, Michael O; Sagay, Soloman A; Egah, Daniel Z; Iya, Daniel; Afolabi, Bangmboye B; Baker, Murray; Ford, Karen; Ford, Robert; Roux, Kenneth H; Keller, Thomas CS

2008-01-01

Background In Plasmodium falciparum-infected children, the relationships between blood cell histopathology, blood plasma components, development of immunocompetence and disease severity remain poorly understood. Blood from Nigerian children with uncomplicated malaria was analysed to gain insight into these relationships. This investigation presents evidence for circulating neutrophil extracellular traps (NETs) and antinuclear IgG antibodies (ANA). The presence of NETs and ANA to double-stranded DNA along with the cytokine profiles found suggests autoimmune mechanisms that could produce pathogenesis in children, but immunoprotection in adults. Methods Peripheral blood smear slides and blood samples obtained from 21 Nigerian children under six years of age, presenting with uncomplicated malaria before and seven days after initiation of sulphadoxine-pyrimethamine (SP) treatment were analysed. The slides were stained with Giemsa and with DAPI. Levels of the pro-inflammatory cytokines IFN-γ, IL-2, TNF, CRP, and IL-6, select anti-inflammatory cytokines TGF-β and IL-10, and ANA were determined by immunoassay. Results The children exhibited circulating NETs with adherent parasites and erythrocytes, elevated ANA levels, a Th2 dominated cytokine profile, and left-shifted leukocyte differential counts. Nonspecific ANA levels were significant in 86% of the children pretreatment and in 100% of the children seven days after SP treatment, but in only 33% of age-matched control samples collected during the season of low parasite transmission. Levels of ANA specific for dsDNA were significant in 81% of the children both pre-treatment and post treatment. Conclusion The results of this investigation suggest that NET formation and ANA to dsDNA may induce pathology in falciparum-infected children, but activate a protective mechanism against falciparum malaria in adults. The significance of in vivo circulating chromatin in NETs and dsDNA ANA as a causative factor in the hyporesponsiveness of CpG oligonucleotide-based malaria vaccines is discussed. PMID:18312656

Long term intravital multiphoton microscopy imaging of immune cells in healthy and diseased liver using CXCR6.Gfp reporter mice.

PubMed

Heymann, Felix; Niemietz, Patricia M; Peusquens, Julia; Ergen, Can; Kohlhepp, Marlene; Mossanen, Jana C; Schneider, Carlo; Vogt, Michael; Tolba, Rene H; Trautwein, Christian; Martin, Christian; Tacke, Frank

2015-03-24

Liver inflammation as a response to injury is a highly dynamic process involving the infiltration of distinct subtypes of leukocytes including monocytes, neutrophils, T cell subsets, B cells, natural killer (NK) and NKT cells. Intravital microscopy of the liver for monitoring immune cell migration is particularly challenging due to the high requirements regarding sample preparation and fixation, optical resolution and long-term animal survival. Yet, the dynamics of inflammatory processes as well as cellular interaction studies could provide critical information to better understand the initiation, progression and regression of inflammatory liver disease. Therefore, a highly sensitive and reliable method was established to study migration and cell-cell-interactions of different immune cells in mouse liver over long periods (about 6 hr) by intravital two-photon laser scanning microscopy (TPLSM) in combination with intensive care monitoring. The method provided includes a gentle preparation and stable fixation of the liver with minimal perturbation of the organ; long term intravital imaging using multicolor multiphoton microscopy with virtually no photobleaching or phototoxic effects over a time period of up to 6 hr, allowing tracking of specific leukocyte subsets; and stable imaging conditions due to extensive monitoring of mouse vital parameters and stabilization of circulation, temperature and gas exchange. To investigate lymphocyte migration upon liver inflammation CXCR6.gfp knock-in mice were subjected to intravital liver imaging under baseline conditions and after acute and chronic liver damage induced by intraperitoneal injection(s) of carbon tetrachloride (CCl4). CXCR6 is a chemokine receptor expressed on lymphocytes, mainly on Natural Killer T (NKT)-, Natural Killer (NK)- and subsets of T lymphocytes such as CD4 T cells but also mucosal associated invariant (MAIT) T cells1. Following the migratory pattern and positioning of CXCR6.gfp+ immune cells allowed a detailed insight into their altered behavior upon liver injury and therefore their potential involvement in disease progression.

Ethnic Variation in Inflammatory Profile in Tuberculosis

PubMed Central

Coussens, Anna K.; Wilkinson, Robert J.; Nikolayevskyy, Vladyslav; Elkington, Paul T.; Hanifa, Yasmeen; Islam, Kamrul; Timms, Peter M.; Bothamley, Graham H.; Claxton, Alleyna P.; Packe, Geoffrey E.; Darmalingam, Mathina; Davidson, Robert N.; Milburn, Heather J.; Baker, Lucy V.; Barker, Richard D.; Drobniewski, Francis A.; Mein, Charles A.; Bhaw-Rosun, Leena; Nuamah, Rosamond A.; Griffiths, Christopher J.; Martineau, Adrian R.

2013-01-01

Distinct phylogenetic lineages of Mycobacterium tuberculosis (MTB) cause disease in patients of particular genetic ancestry, and elicit different patterns of cytokine and chemokine secretion when cultured with human macrophages in vitro. Circulating and antigen-stimulated concentrations of these inflammatory mediators might therefore be expected to vary significantly between tuberculosis patients of different ethnic origin. Studies to characterise such variation, and to determine whether it relates to host or bacillary factors, have not been conducted. We therefore compared circulating and antigen-stimulated concentrations of 43 inflammatory mediators and 14 haematological parameters (inflammatory profile) in 45 pulmonary tuberculosis patients of African ancestry vs. 83 patients of Eurasian ancestry in London, UK, and investigated the influence of bacillary and host genotype on these profiles. Despite having similar demographic and clinical characteristics, patients of differing ancestry exhibited distinct inflammatory profiles at presentation: those of African ancestry had lower neutrophil counts, lower serum concentrations of CCL2, CCL11 and vitamin D binding protein (DBP) but higher serum CCL5 concentrations and higher antigen-stimulated IL-1 receptor antagonist and IL-12 secretion. These differences associated with ethnic variation in host DBP genotype, but not with ethnic variation in MTB strain. Ethnic differences in inflammatory profile became more marked following initiation of antimicrobial therapy, and immunological correlates of speed of elimination of MTB from the sputum differed between patients of African vs. Eurasian ancestry. Our study demonstrates a hitherto unappreciated degree of ethnic heterogeneity in inflammatory profile in tuberculosis patients that associates primarily with ethnic variation in host, rather than bacillary, genotype. Candidate immunodiagnostics and immunological biomarkers of response to antimicrobial therapy should be derived and validated in tuberculosis patients of different ethnic origin. PMID:23853590

Inflammatory responses of stromal fibroblasts to inflammatory epithelial cells are involved in the pathogenesis of bovine mastitis.

PubMed

Zhang, Wenyao; Li, Xuezhong; Xu, Tong; Ma, Mengru; Zhang, Yong; Gao, Ming-Qing

2016-11-15

Hypernomic secretion of epithelial cytokines has several effects on stromal cells. The contributions of inflammatory epithelial cells to stromal fibroblasts in bovine mammary glands with mastitis remain poorly understood. Here, we established an inflammatory epithelial cell model of bovine mastitis with gram-negative lipopolysaccharide (LPS) and gram-positive lipoteichoic acid (LTA) bacterial cell wall components. We characterized immune responses of mammary stromal fibroblasts induced by inflammatory epithelial cells. Our results showed that inflammatory epithelial cells affected stromal fibroblast characteristics by increasing inflammatory mediator expression, elevating extracellular matrix protein deposition, decreasing proliferation capacity, and enhancing migration ability. The changes in stromal fibroblast proliferation and migration abilities were mediated by signal molecules, such as WNT signal pathway components. LPS- and LTA-induced inflammatory epithelial cells triggered different immune responses in stromal fibroblasts. Thus, in mastitis, bovine mammary gland stromal fibroblasts were affected by inflammatory epithelial cells and displayed inflammation-specific changes, suggesting that fibroblasts play crucial roles in bovine mastitis. Copyright © 2016 Elsevier Inc. All rights reserved.

Low-dose endotoxemia and human neuropsychological functions.

PubMed

Krabbe, Karen Suárez; Reichenberg, Abraham; Yirmiya, Raz; Smed, Annelise; Pedersen, Bente Klarlund; Bruunsgaard, Helle

2005-09-01

Epidemiological data demonstrate an association between systemic low-grade inflammation defined as 2- to 3-fold increases in circulating inflammatory mediators and age-related decline in cognitive function. However, it is not known whether small elevations of circulating cytokine levels cause direct effects on human neuropsychological functions. We investigated changes in emotional, cognitive, and inflammatory parameters in an experimental in vivo model of low-grade inflammation. In a double-blind crossover study, 12 healthy young males completed neuropsychological tests before as well as 1.5, 6, and 24 h after an intravenous injection of Escherichia coli endotoxin (0.2 ng/kg) or saline in two experimental sessions. Endotoxin administration had no effect on body temperature, cortisol levels, blood pressure or heart rate, but circulating levels of tumor necrosis factor (TNF) and interleukin (IL)-6 increased 2- and 7-fold, respectively, reaching peak values at 3 h, whereas soluble TNF-receptors and IL-1 receptor antagonist peaked at 4.5 h. The neutrophil count increased and the lymphocyte count declined. In this model, low-dose endotoxemia did not affect cognitive performance significantly but declarative memory performance was inversely correlated with cytokine increases. In conclusion, our findings demonstrate a negative association between circulating IL-6 and memory functions during very low-dose endotoxemia independently of physical stress symptoms, and the hypothalamo-pituitary-adrenal axis.

Endothelial dysfunction: the early predictor of atherosclerosis.

PubMed

Mudau, Mashudu; Genis, Amanda; Lochner, Amanda; Strijdom, Hans

2012-05-01

Since the discovery in the 1980s that nitric oxide (NO) is in fact the elusive endothelium-derived relaxing factor, it has become evident that NO is not only a major cardiovascular signalling molecule, but that changes in its bioavailability are crucial in determining whether atherosclerosis will develop or not. Sustained high levels of harmful circulating stimuli associated with cardiovascular risk factors such as diabetes mellitus elicit responses in endothelial cells that appear sequentially, namely endothelial cell activation and endothelial dysfunction (ED). ED, characterised by reduced NO bioavailability, is now recognised by many as an early, reversible precursor of atherosclerosis. The pathogenesis of ED is multifactorial; however, oxidative stress appears to be the common underlying cellular mechanism in the ensuing loss of vaso-active, inflammatory, haemostatic and redox homeostasis in the body's vascular system. The role of ED as a pathophysiological link between early endothelial cell changes associated with cardiovascular risk factors and the development of ischaemic heart disease is of importance to basic scientists and clinicians alike.

In vivo label-free photoacoustic flow cytography and on-the-spot laser killing of single circulating melanoma cells

NASA Astrophysics Data System (ADS)

He, Yun; Wang, Lidai; Shi, Junhui; Yao, Junjie; Li, Lei; Zhang, Ruiying; Huang, Chih-Hsien; Zou, Jun; Wang, Lihong V.

2016-12-01

Metastasis causes as many as 90% of cancer-related deaths, especially for the deadliest skin cancer, melanoma. Since hematogenous dissemination of circulating tumor cells is the major route of metastasis, detection and destruction of circulating tumor cells are vital for impeding metastasis and improving patient prognosis. Exploiting the exquisite intrinsic optical absorption contrast of circulating melanoma cells, we developed dual-wavelength photoacoustic flow cytography coupled with a nanosecond-pulsed melanoma-specific laser therapy mechanism. We have successfully achieved in vivo label-free imaging of rare single circulating melanoma cells in both arteries and veins of mice. Further, the photoacoustic signal from a circulating melanoma cell immediately hardware-triggers a lethal pinpoint laser irradiation to kill it on the spot in a thermally confined manner without causing collateral damage. A pseudo-therapy study including both in vivo and in vitro experiments demonstrated the performance and the potential clinical value of our method, which can facilitate early treatment of metastasis by clearing circulating tumor cells from vasculature.

Cell-Mediated Drugs Delivery

PubMed Central

Batrakova, Elena V.; Gendelman, Howard E.; Kabanov, Alexander V.

2011-01-01

INTRODUCTION Drug targeting to sites of tissue injury, tumor or infection with limited toxicity is the goal for successful pharmaceutics. Immunocytes (including mononuclear phagocytes (dendritic cells, monocytes and macrophages), neutrophils, and lymphocytes) are highly mobile; they can migrate across impermeable barriers and release their drug cargo at sites of infection or tissue injury. Thus immune cells can be exploited as trojan horses for drug delivery. AREAS COVERED IN THIS REVIEW This paper reviews how immunocytes laden with drugs can cross the blood brain or blood tumor barriers, to facilitate treatments for infectious diseases, injury, cancer, or inflammatory diseases. The promises and perils of cell-mediated drug delivery are reviewed, with examples of how immunocytes can be harnessed to improve therapeutic end points. EXPERT OPINION Using cells as delivery vehicles enables targeted drug transport, and prolonged circulation times, along with reductions in cell and tissue toxicities. Such systems for drug carriage and targeted release represent a novel disease combating strategy being applied to a spectrum of human disorders. The design of nanocarriers for cell-mediated drug delivery may differ from those used for conventional drug delivery systems; nevertheless, engaging different defense mechanisms into drug delivery may open new perspectives for the active delivery of drugs. PMID:21348773

Genome-Wide Interaction Study of Omega-3 PUFAs and Other Fatty Acids on Inflammatory Biomarkers of Cardiovascular Health in the Framingham Heart Study.

PubMed

Veenstra, Jenna; Kalsbeek, Anya; Westra, Jason; Disselkoen, Craig; Smith, Caren; Tintle, Nathan

2017-08-18

Numerous genetic loci have been identified as being associated with circulating fatty acid (FA) levels and/or inflammatory biomarkers of cardiovascular health (e.g., C-reactive protein). Recently, using red blood cell (RBC) FA data from the Framingham Offspring Study, we conducted a genome-wide association study of over 2.5 million single nucleotide polymorphisms (SNPs) and 22 RBC FAs (and associated ratios), including the four Omega-3 FAs (ALA, DHA, DPA, and EPA). Our analyses identified numerous causal loci. In this manuscript, we investigate the extent to which polyunsaturated fatty acid (PUFA) levels moderate the relationship of genetics to cardiovascular health biomarkers using a genome-wide interaction study approach. In particular, we test for possible gene-FA interactions on 9 inflammatory biomarkers, with 2.5 million SNPs and 12 FAs, including all Omega-3 PUFAs. We identified eighteen novel loci, including loci which demonstrate strong evidence of modifying the impact of heritable genetics on biomarker levels, and subsequently cardiovascular health. The identified genes provide increased clarity on the biological functioning and role of Omega-3 PUFAs, as well as other common fatty acids, in cardiovascular health, and suggest numerous candidate loci for future replication and biological characterization.

IGF-1 modulates gene expression of proteins involved in inflammation, cytoskeleton, and liver architecture.

PubMed

Lara-Diaz, V J; Castilla-Cortazar, I; Martín-Estal, I; García-Magariño, M; Aguirre, G A; Puche, J E; de la Garza, R G; Morales, L A; Muñoz, U

2017-05-01

Even though the liver synthesizes most of circulating IGF-1, it lacks its receptor under physiological conditions. However, according to previous studies, a damaged liver expresses the receptor. For this reason, herein, we examine hepatic histology and expression of genes encoding proteins of the cytoskeleton, extracellular matrix, and cell-cell molecules and inflammation-related proteins. A partial IGF-1 deficiency murine model was used to investigate IGF-1's effects on liver by comparing wild-type controls, heterozygous igf1 +/- , and heterozygous mice treated with IGF-1 for 10 days. Histology, microarray for mRNA gene expression, RT-qPCR, and lipid peroxidation were assessed. Microarray analyses revealed significant underexpression of igf1 in heterozygous mice compared to control mice, restoring normal liver expression after treatment, which then normalized its circulating levels. IGF-1 receptor mRNA was overexpressed in Hz mice liver, while treated mice displayed a similar expression to that of the controls. Heterozygous mice showed overexpression of several genes encoding proteins related to inflammatory and acute-phase proteins and underexpression or overexpression of genes which coded for extracellular matrix, cytoskeleton, and cell junction components. Histology revealed an altered hepatic architecture. In addition, liver oxidative damage was found increased in the heterozygous group. The mere IGF-1 partial deficiency is associated with relevant alterations of the hepatic architecture and expression of genes involved in cytoskeleton, hepatocyte polarity, cell junctions, and extracellular matrix proteins. Moreover, it induces hepatic expression of the IGF-1 receptor and elevated acute-phase and inflammation mediators, which all resulted in liver oxidative damage.

Thermoresponsive hyaluronic acid nanogels as hydrophobic drug carrier to macrophages.

PubMed

Fernandes Stefanello, Talitha; Szarpak-Jankowska, Anna; Appaix, Florence; Louage, Benoit; Hamard, Lauriane; De Geest, Bruno G; van der Sanden, Boudewijn; Nakamura, Celso Vataru; Auzély-Velty, Rachel

2014-11-01

Delivery systems for macrophages are particularly attractive since these phagocytic cells play a important role in immunological and inflammatory responses, also acting as host cells for microorganisms that are involved in deadly infectious diseases, such as leishmaniasis. Hyaluronic acid (HA) is specifically recognized by macrophages that are known to express HA receptors. Therefore, in this study, we focused on HA-based nanogels as drug carriers for these cells. The drug delivery was validated in an in vivo study on mice using intravital two-photon laser scanning microscopy. HA derivatives were modified with a biocompatible oligo(ethylene glycol)-based thermoresponsive polymer to form nanogels. These HA conjugates were readily prepared by varying the molar mass of initial HA and the degree of substitution via radical-mediated thiol-ene chemistry in aqueous solution. The derivatives were shown to self-assemble into spherical gel particles with diameters ranging from 150 to 214 nm above 37 °C. A poorly water-soluble two-photon dye was successfully loaded into the nanogels during this self-assembly process. In vitro cellular uptake tests using a RAW 264.7 murine macrophage cell line showed successful intracellular delivery of the hydrophobic dye. After intravenous injection in mice, the nanogels circulated freely in the blood but were rapidly phagocytized within 13 min by circulating macrophages and stored in the liver and spleen, as observed by two-photon microscopy. Benefit can be thus expected in using such a delivery system for the liver and spleen macrophage-associated diseases. Copyright © 2014 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Circulating cell-derived microparticles in patients with minimally symptomatic obstructive sleep apnoea.

PubMed

Ayers, L; Ferry, B; Craig, S; Nicoll, D; Stradling, J R; Kohler, M

2009-03-01

Moderate-severe obstructive sleep apnoea (OSA) has been associated with several pro-atherogenic mechanisms and increased cardiovascular risk, but it is not known if minimally symptomatic OSA has similar effects. Circulating cell-derived microparticles have been shown to have pro-inflammatory, pro-coagulant and endothelial function-impairing effects, as well as to predict subclinical atherosclerosis and cardiovascular risk. In 57 patients with minimally symptomatic OSA, and 15 closely matched control subjects without OSA, AnnexinV-positive, platelet-, leukocyte- and endothelial cell-derived microparticles were measured by flow cytometry. In patients with OSA, median (interquartile range) levels of AnnexinV-positive microparticles were significantly elevated compared with control subjects: 2,586 (1,566-3,964) microL(-1) versus 1,206 (474-2,501) microL(-1), respectively. Levels of platelet-derived and leukocyte-derived microparticles were also significantly higher in patients with OSA (2,267 (1,102-3,592) microL(-1) and 20 (14-31) microL(-1), respectively) compared with control subjects (925 (328-2,068) microL(-1) and 15 (5-23) microL(-1), respectively). Endothelial cell-derived microparticle levels were similar in patients with OSA compared with control subjects (13 (8-25) microL(-1) versus 11 (6-17) microL(-1)). In patients with minimally symptomatic obstructive sleep apnoea, levels of AnnexinV-positive, platelet- and leukocyte-derived microparticles are elevated when compared with closely matched control subjects without obstructive sleep apnoea. These findings suggest that these patients may be at increased cardiovascular risk, despite being minimally symptomatic.

Inflammation in Polycystic Ovary Syndrome: Underpinning of insulin resistance and ovarian dysfunction

PubMed Central

González, Frank

2012-01-01

Chronic low-grade inflammation has emerged as a key contributor to the pathogenesis of Polycystic Ovary Syndrome (PCOS). A dietary trigger such as glucose is capable of inciting oxidative stress and an inflammatory response from mononuclear cells (MNC) of women with PCOS, and this phenomenon is independent of obesity. This is important because MNC-derived macrophages are the primary source of cytokine production in excess adipose tissue, and also promote adipocyte cytokine production in a paracrine fashion. The proinflammatory cytokine tumor necrosis factor-α (TNFα) is a known mediator of insulin resistance. Glucose-stimulated TNFα release from MNC along with molecular markers of inflammation are associated with insulin resistance in PCOS. Hyperandrogenism is capable of activating MNC in the fasting state, thereby increasing MNC sensitivity to glucose; and this may be a potential mechanism for promoting diet-induced inflammation in PCOS. Increased abdominal adiposity is prevalent across all weight classes in PCOS, and this inflamed adipose tissue contributes to the inflammatory load in the disorder. Nevertheless, glucose ingestion incites oxidative stress in normal weight women with PCOS even in the absence of increased abdominal adiposity. In PCOS, markers of oxidative stress and inflammation are highly correlated with circulating androgens. Chronic suppression of ovarian androgen production does not ameliorate inflammation in normal weight women with the disorder. Furthermore, in vitro studies have demonstrated the ability of pro-inflammatory stimuli to upregulate the ovarian theca cell steroidogenic enzyme responsible for androgen production. These findings support the contention that inflammation directly stimulates the polycystic ovary to produce androgens. PMID:22178787

Systems biology of adipose tissue metabolism: regulation of growth, signaling and inflammation.

PubMed

Manteiga, Sara; Choi, Kyungoh; Jayaraman, Arul; Lee, Kyongbum

2013-01-01

Adipose tissue (AT) depots actively regulate whole body energy homeostasis by orchestrating complex communications with other physiological systems as well as within the tissue. Adipocytes readily respond to hormonal and nutritional inputs to store excess nutrients as intracellular lipids or mobilize the stored fat for utilization. Co-ordinated regulation of metabolic pathways balancing uptake, esterification, and hydrolysis of lipids is accomplished through positive and negative feedback interactions of regulatory hubs comprising several pleiotropic protein kinases and nuclear receptors. Metabolic regulation in adipocytes encompasses biogenesis and remodeling of uniquely large lipid droplets (LDs). The regulatory hubs also function as energy and nutrient sensors, and integrate metabolic regulation with intercellular signaling. Over-nutrition causes hypertrophic expansion of adipocytes, which, through incompletely understood mechanisms, initiates a cascade of metabolic and signaling events leading to tissue remodeling and immune cell recruitment. Macrophage activation and polarization toward a pro-inflammatory phenotype drives a self-reinforcing cycle of pro-inflammatory signals in the AT, establishing an inflammatory state. Sustained inflammation accelerates lipolysis and elevates free fatty acids in circulation, which robustly correlates with development of obesity-related diseases. The adipose regulatory network coupling metabolism, growth, and signaling of multiple cell types is exceedingly complex. While components of the regulatory network have been individually studied in exquisite detail, systems approaches have rarely been utilized to comprehensively assess the relative engagements of the components. Thus, need and opportunity exist to develop quantitative models of metabolic and signaling networks to achieve a more complete understanding of AT biology in both health and disease. Copyright © 2013 Wiley Periodicals, Inc.

Emergence of dendritic cells in the myocardium after acute myocardial infarction - implications for inflammatory myocardial damage.

PubMed

Yilmaz, Atilla; Dietel, Barbara; Cicha, Iwona; Schubert, Katja; Hausmann, Roland; Daniel, Werner G; Garlichs, Christoph D; Stumpf, Christian

2010-03-01

Dendritic cells (DC) are crucial for T cell mediated immune responses. Recently, we observed a significant decrease in circulating myeloid DC precursors in patients with acute myocardial infarction (AMI). The aim of the present study was to investigate whether myeloid DC are present in infarcted myocardium. Myocardial specimens of 10 patients with AMI and 7 accident victims (controls) were collected after autopsy. In immunostainings the presence of DC (CD209(+), fascin(+)), T cells (CD3(+)), macrophages (CD68(+)), and HLA-DR expression was analyzed. Significantly higher numbers of CD209(+)-DC (97 vs. 44 cells/0.25 mm(2), p=0.03), fascin(+)-DC (54 vs. 8 cells/0.25 mm(2), p=0.02), T cells (27 vs. 6 cells/0.25 mm(2), p=0.02), and macrophages (44 vs. 6 cells/0.25 mm(2), p=0.01) associated with high HLA-DR expression were detected in infarcted myocardium. Frequent colocalizations of DC and T cells were observed. In occluded coronary arteries numerous DC, T cells, macrophages and high HLA-DR expression were found. We show that DC are present in infarcted myocardium after AMI. High HLA-DR expression and the colocalization with T cells suggest that they might trigger an immune response leading to further myocardial damage.

The number and function of circulating CD34+CD133+ progenitor cells decreased in stable coronary artery disease but not in acute myocardial infarction

PubMed Central

Kondo, Takahisa; Shintani, Satoshi; Maeda, Kengo; Hayashi, Mutsuharu; Inden, Yasuya; Numaguchi, Yasushi; Sugiura, Kaichiro; Morita, Yasuhiro; Kitamura, Tomoya; Kamiya, Haruo; Sone, Takahito; Ohno, Miyoshi; Murohara, Toyoaki

2010-01-01

Objective Circulating CD34+CD133+ cells are one of the main sources of circulating endothelial progenitor cells (EPCs). Age is inversely related to the number and function of CD34+CD133+ progenitor cells in stable coronary artery disease (CAD), but the relationship remains unclear in acute myocardial infarction (AMI). The authors aimed to clarify how ageing affects the number and function of mobilised CD34+CD133+ progenitor cells in AMI. Design and results Circulating CD34+CD133+ progenitor cells were measured by flow cytometry. Measurements were made at admission for CAD, or on day 7 after the onset of AMI. In stable CAD (n=131), circulating CD34+CD133+ cells decreased with age (r=−0.344, p<0.0001). In AMI, circulating CD34+CD133+ cells did not correlate with age (n=50), and multivariate analysis revealed that the decreased number of circulating CD34+CD133+ cells was associated with male sex and higher peak creatinine kinase. The ability to give rise to functional EPCs, which show good migratory and tube-forming capabilities, deteriorated among stable CAD subjects (n=10) compared with AMI subjects (N=6). Conclusions In stable CAD, the number and function of circulating CD34+CD133+ progenitor cells decreased with age, whereas those mobilised and circulating in AMI did not. PMID:27325937

Sickle erythrocytes and platelets augment lung leukotriene synthesis with downregulation of anti-inflammatory proteins: relevance in the pathology of the acute chest syndrome

PubMed Central

Opene, Michael; Kurantsin-Mills, Joseph; Husain, Sumair

2014-01-01

Abstract Initiation, progression, and resolution of vaso-occlusive pain episodes in sickle cell disease (SCD) have been recognized as reperfusion injury, which provokes an inflammatory response in the pulmonary circulation. Some 5-lipoxygenase (5-lox) metabolites are potent vasoconstrictors in the pulmonary circulation. We studied stimulation of production of the inflammatory eicosanoids leukotrienes (LTs) and prostaglandin E2 (PGE2) by isolated rat lungs perfused with sickle (HbSS) erythrocytes. Our hypothesis is that HbSS erythrocytes produce more LTs than normal (HbAA) erythrocytes, which can induce vaso-occlusive episodes in SCD patients. Lung perfusates were collected at specific time points and purified by high-pressure liquid chromatography, and LTC4 and PGE2 contents were measured by enzyme-linked immunosorbent assay (ELISA). Rat lung explants were also cultured with purified HbAA and HbSS peptides, and 5-lox, cyclooxygenase 1/2, and platelet-activating factor receptor (PAFR) proteins were measured by Western blotting, while prostacyclin and LTs produced by cultured lung explants were measured by ELISA. Lung weight gain and blood gas data were not different among the groups. HbSS-perfused lungs produced more LTC4 and PGE2 than HbAA-perfused lungs: 10.40 ± 0.62 versus 0.92 ± 0.2 ng/g dry lung weight (mean ± SEM; P = 0.0001) for LTC4. Inclusion of autologous platelets (platelet-rich plasma) elevated LTC4 production to 12.6 ± 0.96 and 7 ± 0.60 ng/g dry lung weight in HbSS and HbAA perfusates, respectively. HbSS lungs also expressed more 5-lox and PAFR. The data suggest that HbSS erythrocytes and activated platelets in patient’s pulmonary microcirculation will enhance the synthesis and release of the proinflammatory mediators LTC4 and PGE2, both of which may contribute to onset of the acute chest syndrome in SCD. PMID:25621162

Glucose consumption of inflammatory cells masks metabolic deficits in the brain

PubMed Central

Backes, Heiko; Walberer, Maureen; Ladwig, Anne; Rueger, Maria A.; Neumaier, Bernd; Endepols, Heike; Hoehn, Mathias; Fink, Gereon R.; Schroeter, Michael; Graf, Rudolf

2016-01-01

Inflammatory cells such as microglia need energy to exert their functions and to maintain their cellular integrity and membrane potential. Subsequent to cerebral ischemia, inflammatory cells infiltrate tissue with limited blood flow where neurons and astrocytes died due to insufficient supply with oxygen and glucose. Using dual tracer positron emission tomography (PET), we found that concomitant with the presence of inflammatory cells, transport and consumption of glucose increased up to normal levels but returned to pathological levels as soon as inflammatory cells disappeared. Thus, inflammatory cells established sufficient glucose supply to satisfy their energy demands even in regions with insufficient supply for neurons and astrocytes to survive. Our data suggest that neurons and astrocytes died from oxygen deficiency and inflammatory cells metabolized glucose non-oxidatively in regions with residual availability. As a consequence, glucose metabolism of inflammatory cells can mask metabolic deficits in neurodegenerative diseases. We further found that the PET tracer did not bind to inflammatory cells in severely hypoperfused regions and thus only a part of the inflammation was detected. We conclude that glucose consumption of inflammatory cells should be taken into account when analyzing disease-related alterations of local cerebral metabolism. PMID:26747749

Protecting against vascular disease in brain

PubMed Central

2011-01-01

Endothelial cells exert an enormous influence on blood vessels throughout the circulation, but their impact is particularly pronounced in the brain. New concepts have emerged recently regarding the role of this cell type and mechanisms that contribute to endothelial dysfunction and vascular disease. Activation of the renin-angiotensin system plays a prominent role in producing these abnormalities. Both oxidative stress and local inflammation are key mechanisms that underlie vascular disease of diverse etiology. Endogenous mechanisms of vascular protection are also present, including antioxidants, anti-inflammatory molecules, and peroxisome proliferator-activated receptor-γ. Despite their clear importance, studies of mechanisms that underlie cerebrovascular disease continue to lag behind studies of vascular biology in general. Identification of endogenous molecules and pathways that protect the vasculature may result in targeted approaches to prevent or slow the progression of vascular disease that causes stroke and contributes to the vascular component of dementia and Alzheimer's disease. PMID:21335467

One-year enzyme-linked immunosorbent assay follow-up of human interleukin for Da cells/leukemia inhibitory factor in blood and urine of 22 kidney transplant recipients.

PubMed

Morel, D; Taupin, J L; Combe, C; Potaux, L; Gualde, N; Moreau, J F

1994-12-15

The cytokine human interleukin for Da cells/leukemia inhibitory factor (HILDA/LIF) exerts multiple biological effects in vitro. In mice, high circulating levels of HILDA/LIF induce a wide range of pathophysiological events, some of them closely involved with immunological and inflammatory responses. Using a sandwich ELISA recognizing the natural human HILDA/LIF molecule with a threshold of 50 pg/ml in urine and 150 pg/ml in plasma, we monitored the urine and plasma HILDA/LIF levels of 22 patients in their first year after a kidney transplant. HILDA/LIF urine excretion is increased during acute rejection, and infections also trigger heavy HILDA/LIF plasma concentrations or urine excretion. In addition, this study raises the question of HILDA/LIF involvement in post-kidney-transplant phenomena such as hypercalcemia, osteoporosis, or the reversal of anemia.

Prognostic impact of circulating plasma cells in patients with multiple myeloma: implications for plasma cell leukemia definition.

PubMed

Granell, Miquel; Calvo, Xavier; Garcia-Guiñón, Antoni; Escoda, Lourdes; Abella, Eugènia; Martínez, Clara Mª; Teixidó, Montserrat; Gimenez, Mª Teresa; Senín, Alicia; Sanz, Patricia; Campoy, Desirée; Vicent, Ana; Arenillas, Leonor; Rosiñol, Laura; Sierra, Jorge; Bladé, Joan; de Larrea, Carlos Fernández

2017-06-01

The presence of circulating plasma cells in patients with multiple myeloma is considered a marker for highly proliferative disease. In the study herein, the impact of circulating plasma cells assessed by cytology on survival of patients with multiple myeloma was analyzed. Wright-Giemsa stained peripheral blood smears of 482 patients with newly diagnosed myeloma or plasma cell leukemia were reviewed and patients were classified into 4 categories according to the percentage of circulating plasma cells: 0%, 1-4%, 5-20%, and plasma cell leukemia with the following frequencies: 382 (79.2%), 83 (17.2%), 12 (2.5%) and 5 (1.0%), respectively. Median overall survival according to the circulating plasma cells group was 47, 50, 6 and 14 months, respectively. At multivariate analysis, the presence of 5 to 20% circulating plasma cells was associated with a worse overall survival (relative risk 4.9, 95% CI 2.6-9.3) independently of age, creatinine, the Durie-Salmon system stage and the International Staging System (ISS) stage. Patients with ≥5% circulating plasma cells had lower platelet counts (median 86×10 9 /L vs 214×10 9 /L, P <0.0001) and higher bone marrow plasma cells (median 53% vs 36%, P =0.004). The presence of ≥5% circulating plasma cells in patients with multiple myeloma has a similar adverse prognostic impact as plasma cell leukemia. Copyright© Ferrata Storti Foundation.

Complement Factor H Is Expressed in Adipose Tissue in Association With Insulin Resistance

PubMed Central

Moreno-Navarrete, José María; Martínez-Barricarte, Rubén; Catalán, Victoria; Sabater, Mònica; Gómez-Ambrosi, Javier; Ortega, Francisco José; Ricart, Wifredo; Blüher, Mathias; Frühbeck, Gema; Rodríguez de Cordoba, Santiago; Fernández-Real, José Manuel

2010-01-01

OBJECTIVE Activation of the alternative pathway of the complement system, in which factor H (fH; complement fH [CFH]) is a key regulatory component, has been suggested as a link between obesity and metabolic disorders. Our objective was to study the associations between circulating and adipose tissue gene expressions of CFH and complement factor B (fB; CFB) with obesity and insulin resistance. RESEARCH DESIGN AND METHODS Circulating fH and fB were determined by enzyme-linked immunosorbent assay in 398 subjects. CFH and CFB gene expressions were evaluated in 76 adipose tissue samples, in isolated adipocytes, and in stromovascular cells (SVC) (n = 13). The effects of weight loss and rosiglitazone were investigated in independent cohorts. RESULTS Both circulating fH and fB were associated positively with BMI, waist circumference, triglycerides, and inflammatory parameters and negatively with insulin sensitivity and HDL cholesterol. For the first time, CFH gene expression was detected in human adipose tissue (significantly increased in subcutaneous compared with omental fat). CFH gene expression in omental fat was significantly associated with insulin resistance. In contrast, CFB gene expression was significantly increased in omental fat but also in association with fasting glucose and triglycerides. The SVC fraction was responsible for these differences, although isolated adipocytes also expressed fB and fH at low levels. Both weight loss and rosiglitazone led to significantly decreased circulating fB and fH levels. CONCLUSIONS Increased circulating fH and fB concentrations in subjects with altered glucose tolerance could reflect increased SVC-induced activation of the alternative pathway of complement in omental adipose tissue linked to insulin resistance and metabolic disturbances. PMID:19833879

IL-33 promotes the migration and proliferation of circulating fibrocytes from patients with allergen-exacerbated asthma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bianchetti, Lorenza, E-mail: lbianchetti@avail-research.com; Laboratory of Cytopathology and Cytogenetics, Italian ABR Operative Unit, Milan; Marini, Maurizio A., E-mail: mam.marini@yahoo.com

2012-09-14

Highlights: Black-Right-Pointing-Pointer IL-33 is considered a new therapeutic target for reducing inflammation in asthma. Black-Right-Pointing-Pointer This study shows that IL-33 is a potent chemoattractant for fibrocytes in asthma. Black-Right-Pointing-Pointer IL-33 also promotes fibrocyte proliferation without reducing collagen production. Black-Right-Pointing-Pointer The study uncovers a novel non-inflammatory, profibrotic function of IL-33. -- Abstract: The release of IL-33 increases in the bronchial mucosa of asthmatic patients in relation to disease severity and several studies have demonstrated that IL-33 may enhance airway inflammation in asthma. This study tested the hypothesis that IL-33 may also contribute to the development of irreversible structural changes in asthmamore » by favoring the airway recruitment and profibrotic function of circulating fibrocytes during episodes of allergen-induced asthma exacerbation. The circulating fibrocytes from patients with allergen-exacerbated asthma (PwAA) showed increased expression of the specific IL-33 receptor component ST2L in comparison with the cells from non-asthmatic individuals (NAI). Recombinant IL-33 induced the migration of circulating fibrocytes from PwAA at clinically relevant concentrations and stimulated their proliferation in a concentration-dependent manner between 0.1 and 10 ng/ml, without affecting the constitutive release of type I collagen. The recombinant protein did not induce similar responses in circulating fibrocytes from NAI. This study uncovers an important mechanism through which fibrocytes may accumulate in the airways of allergic asthmatics when their disease is not adequately controlled by current treatment and provides novel information on the function of IL-33 in asthma.« less

Noninvasive and label-free detection of circulating melanoma cells by in vivo photoacoustic flow cytometry

NASA Astrophysics Data System (ADS)

Yang, Ping; Liu, Rongrong; Niu, Zhenyu; Suo, Yuanzhen; He, Hao; Wei, Xunbin

2015-03-01

Melanoma is a malignant tumor of melanocytes. Circulating melanoma cell has high light absorption due to melanin highly contained in melanoma cells. This property is employed for the detection of circulating melanoma cell by in vivo photoacoustic flow cytometry (PAFC). PAFC is based on photoacoustic effect. Compared to in vivo flow cytometry based on fluorescence, PAFC can employ high melanin content of melanoma cells as endogenous biomarkers to detect circulating melanoma cells in vivo. In our research, we developed in vitro experiments to prove the ability of PAFC system of detecting PA signals from melanoma cells. For in vivo experiments, we constructed a model of melanoma tumor bearing mice by inoculating highly metastatic murine melanoma cancer cells B16F10 with subcutaneous injection. PA signals were detected in the blood vessels of mouse ears in vivo. By counting circulating melanoma cells termly, we obtained the number variation of circulating melanoma cells as melanoma metastasized. Those results show that PAFC is a noninvasive and label-free method to detect melanoma metastases in blood or lymph circulation. Our PAFC system is an efficient tool to monitor melanoma metastases, cancer recurrence and therapeutic efficacy.

Circulating Bone Marrow-Derived CD45-/CD34+/CD133+/VEGF+ Endothelial Progenitor Cells in Adults with Crohn's Disease.

PubMed

Boltin, Doron; Kamenetsky, Zvi; Perets, Tsachi Tsadok; Snir, Yifat; Sapoznikov, Boris; Schmilovitz-Weiss, Hemda; Ablin, Jacob Nadav; Dickman, Ram; Niv, Yaron

2017-03-01

Circulating endothelial progenitor cells (EPCs) are bone marrow-derived stem cells able to migrate to sites of damaged endothelium and differentiate into endothelial cells. Altered EPC level and function have been described in various inflammatory diseases and have been shown to augment vasculogenesis in murine models. Previous studies of EPC in the context of Crohn's disease (CD) have yielded conflicting results. To determine whether the circulating levels of EPCs are changed in the context of CD. CD patients and healthy controls were recruited. Disease activity was assessed by CDAI. Peripheral blood mononuclear cells were isolated and EPC numbers evaluated by FACS analysis using anti-CD34, anti-VEGF receptor-2, anti-CD133, and anti-CD45 markers. Eighty-three subjects, including 32 CD patients and 51 controls were recruited, including 19 (59.4 %) and 23 (45 %) males (p = 0.26), aged 34.8 ± 14.9 and 43.3 ± 18.5 years (p = 0.64), in cases and controls, respectively. Mean CDAI was 147 ± 97, disease duration was 12.7 ± 11.1 years, and 28 (87.5 %) were receiving biologics for a mean duration of 21.7 ± 16.8 months. The mean level of peripheral EPCs in CD patients was 0.050 ± 0.086 percent and 0.007 ± 0.013 % in controls (p < 0.01). There was no significant correlation between EPC levels and age (r = -0.13, p = 0.47), CDAI (r = -0.26, p = 0.15), disease duration (r = -0.04, p = 0.84), or duration of treatment with biologics (r = 0.004, p = 0.99). EPCs are elevated in patients with CD. Further studies are needed to examine the function of EPCs and their possible role as a marker of disease severity or therapeutic response.

Dynamic movement of cytochrome c from mitochondria into cytosol and peripheral circulation in massive hepatic cell injury.

PubMed

Kobayashi, Yoshinori; Mori, Masaaki; Naruto, Takuya; Kobayashi, Naoki; Sugai, Toshiyuki; Imagawa, Tomoyuki; Yokota, Shumpei

2004-12-01

In the process of apoptosis, it is known that the transition of cytochrome c from mitochondria into the cytosol occurs, and tumor necrosis factor (TNF)-alpha is one of the molecules responsible for this event. But in the state of hypercytokine induced by D-galactosamine (D-GaIN)/Lipopolysaccharide (LPS), the localization of cytochrome c is little known. Rats were administrated with D-GaIN(700 mg/kg)/LPS(200 microg/kg). Blood and tissue samples were collected and examined for levels of pro-inflammatory cytokines, the apoptosis of liver cells, and the localization of cytochrome c. Before administration of D-GaIN/LPS, cytochrome c was definitely localized in the mitochondria. At 2 h after simultaneous administration of D-GaIN/LPS, cytochrome c had accumulated in the cytosol following abrupt increases of plasma TNF-alpha. Massive cell destruction due to apoptosis proved by Terminal deoxynucleo-tidyl transferase-mediated dUTP nick end labeling staining was observed in liver tissue 4 h later and markedly increased levels of cytochrome c were detected in the plasma 12 h after D-GaIN/LPS administration. Liver injury induced by simultaneous administration of D-GaIN/LPS was closely associated with the production of TNF-alpha, and also with the dynamic movement of cytochrome c from the mitochondria into the cytosol, and then into the systemic circulation. The detection of plasma cytochrome c levels may be a useful clinical tool for the detection of apoptosis in vivo.

Autologous circulating angiogenic cells treated with osteopontin and delivered via a collagen scaffold enhance wound healing in the alloxan-induced diabetic rabbit ear ulcer model.

PubMed

O'Loughlin, Aonghus; Kulkarni, Mangesh; Vaughan, Erin E; Creane, Michael; Liew, Aaron; Dockery, Peter; Pandit, Abhay; O'Brien, Timothy

2013-01-01

Diabetic foot ulceration is the leading cause of amputation in people with diabetes mellitus. Peripheral vascular disease is present in the majority of patients with diabetic foot ulcers. Despite standard treatments there exists a high amputation rate. Circulating angiogenic cells previously known as early endothelial progenitor cells are derived from peripheral blood and support angiogenesis and vasculogenesis, providing a potential topical treatment for non-healing diabetic foot ulcers. A scaffold fabricated from Type 1 collagen facilitates topical cell delivery to a diabetic wound. Osteopontin is a matricellular protein involved in wound healing and increases the angiogenic potential of circulating angiogenic cells. A collagen scaffold seeded with circulating angiogenic cells was developed. Subsequently the effect of autologous circulating angiogenic cells that were seeded in a collagen scaffold and topically delivered to a hyperglycemic cutaneous wound was assessed. The alloxan-induced diabetic rabbit ear ulcer model was used to determine healing in response to the following treatments: collagen seeded with autologous circulating angiogenic cells exposed to osteopontin, collagen seeded with autologous circulating angiogenic cells, collagen alone and untreated wound. Stereology was used to assess angiogenesis in wounds. The cells exposed to osteopontin and seeded on collagen increased percentage wound closure as compared to other groups. Increased angiogenesis was observed with the treatment of collagen and collagen seeded with circulating angiogenic cells. These results demonstrate that topical treatment of full thickness cutaneous ulcers with autologous circulating angiogenic cells increases wound healing. Cells exposed to the matricellular protein osteopontin result in superior wound healing. The wound healing benefit is associated with a more efficient vascular network. This topical therapy provides a potential novel therapy for the treatment of non-healing diabetic foot ulcers in humans.

Exercise in fibromyalgia and related inflammatory disorders: known effects and unknown chances.

PubMed

Ortega, E; García, J J; Bote, M E; Martín-Cordero, L; Escalante, Y; Saavedra, J M; Northoff, H; Giraldo, E

2009-01-01

Fibromyalgia (FM) is characterised by chronic widespread pain and allodynia (pain from stimuli which are not normally painful with pain that may occur other than in the area stimulated) of more than 3 months duration. The current hypothesis of the aetiology of FM includes inflammatory and neuroendocrine disorders. The biophysiology of this syndrome, however; remains still widely elusive, and there are no formally approved therapies. Non-pharmacological interventions in FM patients include habitual exercise programs which improve physical function and quality of life of patients and may even reduce pain. However the mechanisms through which exercise benefits FM symptoms needs to be elucidated. In this article we firstly review the main topics and characteristics of the FM syndrome, while focusing our attention on the inflammatory hypothesis of FM, as well as on the beneficial effects of habitual exercise as a co-therapy for FM patients. In this context, the latest developments in research on anti-inflammatory effects of exercise are also reviewed and discussed. To find out what is known about the connection between benefits of exercise for FM and anti-inflammatory effects of exercise, we carried out a PubMed search using the term "fibromyalgia" and "exercise" together with "inflammation", and no more than ten published articles were found (six of them reviews), which are also discussed. In the second part of the article we present a pilot investigation on a group of 14 female FM patients with a diagnosis of FM by a rheumatologist. They took part in a pool-aquatic program in warm water over a period of fourth months (three weekly 60-min sessions). Circulating inflammatory (IL-1beta, IL-2, IFNgamma, TNFalpha, IL-8, IL-6, IL-4, IL-10 and CRP) and neuroendocrine (NA and cortisol) markers were determined. FM patients showed higher circulating levels of IL-8, IFNgamma and CRP as well as cortisol and NA than age-matched healthy control women. After the exercise program, a significant decrease in IL-8, IFNgamma, and CRP were found, in parallel with a decrease in circulating concentrations of cortisol and increased levels of NA. The results confirm an elevated "inflammatory status" in the FM syndrome and strengthen the hypothesis that the benefits of exercise in FM patients are mediated, at least in part, by its anti-inflammatory effects. A better regulation of the cytokine-HPA axis feedback may be also involved.

Activated platelets are the source of elevated levels of soluble CD40 ligand in the circulation of inflammatory bowel disease patients.

PubMed

Danese, S; Katz, J A; Saibeni, S; Papa, A; Gasbarrini, A; Vecchi, M; Fiocchi, C

2003-10-01

The CD40/CD40L system, a key regulator and amplifier of immune reactivity, is activated in inflammatory bowel disease (IBD) mucosa. To determine whether plasma levels of sCD40L are elevated in Crohn's disease (CD) and ulcerative colitis (UC) patients compared with normal controls, to investigate the cellular source of sCD40L, and to explore CD40L induction mechanisms. CD, UC, and normal control subjects were studied. The concentration of sCD40L in plasma and supernatants of freshly isolated platelets and autologous peripheral blood T cells (PBT) was measured by ELISA. Surface CD40L expression level was measured by flow cytometry in resting and thrombin activated platelets, and unstimulated and CD3/CD28 stimulated PBT before and after coculture with human intestinal microvascular endothelial cells (HIMEC). Compared with normal controls, plasma sCD40L levels were significantly higher in both CD and UC patients and proportional to the extent of mucosal inflammation. Platelets from IBD patients displayed a significantly higher surface CD40L expression than those from control subjects, and released greater amounts of sCD40L than autologous PBT. Contact with IL-1beta activated HIMEC induced significant upregulation of CD40L surface expression and release by platelets. Elevated levels of sCD40L in the circulation of IBD patients reflect enhanced surface expression and release of CD40L by platelets. This phenomenon translates to an increased platelet activation state apparently induced by passage through an inflamed mucosal microvascular bed, a conclusion supported by the positive correlation of plasma sCD40L levels with the extent of anatomical involvement by IBD. These results suggest that platelet-endothelial interactions critically contribute to activation of the CD40 pathway in IBD.