Post-Translational Modification Control of Innate Immunity.

PubMed

Liu, Juan; Qian, Cheng; Cao, Xuetao

2016-07-19

A coordinated balance between the positive and negative regulation of pattern-recognition receptor (PRR)-initiated innate inflammatory responses is required to ensure the most favorable outcome for the host. Post-translational modifications (PTMs) of innate sensors and downstream signaling molecules influence their activity and function by inducing their covalent linkage to new functional groups. PTMs including phosphorylation and polyubiquitination have been shown to potently regulate innate inflammatory responses through the activation, cellular translocation, and interaction of innate receptors, adaptors, and downstream signaling molecules in response to infectious and dangerous signals. Other PTMs such as methylation, acetylation, SUMOylation, and succinylation are increasingly implicated in the regulation of innate immunity and inflammation. In this review, we focus on the roles of PTMs in controlling PRR-triggered innate immunity and inflammatory responses. The emerging roles of PTMs in the pathogenesis and potential treatment of infectious and inflammatory immune diseases are also discussed. Copyright © 2016 Elsevier Inc. All rights reserved.

Vagal-immune interactions involved in cholinergic anti-inflammatory pathway.

PubMed

Zila, I; Mokra, D; Kopincova, J; Kolomaznik, M; Javorka, M; Calkovska, A

2017-09-22

Inflammation and other immune responses are involved in the variety of diseases and disorders. The acute response to endotoxemia includes activation of innate immune mechanisms as well as changes in autonomic nervous activity. The autonomic nervous system and the inflammatory response are intimately linked and sympathetic and vagal nerves are thought to have anti-inflammation functions. The basic functional circuit between vagus nerve and inflammatory response was identified and the neuroimmunomodulation loop was called cholinergic anti-inflammatory pathway. Unique function of vagus nerve in the anti-inflammatory reflex arc was found in many experimental and pre-clinical studies. They brought evidence on the cholinergic signaling interacting with systemic and local inflammation, particularly suppressing immune cells function. Pharmacological/electrical modulation of vagal activity suppressed TNF-alpha and other proinflammatory cytokines production and had beneficial therapeutic effects. Many questions related to mapping, linking and targeting of vagal-immune interactions have been elucidated and brought understanding of its basic physiology and provided the initial support for development of Tracey´s inflammatory reflex. This review summarizes and critically assesses the current knowledge defining cholinergic anti-inflammatory pathway with main focus on studies employing an experimental approach and emphasizes the potential of modulation of vagally-mediated anti-inflammatory pathway in the treatment strategies.

Influence of Inflammation on Poststroke Plasticity

PubMed Central

Kossut, Malgorzata

2013-01-01

Age-related brain injuries including stroke are a leading cause of morbidity and mental disability worldwide. Most patients who survive stroke experience some degree of recovery. The restoration of lost functions can be explained by neuronal plasticity, understood as brain ability to reorganize and remodel itself in response to changed environmental requirements. However, stroke triggers a cascade of events which may prevent the normal development of the plastic changes. One of them may be inflammatory response initiated immediately after stroke, which has been found to contribute to neuronal injury. Some recent evidence though has suggested that inflammatory reaction can be also neuroprotective. This paper attempts to discuss the influence of poststroke inflammatory response on brain plasticity and stroke outcome. We also describe the recent anti-inflammatory strategies that have been effective for recovery in experimental stroke. PMID:23533818

Discovering the route from inflammation to pancreatic cancer

PubMed Central

MOMI, N.; KAUR, S.; KRISHN, S. R.; BATRA, S. K.

2013-01-01

Pancreatic cancer (PC) remains a complex malignancy with the worst prognosis, lack of early diagnostic symptoms and resistance to conventional chemo- and radiotherapies. A better understanding of the etiology and early developmental events of PC requires profound attention. The evolution of fully blown PC from initial pancreatic injury is a multi-factorial phenomenon with a series of sequential events. The initial acute infection or tissue damage triggers inflammation that, in conjunction with innate immunity, establishes a state of homeostasis to limit harm to the body. Recurrent pancreatic injuries due to genetic susceptibility, smoking, unhealthy diet, and alcohol abuse induces a pro-inflammatory milieu, consisting of various types of immune cells, cytokines, chemokines, growth factors and restructured extracellular matrix, leading to prolonged inflammatory/chronic conditions. Cells having sustained DNA damage and/or mutagenic assault take advantage of this prolonged inflammatory response and aid in the initiation and development of neoplastic/fibrotic events. Eventually, many tumor-stromal interactions result in a chaotic environment accompanied by a loss of immune surveillance and repair response, thereby leading to PC. A better understanding of the inflammatory markers defining this “injury-inflammation-cancer” pathway would help to identify novel molecular targets for early screening and therapeutic intervention for this lethal malignancy. PMID:23207606

Capsular Polysaccharide is a Main Component of Mycoplasma ovipneumoniae in the Pathogen-Induced Toll-Like Receptor-Mediated Inflammatory Responses in Sheep Airway Epithelial Cells

PubMed Central

Jiang, Zhongjia; Song, Fuyang; Li, Yanan; Xue, Di; Deng, Guangcun; Li, Min

2017-01-01

Mycoplasma ovipneumoniae (M. ovipneumoniae) is characterized as an etiological agent of primary atypical pneumonia that specifically infects sheep and goat. In an attempt to better understand the pathogen-host interaction between the invading M. ovipneumoniae and airway epithelial cells, we investigated the host inflammatory responses against capsular polysaccharide (designated as CPS) of M. ovipneumoniae using sheep bronchial epithelial cells cultured in an air-liquid interface (ALI) model. Results showed that CPS derived from M. ovipneumoniae could activate toll-like receptor- (TLR-) mediated inflammatory responses, along with an elevated expression of nuclear factor kappa B (NF-κB), activator protein-1 (AP-1), and interferon regulatory factor 3 (IRF3) as well as various inflammatory-associated mediators, representatively including proinflammatory cytokines, such as IL1β, TNFα, and IL8, and anti-inflammatory cytokines such as IL10 and TGFβ of TLR signaling cascade. Mechanistically, the CPS-induced inflammation was TLR initiated and was mediated by activations of both MyD88-dependent and MyD88-independent signaling pathways. Of importance, a blockage of CPS with specific antibody led a significant reduction of M. ovipneumoniae-induced inflammatory responses in sheep bronchial epithelial cells. These results suggested that CPS is a key virulent component of M. ovipneumoniae, which may play a crucial role in the inflammatory response induced by M. ovipneumoniae infections. PMID:28553017

Donor brain death predisposes human kidney grafts to a proinflammatory reaction after transplantation.

PubMed

de Vries, D K; Lindeman, J H N; Ringers, J; Reinders, M E J; Rabelink, T J; Schaapherder, A F M

2011-05-01

Donor brain death has profound effects on post-transplantation graft function and survival. We hypothesized that changes initiated in the donor influence the graft's response to ischemia and reperfusion. In this study, human brain dead donor kidney grafts were compared to living and cardiac dead donor kidney grafts. Pretransplant biopsies of brain dead donor kidneys contained notably more infiltrating T lymphocytes and macrophages. To assess whether the different donor conditions result in a different response to reperfusion, local cytokine release from the reperfused kidney was studied by measurement of paired arterial and renal venous blood samples. Reperfusion of kidneys from brain dead donors was associated with the instantaneous release of inflammatory cytokines, such as G-CSF, IL-6, IL-9, IL-16 and MCP-1. In contrast, kidneys from living and cardiac dead donors showed a more modest cytokine response with release of IL-6 and small amounts of MCP-1. In conclusion, this study shows that donor brain death initiates an inflammatory state of the graft with T lymphocyte and macrophage infiltration and massive inflammatory cytokine release upon reperfusion. These observations suggest that brain dead donors require a novel approach for donor pretreatment aimed at preventing this inflammatory response to increase graft survival. ©2011 The Authors Journal compilation©2011 The American Society of Transplantation and the American Society of Transplant Surgeons.

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

Epidermal keratinocytes initiate wound healing and pro-inflammatory immune responses following percutaneous schistosome infection

PubMed Central

Bourke, Claire D.; Prendergast, Catriona T.; Sanin, David E.; Oulton, Tate E.; Hall, Rebecca J.; Mountford, Adrian P.

2015-01-01

Keratinocytes constitute the majority of cells in the skin’s epidermis, the first line of defence against percutaneous pathogens. Schistosome larvae (cercariae) actively penetrate the epidermis to establish infection, however the response of keratinocytes to invading cercariae has not been investigated. Here we address the hypothesis that cercariae activate epidermal keratinocytes to promote the development of a pro-inflammatory immune response in the skin. C57BL/6 mice were exposed to Schistosoma mansoni cercariae via each pinna and non-haematopoietic cells isolated from epidermal tissue were characterised for the presence of different keratinocyte sub-sets at 6, 24 and 96 h p.i. We identified an expansion of epidermal keratinocyte precursors (CD45−, CD326−, CD34+) within 24 h of infection relative to naïve animals. Following infection, cells within the precursor population displayed a more differentiated phenotype (α6integrin−) than in uninfected skin. Parallel immunohistochemical analysis of pinnae cryosections showed that this expansion corresponded to an increase in the intensity of CD34 staining, specifically in the basal bulge region of hair follicles of infected mice, and a higher frequency of keratinocyte Ki67+ nuclei in both the hair follicle and interfollicular epidermis. Expression of pro-inflammatory cytokine and stress-associated keratin 6b genes was also transiently upregulated in the epidermal tissue of infected mice. In vitro exposure of keratinocyte precursors isolated from neonatal mouse skin to excretory/secretory antigens released by penetrating cercariae elicited IL-1α and IL-1β production, supporting a role for keratinocyte precursors in initiating cutaneous inflammatory immune responses. Together, these observations indicate that S.mansoni cercariae and their excretory/secretory products act directly upon epidermal keratinocytes, which respond by initiating barrier repair and pro-inflammatory mechanisms similar to those observed in epidermal wound healing. PMID:25575749

Radiation promotes colorectal cancer initiation and progression by inducing senescence-associated inflammatory responses.

PubMed

Kim, S B; Bozeman, R G; Kaisani, A; Kim, W; Zhang, L; Richardson, J A; Wright, W E; Shay, J W

2016-06-30

Proton radiotherapy is becoming more common as protons induce more precise DNA damage at the tumor site with reduced side effects to adjacent normal tissues. However, the long-term biological effects of proton irradiation in cancer initiation compared with conventional photon irradiation are poorly characterized. In this study, using a human familial adenomatous polyposis syndrome susceptible mouse model, we show that whole-body irradiation with protons are more effective in inducing senescence-associated inflammatory responses (SIRs), which are involved in colon cancer initiation and progression. After proton irradiation, a subset of SIR genes (Troy, Sox17, Opg, Faim2, Lpo, Tlr2 and Ptges) and a gene known to be involved in invasiveness (Plat), along with the senescence-associated gene (P19Arf), are markedly increased. Following these changes, loss of Casein kinase Iα and induction of chronic DNA damage and TP53 mutations are increased compared with X-ray irradiation. Proton irradiation also increases the number of colonic polyps, carcinomas and invasive adenocarcinomas. Pretreatment with the non-steroidal anti-inflammatory drug, 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid-ethyl amide (CDDO-EA), reduces proton irradiation-associated SIR and tumorigenesis. Thus exposure to proton irradiation elicits significant changes in colorectal cancer initiation and progression that can be mitigated using CDDO-EA.

Mathematical modeling of postcoinfection with influenza A virus and Streptococcus pneumoniae, with implications for pneumonia and COPD-risk assessment.

PubMed

Cheng, Yi-Hsien; You, Shu-Han; Lin, Yi-Jun; Chen, Szu-Chieh; Chen, Wei-Yu; Chou, Wei-Chun; Hsieh, Nan-Hung; Liao, Chung-Min

2017-01-01

The interaction between influenza and pneumococcus is important for understanding how coinfection may exacerbate pneumonia. Secondary pneumococcal pneumonia associated with influenza infection is more likely to increase respiratory morbidity and mortality. This study aimed to assess exacerbated inflammatory effects posed by secondary pneumococcal pneumonia, given prior influenza infection. A well-derived mathematical within-host dynamic model of coinfection with influenza A virus and Streptococcus pneumoniae (SP) integrated with dose-response relationships composed of previously published mouse experimental data and clinical studies was implemented to study potentially exacerbated inflammatory responses in pneumonia based on a probabilistic approach. We found that TNFα is likely to be the most sensitive biomarker reflecting inflammatory response during coinfection among three explored cytokines. We showed that the worst inflammatory effects would occur at day 7 SP coinfection, with risk probability of 50% (likely) to develop severe inflammatory responses. Our model also showed that the day of secondary SP infection had much more impact on the severity of inflammatory responses in pneumonia compared to the effects caused by initial virus titers and bacteria loads. People and health care workers should be wary of secondary SP infection on day 7 post-influenza infection for prompt and proper control-measure implementation. Our quantitative risk-assessment framework can provide new insights into improvements in respiratory health especially, predominantly due to chronic obstructive pulmonary disease (COPD).

Fibrin(ogen) mediates acute inflammatory responses to biomaterials

PubMed Central

1993-01-01

Although "biocompatible" polymeric elastomers are generally nontoxic, nonimmunogenic, and chemically inert, implants made of these materials may trigger acute and chronic inflammatory responses. Early interactions between implants and inflammatory cells are probably mediated by a layer of host proteins on the material surface. To evaluate the importance of this protein layer, we studied acute inflammatory responses of mice to samples of polyester terephthalate film (PET) that were implanted intraperitoneally for short periods. Material preincubated with albumin is "passivated," accumulating very few adherent neutrophils or macrophages, whereas uncoated or plasma- coated PET attracts large numbers of phagocytes. Neither IgG adsorption nor surface complement activation is necessary for this acute inflammation; phagocyte accumulation on uncoated implants is normal in hypogammaglobulinemic mice and in severely hypocomplementemic mice. Rather, spontaneous adsorption of fibrinogen appears to be critical: (a) PET coated with serum or hypofibrinogenemic plasma attracts as few phagocytes as does albumin-coated material; (b) in contrast, PET preincubated with serum or hypofibrinogenemic plasma containing physiologic amounts of fibrinogen elicits "normal" phagocyte recruitment; (c) most importantly, hypofibrinogenemic mice do not mount an inflammatory response to implanted PET unless the material is coated with fibrinogen or the animals are injected with fibrinogen before implantation. Thus, spontaneous adsorption of fibrinogen appears to initiate the acute inflammatory response to an implanted polymer, suggesting an interesting nexus between two major iatrogenic effects of biomaterials: clotting and inflammation. PMID:8245787

IGF-I, IGFBPs, and inflammatory cytokine responses during gender-integrated Israeli Army basic combat training.

PubMed

Nindl, Bradley C; Scofield, Dennis E; Strohbach, Cassandra A; Centi, Amanda J; Evans, Rachel K; Yanovich, Ran; Moran, Daniel S

2012-07-01

Insulin-like growth factor 1 (IGF-I) is a robust metabolic and anabolic biomarker that has been demonstrated to be reflective of military training-induced body composition changes and influenced by initial aerobic fitness level. Greater mechanistic insight into the IGF-I response to physical training can potentially be gleaned by also examining other regulatory factors that influence IGF-I biological activity (i.e., insulin-like growth factor-binding proteins [IGFBPs] and inflammatory cytokine responses). The purpose of this study was to assess the influence of sex and initial fitness level on the IGF-I and inflammatory cytokine response to gender-integrated Israeli Defense Forces (IDF) basic combat training (BCT). Recruits (29 men, 19.1 ± 1.3 years; 93 women, 18.8 ± 0.6 years) were recruited from a 4-month gender-integrated BCT of the IDF. Blood was drawn and assayed for total IGF-I, free IGF-I, IGFBPs 1-6, tumor necrosis factor alpha (TNF-α), interleukin 6, and interleukin 1 beta. Body composition was determined via a 4-site skinfold (biceps, triceps, suprailiac, and subscapular) equation. Physical performance was assessed via a maximum volume of oxygen consumption (V[Combining Dot Above]O₂max) test using a treadmill protocol. All measures were obtained pre- and posttraining. A 2-way (sex × time) analysis of variance was used to test for statistical differences (p ≤ 0.05). Additionally, subjects were further partitioned (men and women separately) by tertiles of initial V[Combining Dot Above]O₂max to assess the influence of initial fitness level on the IGF-I system and inflammatory cytokine responses to physical training. Pearson product moment correlational analysis was also used to examine relationships between percent changes in blood measures and physical performance and body composition changes. All data are presented as mean ± SE. Time effects were observed only for total IGF-I, IGFBP-2, TNF-α, V[Combining Dot Above]O₂max, fat-free mass, and fat mass. The only significant (p ≤ 0.05) correlations observed for percent changes were in men between total IGF-I and V[Combining Dot Above]O₂max (r = 0.49) and body mass (r = -0.42) During gender-integrated Israeli Army BCT, men and women generally respond in a similar fashion with regard to blood measures (IGF-I system and inflammatory cytokines) and V[Combining Dot Above]O₂max. Initial fitness level only influenced the IGF-I response to training in women. Although the training-induced changes in total IGF-I (increase), IGFBP-2 (decrease), and TNF-α (decrease) are all indicative of an enhanced circulating anabolic milieu, only total IGF-I for the men was correlated with body composition and fitness improvements.

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

Unrepaired DNA damage in macrophages causes elevation of particulate matter- induced airway inflammatory response.

PubMed

Luo, Man; Bao, Zhengqiang; Xu, Feng; Wang, Xiaohui; Li, Fei; Li, Wen; Chen, Zhihua; Ying, Songmin; Shen, Huahao

2018-04-14

The inflammatory cascade can be initiated with the recognition of damaged DNA. Macrophages play an essential role in particulate matter (PM)-induced airway inflammation. In this study, we aim to explore the PM induced DNA damage response of macrophages and its function in airway inflammation. The DNA damage response and inflammatory response were assessed using bone marrow-derived macrophages following PM treatment and mouse model instilled intratracheally with PM. We found that PM induced significant DNA damage both in vitro and in vivo and simultaneously triggered a rapid DNA damage response, represented by nuclear RPA, 53BP1 and γH2AX foci formation. Genetic ablation or chemical inhibition of the DNA damage response sensor amplified the production of cytokines including Cxcl1, Cxcl2 and Ifn-γ after PM stimulation in bone marrow-derived macrophages. Similar to that seen in vitro , mice with myeloid-specific deletion of RAD50 showed higher levels of airway inflammation in response to the PM challenge, suggesting a protective role of DNA damage sensor during inflammation. These data demonstrate that PM exposure induces DNA damage and activation of DNA damage response sensor MRN complex in macrophages. Disruption of MRN complex lead to persistent, unrepaired DNA damage that causes elevated inflammatory response.

Anti-inflammatory effects of vinpocetine in atherosclerosis and ischemic stroke: a review of the literature.

PubMed

Zhang, Linjie; Yang, Li

2014-12-26

Immune responses play an important role in the pathophysiology of atherosclerosis and ischemic stroke. Atherosclerosis is a common condition that increases the risk of stroke. Hyperlipidemia damages endothelial cells, thus initiating chemokine pathways and the release of inflammatory cytokines-this represents the first step in the inflammatory response to atherosclerosis. Blocking blood flow in the brain leads to ischemic stroke, and deprives neurons of oxygen and energy. Damaged neurons release danger-associated molecular patterns, which promote the activation of innate immune cells and the release of inflammatory cytokines. The nuclear factor κ-light-chain-enhancer of activated B cells κB (NF-κB) pathway plays a key role in the pathogenesis of atherosclerosis and ischemic stroke. Vinpocetine is believed to be a potent anti-inflammatory agent and has been used to treat cerebrovascular disorders. Vinpocetine improves neuronal plasticity and reduces the release of inflammatory cytokines and chemokines from endothelial cells, vascular smooth muscle cells, macrophages, and microglia, by inhibiting the inhibitor of the NF-κB pathway. This review clarifies the anti-inflammatory role of vinpocetine in atherosclerosis and ischemic stroke.

Cross-talk between oxidative stress and pro-inflammatory cytokines in acute pancreatitis: a key role for protein phosphatases.

PubMed

Escobar, Javier; Pereda, Javier; Arduini, Alessandro; Sandoval, Juan; Sabater, Luis; Aparisi, Luis; López-Rodas, Gerardo; Sastre, Juan

2009-01-01

Acute pancreatitis is an acute inflammatory process localized in the pancreatic gland that frequently involves peripancreatic tissues. It is still under investigation why an episode of acute pancreatitis remains mild affecting only the pancreas or progresses to a severe form leading to multiple organ failure and death. Proinflammatory cytokines and oxidative stress play a pivotal role in the early pathophysiological events of the disease. Cytokines such as interleukin 1beta and tumor necrosis factor alpha initiate and propagate almost all consequences of the systemic inflammatory response syndrome. On the other hand, depletion of pancreatic glutathione is an early hallmark of acute pancreatitis and reactive oxygen species are also associated with the inflammatory process. Changes in thiol homestasis and redox signaling decisively contribute to amplification of the inflammatory cascade through mitogen activated protein kinase (MAP kinase) pathways. This review focuses on the relationship between oxidative stress, pro-inflammatory cytokines and MAP kinase/protein phosphatase pathways as major modulators of the inflammatory response in acute pancreatitis. Redox sensitive signal transduction mediated by inactivation of protein phosphatases, particularly protein tyrosin phosphatases, is highlighted.

Regulation of mitochondrial biogenesis and its intersection with inflammatory responses.

PubMed

Cherry, Anne D; Piantadosi, Claude A

2015-04-20

Mitochondria play a vital role in cellular homeostasis and are susceptible to damage from inflammatory mediators released by the host defense. Cellular recovery depends, in part, on mitochondrial quality control programs, including mitochondrial biogenesis. Early-phase inflammatory mediator proteins interact with PRRs to activate NF-κB-, MAPK-, and PKB/Akt-dependent pathways, resulting in increased expression or activity of coactivators and transcription factors (e.g., PGC-1α, NRF-1, NRF-2, and Nfe2l2) that regulate mitochondrial biogenesis. Inflammatory upregulation of NOS2-induced NO causes mitochondrial dysfunction, but NO is also a signaling molecule upregulating mitochondrial biogenesis via PGC-1α, participating in Nfe2l2-mediated antioxidant gene expression and modulating inflammation. NO and reactive oxygen species generated by the host inflammatory response induce the redox-sensitive HO-1/CO system, causing simultaneous induction of mitochondrial biogenesis and antioxidant gene expression. Recent evidence suggests that mitochondrial biogenesis and mitophagy are coupled through redox pathways; for instance, parkin, which regulates mitophagy in chronic inflammation, may also modulate mitochondrial biogenesis and is upregulated through NF-κB. Further research on parkin in acute inflammation is ongoing. This highlights certain common features of the host response to acute and chronic inflammation, but caution is warranted in extrapolating findings across inflammatory conditions. Inflammatory mitochondrial dysfunction and oxidative stress initiate further inflammatory responses through DAMP/PRR interactions and by inflammasome activation, stimulating mitophagy. A deeper understanding of mitochondrial quality control programs' impact on intracellular inflammatory signaling will improve our approach to the restoration of mitochondrial homeostasis in the resolution of acute inflammation.

Commonly used air filters fail to eliminate secondhand smoke induced oxidative stress and inflammatory responses.

PubMed

Muthumalage, Thivanka; Pritsos, Karen; Hunter, Kenneth; Pritsos, Chris

2017-07-01

Secondhand smoke (SHS) causes approximately 50,000 deaths per year. Despite all the health warnings, smoking is still allowed indoors in many states exposing both workers and patrons to SHS on a daily basis. The opponents of smoking bans suggest that present day air filtration systems remove the health hazards of exposure to SHS. In this study, using an acute SHS exposure model, we looked at the impact of commonly used air filters (MERV-8 pleated and MERV-8 pleated activated charcoal) on SHS by assessing the inflammatory response and the oxidative stress response in C57BL/6 mice. In order to assess the inflammatory response, we looked at the tumor necrosis factor alpha (TNF-α) cytokine production by alveolar macrophages (AMs), and for the oxidative response, we quantified the products of lipid peroxidation and the total glutathione (tGSH) production in lung homogenates. Our results showed that SHS caused significant immune and oxidative stress responses. The tested filters resulted in only a modest alleviation of inflammatory and oxidative responses due to SHS exposure. Our data show that these air filters cannot eliminate the risk of SHS exposure and that a short-term exposure to SHS is sufficient to alter the inflammatory cytokine response and to initiate a complex oxidative stress response. Our results are consistent with the statement made by the Surgeon General's reports that there is no risk free level of exposure to SHS.

Potential Use of Salivary Markers for Longitudinal Monitoring of Inflammatory Immune Responses to Vaccination

PubMed Central

Garssen, Johan; Sandalova, Elena

2016-01-01

Vaccination, designed to trigger a protective immune response against infection, is a trigger for mild inflammatory responses. Vaccination studies can address the question of inflammation initiation, levels, and resolution as well as its regulation for respective studied pathogens. Such studies largely based on analyzing the blood components including specific antibodies and cytokines were usually constrained by number of participants and volume of collected blood sample. Hence, blood-based studies may not be able to cover the full dynamic range of inflammation responses induced by vaccination. In this review, the potential of using saliva in addition to blood for studying the kinetics of inflammatory response studies was assessed. Saliva sampling is noninvasive and has a great potential to be used for studies aimed at analysing the magnitude, time course, and variance in immune responses, including inflammation after vaccination. Based on a literature survey of inflammatory biomarkers that can be determined in saliva and an analysis of how these biomarkers could help to understand the mechanisms and dynamics of immune reactivity and inflammation, we propose that the saliva-based approach might have potential to add substantial value to clinical studies, particularly in vulnerable populations such as infants, toddlers, and ill individuals. PMID:27022211

In Vitro and In Vivo Biocompatibility Evaluation of Polyallylamine and Macromolecular Heparin Conjugates Modified Alginate Microbeads.

PubMed

Vaithilingam, Vijayaganapathy; Steinkjer, Bjørg; Ryan, Liv; Larsson, Rolf; Tuch, Bernard Edward; Oberholzer, Jose; Rokstad, Anne Mari

2017-09-15

Host reactivity to biocompatible immunoisolation devices is a major challenge for cellular therapies, and a human screening model would be of great value. We designed new types of surface modified barium alginate microspheres, and evaluated their inflammatory properties using human whole blood, and the intraperitoneal response after three weeks in Wistar rats. Microspheres were modified using proprietary polyallylamine (PAV) and coupled with macromolecular heparin conjugates (Corline Heparin Conjugate, CHC). The PAV-CHC strategy resulted in uniform and stable coatings with increased anti-clot activity and low cytotoxicity. In human whole blood, PAV coating at high dose (100 µg/ml) induced elevated complement, leukocyte CD11b and inflammatory mediators, and in Wistar rats increased fibrotic overgrowth. Coating of high dose PAV with CHC significantly reduced these responses. Low dose PAV (10 µg/ml) ± CHC and unmodified alginate microbeads showed low responses. That the human whole blood inflammatory reactions paralleled the host response shows a link between inflammatory potential and initial fibrotic response. CHC possessed anti-inflammatory activity, but failed to improve overall biocompatibility. We conclude that the human whole blood assay is an efficient first-phase screening model for inflammation, and a guiding tool in development of new generation microspheres for cell encapsulation therapy.

Inflammation and fertility in the mare.

PubMed

Christoffersen, M; Troedsson, Mht

2017-08-01

A transient uterine inflammation post-breeding is a normal physiological reaction in the mare, and it is believed that the inflammatory response is necessary to eliminate bacteria and excess spermatozoa introduced into the uterine lumen. A tight balance between multiple pro- and anti-inflammatory factors is required for resolving the breeding-induced inflammation within 24-36 hr in the reproductively healthy mare, whereas a subpopulation of mares is susceptible to development of a persistent infection that can interfere with fertility. The aetiology of persistent endometritis can be either bacterial or semen-induced and both scenarios can threaten the establishment of pregnancy. Several factors associated with susceptibility to persistent endometritis have been identified including altered innate immune response in the early inflammatory process, reduced myometrial contractions and impaired opsonization; however, the pathogenesis to susceptibility has not been fully elucidated. Current research focuses on the initial hours of uterine inflammatory responses to semen and bacteria, and potential treatments to modify this altered innate immune response. An increased understanding of the mechanisms involved in the disease progression is necessary to improve the treatment and management of these mares. This review attempts to summarize the current knowledge of the uterine inflammatory and immunological responses to breeding-induced endometritis, persistent breeding-induced endometritis (PBIE) and bacterial endometritis in the mare. © 2017 Blackwell Verlag GmbH.

VIP modulates the pro-inflammatory maternal response, inducing tolerance to trophoblast cells

PubMed Central

Fraccaroli, Laura; Alfieri, Julio; Larocca, Luciana; Calafat, Mario; Roca, Valeria; Lombardi, Eduardo; Ramhorst, Rosanna; Leirós, Claudia Pérez

2009-01-01

Background and purpose Successful embryo implantation is followed by a local pro-inflammatory and Th1 response, subsequently controlled by a Th2 response. Vasoactive intestinal peptide (VIP) has anti-inflammatory effects and promotes tolerogenic/Th2 responses while favouring embryonic development. We investigated the potential regulatory role of VIP on human trophoblast cells, maternal pro-inflammatory responses and trophoblast-maternal leukocyte interactions. Experimental approach We tested VIP effects directly on a trophoblast cell line (Swan 71 cells) and after co-culture with maternal peripheral blood mononuclear cells (PBMCs) as models of the feto-maternal dialogue. We also co-cultured maternal and paternal PBMCs to test effects of endogenous VIP on maternal alloresponses. Key results Swan 71 cells express VPAC1 receptors and VIP induced their proliferation and the expression of leukaemia inhibitor factor, a pro-implantatory marker. After interaction with trophoblast cells, VIP increased Foxp3, the proportion of CD4+CD25+Foxp3+ cells within maternal PBMCs and transforming growth factor β expression. Also, during the trophoblast-maternal PBMCs interaction, VIP reduced pro-inflammatory mediators [interleukin (IL)-6, monocyte chemoattractant protein 1, nitric oxide], while increasing IL-10. Trophoblast cells produced VIP which dose-dependently suppressed allomaternal responses, accompanied by reduced expression of the T cell transcription factor, T-bet. Conclusions and implications Vasoactive intestinal peptide induced pro-implantatory markers and trophoblast cell proliferation, while controlling the initial pro-inflammatory response, by increasing maternal regulatory T cells and anti-inflammatory cytokines. As an autocrine regulatory peptide VIP might contribute to fetal survival through two mechanisms; a direct trophic effect on trophoblast cells and an immunomodulatory effect that favours tolerance to fetal antigens. PMID:19133995

Immunopharmacological role of the leukotriene receptor antagonists and inhibitors of leukotrienes generating enzymes in multiple sclerosis.

PubMed

Mirshafiey, Abbas; Jadidi-Niaragh, Farhad

2010-06-01

Multiple sclerosis (MS) is a chronic inflammatory disease that involves central nervous system, and is generally associated with demyelination and axonal lesion. The effective factors for initiation of the inflammatory responses have not been known precisely so far. Leukotrienes (LTs) are inflammatory mediators with increased levels in the cerebrospinal fluid of MS patients and in experimental models of multiple sclerosis. Inhibition of LT receptors with specific antagonists can decrease inflammatory responses. In this review article we try to clarify the role of LT receptor antagonists and also inhibitors of enzymes which are involved in LTs generating pathway for treating multiple sclerosis as new targets for MS therapy. Moreover, we suggest that blockage of LT receptors by potent specific antagonists and/or agonists can be as a novel useful method in treatment of MS.

The role of the JAK2-STAT3 pathway in pro-inflammatory responses of EMF-stimulated N9 microglial cells

PubMed Central

2010-01-01

Background In several neuropathological conditions, microglia can become overactivated and cause neurotoxicity by initiating neuronal damage in response to pro-inflammatory stimuli. Our previous studies have shown that exposure to electromagnetic fields (EMF) activates cultured microglia to produce tumor necrosis factor (TNF)-α and nitric oxide (NO) through signal transduction involving the activator of transcription STAT3. Here, we investigated the role of STAT3 signaling in EMF-induced microglial activation and pro-inflammatory responses in more detail than the previous study. Methods N9 microglial cells were treated with EMF exposure or a sham treatment, with or without pretreatment with an inhibitor (Pyridone 6, P6) of the Janus family of tyrosine kinases (JAK). The activation state of microglia was assessed via immunoreaction using the microglial marker CD11b. Levels of inducible nitric oxide synthase (iNOS), TNF-α and NO were measured using real-time reverse transcription-polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA) and the nitrate reductase method. Activation of JAKs and STAT3 proteins was evaluated by western blotting for specific tyrosine phosphorylation. The ability of STAT3 to bind to DNA was detected with an electrophoresis mobility shift assay (EMSA). Results EMF was found to significantly induce phosphorylation of JAK2 and STAT3, and DNA-binding ability of STAT3 in N9 microglia. In addition, EMF dramatically increased the expression of CD11b, TNF-α and iNOS, and the production of NO. P6 strongly suppressed the phosphorylation of JAK2 and STAT3 and diminished STAT3 activity in EMF-stimulated microglia. Interestingly, expression of CD11b as well as gene expression and production of TNF-α and iNOS were suppressed by P6 at 12 h, but not at 3 h, after EMF exposure. Conclusions EMF exposure directly triggers initial activation of microglia and produces a significant pro-inflammatory response. Our findings confirm that the JAK2-STAT3 pathway may not mediate this initial microglial activation but does promote pro-inflammatory responses in EMF-stimulated microglial cells. Thus, the JAK2-STAT3 pathway might be a therapeutic target for reducing pro-inflammatory responses in EMF-activated microglia. PMID:20828402

Immunological Responses to Total Hip Arthroplasty.

PubMed

Man, Kenny; Jiang, Lin-Hua; Foster, Richard; Yang, Xuebin B

2017-08-01

The use of total hip arthroplasties (THA) has been continuously rising to meet the demands of the increasingly ageing population. To date, this procedure has been highly successful in relieving pain and restoring the functionality of patients' joints, and has significantly improved their quality of life. However, these implants are expected to eventually fail after 15-25 years in situ due to slow progressive inflammatory responses at the bone-implant interface. Such inflammatory responses are primarily mediated by immune cells such as macrophages, triggered by implant wear particles. As a result, aseptic loosening is the main cause for revision surgery over the mid and long-term and is responsible for more than 70% of hip revisions. In some patients with a metal-on-metal (MoM) implant, metallic implant wear particles can give rise to metal sensitivity. Therefore, engineering biomaterials, which are immunologically inert or support the healing process, require an in-depth understanding of the host inflammatory and wound-healing response to implanted materials. This review discusses the immunological response initiated by biomaterials extensively used in THA, ultra-high-molecular-weight polyethylene (UHMWPE), cobalt chromium (CoCr), and alumina ceramics. The biological responses of these biomaterials in bulk and particulate forms are also discussed. In conclusion, the immunological responses to bulk and particulate biomaterials vary greatly depending on the implant material types, the size of particulate and its volume, and where the response to bulk forms of differing biomaterials are relatively acute and similar, while wear particles can initiate a variety of responses such as osteolysis, metal sensitivity, and so on.

A Detailed Characterization of the Dysfunctional Immunity and Abnormal Myelopoiesis Induced by Severe Shock and Trauma in the Aged

PubMed Central

Nacionales, Dina C.; Szpila, Benjamin; Ungaro, Ricardo; Lopez, M. Cecilia; Zhang, Jianyi; Gentile, Lori F.; Cuenca, Angela L.; Vanzant, Erin; Mathias, Brittany; Jyot, Jeevan; Westerveld, Donevan; Bihorac, Azra; Joseph, Anna; Mohr, Alicia; Duckworth, Lizette V.; Moore, Frederick A.; Baker, Henry V.; Leeuwenburgh, Christiaan; Moldawer, Lyle L.; Brakenridge, Scott; Efron, Philip A.

2015-01-01

The elderly are particularly susceptible to trauma, and their outcomes are frequently dismal. Such patients often have complicated clinical courses and ultimately die from infection and sepsis. Recent research has revealed that although elderly subjects have increased baseline inflammation as compared to their younger counterparts, the elderly do not respond to severe infection/injury with an exaggerated inflammatory response. Initial retrospective analysis of clinical data from the Glue Grant trauma database demonstrated that despite a similar frequency, elderly trauma patients have worse outcomes to pneumonia than younger subjects. Subsequent analysis with a murine trauma model also demonstrated that elderly mice had increased mortality after post-trauma Pseudomonas pneumonia. Blood, bone marrow, and bronchoalveolar lavage sample analyses from juvenile and 20–24 month old mice showed that increased mortality to trauma combined with secondary infection in the aged are not due to an exaggerated inflammatory response. Rather, they are due to a failure of bone marrow progenitors, blood neutrophils, and bronchoalveolar lavage cells to initiate and complete an ‘emergency myelopoietic’ response, engendering myeloid cells that fail to clear secondary infection. In addition, the elderly appeared unable to effectively resolve their inflammatory response to severe injury. PMID:26246141

The Synthetic Peroxisome Proliferator-Activated Receptor-γ Agonist Ciglitazone Attenuates Neuroinflammation and Accelerates Encapsulation in Bacterial Brain Abscesses1

PubMed Central

Kielian, Tammy; Md. Syed, Mohsin; Liu, Shuliang; Phulwani, Nirmal K.; Phillips, Napoleon; Wagoner, Gail; Drew, Paul D.; Esen, Nilufer

2008-01-01

Brain abscesses result from a pyogenic parenchymal infection commonly initiated by Gram-positive bacteria such as Staphylococcus aureus. Although the host immune response elicited following infection is essential for effective bacterial containment, this response also contributes to the significant loss of brain parenchyma by necrosis that may be reduced by modulating the inflammatory response. Ciglitazone, a PPAR-γ agonist with anti-inflammatory properties, was evaluated for its ability to influence the course of brain abscess development when treatment was initiated 3 days following infection. Interestingly, abscess-associated bacterial burdens were significantly lower following ciglitazone administration, which could be explained, in part, by the finding that ciglitazone enhanced S. aureus phagocytosis by microglia. In addition, ciglitazone attenuated the expression of select inflammatory mediators during brain abscess development including inducible NO synthase, TNF-α, IL-1β, CXCL2, and CCL3. Unexpectedly, ciglitazone also accelerated brain abscess encapsulation, which was typified by the heightened expression of fibronectin and α-smooth muscle actin-positive myofibroblasts. Collectively, through its ability to attenuate excessive inflammation and accelerate abscess encapsulation, ciglitazone may effectively sequester brain abscesses and limit bacterial dissemination. PMID:18354226

Assessment of Antibody-based Drugs Effects on Murine Bone Marrow and Peritoneal Macrophage Activation.

PubMed

Kozicky, Lisa; Sly, Laura M

2017-12-26

Macrophages are phagocytic innate immune cells, which initiate immune responses to pathogens and contribute to healing and tissue restitution. Macrophages are equally important in turning off inflammatory responses. We have shown that macrophages stimulated with intravenous immunoglobulin (IVIg) can produce high amounts of the anti-inflammatory cytokine, interleukin 10 (IL-10), and low levels of pro-inflammatory cytokines in response to bacterial lipopolysaccharides (LPS). IVIg is a polyvalent antibody, primarily immunoglobulin Gs (IgGs), pooled from the plasma of more than 1,000 blood donors. It is used to supplement antibodies in patients with immune deficiencies or to suppress immune responses in patients with autoimmune or inflammatory conditions. Infliximab, a therapeutic anti-tumor necrosis factor alpha (TNFα) antibody, has also been shown to activate macrophages to produce IL-10 in response to inflammatory stimuli. IVIg and other antibody-based biologics can be tested to determine their effects on macrophage activation. This paper describes methods for derivation, stimulation, and assessment of murine bone marrow macrophages activated by antibodies in vitro and murine peritoneal macrophages activated with antibodies in vivo. Finally, we demonstrate the use of western blotting to determine the contribution of specific cell signaling pathways to anti-inflammatory macrophage activity. These protocols can be used with genetically modified mice, to determine the effect of a specific protein(s) on anti-inflammatory macrophage activation. These techniques can also be used to assess whether specific biologics may act by changing macrophages to an IL-10-producing anti-inflammatory activation state that reduces inflammatory responses in vivo. This can provide information on the role of macrophage activation in the efficacy of biologics during disease models in mice, and provide insight into a potential new mechanism of action in people. Conversely, this may caution against the use of specific antibody-based biologics to treat infectious disease, particularly if macrophages play an important role in host defense against that infection.

A Pseudopterane Diterpene Isolated From the Octocoral Pseudopterogorgia acerosa Inhibits the Inflammatory Response Mediated by TLR-Ligands and TNF-Alpha in Macrophages

PubMed Central

González, Yisett; Doens, Deborah; Santamaría, Ricardo; Ramos, Marla; Restrepo, Carlos M.; Barros de Arruda, Luciana; Lleonart, Ricardo; Gutiérrez, Marcelino; Fernández, Patricia L.

2013-01-01

Several diterpenoids isolated from terrestrial and marine environments have been identified as important anti-inflammatory agents. Although considerable progress has been made in the area of anti-inflammatory treatment, the search for more effective and safer compounds is a very active field of research. In this study we investigated the anti-inflammatory effects of a known pseudopterane diterpene (referred here as compound 1) isolated from the octocoral Pseudopterogorgia acerosa on the tumor necrosis factor- alpha (TNF-α) and TLRs- induced response in macrophages. Compound 1 inhibited the expression and secretion of the inflammatory mediators TNF-α, interleukin (IL)-6, IL-1β, nitric oxide (NO), interferon gamma-induced protein 10 (IP-10), ciclooxygenase (COX)-2, inducible nitric oxide synthase (iNOS) and monocyte chemoattractant protein-1 (MCP-1) induced by LPS in primary murine macrophages. This effect was associated with the inhibition of IκBα degradation and subsequent activation of NFκB. Compound 1 also inhibited the expression of the co-stimulatory molecules CD80 and CD86, which is a hallmark of macrophage activation and consequent initiation of an adaptive immune response. The anti-inflammatory effect was not exclusive to LPS because compound 1 also inhibited the response of macrophages to TNF-α and TLR2 and TLR3 ligands. Taken together, these results indicate that compound 1 is an anti-inflammatory molecule, which modulates a variety of processes occurring in macrophage activation. PMID:24358331

Inflammasomes in the lung.

PubMed

Pinkerton, James W; Kim, Richard Y; Robertson, Avril A B; Hirota, Jeremy A; Wood, Lisa G; Knight, Darryl A; Cooper, Matthew A; O'Neill, Luke A J; Horvat, Jay C; Hansbro, Philip M

2017-06-01

Innate immune responses act as first line defences upon exposure to potentially noxious stimuli. The innate immune system has evolved numerous intracellular and extracellular receptors that undertake surveillance for potentially damaging particulates. Inflammasomes are intracellular innate immune multiprotein complexes that form and are activated following interaction with these stimuli. Inflammasome activation leads to the cleavage of pro-IL-1β and release of the pro-inflammatory cytokine, IL-1β, which initiates acute phase pro-inflammatory responses, and other responses are also involved (IL-18, pyroptosis). However, excessive activation of inflammasomes can result in chronic inflammation, which has been implicated in a range of chronic inflammatory diseases. The airways are constantly exposed to a wide variety of stimuli. Inflammasome activation and downstream responses clears these stimuli. However, excessive activation may drive the pathogenesis of chronic respiratory diseases such as severe asthma and chronic obstructive pulmonary disease. Thus, there is currently intense interest in the role of inflammasomes in chronic inflammatory lung diseases and in their potential for therapeutic targeting. Here we review the known associations between inflammasome-mediated responses and the development and exacerbation of chronic lung diseases. Copyright © 2017 Elsevier Ltd. All rights reserved.

AIP1-mediated stress signaling in atherosclerosis and arteriosclerosis

PubMed Central

Zhang, Jiqin; Zhou, Huanjiao Jenny; Ji, Weidong; Min, Wang

2016-01-01

AIP1 (encoded by the DAB2IP gene), a signaling scaffolding protein, is abundantly expressed in vascular endothelial cells (EC). While it was initially discovered as an ASK1-interacting protein, AIP1 broadly suppresses inflammatory responses triggered by cytokines and stresses such as TNF, LPS, VEGF and ER stress in EC (therefore AIP1 is an Anti-Inflammatory Protein). Human genome-wide association study (GWAS) has identified DAB2IP gene variants conferring susceptibility to cardiovascular diseases. Consistently, a global or vascular EC-specific deletion of DAB2IP in mice strongly enhances inflammatory responses and exacerbates atherosclerosis and graft arteriosclerosis progression in mouse models. Mechanisms for AIP1 function and regulation associated with human cardiovascular diseases need further investigations. PMID:25732743

Magnolol inhibits LPS-induced inflammatory response in uterine epithelial cells : magnolol inhibits LPS-induced inflammatory response.

PubMed

Luo, Jia; Xu, Yanwen; Zhang, Minfang; Gao, Ling; Fang, Cong; Zhou, Canquan

2013-10-01

Endometritis is an inflammation of the uterine lining that is commonly initiated at parturition. The uterine epithelial cells play an important role in defending against invading pathogens. Magnolol, a hydroxylated biphenyl compound isolated from Magnolia officinalis, has been shown to have anti-inflammatory effects. The aim of this study was to investigate the anti-inflammatory effect of magnolol in modifying lipopolysaccharide (LPS)-induced signal pathways in mouse uterine epithelial cells. We found that magnolol inhibited TNF-α and IL-6 production in LPS-stimulated mouse uterine epithelial cells. We also found that magnolol inhibited LPS-induced NF-κB activation, IκBα degradation, phosphorylation of ERK, JNK, and P38. Furthermore, magnolol could significantly inhibit the expression of TLR4 stimulating by LPS. These results suggest that magnolol exerts an anti-inflammatory property by downregulating the expression of TLR4 upregulated by LPS, thereby attenuating TLR4-mediated NF-κB and MAPK signaling and the release of pro-inflammatory cytokines. These findings suggest that magnolol may be a therapeutic agent against endometritis.

Treatment of inflammatory bowel disease: what's new in Digestive Disease Week 2016.

PubMed

Chaparro, María

2016-09-01

Inflammatory bowel disease is a chronic disorder of unknown aetiology that results from a pathologic response from both the innate and acquired immune systems, leading to chronic inflammation of the gastrointestinal tract. New drugs have been introduced into the therapeutic armamentarium of inflammatory bowel disease but are not effective in all patients; moreover, among initial responders, there have been reports of loss of response over time. In addition, these drugs sometimes have adverse effects and are often expensive. The present article reviews the studies presented at Digestive Disease Week 2016 that provided new data on the optimisation of currently approved treatments for inflammatory bowel disease, experience with recently approved drugs in clinical practice, and some studies on molecules that are under development for the treatment of these diseases. Copyright © 2016 Elsevier España, S.L.U. All rights reserved.

Mathematical Modeling of Early Cellular Innate and Adaptive Immune Responses to Ischemia/Reperfusion Injury and Solid Organ Allotransplantation

PubMed Central

Day, Judy D.; Metes, Diana M.; Vodovotz, Yoram

2015-01-01

A mathematical model of the early inflammatory response in transplantation is formulated with ordinary differential equations. We first consider the inflammatory events associated only with the initial surgical procedure and the subsequent ischemia/reperfusion (I/R) events that cause tissue damage to the host as well as the donor graft. These events release damage-associated molecular pattern molecules (DAMPs), thereby initiating an acute inflammatory response. In simulations of this model, resolution of inflammation depends on the severity of the tissue damage caused by these events and the patient’s (co)-morbidities. We augment a portion of a previously published mathematical model of acute inflammation with the inflammatory effects of T cells in the absence of antigenic allograft mismatch (but with DAMP release proportional to the degree of graft damage prior to transplant). Finally, we include the antigenic mismatch of the graft, which leads to the stimulation of potent memory T cell responses, leading to further DAMP release from the graft and concomitant increase in allograft damage. Regulatory mechanisms are also included at the final stage. Our simulations suggest that surgical injury and I/R-induced graft damage can be well-tolerated by the recipient when each is present alone, but that their combination (along with antigenic mismatch) may lead to acute rejection, as seen clinically in a subset of patients. An emergent phenomenon from our simulations is that low-level DAMP release can tolerize the recipient to a mismatched allograft, whereas different restimulation regimens resulted in an exaggerated rejection response, in agreement with published studies. We suggest that mechanistic mathematical models might serve as an adjunct for patient- or sub-group-specific predictions, simulated clinical studies, and rational design of immunosuppression. PMID:26441988

Brd4 modulates the innate immune response through Mnk2-eIF4E pathway-dependent translational control of IκBα.

PubMed

Bao, Yan; Wu, Xuewei; Chen, Jinjing; Hu, Xiangming; Zeng, Fuxing; Cheng, Jianjun; Jin, Hong; Lin, Xin; Chen, Lin-Feng

2017-05-16

Bromodomain-containing factor Brd4 has emerged as an important transcriptional regulator of NF-κB-dependent inflammatory gene expression. However, the in vivo physiological function of Brd4 in the inflammatory response remains poorly defined. We now demonstrate that mice deficient for Brd4 in myeloid-lineage cells are resistant to LPS-induced sepsis but are more susceptible to bacterial infection. Gene-expression microarray analysis of bone marrow-derived macrophages (BMDMs) reveals that deletion of Brd4 decreases the expression of a significant amount of LPS-induced inflammatory genes while reversing the expression of a small subset of LPS-suppressed genes, including MAP kinase-interacting serine/threonine-protein kinase 2 ( Mknk2 ). Brd4 -deficient BMDMs display enhanced Mnk2 expression and the corresponding eukaryotic translation initiation factor 4E (eIF4E) activation after LPS stimulation, leading to an increased translation of IκBα mRNA in polysomes. The enhanced newly synthesized IκBα reduced the binding of NF-κB to the promoters of inflammatory genes, resulting in reduced inflammatory gene expression and cytokine production. By modulating the translation of IκBα via the Mnk2-eIF4E pathway, Brd4 provides an additional layer of control for NF-κB-dependent inflammatory gene expression and inflammatory response.

Inflammatory Cytokines and White Blood Cell Counts Response to Environmental Levels of Diesel Exhaust and Ozone Inhalation Exposures

EPA Science Inventory

Epidemiological observations of urban inhalation exposures to diesel exhaust (DE) and ozone (O3) have shown pre-clinical cardiopulmonary responses in humans. Identifying the key biological mechanisms that initiate these health bioindicators is difficult due to variability in envi...

Interleukin-17A as a biomarker for bovine tuberculosis

USDA-ARS?s Scientific Manuscript database

T helper (Th) 17-associated cytokines are integral in the immune response to tuberculosis, initiating both protective and harmful inflammatory responses. The aim of the present study was to evaluate applied aspects of IL-17 biology in the context of Mycobacterium bovis infection of cattle. Using RNA...

TLR stimulation initiates a CD39-based autoregulatory mechanism that limits macrophage inflammatory responses

PubMed Central

Cohen, Heather B.; Briggs, Katharine T.; Marino, John P.; Ravid, Katya; Robson, Simon C.

2013-01-01

Sepsis is a highly fatal disease caused by an initial hyperinflammatory response followed by a state of profound immunosuppression. Although it is well appreciated that the initial production of proinflammatory cytokines by macrophages accompanies the onset of sepsis, it remains unclear what causes the transition to an immunosuppressive state. In this study, we reveal that macrophages themselves are key regulators of this transition and that the surface enzyme CD39 plays a critical role in self-limiting the activation process. We demonstrate that Toll-like receptor (TLR)-stimulated macrophages modulate their activation state by increasing the synthesis and secretion of adenosine triphosphate (ATP). This endogenous ATP is paradoxically immunosuppressive due to its rapid catabolism into adenosine by CD39. Macrophages lacking CD39 are unable to transition to a regulatory state and consequently continue to produce inflammatory cytokines. The importance of this transition is demonstrated in a mouse model of sepsis, where small numbers of CD39-deficient macrophages were sufficient to induce lethal endotoxic shock. Thus, these data implicate CD39 as a key “molecular switch” that allows macrophages to self-limit their activation state. We propose that therapeutics targeting the release and hydrolysis of ATP by macrophages may represent new ways to treat inflammatory diseases. PMID:23908469

The Immune Response to Acute Focal Cerebral Ischemia and Associated Post-stroke Immunodepression: A Focused Review

PubMed Central

Famakin, Bolanle M.

2014-01-01

It is currently well established that the immune system is activated in response to transient or focal cerebral ischemia. This acute immune activation occurs in response to damage, and injury, to components of the neurovascular unit and is mediated by the innate and adaptive arms of the immune response. The initial immune activation is rapid, occurs via the innate immune response and leads to inflammation. The inflammatory mediators produced during the innate immune response in turn lead to recruitment of inflammatory cells and the production of more inflammatory mediators that result in activation of the adaptive immune response. Under ideal conditions, this inflammation gives way to tissue repair and attempts at regeneration. However, for reasons that are just being understood, immunosuppression occurs following acute stroke leading to post-stroke immunodepression. This review focuses on the current state of knowledge regarding innate and adaptive immune activation in response to focal cerebral ischemia as well as the immunodepression that can occur following stroke. A better understanding of the intricate and complex events that take place following immune response activation, to acute cerebral ischemia, is imperative for the development of effective novel immunomodulatory therapies for the treatment of acute stroke. PMID:25276490

Histopathology of nymphal pentastomid infections (Sebekia mississippiensis) in paratenic hosts.

PubMed

Boyce, W M; Kazacos, E A

1991-02-01

The histopathologic alterations occurring in mice, hamsters, turtles, and a frog were described following experimental infection with nymphs of Sebekia mississippiensis. Initially, nymphal migration caused traumatic tissue damage and hemorrhage characteristic of larva migrans. Subsequent inflammatory responses included cellular infiltration with eosinophils, macrophages, and lymphocytes, and fibrotic encapsulation of the nymphs. Dead nymphs were surrounded by a necrotic granulomatous response similar to that reported previously in humans and other animals. Differences were not seen in animals given single or multiple infections, but mice and hamsters exhibited a more marked inflammatory response than turtles. Overall, the histopathologic response to nymphal infections resembled those seen in infections resulting from ingestion of eggs, and both sources of infection should be considered in epidemiologic investigations of naturally occurring pentastomiasis.

Modulation of inflammation by low and high doses of ionizing radiation: Implications for benign and malign diseases.

PubMed

Frey, Benjamin; Hehlgans, Stephanie; Rödel, Franz; Gaipl, Udo S

2015-11-28

Inflammation is a homeostatic mechanism aiming to maintain tissue integrity. The underlying immunological mechanisms and the interrelationship between ionizing radiation and inflammation are complex and multifactorial on cellular and chemical levels. On the one hand, radiation with single doses exceeding 1 Gy might initiate inflammatory reactions and thereby impact on tumor development. On the other hand, radiation is capable of attenuating an established inflammatory process, which is clinically used for the treatment of inflammatory and degenerative diseases with low-dose radiotherapy (single dose <1 Gy). At higher doses, ionizing radiation, especially in combination with additional immune stimulation, fosters the induction of immunogenic forms of tumor cell death and shifts the tumor microenvironment as well as the infiltration of immune cells from an anti- to a pro-inflammatory state. Distinct tumor infiltrating immune cells predict the response to radiochemotherapy in a multitude of tumor entities. While a high tumor infiltration of these adaptive immune cells mostly predicts a favorable disease outcome, a high infiltration of tumor-associated macrophages predicts an unfavorable response. Pro-inflammatory events should dominate over anti-inflammatory ones in this scenario. This review focuses on how ionizing radiation modulates inflammatory events in benign inflammatory and in malign diseases. A special focus is set on the role of tumor infiltrating lymphocytes and macrophages as biomarkers to predict treatment response and anti-tumor immunity and on mechanisms implicated in the anti-inflammatory effects of low-dose radiation therapy. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Myeloid differentiation protein 2-dependent mechanisms in retinal ischemia-reperfusion injury

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

Ren, Luqing

Retinal ischemia-reperfusion (I/R) injury is a common pathological process in many eye disorders. Oxidative stress and inflammation play a role in retinal I/R injury. Recent studies show that toll-like receptor 4 (TLR4) is involved in initiating sterile inflammatory response in retinal I/R. However, the molecular mechanism by which TLR4 is activated is not known. In this study, we show that retinal I/R injury involves a co-receptor of TLR4, myeloid differentiation 2 (MD2). Inhibition of MD2 prevented cell death and preserved retinal function following retinal I/R injury. We confirmed these findings using MD2 knockout mice. Furthermore, we utilized human retinal pigmentmore » epithelial cells (ARPE-19 cells) to show that oxidative stress-induced cell death as well as inflammatory response are mediated through MD2. Inhibition of MD2 through a chemical inhibitor or knockdown prevented oxidative stress-induced cell death and expression of inflammatory cytokines. Oxidative stress was found to activate TLR4 in a MD2-dependent manner via increasing the expression of high mobility group box 1. In summary, our study shows that oxidative stress in retinal I/R injury can activate TLR4 signaling via MD2, resulting in induction of inflammatory genes and retinal damage. MD2 may represent an attractive therapeutic target for retinal I/R injury. - Highlights: • MD2 inhibition reduced retinal damage after I/R induction in mice. • TBHP induced TLR4/MD2 binding via increasing HMGB-1 expression. • TLR4/MD2 initiated inflammatory response via activation of MAPKs and NF-κB. • MD2 could be the therapeutic target for the treatment of retinal I/R.« less

Spiral ganglion cells and macrophages initiate neuro-inflammation and scarring following cochlear implantation

PubMed Central

Bas, Esperanza; Goncalves, Stefania; Adams, Michelle; Dinh, Christine T.; Bas, Jose M.; Van De Water, Thomas R.; Eshraghi, Adrien A.

2015-01-01

Conservation of a patient's residual hearing and prevention of fibrous tissue/new bone formation around an electrode array are some of the major challenges in cochlear implant (CI) surgery. Although it is well-known that fibrotic tissue formation around the electrode array can interfere with hearing performance in implanted patients, and that associated intracochlear inflammation can initiate loss of residual hearing, little is known about the molecular and cellular mechanisms that promote this response in the cochlea. In vitro studies in neonatal rats and in vivo studies in adult mice were performed to gain insight into the pro-inflammatory, proliferative, and remodeling phases of pathological wound healing that occur in the cochlea following an electrode analog insertion. Resident Schwann cells (SC), macrophages, and fibroblasts had a prominent role in the inflammatory process in the cochlea. Leukocytes were recruited to the cochlea following insertion of a nylon filament in adult mice, where contributed to the inflammatory response. The reparative stages in wound healing are characterized by persistent neuro-inflammation of spiral ganglion neurons (SGN) and expression of regenerative monocytes/macrophages in the cochlea. Accordingly, genes involved in extracellular matrix (ECM) deposition and remodeling were up-regulated in implanted cochleae. Maturation of scar tissue occurs in the remodeling phase of wound healing in the cochlea. Similar to other damaged peripheral nerves, M2 macrophages and de-differentiated SC were observed in damaged cochleae and may play a role in cell survival and axonal regeneration. In conclusion, the insertion of an electrode analog into the cochlea is associated with robust early and chronic inflammatory responses characterized by recruitment of leukocytes and expression of pro-inflammatory cytokines that promote intracochlear fibrosis and loss of the auditory hair cells (HC) and SGN important for hearing after CI surgery. PMID:26321909

The Frustrated Host Response to Legionella pneumophila Is Bypassed by MyD88-Dependent Translation of Pro-inflammatory Cytokines

PubMed Central

Asrat, Seblewongel; Dugan, Aisling S.; Isberg, Ralph R.

2014-01-01

Many pathogens, particularly those that require their host for survival, have devised mechanisms to subvert the host immune response in order to survive and replicate intracellularly. Legionella pneumophila, the causative agent of Legionnaires' disease, promotes intracellular growth by translocating proteins into its host cytosol through its type IV protein secretion machinery. At least 5 of the bacterial translocated effectors interfere with the function of host cell elongation factors, blocking translation and causing the induction of a unique host cell transcriptional profile. In addition, L. pneumophila also interferes with translation initiation, by preventing cap-dependent translation in host cells. We demonstrate here that protein translation inhibition by L. pneumophila leads to a frustrated host MAP kinase response, where genes involved in the pathway are transcribed but fail to be translated due to the bacterium-induced protein synthesis inhibition. Surprisingly, few pro-inflammatory cytokines, such as IL-1α and IL-1β, bypass this inhibition and get synthesized in the presence of Legionella effectors. We show that the selective synthesis of these genes requires MyD88 signaling and takes place in both infected cells that harbor bacteria and neighboring bystander cells. Our findings offer a perspective of how host cells are able to cope with pathogen-encoded activities that disrupt normal cellular process and initiate a successful inflammatory response. PMID:25058342

Subacromial bursitis with giant rice bodies as initial presentation of rheumatoid arthritis.

PubMed

Subramaniam, Ramesh; Tan, Justina Wei Lyn; Chau, Cora Yuk Ping; Lee, Keng Thiam

2012-10-01

Rice body formation is a nonspecific response to chronic synovial inflammation associated with tuberculous arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, seronegative inflammatory arthritis, and even osteoarthritis. Such bodies were termed rice bodies because of their close resemblance to grains of polished white rice. We present a case report of a middle-aged woman with right shoulder subacromial/subdeltoid bursitis with giant rice body formation as her initial presentation of rheumatoid arthritis. Her right shoulder symptoms resolved after subacromial and subdeltoid bursectomy and removal of the rice bodies. She subsequently developed inflammatory arthritis of other joints, met the criteria for rheumatoid arthritis, and has been treated medically.

Evaluation of a nanotechnology-based approach to induce gene-expression in human THP-1 macrophages under inflammatory conditions.

PubMed

Bernal, Laura; Alvarado-Vázquez, Abigail; Ferreira, David Wilson; Paige, Candler A; Ulecia-Morón, Cristina; Hill, Bailey; Caesar, Marina; Romero-Sandoval, E Alfonso

2017-02-01

Macrophages orchestrate the initiation and resolution of inflammation by producing pro- and anti-inflammatory products. An imbalance in these mediators may originate from a deficient or excessive immune response. Therefore, macrophages are valid therapeutic targets to restore homeostasis under inflammatory conditions. We hypothesize that a specific mannosylated nanoparticle effectively induces gene expression in human macrophages under inflammatory conditions without undesirable immunogenic responses. THP-1 macrophages were challenged with lipopolysaccharide (LPS, 5μg/mL). Polyethylenimine (PEI) nanoparticles grafted with a mannose receptor ligand (Man-PEI) were used as a gene delivery method. Nanoparticle toxicity, Man-PEI cellular uptake rate and gene induction efficiency (GFP, CD14 or CD68) were studied. Potential immunogenic responses were evaluated by measuring the production of tumor necrosis factor-alpha (TNF-α), Interleukin (IL)-6 and IL-10. Man-PEI did not produce cytotoxicity, and it was effectively up-taken by THP-1 macrophages (69%). This approach produced a significant expression of GFP (mRNA and protein), CD14 and CD68 (mRNA), and transiently and mildly reduced IL-6 and IL-10 levels in LPS-challenged macrophages. Our results indicate that Man-PEI is suitable for inducing an efficient gene overexpression in human macrophages under inflammatory conditions with limited immunogenic responses. Our promising results set the foundation to test this technology to induce functional anti-inflammatory genes. Copyright © 2016 Elsevier GmbH. All rights reserved.

Arginine and Citrulline and the Immune Response in Sepsis

PubMed Central

Wijnands, Karolina A.P.; Castermans, Tessy M.R.; Hommen, Merel P.J.; Meesters, Dennis M.; Poeze, Martijn

2015-01-01

Arginine, a semi-essential amino acid is an important initiator of the immune response. Arginine serves as a precursor in several metabolic pathways in different organs. In the immune response, arginine metabolism and availability is determined by the nitric oxide synthases and the arginase enzymes, which convert arginine into nitric oxide (NO) and ornithine, respectively. Limitations in arginine availability during inflammatory conditions regulate macrophages and T-lymfocyte activation. Furthermore, over the past years more evidence has been gathered which showed that arginine and citrulline deficiencies may underlie the detrimental outcome of inflammatory conditions, such as sepsis and endotoxemia. Not only does the immune response contribute to the arginine deficiency, also the impaired arginine de novo synthesis in the kidney has a key role in the eventual observed arginine deficiency. The complex interplay between the immune response and the arginine-NO metabolism is further underscored by recent data of our group. In this review we give an overview of physiological arginine and citrulline metabolism and we address the experimental and clinical studies in which the arginine-citrulline NO pathway plays an essential role in the immune response, as initiator and therapeutic target. PMID:25699985

Gut Microbiome Function Predicts Response to Anti-integrin Biologic Therapy in Inflammatory Bowel Diseases.

PubMed

Ananthakrishnan, Ashwin N; Luo, Chengwei; Yajnik, Vijay; Khalili, Hamed; Garber, John J; Stevens, Betsy W; Cleland, Thomas; Xavier, Ramnik J

2017-05-10

The gut microbiome plays a central role in inflammatory bowel diseases (IBDs) pathogenesis and propagation. To determine whether the gut microbiome may predict responses to IBD therapy, we conducted a prospective study with Crohn's disease (CD) or ulcerative colitis (UC) patients initiating anti-integrin therapy (vedolizumab). Disease activity and stool metagenomes at baseline, and weeks 14, 30, and 54 after therapy initiation were assessed. Community α-diversity was significantly higher, and Roseburia inulinivorans and a Burkholderiales species were more abundant at baseline among CD patients achieving week 14 remission. Several significant associations were identified with microbial function; 13 pathways including branched chain amino acid synthesis were significantly enriched in baseline samples from CD patients achieving remission. A neural network algorithm, vedoNet, incorporating microbiome and clinical data, provided highest classifying power for clinical remission. We hypothesize that the trajectory of early microbiome changes may be a marker of response to IBD treatment. Copyright © 2017 Elsevier Inc. All rights reserved.

Development of protective immunity to Salmonella, a mucosal pathogen with a systemic agenda

PubMed Central

Griffin, Amanda J.; McSorley, Stephen J.

2014-01-01

Salmonella infections can cause a range of intestinal and systemic disease in human and animal hosts. While some Salmonella serovars initiate a localized intestinal inflammatory response, others use the intestine as a portal of entry to initiate a systemic infection. Considerable progress has been made in understanding bacterial invasion and dissemination strategies and the nature of the Salmonella-specific immune response to oral infection. Innate and adaptive immunity are rapidly initiated after oral infection but these effector responses can also be hindered by bacterial evasion strategies. Furthermore, although Salmonella resides within intramacrophage phagosomes, recent studies highlight a surprising collaboration of CD4 Th1, Th17, and B cell responses in mediating resistance to Salmonella infection. PMID:21307847

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.

Role of the inflammasome in defense against venoms

PubMed Central

Palm, Noah W.; Medzhitov, Ruslan

2013-01-01

Venoms consist of a complex mixture of toxic components that are used by a variety of animal species for defense and predation. Envenomation of mammalian species leads to an acute inflammatory response and can lead to the development of IgE-dependent venom allergy. However, the mechanisms by which the innate immune system detects envenomation and initiates inflammatory and allergic responses to venoms remain largely unknown. Here we show that bee venom is detected by the NOD-like receptor family, pyrin domain-containing 3 inflammasome and can trigger activation of caspase-1 and the subsequent processing and unconventional secretion of the leaderless proinflammatory cytokine IL-1β in macrophages. Whereas activation of the inflammasome by bee venom induces a caspase-1–dependent inflammatory response, characterized by recruitment of neutrophils to the site or envenomation, the inflammasome is dispensable for the allergic response to bee venom. Finally, we find that caspase-1–deficient mice are more susceptible to the noxious effects of bee and snake venoms, suggesting that a caspase-1–dependent immune response can protect against the damaging effects of envenomation. PMID:23297192

Naproxen Attenuates Sensitization of Depressive-Like Behavior and Fever during Maternal Separation

PubMed Central

Hennessy, Michael B.; Stafford, Nathan P.; Yusko-Osborne, Brittany; Schiml, Patricia A.; Xanthos, Evan D.; Deak, Terrence

2014-01-01

Early life stress can increase susceptibility for later development of depressive illness though a process thought to involve inflammatory mediators. Isolated guinea pig pups exhibit a passive, depressive-like behavioral response and fever that appear mediated by proinflammatory activity, and which sensitize with repeated separations. Treatment with an anti-inflammatory can attenuate the behavioral response during the initial separation and separation the following day. Here we used the cyclooxygenase inhibitor naproxen to examine the role of prostaglandins in mediating the depressive-like behavior and core body temperature of young guinea pigs during an initial separation, separation the next day, and separation 10 days after the first. The passive, depressive-like behavior as well as fever sensitized with repeated separation. Three days of injection with 14 mg/kg of naproxen prior to the initial separation reduced depressive-like behavior during all three separations. A 28 mg/kg dose of naproxen, however, had minimal effect on behavior. Fever during the early separations was moderated by naproxen, but only at the higher dose. These results suggest a role of prostaglandins in the behavioral and febrile response to maternal separation, and particularly in the sensitization of depressive-like behavior following repeated separation. PMID:25449392

Macrophage Integrins Modulate Response to Ultra-High Molecular Weight Polyethylene Particles and Direct Particle-Induced Osteolysis

PubMed Central

Zaveri, Toral D.; Dolgova, Natalia V.; Lewis, Jamal S.; Hamaker, Kiri; Clare-Salzler, Michael J.; Keselowsky, Benjamin G.

2016-01-01

Aseptic loosening due to peri-prosthetic osteolysis is one of the primary causes for failure of artificial joint replacements. Implant-derived wear particles, often ultra-high molecular weight polyethylene (UHMWPE) microparticles, initiate an inflammatory cascade upon phagocytosis by macrophages, which leads to osteoclast recruitment and activation, ultimately resulting in osteolysis. Investigation into integrin receptors, involved in cellular interactions with biomaterial-adsorbed adhesive proteins, is of interest to understand and modulate inflammatory processes. In this work, we investigate the role of macrophage integrins Mac-1 and RGD-binding integrins in response to UHMWPE wear particles. Using integrin knockout mice as well as integrin blocking techniques, reduction in macrophage phagocytosis and inflammatory cytokine secretion is demonstrated when these receptors are either absent or blocked. Along this line, various opsonizing proteins are shown to differentially modulate microparticle uptake and macrophage secretion of inflammatory cytokines. Furthermore, using a calvarial osteolysis model it is demonstrated that both Mac-1 integrin and RGD-binding integrins modulate the particle induced osteolysis response to UHMWPE microparticles, with a 40% decrease in the area of osteolysis by the absence or blocking of these integrins, in vivo. Altogether, these findings indicate Mac-1 and RGD-binding integrins are involved in macrophage-directed inflammatory responses to UHMWPE and may serve as therapeutic targets to mitigate wear particle induced peri-prosthetic osteolysis for improved performance of implanted joints. PMID:27889664

Defining the neurotoxin derived illness chronic ciguatera using markers of chronic systemic inflammatory disturbances: a case/control study.

PubMed

Shoemaker, Ritchie C; House, Dennis; Ryan, James C

2010-01-01

Ciguatoxins are extremely potent neurotoxins, produced by tropical marine dinoflagellates, that persistently enter into our food web. Over 100,000 people annually experience acute ciguatera poisoning from consuming toxic fish. Roughly 5% of these victims will develop chronic ciguatera (CC), a widespread, multisymptom, multisystem, chronic illness that can last tens of years. CC is marked by disproportionate disability and non-specific refractory symptoms such as fatigue, cognitive deficits and pain, and is suggestive of other illnesses. Its unknown pathophysiology makes both diagnosis and treatment difficult. We wanted to compare objective parameters of visual contrast sensitivity testing, measures of innate immune response and genetic markers in cases to controls to assess the potential for the presence of persistent inflammatory parameters that are demonstrated in other biotoxin associated illnesses at a single specialty clinic. Using 59 CC cases and 59 controls we present in retrospective review, in all cases, abnormalities in immune responses paralleling the chronic systemic inflammatory response syndrome seen in several other chronic diseases. This study defines a preliminary case definition using medical history, total symptoms, visual contrast sensitivity, HLA DR genotype analysis, reduction of regulatory neuropeptides VIP and MSH, and multiple measures of inflammatory immune response, especially C4a and TGFβ1, thereby providing a basis for identification and targeted therapy. CC provides a model for chronic human illness associated with initiation of inflammatory responses by biologically produced neurotoxins. Copyright © 2010 Elsevier Inc. All rights reserved.

Hematoma-inspired alginate/platelet releasate/CaPO4 composite: initiation of the inflammatory-mediated response associated with fracture repair in vitro and ex vivo injection delivery.

PubMed

McCanless, Jonathan D; Jennings, Lisa K; Bumgardner, Joel D; Cole, Judith A; Haggard, Warren O

2012-08-01

A clinical need continues for consistent bone remodeling within problematic sites such as those of fracture nonunion, avascular necrosis, or irregular bone formations. In attempt to address such needs, a biomaterial system is proposed to induce early inflammatory responses after implantation and to provide later osteoconductive scaffolding for bone regeneration. Biomaterial-induced inflammation would parallel the early stage of hematoma-induced fracture repair and allow scaffold-promoted remodeling of osseous tissue to a healthy state. Initiation of the wound healing cascade by two human concentrated platelet releasate-containing alginate/β-tricalcium phosphate biocomposites has been studied in vitro using the TIB-71™ RAW264.7 mouse monocyte cell line. Inflammatory responses inherent to the base material were found and could be modulated through incorporation of platelet releasate. Differences in hydrogel wt% (2 vs. 8 %) and/or calcium phosphate granule vol.% (20 vs. 10 %) allowed for tuning the response associated with platelet releasate-associated growth factor elution. Tunability from completely suppressing the inflammatory response to augmenting the response was observed through varied elution profiles of both releasate-derived bioagents and impurities inherent to alginate. A 2.5-fold upregulation of inducible-nitric oxide synthase gene expression followed by a tenfold increase in nitrite media levels was induced by inclusion of releasate within the 8 wt%/10 vol.% formulation and was comparable to an endotoxin positive control. Whereas, near complete elimination of inflammation was seen when releasate was included within the 2 wt%/20 vol.% formulation. These in vitro results suggested tunable interactions between the multiple platelet releasate-derived bioagents and the biocomposites for enhancing hematoma-like fracture repair. Additionally, minimally invasive delivery for in situ curing of the implant system via injection was demonstrated in rat tail vertebrae using microcomputed tomography.

Sterol intermediates of cholesterol biosynthesis inhibit hair growth and trigger an innate immune response in cicatricial alopecia.

PubMed

Panicker, Sreejith P; Ganguly, Taneeta; Consolo, Mary; Price, Vera; Mirmirani, Paradi; Honda, Kord; Karnik, Pratima

2012-01-01

Primary cicatricial alopecia (PCA) is a group of inflammatory hair disorders that cause scarring and permanent hair loss. Previous studies have implicated PPARγ, a transcription factor that integrates lipogenic and inflammatory signals, in the pathogenesis of PCA. However, it is unknown what triggers the inflammatory response in these disorders, whether the inflammation is a primary or secondary event in disease pathogenesis, and whether the inflammatory reaction reflects an autoimmune process. In this paper, we show that the cholesterol biosynthetic pathway is impaired in the skin and hair follicles of PCA patients. Treatment of hair follicle cells with BM15766, a cholesterol biosynthesis inhibitor, or 7-dehydrocholesterol (7-DHC), a sterol precursor, stimulates the expression of pro-inflammatory chemokine genes. Painting of mouse skin with 7-DHC or BM15766 inhibits hair growth, causes follicular plugging and induces the infiltration of inflammatory cells into the interfollicular dermis. Our results demonstrate that cholesterologenic changes within hair follicle cells trigger an innate immune response that is associated with the induction of toll-like receptor (TLR) and interferon (IFN) gene expression, and the recruitment of macrophages that surround the hair follicles and initiate their destruction. These findings reveal a previously unsuspected role for cholesterol precursors in PCA pathogenesis and identify a novel link between sterols and inflammation that may prove transformative in the diagnosis and treatment of these disorders.

Molecular targets of celastrol derived from Thunder of God Vine: potential role in the treatment of inflammatory disorders and cancer.

PubMed

Kannaiyan, Radhamani; Shanmugam, Muthu K; Sethi, Gautam

2011-04-01

Identification of active constituents and their molecular targets from traditional medicine is an enormous opportunity for modern pharmacology. Celastrol is one such compound that was originally identified from traditional Chinese medicine (Thunder of God Vine) almost three decades ago and generally used for the treatment of inflammatory and auto-immune diseases. Celastrol has attracted great interest recently, especially for its potential anti-inflammatory and anti-cancer activities. The anti-inflammatory effects of this triterpene have been demonstrated in animal models of different inflammatory diseases, including arthritis, Alzheimer's disease, asthma, and systemic lupus erythematosus. This triterpene has also been found to inhibit the proliferation of a variety of tumor cells and suppress tumor initiation, promotion and metastasis in various cancer models in vivo. Celastrol's ability to modulate the expression of pro-inflammatory cytokines, MHC II, HO-1, iNOS, NF-κB, Notch-1, AKT/mTOR, CXCR4, TRAIL receptors DR4 and DR5, CHOP, JNK, VEGF, adhesion molecules, proteasome activity, topoisomerase II, potassium channels, and heat shock response has been reported. This review describes the various molecular targets of celastrol, cellular responses to celastrol, and animal studies with celastrol in cancer and other inflammatory disorders. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Macrophages and fibroblasts during inflammation and tissue repair in models of organ regeneration

PubMed Central

2017-01-01

Abstract This review provides a concise summary of the changing phenotypes of macrophages and fibroblastic cells during the local inflammatory response, the onset of tissue repair, and the resolution of inflammation which follow injury to an organ. Both cell populations respond directly to damage and present coordinated sequences of activation states which determine the reparative outcome, ranging from true regeneration of the organ to fibrosis and variable functional deficits. Recent work with mammalian models of organ regeneration, including regeneration of full‐thickness skin, hair follicles, ear punch tissues, and digit tips, is summarized and the roles of local immune cells in these systems are discussed. New investigations of the early phase of amphibian limb and tail regeneration, including the effects of pro‐inflammatory and anti‐inflammatory agents, are then briefly discussed, focusing on the transition from the normally covert inflammatory response to the initiation of the regeneration blastema by migrating fibroblasts and the expression of genes for limb patterning. PMID:28616244

Characterization of intestinal inflammation and identification of related gene expression changes in mdr1a−/− mice

PubMed Central

Dommels, Y. E.M.; Zhu, S.; Davy, M.; Martell, S.; Hedderley, D.; Barnett, M. P.G.; McNabb, W. C.; Roy, N. C.

2007-01-01

Multidrug resistance targeted mutation (mdr1a−/−) mice spontaneously develop intestinal inflammation. The aim of this study was to further characterize the intestinal inflammation in mdr1a−/− mice. Intestinal samples were collected to measure inflammation and gene expression changes over time. The first signs of inflammation occurred around 16 weeks of age and most mdr1a−/− mice developed inflammation between 16 and 27 weeks of age. The total histological injury score was the highest in the colon. The inflammatory lesions were transmural and discontinuous, revealing similarities to human inflammatory bowel diseases (IBD). Genes involved in inflammatory response pathways were up-regulated whereas genes involved in biotransformation and transport were down-regulated in colonic epithelial cell scrapings of inflamed mdra1−/− mice at 25 weeks of age compared to non-inflamed FVB mice. These results show overlap to human IBD and strengthen the use of this in vivo model to study human IBD. The anti-inflammatory regenerating islet-derived genes were expressed at a lower level during inflammation initiation in non-inflamed colonic epithelial cell scrapings of mdr1a−/− mice at 12 weeks of age. This result suggests that an insufficiently suppressed immune response could be crucial to the initiation and development of intestinal inflammation in mdr1a−/− mice. PMID:18850176

Leukocyte Trafficking in Cardiovascular Disease: Insights from Experimental Models

PubMed Central

2017-01-01

Chemokine-induced leukocyte migration into the vessel wall is an early pathological event in the progression of atherosclerosis, the underlying cause of myocardial infarction. The immune-inflammatory response, mediated by both the innate and adaptive immune cells, is involved in the initiation, recruitment, and resolution phases of cardiovascular disease progression. Activation of leukocytes via inflammatory mediators such as chemokines, cytokines, and adhesion molecules is instrumental in these processes. In this review, we highlight leukocyte activation with the main focus being on the mechanisms of chemokine-mediated recruitment in atherosclerosis and the response postmyocardial infarction with key examples from experimental models of cardiovascular inflammation. PMID:28465628

Leukocyte Trafficking in Cardiovascular Disease: Insights from Experimental Models.

PubMed

Jones, Daniel P; True, Harry D; Patel, Jyoti

2017-01-01

Chemokine-induced leukocyte migration into the vessel wall is an early pathological event in the progression of atherosclerosis, the underlying cause of myocardial infarction. The immune-inflammatory response, mediated by both the innate and adaptive immune cells, is involved in the initiation, recruitment, and resolution phases of cardiovascular disease progression. Activation of leukocytes via inflammatory mediators such as chemokines, cytokines, and adhesion molecules is instrumental in these processes. In this review, we highlight leukocyte activation with the main focus being on the mechanisms of chemokine-mediated recruitment in atherosclerosis and the response postmyocardial infarction with key examples from experimental models of cardiovascular inflammation.

Therapeutic Effects of Resiniferatoxin Related with Immunological Responses for Intestinal Inflammation in Trichinellosis.

PubMed

Muñoz-Carrillo, José Luis; Muñoz-López, José Luis; Muñoz-Escobedo, José Jesús; Maldonado-Tapia, Claudia; Gutiérrez-Coronado, Oscar; Contreras-Cordero, Juan Francisco; Moreno-García, María Alejandra

2017-12-01

The immune response against Trichinella spiralis at the intestinal level depends on the CD4+ T cells, which can both suppress or promote the inflammatory response through the synthesis of diverse cytokines. During the intestinal phase, the immune response is mixed (Th1/Th2) with the initial predominance of the Th1 response and the subsequent domination of Th2 response, which favor the development of intestinal pathology. In this context, the glucocorticoids (GC) are the pharmacotherapy for the intestinal inflammatory response in trichinellosis. However, its therapeutic use is limited, since studies have shown that treatment with GC suppresses the host immune system, favoring T. spiralis infection. In the search for novel pharmacological strategies that inhibit the Th1 immune response (proinflammatory) and assist the host against T. spiralis infection, recent studies showed that resiniferatoxin (RTX) had anti-inflammatory activity, which decreased the serum levels of IL-12, INF-γ, IL-1β, TNF-α, NO, and PGE2, as well the number of eosinophils in the blood, associated with decreased intestinal pathology and muscle parasite burden. These researches demonstrate that RTX is capable to inhibit the production of Th1 cytokines, contributing to the defense against T. spiralis infection, which places it as a new potential drug modulator of the immune response.

Therapeutic Effects of Resiniferatoxin Related with Immunological Responses for Intestinal Inflammation in Trichinellosis

PubMed Central

Muñoz-Carrillo, José Luis; Muñoz-López, José Luis; Muñoz-Escobedo, José Jesús; Maldonado-Tapia, Claudia; Gutiérrez-Coronado, Oscar; Contreras-Cordero, Juan Francisco; Moreno-García, María Alejandra

2017-01-01

The immune response against Trichinella spiralis at the intestinal level depends on the CD4+ T cells, which can both suppress or promote the inflammatory response through the synthesis of diverse cytokines. During the intestinal phase, the immune response is mixed (Th1/Th2) with the initial predominance of the Th1 response and the subsequent domination of Th2 response, which favor the development of intestinal pathology. In this context, the glucocorticoids (GC) are the pharmacotherapy for the intestinal inflammatory response in trichinellosis. However, its therapeutic use is limited, since studies have shown that treatment with GC suppresses the host immune system, favoring T. spiralis infection. In the search for novel pharmacological strategies that inhibit the Th1 immune response (proinflammatory) and assist the host against T. spiralis infection, recent studies showed that resiniferatoxin (RTX) had anti-inflammatory activity, which decreased the serum levels of IL-12, INF-γ, IL-1β, TNF-α, NO, and PGE2, as well the number of eosinophils in the blood, associated with decreased intestinal pathology and muscle parasite burden. These researches demonstrate that RTX is capable to inhibit the production of Th1 cytokines, contributing to the defense against T. spiralis infection, which places it as a new potential drug modulator of the immune response. PMID:29320813

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

Husain, Mainul, E-mail: mainul.husain@hc-sc.gc.ca; Kyjovska, Zdenka O., E-mail: zky@nrcwe.dk; Bourdon-Lacombe, Julie, E-mail: julie.bourdon-lacombe@hc-sc.gc.ca

Inhalation of carbon black nanoparticles (CBNPs) causes pulmonary inflammation; however, time course data to evaluate the detailed evolution of lung inflammatory responses are lacking. Here we establish a time-series of lung inflammatory response to CBNPs. Female C57BL/6 mice were intratracheally instilled with 162 μg CBNPs alongside vehicle controls. Lung tissues were examined 3 h, and 1, 2, 3, 4, 5, 14, and 42 days (d) post-exposure. Global gene expression and pulmonary inflammation were assessed. DNA damage was evaluated in bronchoalveolar lavage (BAL) cells and lung tissue using the comet assay. Increased neutrophil influx was observed at all time-points. DNA strandmore » breaks were increased in BAL cells 3 h post-exposure, and in lung tissues 2–5 d post-exposure. Approximately 2600 genes were differentially expressed (± 1.5 fold; p ≤ 0.05) across all time-points in the lungs of exposed mice. Altered transcript levels were associated with immune-inflammatory response and acute phase response pathways, consistent with the BAL profiles and expression changes found in common respiratory infectious diseases. Genes involved in DNA repair, apoptosis, cell cycle regulation, and muscle contraction were also differentially expressed. Gene expression changes associated with inflammatory response followed a biphasic pattern, with initial changes at 3 h post-exposure declining to base-levels by 3 d, increasing again at 14 d, and then persisting to 42 d post-exposure. Thus, this single CBNP exposure that was equivalent to nine 8-h working days at the current Danish occupational exposure limit induced biphasic inflammatory response in gene expression that lasted until 42 d post-exposure, raising concern over the chronic effects of CBNP exposure. - Highlights: • A single exposure to CBNPs induced expression changes in over 2600 genes in mouse lungs. • Altered genes were associated with immune-inflammatory and acute phase responses. • Several genes were involved in DNA repair, apoptosis, and muscle contraction. • Effects of a single exposure to CBNPs lasted until 42 d post-exposure. • A single exposure to CBNPs induced a biphasic inflammatory response in gene expression.« less

Anti-Donor Immune Responses Elicited by Allogeneic Mesenchymal Stem Cells and Their Extracellular Vesicles: Are We Still Learning?

PubMed Central

Lohan, Paul; Treacy, Oliver; Griffin, Matthew D.; Ritter, Thomas; Ryan, Aideen E.

2017-01-01

Mesenchymal stromal cells (MSC) have been used to treat a broad range of disease indications such as acute and chronic inflammatory disorders, autoimmune diseases, and transplant rejection due to their potent immunosuppressive/anti-inflammatory properties. The breadth of their usage is due in no small part to the vast quantity of published studies showing their ability to modulate multiple immune cell types of both the innate and adaptive immune response. While patient-derived (autologous) MSC may be the safer choice in terms of avoiding unwanted immune responses, factors including donor comorbidities may preclude these cells from use. In these situations, allogeneic MSC derived from genetically unrelated individuals must be used. While allogeneic MSC were initially believed to be immune-privileged, substantial evidence now exists to prove otherwise with multiple studies documenting specific cellular and humoral immune responses against donor antigens following administration of these cells. In this article, we will review recent published studies using non-manipulated, inflammatory molecule-activated (licensed) and differentiated allogeneic MSC, as well as MSC extracellular vesicles focusing on the immune responses to these cells and whether or not such responses have an impact on allogeneic MSC-mediated safety and efficacy. PMID:29225601

Modification of composition and spatial distribution of intestinal microbiota following antibiotic therapy in immunocompetent defined flora C3H/HeN mice

USDA-ARS?s Scientific Manuscript database

Background: Luminal bacteria and/or their products play a pivotal role in the pathogenesis of chronic intestinal inflammation associated with inflammatory bowel diseases (IBD). While host responses to resident flora may initiate IBD, the subsets of bacteria responsible for mediating inflammation in ...

NLR-Dependent Regulation of Inflammation in Multiple Sclerosis

PubMed Central

Gharagozloo, Marjan; Gris, Katsiaryna V.; Mahvelati, Tara; Amrani, Abdelaziz; Lukens, John R.; Gris, Denis

2018-01-01

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) associated with inappropriate activation of lymphocytes, hyperinflammatory responses, demyelination, and neuronal damage. In the past decade, a number of biological immunomodulators have been developed that suppress the peripheral immune responses and slow down the progression of the disease. However, once the inflammation of the CNS has commenced, it can cause serious permanent neuronal damage. Therefore, there is a need for developing novel therapeutic approaches that control and regulate inflammatory responses within the CNS. Nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) are intracellular regulators of inflammation expressed by many cell types within the CNS. They redirect multiple signaling pathways initiated by pathogens and molecules released by injured tissues. NLR family members include positive regulators of inflammation, such as NLRP3 and NLRC4 and anti-inflammatory NLRs, such as NLRX1 and NLRP12. They exert immunomodulatory effect at the level of peripheral immune responses, including antigen recognition and lymphocyte activation and differentiation. Also, NLRs regulate tissue inflammatory responses. Understanding the molecular mechanisms that are placed at the crossroad of innate and adaptive immune responses, such as NLR-dependent pathways, could lead to the discovery of new therapeutic targets. In this review, we provide a summary of the role of NLRs in the pathogenesis of MS. We also summarize how anti-inflammatory NLRs regulate the immune response within the CNS. Finally, we speculate the therapeutic potential of targeting NLRs in MS. PMID:29403486

Disruption of glycolytic flux is a signal for inflammasome signaling and pyroptotic cell death

PubMed Central

Sanman, Laura E; Qian, Yu; Eisele, Nicholas A; Ng, Tessie M; van der Linden, Wouter A; Monack, Denise M; Weerapana, Eranthie; Bogyo, Matthew

2016-01-01

When innate immune cells such as macrophages are challenged with environmental stresses or infection by pathogens, they trigger the rapid assembly of multi-protein complexes called inflammasomes that are responsible for initiating pro-inflammatory responses and a form of cell death termed pyroptosis. We describe here the identification of an intracellular trigger of NLRP3-mediated inflammatory signaling, IL-1β production and pyroptosis in primed murine bone marrow-derived macrophages that is mediated by the disruption of glycolytic flux. This signal results from a drop of NADH levels and induction of mitochondrial ROS production and can be rescued by addition of products that restore NADH production. This signal is also important for host-cell response to the intracellular pathogen Salmonella typhimurium, which can disrupt metabolism by uptake of host-cell glucose. These results reveal an important inflammatory signaling network used by immune cells to sense metabolic dysfunction or infection by intracellular pathogens. DOI: http://dx.doi.org/10.7554/eLife.13663.001 PMID:27011353

Assessing NLRP3 Inflammasome Activation by Nanoparticles.

PubMed

Sharma, Bhawna; McLeland, Christopher B; Potter, Timothy M; Stern, Stephan T; Adiseshaiah, Pavan P

2018-01-01

NLRP3 inflammasome activation is one of the initial steps in an inflammatory cascade against pathogen/danger-associated molecular patterns (PAMPs/DAMPs), such as those arising from environmental toxins or nanoparticles, and is essential for innate immune response. NLRP3 inflammasome activation in cells can lead to the release of IL-1β cytokine via caspase-1, which is required for inflammatory-induced programmed cell death (pyroptosis). Nanoparticles are commonly used as vaccine adjuvants and drug delivery vehicles to improve the efficacy and reduce the toxicity of chemotherapeutic agents. Several studies indicate that different nanoparticles (e.g., liposomes, polymer-based nanoparticles) can induce NLRP3 inflammasome activation. Generation of a pro-inflammatory response is beneficial for vaccine delivery to provide adaptive immunity, a necessary step for successful vaccination. However, similar immune responses for intravenously injected, drug-containing nanoparticles can result in immunotoxicity (e.g., silica nanoparticles). Evaluation of NLRP3-mediated inflammasome activation by nanoparticles may predict pro-inflammatory responses in order to determine if these effects may be mitigated for drug delivery or optimized for vaccine development. In this protocol, we outline steps to monitor the release of IL-1β using PMA-primed THP-1 cells, a human monocytic leukemia cell line, as a model system. IL-1β release is used as a marker of NLRP3 inflammasome activation.

Programmed death (PD)-1 attenuates macrophage activation and brain inflammation via regulation of fibrinogen-like protein 2 (Fgl-2) after intracerebral hemorrhage in mice.

PubMed

Yuan, Bangqing; Huang, Shaokuan; Gong, Shuangfeng; Wang, Feihong; Lin, Li; Su, Tonggang; Sheng, Hanchao; Shi, Hui; Ma, Kunlong; Yang, Zhao

2016-11-01

Neuroinflammation plays an important role in the recovery of brain injury in ICH. Macrophage is the major executor in the neuroinflammation and initiates neurological defects. Programmed death 1 (PD-1) delivers inhibitory signals that regulate the balance between T cell activation, tolerance, and immunopathology. PD-1 expression by macrophages plays a pathologic role in the innate inflammatory response. However, the exact role of PD-1 on inflammatory responses following ICH has not been well identified. In this experiment, PD-1 KO (PD-1 -/-) ICH mice and Wild-type (WT) ICH mice were caused by intracranial injection of type IV collagenase. The level of macrophage activation, inflammatory cytokines and fibrinogen-like protein 2 (Fgl-2) were detected using immunofluorescence staining and ELISA assays. In addition, brain edema and neurological scores of ICH mice were also measured. Our data demonstrated that ICH promoted PD-1 expression of macrophage and enhanced inflammatory cytokines and Fgl-2 concentrations. PD-1 -/- mice exhibited significantly higher expression of the inflammatory cytokines which initiate Fgl-2, than did their wild-type (WT) littermates. As a result, macrophage activation, cerebral edema and neurological deficit scores of PD-1 -/- mice were higher. In conclusion, our data demonstrate that PD-1 plays a vital role in brain inflammation via regulation of Fgl-2 after ICH, and that manipulation of PD-1 might be a promising therapeutical target in ICH. Copyright © 2016 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.

The sterile inflammatory response

PubMed Central

Rock, Kenneth L.; Latz, Eicke; Ontiveros, Fernando; Kono, Hajime

2015-01-01

The acute inflammatory response is a double-edged sword. On the one hand it plays a key role in initial host defense particularly against many infections. On the other hand its aim is imprecise and as a consequence, when it is drawn into battle, it can cause collateral damage in tissues. In situations where the inciting stimulus is sterile, the cost-benefit ratio may be high; because of this, sterile inflammation underlies the pathogenesis of a number of diseases. While there have been major advances in our understanding of how microbes trigger inflammation, much less has been learned about this process in sterile situations. This review focuses on a subset of the many sterile stimuli that can induce inflammation – specifically dead cells and a variety of irritant particles, including crystals, minerals, and protein aggregates. Although this subset of stimuli is structurally very diverse and might appear to be unrelated, there is accumulating evidence that the innate immune system may recognize them in similar ways and stimulate the sterile inflammatory response via common pathways. Here we review established and emerging data about these responses. PMID:20307211

Role of Macrophages in the Repair Process during the Tissue Migrating and Resident Helminth Infections

PubMed Central

Faz-López, Berenice

2016-01-01

The Th1/Th2/Th17 balance is a fundamental feature in the regulation of the inflammatory microenvironment during helminth infections, and an imbalance in this paradigm greatly contributes to inflammatory disorders. In some cases of helminthiasis, an initial Th1 response could occur during the early phases of infection (acute), followed by a Th2 response that prevails in chronic infections. During the late phase of infection, alternatively activated macrophages (AAMs) are important to counteract the inflammation caused by the Th1/Th17 response and larval migration, limiting damage and repairing the tissue affected. Macrophages are the archetype of phagocytic cells, with the primary role of pathogen destruction and antigen presentation. Nevertheless, other subtypes of macrophages have been described with important roles in tissue repair and immune regulation. These types of macrophages challenge the classical view of macrophages activated by an inflammatory response. The role of these subtypes of macrophages during helminthiasis is a controversial topic in immunoparasitology. Here, we analyze some of the studies regarding the role of AAMs in tissue repair during the tissue migration of helminths. PMID:27648452

CD14 Signaling Restrains Chronic Inflammation through Induction of p38-MAPK/SOCS-Dependent Tolerance

PubMed Central

Sahay, Bikash; Patsey, Rebeca L.; Eggers, Christian H.; Salazar, Juan C.; Radolf, Justin D.; Sellati, Timothy J.

2009-01-01

Current thinking emphasizes the primacy of CD14 in facilitating recognition of microbes by certain TLRs to initiate pro-inflammatory signaling events and the importance of p38-MAPK in augmenting such responses. Herein, this paradigm is challenged by demonstrating that recognition of live Borrelia burgdorferi not only triggers an inflammatory response in the absence of CD14, but one that is, in part, a consequence of altered PI3K/AKT/p38-MAPK signaling and impaired negative regulation of TLR2. CD14 deficiency results in increased localization of PI3K to lipid rafts, hyperphosphorylation of AKT, and reduced activation of p38. Such aberrant signaling leads to decreased negative regulation by SOCS1, SOCS3, and CIS, thereby compromising the induction of tolerance in macrophages and engendering more severe and persistent inflammatory responses to B. burgdorferi. Importantly, these altered signaling events and the higher cytokine production observed can be mimicked through shRNA and pharmacological inhibition of p38 activity in CD14-expressing macrophages. Perturbation of this CD14/p38-MAPK-dependent immune regulation may underlie development of infectious chronic inflammatory syndromes. PMID:20011115

Drugs for Autoimmune Inflammatory Diseases: From Small Molecule Compounds to Anti-TNF Biologics

PubMed Central

Li, Ping; Zheng, Ying; Chen, Xin

2017-01-01

Although initially described as an anti-tumor mediator, tumor necrosis factor-alpha (TNF) is generally considered as the master pro-inflammatory cytokine. It plays a crucial role in the pathogenesis of inflammatory diseases, such as rheumatoid arthritis (RA), inflammatory bowel disease, ankylosing spondylitis (AS), and psoriasis. Consequently, anti-TNF therapy has become mainstay treatment for autoimmune diseases. Historically, anti-inflammatory agents were developed before the identification of TNF. Salicylates, the active components of Willow spp., were identified in the mid-19th century for the alleviation of pain, fever, and inflammatory responses. Study of this naturally occurring compound led to the discovery of aspirin, which was followed by the development of non-steroidal anti-inflammatory drugs (NSAIDs) due to the chemical advances in the 19th–20th centuries. Initially, the most of NSAIDs were organic acid, but the non-acidic compounds were also identified as NSAIDs. Although effective in the treatment of inflammatory diseases, NSAIDs have some undesirable and adverse effect, such as ulcers, kidney injury, and bleeding in the gastrointestinal tract. In the past two decades, anti-TNF biologics were developed. Drugs belong to this class include soluble TNF receptor 2 fusion protein and anti-TNF antibodies. The introduction of anti-TNF therapeutics has revolutionized the management of autoimmune diseases, such as RA, psoriatic arthritis (PsA), plaque psoriasis (PP), AS, CD and ulcerative colitis (UC). Nevertheless, up to 40% of patients have no response to anti-TNF treatment. Furthermore, this treatment is associated with some adverse effects such as increased risk of infection, and even triggered the de novo development of autoimmune diseases. Such harmful effect of anti-TNF treatment is likely caused by the global inhibition of TNF biological functions. Therefore, specific inhibition of TNF receptor (TNFR1 or TNFR2) may represent a safer and more effective treatment, as proposed by some recent studies. In this review article, the historical development of anti-inflammatory drugs after World War II as briefly described above will be reviewed and analyzed. The future trend in the development of novel TNF receptor-targeting therapeutics will be discussed in the context of latest progress in the research of TNF biology. PMID:28785220

Mesenchymal Stem Cell Attenuates Neutrophil-predominant Inflammation and Acute Lung Injury in an In Vivo Rat Model of Ventilator-induced Lung Injury

PubMed Central

Lai, Tian-Shun; Wang, Zhi-Hong; Cai, Shao-Xi

2015-01-01

Background: Subsequent neutrophil (polymorphonuclear neutrophil [PMN])-predominant inflammatory response is a predominant feature of ventilator-induced lung injury (VILI), and mesenchymal stem cell (MSC) can improve mice survival model of endotoxin-induced acute lung injury, reduce lung impairs, and enhance the repair of VILI. However, whether MSC could attenuate PMN-predominant inflammatory in the VILI is still unknown. This study aimed to test whether MSC intervention could attenuate the PMN-predominate inflammatory in the mechanical VILI. Methods: Sprague-Dawley rats were ventilated for 2 hours with large tidal volume (20 mL/kg). MSCs were given before or after ventilation. The inflammatory chemokines and gas exchange were observed and compared dynamically until 4 hours after ventilation, and pulmonary pathological change and activation of PMN were observed and compared 4 hours after ventilation. Results: Mechanical ventilation (MV) caused significant lung injury reflected by increasing in PMN pulmonary sequestration, inflammatory chemokines (tumor necrosis factor-alpha, interleukin-6 and macrophage inflammatory protein 2) in the bronchoalveolar lavage fluid, and injury score of the lung tissue. These changes were accompanied with excessive PMN activation which reflected by increases in PMN elastase activity, production of radical oxygen series. MSC intervention especially pretreatment attenuated subsequent lung injury, systemic inflammation response and PMN pulmonary sequestration and excessive PMN activation initiated by injurious ventilation. Conclusions: MV causes profound lung injury and PMN-predominate inflammatory responses. The protection effect of MSC in the VILI rat model is related to the suppression of the PMN activation. PMID:25635432

Targeting inflammatory pathways in myocardial infarction

PubMed Central

Christia, Panagiota; Frangogiannis, Nikolaos G

2013-01-01

Acute cardiomyocyte necrosis in the infarcted heart generates Damage-Associated Molecular Patterns (DAMPs), activating complement and Toll-Like Receptor (TLR)/Interleukin (IL)-1 signaling, and triggering an intense inflammatory reaction. Infiltrating leukocytes clear the infarct from dead cells, while activating reparative pathways that lead to formation of a scar. As the infarct heals the ventricle remodels; the geometric, functional and molecular alterations associated with post-infarction remodeling are driven by the inflammatory cascade and are involved in the development of heart failure. Because unrestrained inflammation in the infarcted heart induces matrix degradation and cardiomyocyte apoptosis, timely suppression of the post-infarction inflammatory reaction may be crucial to protect the myocardium from dilative remodeling and progressive dysfunction. Inhibition and resolution of post-infarction inflammation involves mobilization of inhibitory mononuclear cell subsets and requires activation of endogenous STOP signals. Our manuscript discusses the basic cellular and molecular events involved in initiation, activation and resolution of the post-infarction inflammatory response, focusing on identification of therapeutic targets. The failure of anti-integrin approaches in patients with myocardial infarction and a growing body of experimental evidence suggest that inflammation may not increase ischemic cardiomyocyte death, but accentuates matrix degradation causing dilative remodeling. Given the pathophysiologic complexity of post-infarction remodeling, personalized biomarker-based approaches are needed to target patient subpopulations with dysregulated inflammatory and reparative responses. Inhibition of pro-inflammatory signals (such as IL-1 and Monocyte Chemoattractant Protein-1) may be effective in patients with defective resolution of post-infarction inflammation who exhibit progressive dilative remodeling. In contrast, patients with predominant hypertrophic/fibrotic responses may benefit from anti-TGF strategies. PMID:23772948

The "Big Bang" in obese fat: Events initiating obesity-induced adipose tissue inflammation.

PubMed

Wensveen, Felix M; Valentić, Sonja; Šestan, Marko; Turk Wensveen, Tamara; Polić, Bojan

2015-09-01

Obesity is associated with the accumulation of pro-inflammatory cells in visceral adipose tissue (VAT), which is an important underlying cause of insulin resistance and progression to diabetes mellitus type 2 (DM2). Although the role of pro-inflammatory cytokines in disease development is established, the initiating events leading to immune cell activation remain elusive. Lean adipose tissue is predominantly populated with regulatory cells, such as eosinophils and type 2 innate lymphocytes. These cells maintain tissue homeostasis through the excretion of type 2 cytokines, such as IL-4, IL-5, and IL-13, which keep adipose tissue macrophages (ATMs) in an anti-inflammatory, M2-like state. Diet-induced obesity is associated with the loss of tissue homeostasis and development of type 1 inflammatory responses in VAT, characterized by IFN-γ. A key event is a shift of ATMs toward an M1 phenotype. Recent studies show that obesity-induced adipocyte hypertrophy results in upregulated surface expression of stress markers. Adipose stress is detected by local sentinels, such as NK cells and CD8(+) T cells, which produce IFN-γ, driving M1 ATM polarization. A rapid accumulation of pro-inflammatory cells in VAT follows, leading to inflammation. In this review, we provide an overview of events leading to adipose tissue inflammation, with a special focus on adipose homeostasis and the obesity-induced loss of homeostasis which marks the initiation of VAT inflammation. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Combined Chromatin and Expression Analysis Reveals Specific Regulatory Mechanisms within Cytokine Genes in the Macrophage Early Immune Response

PubMed Central

Emanuelsson, Olof; Sennblad, Bengt; Pirmoradian Najafabadi, Mohammad; Folkersen, Lasse; Mälarstig, Anders; Lagergren, Jens; Eriksson, Per; Hamsten, Anders; Odeberg, Jacob

2012-01-01

Macrophages play a critical role in innate immunity, and the expression of early response genes orchestrate much of the initial response of the immune system. Macrophages undergo extensive transcriptional reprogramming in response to inflammatory stimuli such as Lipopolysaccharide (LPS). To identify gene transcription regulation patterns involved in early innate immune responses, we used two genome-wide approaches - gene expression profiling and chromatin immunoprecipitation-sequencing (ChIP-seq) analysis. We examined the effect of 2 hrs LPS stimulation on early gene expression and its relation to chromatin remodeling (H3 acetylation; H3Ac) and promoter binding of Sp1 and RNA polymerase II phosphorylated at serine 5 (S5P RNAPII), which is a marker for transcriptional initiation. Our results indicate novel and alternative gene regulatory mechanisms for certain proinflammatory genes. We identified two groups of up-regulated inflammatory genes with respect to chromatin modification and promoter features. One group, including highly up-regulated genes such as tumor necrosis factor (TNF), was characterized by H3Ac, high CpG content and lack of TATA boxes. The second group, containing inflammatory mediators (interleukins and CCL chemokines), was up-regulated upon LPS stimulation despite lacking H3Ac in their annotated promoters, which were low in CpG content but did contain TATA boxes. Genome-wide analysis showed that few H3Ac peaks were unique to either +/−LPS condition. However, within these, an unpacking/expansion of already existing H3Ac peaks was observed upon LPS stimulation. In contrast, a significant proportion of S5P RNAPII peaks (approx 40%) was unique to either condition. Furthermore, data indicated a large portion of previously unannotated TSSs, particularly in LPS-stimulated macrophages, where only 28% of unique S5P RNAPII peaks overlap annotated promoters. The regulation of the inflammatory response appears to occur in a very specific manner at the chromatin level for specific genes and this study highlights the level of fine-tuning that occurs in the immune response. PMID:22384210

Current advances in orthodontic pain

PubMed Central

Long, Hu; Wang, Yan; Jian, Fan; Liao, Li-Na; Yang, Xin; Lai, Wen-Li

2016-01-01

Orthodontic pain is an inflammatory pain that is initiated by orthodontic force-induced vascular occlusion followed by a cascade of inflammatory responses, including vascular changes, the recruitment of inflammatory and immune cells, and the release of neurogenic and pro-inflammatory mediators. Ultimately, endogenous analgesic mechanisms check the inflammatory response and the sensation of pain subsides. The orthodontic pain signal, once received by periodontal sensory endings, reaches the sensory cortex for pain perception through three-order neurons: the trigeminal neuron at the trigeminal ganglia, the trigeminal nucleus caudalis at the medulla oblongata and the ventroposterior nucleus at the thalamus. Many brain areas participate in the emotion, cognition and memory of orthodontic pain, including the insular cortex, amygdala, hippocampus, locus coeruleus and hypothalamus. A built-in analgesic neural pathway—periaqueductal grey and dorsal raphe—has an important role in alleviating orthodontic pain. Currently, several treatment modalities have been applied for the relief of orthodontic pain, including pharmacological, mechanical and behavioural approaches and low-level laser therapy. The effectiveness of nonsteroidal anti-inflammatory drugs for pain relief has been validated, but its effects on tooth movement are controversial. However, more studies are needed to verify the effectiveness of other modalities. Furthermore, gene therapy is a novel, viable and promising modality for alleviating orthodontic pain in the future. PMID:27341389

Collective cell migration during inflammatory response

NASA Astrophysics Data System (ADS)

Wu, Di; Stroka, Kimberly; Aranda-Espinoza, Helim

2012-02-01

Wound scratch healing assays of endothelial cell monolayers is a simple model to study collective cell migration as a function of biological signals. A signal of particular interest is the immune response, which after initial wounding in vivo causes the release of various inflammatory factors such as tumor necrosis alpha (TNF-α). TNF-α is an innate inflammatory cytokine that can induce cell growth, cell necrosis, and change cell morphology. We studied the effects of TNF-α on collective cell migration using the wound healing assays and measured several migration metrics, such as rate of scratch closure, velocities of leading edge and bulk cells, closure index, and velocity correlation functions between migrating cells. We observed that TNF-α alters all migratory metrics as a function of the size of the scratch and TNF-α content. The changes observed in migration correlate with actin reorganization upon TNF-α exposure.

Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy

PubMed Central

Hotchkiss, Richard S.; Monneret, Guillaume; Payen, Didier

2014-01-01

Sepsis — severe life-threatening infection with organ dysfunction — initiates a complex interplay of host pro- and anti-inflammatory processes. In a real sense, sepsis can be considered a race to the death between the pathogens and the host immune system. It is the proper balance between the often competing pro- and anti-inflammatory pathways that determines the fate of the individual. Although the field of sepsis research has witnessed the failure of many highly-touted clinical trials, a better understanding of the pathophysiological basis of the disorder and the mechanisms responsible for the associated pro- and anti-inflammatory responses is leading to a novel approach to treat this highly lethal condition. Biomarker-guided immunotherapy administered to patients at the proper immune phase of sepsis represents a potential major advance in the treatment of sepsis and more broadly in the field of infectious disease. PMID:24232462

Pathways leading to an immunological disease: systemic lupus erythematosus

PubMed Central

Zharkova, Olga; Celhar, Teja; Cravens, Petra D.; Satterthwaite, Anne B.; Fairhurst, Anna-Marie

2017-01-01

Abstract SLE is a chronic autoimmune disease caused by perturbations of the immune system. The clinical presentation is heterogeneous, largely because of the multiple genetic and environmental factors that contribute to disease initiation and progression. Over the last 60 years, there have been a number of significant leaps in our understanding of the immunological mechanisms driving disease processes. We now know that multiple leucocyte subsets, together with inflammatory cytokines, chemokines and regulatory mediators that are normally involved in host protection from invading pathogens, contribute to the inflammatory events leading to tissue destruction and organ failure. In this broad overview, we discuss the main pathways involved in SLE and highlight new findings. We describe the immunological changes that characterize this form of autoimmunity. The major leucocytes that are essential for disease progression are discussed, together with key mediators that propagate the immune response and drive the inflammatory response in SLE. PMID:28375453

Immune-modulating therapy in acute pancreatitis: Fact or fiction

PubMed Central

Akinosoglou, Karolina; Gogos, Charalambos

2014-01-01

Acute pancreatitis (AP) is one of the most common diseases of the gastrointestinal tract, bearing significant morbidity and mortality worldwide. Current treatment of AP remains unspecific and supportive and is mainly targeted to aggressively prevent systemic complications and organ failure by intensive care. As acute pancreatitis shares an indistinguishable profile of inflammation with sepsis, therapeutic approaches have turned towards modulating the systemic inflammatory response. Targets, among others, have included pro- and anti-inflammatory modulators, cytokines, chemokines, immune cells, adhesive molecules and platelets. Even though, initial results in experimental models have been encouraging, clinical implementation of immune-regulating therapies in acute pancreatitis has had a slow progress. Main reasons include difficulty in clinical translation of experimental data, poor understanding of inflammatory response time-course, flaws in experimental designs, need for multimodal approaches and commercial drawbacks. Whether immune-modulation in acute pancreatitis remains a fact or just fiction remains to be seen in the future. PMID:25386069

Innate Immune Regulations and Liver Ischemia Reperfusion Injury

PubMed Central

Lu, Ling; Zhou, Haoming; Ni, Ming; Wang, Xuehao; Busuttil, Ronald; Kupiec-Weglinski, Jerzy; Zhai, Yuan

2016-01-01

Liver ischemia reperfusion activates innate immune system to drive the full development of inflammatory hepatocellular injury. Damage-associated molecular patterns (DAMPs) stimulate myeloid and dendritic cells via pattern recognition receptors (PRRs) to initiate the immune response. Complex intracellular signaling network transduces inflammatory signaling to regulate both innate immune cell activation and parenchymal cell death. Recent studies have revealed that DAMPs may trigger not only proinflammatory, but also immune regulatory responses by activating different PRRs or distinctive intracellular signaling pathways or in special cell populations. Additionally, tissue injury milieu activates PRR-independent receptors which also regulate inflammatory disease processes. Thus, the innate immune mechanism of liver IRI involves diverse molecular and cellular interactions, subjected to both endogenous and exogenous regulation in different cells. A better understanding of these complicated regulatory pathways/network is imperative for us in designing safe and effective therapeutic strategy to ameliorate liver IRI in patients. PMID:27861288

Macrophage Death following Influenza Vaccination Initiates the Inflammatory Response that Promotes Dendritic Cell Function in the Draining Lymph Node.

PubMed

Chatziandreou, Nikolaos; Farsakoglu, Yagmur; Palomino-Segura, Miguel; D'Antuono, Rocco; Pizzagalli, Diego Ulisse; Sallusto, Federica; Lukacs-Kornek, Veronika; Uguccioni, Mariagrazia; Corti, Davide; Turley, Shannon J; Lanzavecchia, Antonio; Carroll, Michael C; Gonzalez, Santiago F

2017-03-07

The mechanism by which inflammation influences the adaptive response to vaccines is not fully understood. Here, we examine the role of lymph node macrophages (LNMs) in the induction of the cytokine storm triggered by inactivated influenza virus vaccine. Following vaccination, LNMs undergo inflammasome-independent necrosis-like death that is reliant on MyD88 and Toll-like receptor 7 (TLR7) expression and releases pre-stored interleukin-1α (IL-1α). Furthermore, activated medullary macrophages produce interferon-β (IFN-β) that induces the autocrine secretion of IL-1α. We also found that macrophage depletion promotes lymph node-resident dendritic cell (LNDC) relocation and affects the capacity of CD11b + LNDCs to capture virus and express co-stimulatory molecules. Inhibition of the IL-1α-induced inflammatory cascade reduced B cell responses, while co-administration of recombinant IL-1α increased the humoral response. Stimulation of the IL-1α inflammatory pathway might therefore represent a strategy to enhance antigen presentation by LNDCs and improve the humoral response against influenza vaccines. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Inflammation in Alcoholic Liver Disease

PubMed Central

Wang, H. Joe; Gao, Bin; Zakhari, Samir; Nagy, Laura E.

2013-01-01

Frank Burr Mallory’s landmark observation in 1911 on the histopathology of alcoholic liver disease (ALD) was the first identification of a link between an inflammation and ALD. In this review, we summarize recent advances regarding the origins and roles of various inflammatory components in ALD. Metabolism of ethanol generates a number of metabolites, including acetate, reactive oxygen species, acetaldehyde, and epigenetic changes, that can induce inflammatory responses. Alcohol and its metabolites can also initiate and aggravate inflammatory conditions by promoting gut leakiness of microbial products, by sensitizing immune cells to stimulation and by activating innate immune pathways, such as complement. Chronic alcohol consumption also sensitizes non-immune cells, e.g., hepatocytes, to inflammatory signals and impairs their ability to respond to protective signals. Based on these advances, a number of inflammatory targets have been identified with potential for therapeutic intervention in ALD, presenting new opportunities and challenges for translational research. PMID:22524187

Inflammatory and immunological aspects of dental pulp repair

PubMed Central

Goldberg, Michel; Farges, Jean-Christophe; Lacerda-Pinheiro, Sally; Six, Ngampis; Jegat, Nadège; Decup, Frank; Septier, Dominique; Carrouel, Florence; Durand, Stéphanie; Chaussain-Miller, Catherine; DenBesten, Pamela; Veis, Arthur; Poliard, Anne

2010-01-01

The repair of dental pulp by direct capping with calcium hydroxide or by implantation of bioactive extracellular matrix (ECM) molecules implies a cascade of four steps: a moderate inflammation, the commitment of adult reserve stem cells, their proliferation and terminal differentiation. The link between the initial inflammation and cell commitment is not yet well established but appears as a potential key factor in the reparative process. Either the release of cytokines due to inflammatory events activates resident stem (progenitor) cells, or inflammatory cells or pulp fibroblasts undergo a phenotypic conversion into osteoblast/odontoblast-like progenitors implicated in reparative dentin formation. Activation of antigen-presenting dendritic cells by mild inflammatory processes may also promote osteoblast/odontoblast-like differentiation and expression of ECM molecules implicated in mineralization. Recognition of bacteria by specific odontoblast and fibroblast membrane receptors triggers an inflammatory and immune response within the pulp tissue that would also modulate the repair process. PMID:18602009

EXTRINSIC COAGULATION BLOCKADE ATTENUATES LUNG INJURY AND PROINFLAMMATORY CYTOKINE RELEASE AFTER INTRATRACHEAL LIPOPOLYSACCHARIDE

EPA Science Inventory

Initiation of coagulation by tissue factor (TF) is a potentially powerful regulator of local inflammatory responses. We hypothesized that blockade of TF-factor VIIa (FVIIa) complex would decrease lung inflammation and proinflammatory cytokine release after tracheal instillation o...

Dry eye disease: an immune-mediated ocular surface disorder

PubMed Central

Stevenson, William; Chauhan, Sunil K.; Dana, Reza

2013-01-01

Dry eye disease is a multifactorial disorder of the tears and ocular surface characterized by symptoms of dryness and irritation. Although the pathogenesis of dry eye disease is not fully understood, it is recognized that inflammation has a prominent role in the development and propagation of this debilitating condition. Factors that adversely affect tear film stability and osmolarity can induce ocular surface damage and initiate an inflammatory cascade that generates innate and adaptive immune responses. These immunoinflammatory responses lead to further ocular surface damage and the development of a self-perpetuating inflammatory cycle. Herein, we review the fundamental links between inflammation and dry eye disease and discuss the clinical implications of inflammation in disease management. PMID:22232476

Effect of hyperglycaemia on inflammatory and stress responses and clinical outcome of pneumonia in non-critical-care inpatients: results from an observational cohort study.

PubMed

Schuetz, Philipp; Friedli, Natalie; Grolimund, Eva; Kutz, Alexander; Haubitz, Sebastian; Christ-Crain, Mirjam; Thomann, Robert; Zimmerli, Werner; Hoess, Claus; Henzen, Christoph; Mueller, Beat

2014-02-01

Despite the condition's high prevalence, the influence of hyperglycaemia on clinical outcomes in non-critical-care inpatients with infections remains ill defined. In this study, we analysed associations of glucose levels at admission and during initial inpatient treatment with the inflammatory response and clinical outcome in community-acquired pneumonia (CAP) patients. This secondary observational analysis included 880 confirmed CAP patients. We used severity-adjusted multivariate regression models to investigate associations of initial and 96 h mean glucose levels with serially measured biomarker levels over 7 days (C-reactive protein [CRP], procalcitonin, white blood cell count [WBC], pro-adrenomedullin [ProADM]) and adverse clinical course (death and intensive-care unit admission). In the 724 non-diabetic patients (82.3% of the study population), moderate or severe hyperglycaemia (glucose 6-11 mmol/l and >11 mmol/l, respectively) was associated with increased risk for adverse clinical course (adjusted OR [95% CI] 1.4 [0.8, 2.4] and 3.0 [1.1, 8.0], respectively) and with higher CRP, WBC and ProADM levels over 7 days (p < 0.05, ANOVA, all days). In diabetic patients (n = 156), no similar associations were found for initial hyperglycaemia, although mean 96 h glucose levels  ≥ 9 mmol/l were associated with adverse clinical course (adjusted OR 5.4 [1.1, 25.8]; p = 0.03). No effect modification by insulin treatment was detected (interaction terms p > 0.2 for all analyses). Initial hyperglycaemia in non-diabetic CAP patients, and prolonged hyperglycaemia in diabetic or non-diabetic CAP patients, are associated with a more pronounced inflammatory response and CAP-related adverse clinical outcome. Optimal glucose targets for insulin treatment of hyperglycaemia in non-critical-care settings should be defined.

The impact of eicosanoids on the crosstalk between innate and adaptive immunity: the key roles of dendritic cells.

PubMed

Harizi, H; Gualde, N

2005-06-01

The innate immune response is essentially the first line of defense against an invading pathogen. Through specialized receptors, known as pattern recognition receptors, especially Toll-like receptors, specialized cells of myeloid origin, including macrophages and dendritic cells (DCs) are able to phagocytose microorganisms and induce an innate inflammatory response. Although B and T lymphocytes recognize tissue antigens with high specificity, they are unable to initiate immune responses. The decision to activate an appropriate immune response is made by unique DC, the most professional antigen-presenting cells (APCs) which control the responses of several types of lymphocytes and play central role in the transition between innate and adaptive immunity. Increased secretion of inflammatory endogenous mediators such as cytokines and arachidonic acid-derived lipid mediators, also termed eicosanoids, can activate APC, particularly DC, which in turn induce an adaptive immune response. There is an increasing evidence that eicosanoids play an important role in connecting innate and adaptive immunity by acting on cells of both systems. Prostanoids, a major class of eicosanoids, have a great impact on inflammatory and immune responses. PGE(2) is one of the best known and most well-characterized prostanoids in terms of immunomodulation. Although cytokines are known as key regulators of immunity, eicosanoids, including PGE(2), PGD(2), LTB(4), and LTC(4), may also affect cells of immune system by modulating cytokine release, cell differentiation, survival, migration, antigen presentation, and apoptosis. By acting on various aspects of immune and inflammatory reactions, these lipid mediators emerge as key regulators of the crosstalk between innate and adaptive immunity.

A mushroom-derived amino acid, ergothioneine, is a potential inhibitor of inflammation-related DNA halogenation.

PubMed

Asahi, Takashi; Wu, Xiaohong; Shimoda, Hiroshi; Hisaka, Shinsuke; Harada, Etsuko; Kanno, Tomomi; Nakamura, Yoshimasa; Kato, Yoji; Osawa, Toshihiko

2016-01-01

Myeloperoxidase (MPO)-generated halogenating molecules, such as hypochlorous acid and hypobromous acid (HOBr), in inflammatory regions are postulated to contribute to disease progression. In this study, we showed that ergothioneine (EGT), derived from an edible mushroom, inhibited MPO activity as well as the formation of 8-bromo-2'-deoxyguanosine in vitro. The HOBr scavenging effect of EGT is higher than those of ascorbic acid and glutathione. We initially observed that the administration of Coprinus comatus, an edible mushroom containing a high amount of EGT, inhibited the UV-B-induced inflammatory responses and DNA halogenation, suggesting that EGT is a promising anti-inflammatory agent from mushrooms.

Monocyte Phenotype and IFN-γ-Inducible Cytokine Responses Are Associated with Cryptococcal Immune Reconstitution Inflammatory Syndrome

PubMed Central

Meya, David B.; Okurut, Samuel; Zziwa, Godfrey; Cose, Stephen; Bohjanen, Paul R.; Mayanja-Kizza, Harriet; Joloba, Moses; Boulware, David R.; Yukari Manabe, Carol; Wahl, Sharon; Janoff, Edward N.

2017-01-01

A third of adults with AIDS and cryptococcal meningitis (CM) develop immune reconstitution inflammatory syndrome (IRIS) after initiating antiretroviral therapy (ART), which is thought to result from exaggerated inflammatory antigen-specific T cell responses. The contribution of monocytes to the immunopathogenesis of cryptococcal IRIS remains unclear. We compared monocyte subset frequencies and immune responses in HIV-infected Ugandans at time of CM diagnosis (IRIS-Baseline) for those who later developed CM-IRIS, controls who did not develop CM-IRIS (Control-Baseline) at CM-IRIS (IRIS-Event), and for controls at a time point matched for ART duration (Control-Event) to understand the association of monocyte distribution and immune responses with cryptococcal IRIS. At baseline, stimulation with IFN-γ ex vivo induced a higher frequency of TNF-α- and IL-6-producing monocytes among those who later developed IRIS. Among participants who developed IRIS, ex vivo IFN-γ stimulation induced higher frequencies of activated monocytes, IL-6+, TNF-α+ classical, and IL-6+ intermediate monocytes compared with controls. In conclusion, we have demonstrated that monocyte subset phenotype and cytokine responses prior to ART are associated with and may be predictive of CM-IRIS. Larger studies to further delineate innate immunological responses and the efficacy of immunomodulatory therapies during cryptococcal IRIS are warranted. PMID:29371546

Biological responses to M13 bacteriophage modified titanium surfaces in vitro.

PubMed

Sun, Yuhua; Li, Yiting; Wu, Baohua; Wang, Jianxin; Lu, Xiong; Qu, Shuxin; Weng, Jie; Feng, Bo

2017-08-01

Phage-based materials have showed great potential in tissue engineering application. However, it is unknown what inflammation response will happen to this kind of materials. This work is to explore the biological responses to M13 bacteriophage (phage) modified titanium surfaces in vitro from the aspects of their interaction with macrophages, osteoblasts and mineralization behavior. Pretreated Ti surface, Ti surfaces with noncrosslinked phage film (APP) and crosslinked phage film (APPG) were compared. Phage films could limit the macrophage adhesion and activity due to inducing adherent-cell apoptosis. The initial inflammatory activity (24h) caused by phage films was relatively high with more production of TNF-α, but in the later stage (7-10days) inflammatory response was reduced with lower TNF-α, IL-6 and higher IL-10. In addition, phage films improved osteoblast adhesion, differentiation, and hydroapatite (HA)-forming via a combination of topographical and biochemcial cues. The noncrosslinked phage film displayed the best immunomodulatory property, osteogenic activity and HA mineralization ability. This work provides better understanding of inflammatory and osteogenetic activity of phage-based materials and contributes to their future application in tissue engineering. In vivo, the bone and immune cells share a common microenvironment, and are being affected by similar cytokines, signaling molecules, transcription factors and membrane receptors. Ideal implants should cause positive biological response, including adequate and appropriate inflammatory reaction, well-balanced bone formation and absorption. Phage-based materials have showed great potential in tissue engineering application. However, at present it is unknown what inflammation response will happen to this kind of materials. A good understanding of the immune response possibly induced by phage-based materials is needed. This work studied the osteoimmunomodulation property of phage films on titanium surface, involving inflammatory response, osteogenic activity and biomineralization ability. It provides more understanding of the phage-based materials and contributes to their future application in tissue engineering. Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Transient inflammatory response mediated by interleukin-1β is required for proper regeneration in zebrafish fin fold.

PubMed

Hasegawa, Tomoya; Hall, Christopher J; Crosier, Philip S; Abe, Gembu; Kawakami, Koichi; Kudo, Akira; Kawakami, Atsushi

2017-02-23

Cellular responses to injury are crucial for complete tissue regeneration, but their underlying processes remain incompletely elucidated. We have previously reported that myeloid-defective zebrafish mutants display apoptosis of regenerative cells during fin fold regeneration. Here, we found that the apoptosis phenotype is induced by prolonged expression of interleukin 1 beta ( il1b ). Myeloid cells are considered to be the principal source of Il1b, but we show that epithelial cells express il1b in response to tissue injury and initiate the inflammatory response, and that its resolution by macrophages is necessary for survival of regenerative cells. We further show that Il1b plays an essential role in normal fin fold regeneration by regulating expression of regeneration-induced genes. Our study reveals that proper levels of Il1b signaling and tissue inflammation, which are tuned by macrophages, play a crucial role in tissue regeneration.

T regulatory cells in childhood asthma.

PubMed

Strickland, Deborah H; Holt, Patrick G

2011-09-01

Asthma is a chronic disease of the airways, most commonly driven by immuno-inflammatory responses to ubiquitous airborne antigens. Epidemiological studies have shown that disease is initiated early in life when the immune and respiratory systems are functionally immature and less able to maintain homeostasis in the face of continuous antigen challenge. Here, we examine the cellular and molecular mechanisms that underlie initial aeroallergen sensitization and the ensuing regulation of secondary responses to inhaled allergens in the airway mucosa. In particular, we focus on how T-regulatory (Treg) cells influence early asthma initiation and the potential of Treg cells as therapeutic targets for drug development in asthma. Copyright © 2011 Elsevier Ltd. All rights reserved.

Cytokine levels (IL-4, IL-6, IL-8 and TGFβ) as potential biomarkers of systemic inflammatory response in trauma patients.

PubMed

Volpin, Gershon; Cohen, Miri; Assaf, Michael; Meir, Tamar; Katz, Rina; Pollack, Shimon

2014-06-01

Much research is now being conducted in order to understand the role of cytokines in the development of the inflammatory response following trauma. The purpose of this study was to evaluate whether serum levels of certain cytokines, measured immediately after initial injury, can be used as potential biomarkers for predicting the development and the degree of severity of the systemic inflammatory response (SIRS) in patients with moderate and severe trauma. We conducted a prospective study with 71 individuals of whom 13 (18.3 %) were healthy controls and 58 (81.7 %) were traumatized orthopaedic patients who were categorized into two groups: 31 (43.6 %) with moderate injuries and 27 (38.1 %) patients with severe orthopaedic trauma. Thirty cc of heparinized blood were drawn from each individual within a few hours after the injury. Serum levels of pro-inflammatory, regulatory and anti-inflammatory cytokines were measured in each individual participant. High levels of pro-inflammatory cytokines IL-1β,-6,-8,-12, tumour necrosis factor alpha and interferon gamma were found in all injured patients compared to healthy controls. Only IL-6 and IL-8 were significantly higher in the injured patients. Levels of the regulatory cytokines, transformed growth factor beta (TGF-β) and IL-10 were higher in the injured patients, but significant only for TGF-β. Levels of IL-4 were significantly lower in the injured groups as compared to the controls. Secretion of large amounts of pro-inflammatory cytokines and decreased level of anti-inflammatory cytokines during the acute phase of trauma may lead to the development of systemic inflammatory response syndrome (SIRS) in unstable polytraumatized patients. SIRS may result in life threatening conditions as acute respiratory distress syndrome (ARDS) and multiple organ failure (MOF). High levels of IL-6, IL-8, TGFβ and low levels of IL-4 were found to be reliable markers for the existence of immune reactivity in trauma patients. More research is needed to study pattern of cytokine levels along the acute period of injury, after surgical interventions and during recovery.

Immune Evasion Strategies of Pathogens in Macrophages: the Potential for Limiting Pathogen Transmission.

PubMed

Ren, Yuwei; Khan, Faheem Ahmed; Pandupuspitasari, Nuruliarizki Shinta; Zhang, Shujun

2017-01-01

Preventing pathogen transmission to a new host is of major interest to the immunologist and could benefit from a detailed investigation of pathogen immune evasion strategies. The first line of defense against pathogen invasion is provided by macrophages. When they sense pathogens, macrophages initiate signals to inflammatory and pro-inflammatory cytokines through pattern recognition receptors (PRRs) subsequently mediating phagocytosis and inflammation. The macrophage immune machinery classically includes two subsets: the activated M1 and the activated M2 that respond accordingly in diverse immune challenges. The lipid and glycogen metabolic pathways work together with the lysosome to help the mature phagosome to degrade and eliminate intracellular pathogens in macrophages. The viral evasion strategies are even more complex due to the interplay between autophagy and apoptosis. However, pathogens evolve several strategies to camouflage themselves against immune responses in order to ensure their survival, replication and transmission. These strategies include the muting of PRRs initiated inflammatory responses, attenuation of M1 and/or induction of M2 macrophages, suppression of autophago-lysosomal formation, interference with lipid and glycogen metabolism, and viral mediation of autophagy and apoptosis cross-talk to enhance viral replication. This review focuses on pathogen immune evasion methods and on the strategies used by the host against camouflaged pathogens.

Toll-Like Receptor Function in Acute Wounds

PubMed Central

Chen, Lin; DiPietro, Luisa A.

2017-01-01

Significance: Inflammation is an integral part of immune response and supports optimal wound healing in adults. Inflammatory cells such as neutrophils, macrophages, dendritic cells, lymphocytes, and mast cells produce important cytokines, chemokines, and growth factors. These immune cells interact with keratinocytes, fibroblasts, and endothelial cells (ECs), as well as the extracellular matrix within a complicated network that promotes and regulates wound healing. Aberrant and persistent inflammation may result in delayed wound healing, scar formation, or chronic wounds. Targeting the molecules involved in the inflammatory response may have great potential therapeutic value. Recent Advances and Critical Issues: Toll-like receptors (TLRs) are pattern recognition receptors that recognize pathogen-associated molecular patterns from microbes or danger-associated molecular patterns from damaged cells. The discovery of TLRs sheds new light on the mechanism by which the inflammatory or innate immune response is initiated in wound healing. Convincing evidence now shows that multiple types of cells, including infiltrating or resident inflammatory cells, keratinocytes, fibroblasts, and ECs, express specific types of TLRs. Experimental reduction of certain TLRs or treatment of wounds with TLR ligands has been shown to affect wound healing. A better understanding of the involvement of TLRs in the innate immune response during skin wound healing may suggest novel strategies to improve the quality of tissue repair. Future Directions: Despite the indisputable role of TLRs in regulating the immune response in acute wound healing, the functions of TLRs that are relevant to human wound healing and chronic wounds are poorly understood. PMID:29062591

Post-mating inflammatory responses of the uterus.

PubMed

Katila, T

2012-08-01

This review attempts to summarize the current knowledge on uterine inflammatory response after mating in horses, pigs and cattle. Post-mating endometritis has been extensively studied in horses as it has been considered to cause infertility. The inflammation is known to occur also in cattle, but it has not been investigated to a similar extent. There are a number of publications about mechanisms of post-mating uterine inflammation in pigs, which seem to resemble those in horses. The major focus of this review is the horse, but relevant literature is presented also on swine and cattle. Spermatozoa, seminal plasma and semen extenders play roles in the induction of inflammation. In addition, sperm numbers, concentration and viability, as well as the site of semen deposition may modulate the inflammatory response. Cytokines, polymorphonuclear leucocytes (PMN) and mononuclear cells represent the uterine inflammatory response to mating. Inflammation is the first line of defence against invasion and eliminates excess spermatozoa and bacteria. Semen deposition elicits a massive PMN invasion, followed by phagocytosis of sperm aided by the formation of neutrophil extracellular traps. Exposure of the female genital tract to semen is important also for endometrial receptivity and pre-implantation embryo development. Seminal plasma (SP) and inflammation elicit transient immune tolerance to antigens present in semen. SP contains immune-regulatory molecules that activate and control immune responses to antigens by stimulating expression of cytokines and growth factors and by initiating tissue remodelling. SP also regulates ovarian function. Effective elimination of excess sperm and inflammatory by-products and subsequent rapid return of the endometrium to the normal state is a prerequisite for pregnancy. Uterine backflow, driven by myometrial contractions and requiring a patent cervix, is an important physical tool in uterine drainage. © 2012 Blackwell Verlag GmbH.

HETEROGENEITY OF SYSTEMIC INFLAMMATORY RESPONSES TO PERIODONTAL THERAPY

PubMed Central

Behle, Jan H.; Sedaghatfar, Michael H.; Demmer, Ryan T.; Wolf, Dana L.; Celenti, Romanita; Kebschull, Moritz; Belusko, Paul B.; Herrera-Abreu, Miriam; Lalla, Evanthia; Papapanou, Panos N.

2009-01-01

Aims We investigated the effect of comprehensive periodontal therapy on the levels of multiple systemic inflammatory biomarkers. Methods Thirty patients with severe periodontitis received comprehensive periodontal therapy within a 6-week period. Blood samples were obtained at: one week pre- therapy (T1), therapy initiation (T2), treatment completion (T3), and 4 weeks thereafter (T4). We assessed plasma concentrations of 19 biomarkers using multiplex assays, and serum IgG antibodies to periodontal bacteria using checkerboard immunoblotting. At T2 and T4, dental plaque samples were analyzed using checkerboard hybridizations. Results At T3, PAI-1, sE-selectin, sVCAM-1, MMP-9, myeloperoxidase, and a composite Summary Inflammatory Score (SIS) were significantly reduced. However, only sE-selectin, sICAM, and serum amyloid P sustained a reduction at T4. Responses were highly variable: analyses of SIS slopes between baseline and T4 showed that approximately 1/3 and 1/4 of the patients experienced marked reduction and pronounced increase in systemic inflammation, respectively, while the remainder were seemingly unchanged. Changes in inflammatory markers correlated poorly with clinical, microbiological and serological markers of periodontitis. Conclusions Periodontal therapy resulted in an overall reduction of systemic inflammation, but the responses were inconsistent across subjects and largely not sustainable. The determinants of this substantial heterogeneity need to be explored further. PMID:19426174

"TRP inflammation" relationship in cardiovascular system.

PubMed

Numata, Tomohiro; Takahashi, Kiriko; Inoue, Ryuji

2016-05-01

Despite considerable advances in the research and treatment, the precise relationship between inflammation and cardiovascular (CV) disease remains incompletely understood. Therefore, understanding the immunoinflammatory processes underlying the initiation, progression, and exacerbation of many cardiovascular diseases is of prime importance. The innate immune system has an ancient origin and is well conserved across species. Its activation occurs in response to pathogens or tissue injury. Recent studies suggest that altered ionic balance, and production of noxious gaseous mediators link to immune and inflammatory responses with altered ion channel expression and function. Among plausible candidates for this are transient receptor potential (TRP) channels that function as polymodal sensors and scaffolding proteins involved in many physiological and pathological processes. In this review, we will first focus on the relevance of TRP channel to both exogenous and endogenous factors related to innate immune response and transcription factors related to sustained inflammatory status. The emerging role of inflammasome to regulate innate immunity and its possible connection to TRP channels will also be discussed. Secondly, we will discuss about the linkage of TRP channels to inflammatory CV diseases, from a viewpoint of inflammation in a general sense which is not restricted to the innate immunity. These knowledge may serve to provide new insights into the pathogenesis of various inflammatory CV diseases and their novel therapeutic strategies.

Epithelioid inflammatory myofibroblastic sarcoma: a case report

PubMed Central

Clevenger, Jessica A.; Masters, Gregory A.; Bauer, Thomas L.; Nam, Brian T.

2015-01-01

Inflammatory myofibroblastic tumor (IMT) of the lung is a rare malignancy with few cases reported in the literature. Histologically, it is composed by spindle cells and an infiltrate of inflammatory cells. Children and young, non-smoking adults constitute the majority of cases, the clinical behavior ranges from a benign entity to a malignant process with rapid recurrence and metastatic progression. We present a case of epithelioid inflammatory myofibroblastic sarcoma (EIMS) of the pleura, a malignant variant of IMT, which was initially treated with debulking surgical resection followed by systemic chemotherapy. The tumor was found to have an anaplastic lymphoma kinase (ALK) gene rearrangement. An ALK directed tyrosine kinase inhibitor was used with an impressive response, the patient remains in remission nearly 1 year after presentation. The pathogenesis, pathologic findings, clinical behavior and imaging of pulmonary EIMS are discussed. PMID:26623133

Toll-like receptor signaling in cell proliferation and survival

PubMed Central

Li, Xinyan; Jiang, Song; Tapping, Richard I.

2009-01-01

Toll-like receptors (TLRs) are important sensors of foreign microbial components as well as products of damaged or inflamed self tissues. Upon sensing these molecules, TLRs initiate a series of downstream signaling events that drive cellular responses including the production of cytokines, chemokines and other inflammatory mediators. This outcome results from the intracellular assembly of protein complexes that drive phosphorylation and other signaling cascades ultimately leading to chromatin remodeling and transcription factor activation. In addition to driving inflammatory responses, TLRs also regulate cell proliferation and survival which serves to expand useful immune cells and integrate inflammatory responses and tissue repair processes. In this context, central TLR signaling molecules, such as the mitogen-activated protein kinases (MAPK) and phosphoinositide 3-kinase (PI3K), play key roles. In addition, four major groups of transcription factors which are targets of TLR activation also control cell fate. This review focuses on the role of TLR signaling as it relates to cell proliferation and survival. This topic not only has important implications for understanding host defense and tissue repair, but also cancer which is often associated with conditions of chronic inflammation. PMID:19775907

Prostanoids and their receptors that modulate dendritic cell-mediated immunity.

PubMed

Gualde, Norbert; Harizi, Hedi

2004-08-01

Dendritic cells (DC) are essential for the initiation of immune responses by capturing, processing and presenting antigens to T cells. In addition to their important role as professional APC, they are able to produce immunosuppressive and pro-inflammatory prostanoids from arachidonic acid (AA) by the action of cyclooxygenase (COX) enzymes. In an autocrine and paracrine fashion, the secreted lipid mediators subsequently modulate the maturation, cytokine production, Th-cell polarizing ability, chemokine receptor expression, migration, and apoptosis of these extremely versatile APC. The biological actions of prostanoids, including their effects on APC-mediated immunity and acute inflammatory responses, are exerted by G protein-coupled receptors on plasma membrane. Some COX metabolites act as anti-inflammatory lipid mediators by binding to nuclear receptors and modulating DC functions. Although the role of cytokines in DC function has been studied extensively, the effects of prostanoids on DC biology have only recently become the focus of investigation. This review summarizes the current knowledge about the role of prostanoids and their receptors in modulating DC function and the subsequent immune responses.

Corrosion and mechanical performance of AZ91 exposed to simulated inflammatory conditions.

PubMed

Brooks, Emily K; Der, Stephanie; Ehrensberger, Mark T

2016-03-01

Magnesium (Mg) and its alloys, including Mg-9%Al-1%Zn (AZ91), are biodegradable metals with potential use as temporary orthopedic implants. Invasive orthopedic procedures can provoke an inflammatory response that produces hydrogen peroxide (H2O2) and an acidic environment near the implant. This study assessed the influence of inflammation on both the corrosion and mechanical properties of AZ91. The AZ91 samples in the inflammatory protocol were immersed for three days in a complex biologically relevant electrolyte (AMEM culture media) that contained serum proteins (FBS), 150 mM of H2O2, and was titrated to a pH of 5. The control protocol immersed AZ91 samples in the same biologically relevant electrolyte (AMEM & FBS) but without H2O2 and the acid titration. After 3 days all samples were switched into fresh AMEM & FBS for an additional 3-day immersion. During the initial immersion, inflammatory protocol samples showed increased corrosion rate determined by mass loss testing, increased Mg and Al ion released to solution, and a completely corroded surface morphology as compared to the control protocol. Although corrosion in both protocols slowed once the test electrolyte solution was replaced at 3 days, the samples originally exposed to the simulated inflammatory conditions continued to display enhanced corrosion rates as compared to the control protocol. These lingering effects may indicate the initial inflammatory corrosion processes modified components of the surface oxide and corrosion film or initiated aggressive localized processes that subsequently left the interface more vulnerable to continued enhanced corrosion. The electrochemical properties of the interfaces were also evaluated by EIS, which found that the corrosion characteristics of the AZ91 samples were potentially influenced by the role of intermediate adsorption layer processes. The increased corrosion observed for the inflammatory protocol did not affect the flexural mechanical properties of the AZ91 at any time point assessed. Copyright © 2015 Elsevier B.V. All rights reserved.

[Immunopathogenesis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)].

PubMed

Yamamura, Takashi; Ono, Hirohiko; Sato, Wakiro

2018-01-01

A recent study on the pathogenesis of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) has revealed an elevation of inflammatory and anti-inflammatory cytokines in the sera and cerebrospinal fluids of the patients and presence of autoantibodies in subgroups of ME/CFS patients. Furthermore, investigator-initiated clinical trials have proved the efficacy of anti-CD20 antibody (rituximab), that eliminate B cells, in the treatment of ME/CFS. Based on these findings, we hypothesize that immune abnormalities, such as enhanced autoimmune responses, may play an essential role in the neuroinflammatory pathogenesis of ME/CFS.

Incidence of adrenal insufficiency and impact of corticosteroid supplementation in critically ill children with systemic inflammatory syndrome and vasopressor-dependent shock.

PubMed

Hebbar, Kiran B; Stockwell, Jana A; Leong, Traci; Fortenberry, James D

2011-05-01

Adrenal insufficiency may be common in adults and children with vasopressor-resistant shock. We developed a protocolized approach to low-dose adrenocorticotropin testing and empirical low-dose glucocorticoid/mineralocorticoid supplementation in children with systemic inflammatory response syndrome and persistent hypotension following fluid resuscitation and vasopressor infusion. We hypothesized that absolute and relative adrenal insufficiency was common in children with systemic inflammatory response syndrome requiring vasopressor support and that steroid administration would be associated with decreased vasopressor need. Retrospective review of pediatric patients with systemic inflammatory response syndrome and vasopressor-dependent shock receiving protocol-based adrenocorticotropin testing and low-dose steroid supplementation. The incidence of absolute and relative adrenal insufficiency was determined using several definitions. Vasopressor dose requirements were evaluated before, and following, initiation of corticosteroids. Seventy-eight patients met inclusion criteria for systemic inflammatory response syndrome and shock; 40 had septic shock. Median age was 84 months (range, 0.5-295). By adrenocorticotropin testing, 44 (56%) had absolute adrenal insufficiency, 39 (50%) had relative adrenal insufficiency, and 69 (88%) had either form of adrenal insufficiency. Adrenal insufficiency incidence was significantly higher in children >2 yrs (p = .0209). Therapeutic interventions included median 80-mL/kg fluid resuscitation; 65% of patients required dopamine, 58% norepinephrine, and 49% dopamine plus norepinephrine. With steroid supplementation, median dopamine dose decreased from 10 to 4 μg/kg/min at 4 hrs (p = .0001), and median dose of norepinephrine decreased from 0.175 μg/kg/min to 0.05 μg/kg/min at 4 hrs (p = .039). Absolute and relative adrenal insufficiency was prevalent in this cohort of children with systemic inflammatory response syndrome and vasopressor-dependent shock and increased with age. Introduction of steroids produced a significant reduction in vasopressor duration and dosage. Use of low-dose adrenocorticotropin testing may help further delineate populations who require steroid supplementation.

Activation of bradykinin B2 receptor induced the inflammatory responses of cytosolic phospholipase A2 after the early traumatic brain injury.

PubMed

Chao, Honglu; Liu, Yinlong; Lin, Chao; Xu, Xiupeng; Li, Zheng; Bao, Zhongyuan; Fan, Liang; Tao, Chao; Zhao, Lin; Liu, Yan; Wang, Xiaoming; You, Yongping; Liu, Ning; Ji, Jing

2018-06-09

Phospholipase A 2 is a known aggravator of inflammation and deteriorates neurological outcomes after traumatic brain injury (TBI), however the exact inflammatory mechanisms remain unknown. This study investigated the role of bradykinin and its receptor, which are known initial mediators within inflammation activation, as well as the mechanisms of the cytosolic phospholipase A 2 (cPLA 2 )-related inflammatory responses after TBI. We found that cPLA 2 and bradykinin B2 receptor were upregulated after a TBI. Rats treated with the bradykinin B2 receptor inhibitor LF 16-0687 exhibited significantly less cPLA 2 expression and related inflammatory responses in the brain cortex after sustaining a controlled cortical impact (CCI) injury. Both the cPLA 2 inhibitor and the LF16-0687 improved CCI rat outcomes by decreasing neuron death and reducing brain edema. The following TBI model utilized both primary astrocytes and primary neurons in order to gain further understanding of the inflammation mechanisms of the B2 bradykinin receptor and the cPLA 2 in the central nervous system. There was a stronger reaction from the astrocytes as well as a protective effect of LF16-0687 after the stretch injury and bradykinin treatment. The protein kinase C pathway was thought to be involved in the B2 bradykinin receptor as well as the cPLA 2 -related inflammatory responses. Rottlerin, a Protein Kinase C (PKC) δ inhibitor, decreased the activity of the cPLA 2 activity post-injury, and LF16-0687 suppressed both the PKC pathway and the cPLA 2 activity within the astrocytes. These results indicated that the bradykinin B2 receptor-mediated pathway is involved in the cPLA 2 -related inflammatory response from the PKC pathway. Copyright © 2018. Published by Elsevier B.V.

Neisseria meningitidis elicits a pro-inflammatory response involving IκBζ in a human blood-cerebrospinal fluid barrier model.

PubMed

Borkowski, Julia; Li, Li; Steinmann, Ulrike; Quednau, Natascha; Stump-Guthier, Carolin; Weiss, Christel; Findeisen, Peter; Gretz, Norbert; Ishikawa, Hiroshi; Tenenbaum, Tobias; Schroten, Horst; Schwerk, Christian

2014-09-13

The human-specific, Gram-negative bacterium Neisseria meningitidis (Nm) is a leading cause of bacterial meningitis worldwide. The blood-cerebrospinal fluid barrier (BCSFB), which is constituted by the epithelial cells of the choroid plexus (CP), has been suggested as one of the potential entry sites of Nm into the CSF and can contribute to the inflammatory response during infectious diseases of the brain. Toll-like receptors (TLRs) are involved in mediating signal transduction caused by the pathogens. Using a recently established in vitro model of the human BCSFB based on human malignant CP papilloma (HIBCPP) cells we investigated the cellular response of HIBCPP cells challenged with the meningitis-causing Nm strain, MC58, employing transcriptome and RT-PCR analysis, cytokine bead array, and enzyme-linked immunosorbent assay (ELISA). In comparison, we analyzed the answer to the closely related unencapsulated carrier isolate Nm α14. The presence of TLRs in HIBCPP and their role during signal transduction caused by Nm was studied by RT-PCR and the use of specific agonists and mutant bacteria. We observed a stronger transcriptional response after infection with strain MC58, in particular with its capsule-deficient mutant MC58siaD-, which correlated with bacterial invasion levels. Expression evaluation and Gene Set Enrichment Analysis pointed to a NFκB-mediated pro-inflammatory immune response involving up-regulation of the transcription factor IκBζ. Infected cells secreted significant levels of pro-inflammatory chemokines and cytokines, including, among others, IL8, CXCL1-3, and the IκBζ target gene product IL6. The expression profile of pattern recognition receptors in HIBCPP cells and the response to specific agonists indicates that TLR2/TLR6, rather than TLR4 or TLR2/TLR1, is involved in the cellular reaction following Nm infection. Our data show that Nm can initiate a pro-inflammatory response in human CP epithelial cells probably involving TLR2/TLR6 signaling and the transcriptional regulator IκBζ.

Review of osteoimmunology and the host response in endodontic and periodontal lesions

PubMed Central

Graves, Dana T.; Oates, Thomas; Garlet, Gustavo P.

2011-01-01

Both lesions of endodontic origin and periodontal diseases involve the host response to bacteria and the formation of osteolytic lesions. Important for both is the upregulation of inflammatory cytokines that initiate and sustain the inflammatory response. Also important are chemokines that induce recruitment of leukocyte subsets and bone-resorptive factors that are largely produced by recruited inflammatory cells. However, there are differences also. Lesions of endodontic origin pose a particular challenge since that bacteria persist in a protected reservoir that is not readily accessible to the immune defenses. Thus, experiments in which the host response is inhibited in endodontic lesions tend to aggravate the formation of osteolytic lesions. In contrast, bacteria that invade the periodontium appear to be less problematic so that blocking arms of the host response tend to reduce the disease process. Interestingly, both lesions of endodontic origin and periodontitis exhibit inflammation that appears to inhibit bone formation. In periodontitis, the spatial location of the inflammation is likely to be important so that a host response that is restricted to a subepithelial space is associated with gingivitis, while a host response closer to bone is linked to bone resorption and periodontitis. However, the persistence of inflammation is also thought to be important in periodontitis since inflammation present during coupled bone formation may limit the capacity to repair the resorbed bone. PMID:21547019

Innate lymphoid cells in the initiation, regulation and resolution of inflammation

PubMed Central

Sonnenberg, Gregory F.; Artis, David

2016-01-01

A previously unappreciated cell type of the innate immune system, termed innate lymphoid cells (ILCs), has been characterized in mice and humans, and found to profoundly influence the induction, regulation and resolution of inflammation. ILCs play an important role in these processes in murine models of infection, inflammatory disease and tissue repair. Further, disease association studies in defined patient populations have identified significant alterations in ILC responses, suggesting a potential role for these cell populations in human health and disease. In this review, we discuss the emerging family of ILCs, the role of ILCs in inflammation, and how current or novel therapeutic strategies could be employed to selectively modulate ILC responses and limit chronic inflammatory diseases in patients. PMID:26121198

Importance of basophils in eosinophilic asthma: the murine counterpart.

PubMed

Poddighe, D; Mathias, C B; Brambilla, I; Marseglia, G L; Oettgen, H C

2018-01-01

Several experimental studies in mice showed that basophils participate in the initiation of Th2 adaptive immune response, in addition to the effector phase. However, the role of basophils in allergic airway inflammation is less clear. The aim of this experiment was to assess the importance of basophils in recruiting inflammatory cells and, in particular, eosinophils in a murine model of asthma induced by Aspergillus fumigatus allergens. Additionally, bronchial reactivity was evaluated. Basophil depletion resulted in a reduction of inflammatory cells in the airways and eosinophil recruitment was significantly impaired. Also bronchial reactivity seemed to be impaired in basophil-depleted mice, but the result was not statistically significant. According to these preliminary data, basophils seem to influence the local eosinophilic response of allergic asthma.

Mycobacterial Antigen Driven Activation of CD14++CD16− Monocytes Is a Predictor of Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome

PubMed Central

Andrade, Bruno B.; Singh, Amrit; Narendran, Gopalan; Schechter, Melissa E.; Nayak, Kaustuv; Subramanian, Sudha; Anbalagan, Selvaraj; Jensen, Stig M. R.; Porter, Brian O.; Antonelli, Lis R.; Wilkinson, Katalin A.; Wilkinson, Robert J.; Meintjes, Graeme; van der Plas, Helen; Follmann, Dean; Barber, Daniel L.; Swaminathan, Soumya; Sher, Alan; Sereti, Irini

2014-01-01

Paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is an aberrant inflammatory response occurring in a subset of TB-HIV co-infected patients initiating anti-retroviral therapy (ART). Here, we examined monocyte activation by prospectively quantitating pro-inflammatory plasma markers and monocyte subsets in TB-HIV co-infected patients from a South Indian cohort at baseline and following ART initiation at the time of IRIS, or at equivalent time points in non-IRIS controls. Pro-inflammatory biomarkers of innate and myeloid cell activation were increased in plasma of IRIS patients pre-ART and at the time of IRIS; this association was confirmed in a second cohort in South Africa. Increased expression of these markers correlated with elevated antigen load as measured by higher sputum culture grade and shorter duration of anti-TB therapy. Phenotypic analysis revealed the frequency of CD14++CD16− monocytes was an independent predictor of TB-IRIS, and was closely associated with plasma levels of CRP, TNF, IL-6 and tissue factor during IRIS. In addition, production of inflammatory cytokines by monocytes was higher in IRIS patients compared to controls pre-ART. These data point to a major role of mycobacterial antigen load and myeloid cell hyperactivation in the pathogenesis of TB-IRIS, and implicate monocytes and monocyte-derived cytokines as potential targets for TB-IRIS prevention or treatment. PMID:25275318

Differential IL-1β secretion by monocyte subsets is regulated by Hsp27 through modulating mRNA stability.

PubMed

Hadadi, Eva; Zhang, Biyan; Baidžajevas, Kajus; Yusof, Nurhashikin; Puan, Kia Joo; Ong, Siew Min; Yeap, Wei Hseun; Rotzschke, Olaf; Kiss-Toth, Endre; Wilson, Heather; Wong, Siew Cheng

2016-12-15

Monocytes play a central role in regulating inflammation in response to infection or injury, and during auto-inflammatory diseases. Human blood contains classical, intermediate and non-classical monocyte subsets that each express characteristic patterns of cell surface CD16 and CD14; each subset also has specific functional properties, but the mechanisms underlying many of their distinctive features are undefined. Of particular interest is how monocyte subsets regulate secretion of the apical pro-inflammatory cytokine IL-1β, which is central to the initiation of immune responses but is also implicated in the pathology of various auto-immune/auto-inflammatory conditions. Here we show that primary human non-classical monocytes, exposed to LPS or LPS + BzATP (3'-O-(4-benzoyl)benzyl-ATP, a P2X7R agonist), produce approx. 80% less IL-1β than intermediate or classical monocytes. Despite their low CD14 expression, LPS-sensing, caspase-1 activation and P2X7R activity were comparable in non-classical monocytes to other subsets: their diminished ability to produce IL-1β instead arose from 50% increased IL-1β mRNA decay rates, mediated by Hsp27. These findings identify the Hsp27 pathway as a novel therapeutic target for the management of conditions featuring dysregulated IL-1β production, and represent an advancement in understanding of both physiological inflammatory responses and the pathogenesis of inflammatory diseases involving monocyte-derived IL-1β.

Resveratrol pretreatment attenuates traumatic brain injury in rats by suppressing NLRP3 inflammasome activation via SIRT1.

PubMed

Zou, Peng; Liu, Xiaoxiao; Li, Gang; Wang, Yangang

2018-02-01

The inflammatory response in the cerebral cortex serves an important role in the progression of secondary injury following traumatic brain injury (TBI). The NLR family pyrin domain containing 3 (NLRP3) inflammasome is necessary for initiating inflammation and is involved in various central nervous system disorders. The aim of the present study was to investigate the neuroprotective effect of resveratrol and elucidate the underlying mechanisms of resveratrol associated regulation of the NLRP3 inflammasome in TBI. The results demonstrated that the activation of NLRP3, caspase‑1 and sirtuin 1 (SIRT1), enhanced the production of inflammatory cytokines and reactive oxygen species (ROS) following TBI. Administration of resveratrol alleviated the degree of TBI, as evidenced by the reduced neuron‑specific enolase (NSE) and brain water content (WBC). Resveratrol pretreatment also inhibited the activation of NLRP3 and caspase‑1, and reduced the production of inflammatory cytokines and ROS. In addition, resveratrol further promoted SIRT1 activation. Furthermore, the suppressing effect of resveratrol on the NLRP3 inflammasome and ROS was blocked by the SIRT1 inhibitor, sirtinol. The results revealed that the activation of the NLRP3 inflammasome and the subsequent inflammatory responses in the cerebral cortex were involved in the process of TBI. Resveratrol may attenuate the inflammatory response and relieve TBI by reducing ROS production and inhibiting NLRP3 activation. The effect of resveratrol on NLRP3 inflammasome and ROS may also be SIRT1 dependent.

The cytokine temporal profile in rat cortex after controlled cortical impact

PubMed Central

Dalgard, Clifton L.; Cole, Jeffrey T.; Kean, William S.; Lucky, Jessica J.; Sukumar, Gauthaman; McMullen, David C.; Pollard, Harvey B.; Watson, William D.

2012-01-01

Cerebral inflammatory responses may initiate secondary cascades following traumatic brain injury (TBI). Changes in the expression of both cytokines and chemokines may activate, regulate, and recruit innate and adaptive immune cells associated with secondary degeneration, as well as alter a host of other cellular processes. In this study, we quantified the temporal expression of a large set of inflammatory mediators in rat cortical tissue after brain injury. Following a controlled cortical impact (CCI) on young adult male rats, cortical and hippocampal tissue of the injured hemisphere and matching contralateral material was harvested at early (4, 12, and 24 hours) and extended (3 and 7 days) time points post-procedure. Naïve rats that received only anesthesia were used as controls. Processed brain homogenates were assayed for chemokine and cytokine levels utilizing an electrochemiluminescence-based multiplex ELISA platform. The temporal profile of cortical tissue samples revealed a multi-phasic injury response following brain injury. CXCL1, IFN-γ, TNF-α levels significantly peaked at four hours post-injury compared to levels found in naïve or contralateral tissue. CXCL1, IFN-γ, and TNF-α levels were then observed to decrease at least 3-fold by 12 hours post-injury. IL-1β, IL-4, and IL-13 levels were also significantly elevated at four hours post-injury although their expression did not decrease more than 3-fold for up to 24 hours post-injury. Additionally, IL-1β and IL-4 levels displayed a biphasic temporal profile in response to injury, which may suggest their involvement in adaptive immune responses. Interestingly, peak levels of CCL2 and CCL20 were not observed until after four hours post-injury. CCL2 levels in injured cortical tissue were significantly higher than peak levels of any other inflammatory mediator measured, thus suggesting a possible use as a biomarker. Fully elucidating chemokine and cytokine signaling properties after brain injury may provide increased insight into a number of secondary cascade events that are initiated or regulated by inflammatory responses. PMID:22291617

The cytokine temporal profile in rat cortex after controlled cortical impact.

PubMed

Dalgard, Clifton L; Cole, Jeffrey T; Kean, William S; Lucky, Jessica J; Sukumar, Gauthaman; McMullen, David C; Pollard, Harvey B; Watson, William D

2012-01-01

Cerebral inflammatory responses may initiate secondary cascades following traumatic brain injury (TBI). Changes in the expression of both cytokines and chemokines may activate, regulate, and recruit innate and adaptive immune cells associated with secondary degeneration, as well as alter a host of other cellular processes. In this study, we quantified the temporal expression of a large set of inflammatory mediators in rat cortical tissue after brain injury. Following a controlled cortical impact (CCI) on young adult male rats, cortical and hippocampal tissue of the injured hemisphere and matching contralateral material was harvested at early (4, 12, and 24 hours) and extended (3 and 7 days) time points post-procedure. Naïve rats that received only anesthesia were used as controls. Processed brain homogenates were assayed for chemokine and cytokine levels utilizing an electrochemiluminescence-based multiplex ELISA platform. The temporal profile of cortical tissue samples revealed a multi-phasic injury response following brain injury. CXCL1, IFN-γ, TNF-α levels significantly peaked at four hours post-injury compared to levels found in naïve or contralateral tissue. CXCL1, IFN-γ, and TNF-α levels were then observed to decrease at least 3-fold by 12 hours post-injury. IL-1β, IL-4, and IL-13 levels were also significantly elevated at four hours post-injury although their expression did not decrease more than 3-fold for up to 24 hours post-injury. Additionally, IL-1β and IL-4 levels displayed a biphasic temporal profile in response to injury, which may suggest their involvement in adaptive immune responses. Interestingly, peak levels of CCL2 and CCL20 were not observed until after four hours post-injury. CCL2 levels in injured cortical tissue were significantly higher than peak levels of any other inflammatory mediator measured, thus suggesting a possible use as a biomarker. Fully elucidating chemokine and cytokine signaling properties after brain injury may provide increased insight into a number of secondary cascade events that are initiated or regulated by inflammatory responses.

Inflammatory Monocytes Recruited to the Liver within 24 Hours after Virus-Induced Inflammation Resemble Kupffer Cells but Are Functionally Distinct

PubMed Central

Movita, Dowty; Biesta, Paula; Kreefft, Kim; Haagmans, Bart; Zuniga, Elina; Herschke, Florence; De Jonghe, Sandra; Janssen, Harry L. A.; Gama, Lucio; Boonstra, Andre

2015-01-01

ABSTRACT Due to a scarcity of immunocompetent animal models for viral hepatitis, little is known about the early innate immune responses in the liver. In various hepatotoxic models, both pro- and anti-inflammatory activities of recruited monocytes have been described. In this study, we compared the effect of liver inflammation induced by the Toll-like receptor 4 ligand lipopolysaccharide (LPS) with that of a persistent virus, lymphocytic choriomeningitis virus (LCMV) clone 13, on early innate intrahepatic immune responses in mice. LCMV infection induces a remarkable influx of inflammatory monocytes in the liver within 24 h, accompanied by increased transcript levels of several proinflammatory cytokines and chemokines in whole liver. Importantly, while a single LPS injection results in similar recruitment of inflammatory monocytes to the liver, the functional properties of the infiltrating cells are dramatically different in response to LPS versus LCMV infection. In fact, intrahepatic inflammatory monocytes are skewed toward a secretory phenotype with impaired phagocytosis in LCMV-induced liver inflammation but exhibit increased endocytic capacity after LPS challenge. In contrast, F4/80high-Kupffer cells retain their steady-state endocytic functions upon LCMV infection. Strikingly, the gene expression levels of inflammatory monocytes dramatically change upon LCMV exposure and resemble those of Kupffer cells. Since inflammatory monocytes outnumber Kupffer cells 24 h after LCMV infection, it is highly likely that inflammatory monocytes contribute to the intrahepatic inflammatory response during the early phase of infection. Our findings are instrumental in understanding the early immunological events during virus-induced liver disease and point toward inflammatory monocytes as potential target cells for future treatment options in viral hepatitis. IMPORTANCE Insights into how the immune system deals with hepatitis B virus (HBV) and HCV are scarce due to the lack of adequate animal model systems. This knowledge is, however, crucial to developing new antiviral strategies aimed at eradicating these chronic infections. We model virus-host interactions during the initial phase of liver inflammation 24 h after inoculating mice with LCMV. We show that infected Kupffer cells are rapidly outnumbered by infiltrating inflammatory monocytes, which secrete proinflammatory cytokines but are less phagocytic. Nevertheless, these recruited inflammatory monocytes start to resemble Kupffer cells on a transcript level. The specificity of these cellular changes for virus-induced liver inflammation is corroborated by demonstrating opposite functions of monocytes after LPS challenge. Overall, this demonstrates the enormous functional and genetic plasticity of infiltrating monocytes and identifies them as an important target cell for future treatment regimens. PMID:25673700

Resident fibroblasts in the kidney: a major driver of fibrosis and inflammation.

PubMed

Sato, Yuki; Yanagita, Motoko

2017-01-01

Chronic kidney disease (CKD) is a leading cause of end stage renal disease (ESRD) and cardiovascular morbidity and mortality worldwide, resulting in a growing social and economic burden. The prevalence and burden of CKD is anticipated to further increase over the next decades as a result of aging. In the pathogenesis of CKD, irrespective of the etiology, resident fibroblasts are key players and have been demonstrated to play crucial roles for disease initiation and progression. In response to injury, resident fibroblasts transdifferentiate into myofibroblasts that express alpha smooth muscle actin (αSMA) and have an increased capacity to produce large amounts of extracellular matrix (ECM) proteins, leading to renal fibrosis. In addition to this fundamental role of fibroblasts as drivers for renal fibrosis, growing amounts of evidence have shown that resident fibroblasts are also actively involved in initiating and promoting inflammation during kidney injury. During the myofibroblastic transition described above, resident fibroblasts activate NF-κB signaling and produce pro-inflammatory cytokines and chemokines, promoting inflammation. Furthermore, under aging milieu, resident fibroblasts transdifferentiate into several distinct phenotypic fibroblasts, including CXCL13/CCL19-producing fibroblasts, retinoic acid-producing fibroblasts, and follicular dendritic cells, in response to injury and orchestrate tertiary lymphoid tissue (TLT) formation, which results in uncontrolled aberrant inflammation and retards tissue repair. Anti-inflammatory agents can improve myofibroblastic transdifferentiation and abolish TLT formation, suggesting that targeting these inflammatory fibroblasts can potentially ameliorate kidney disease. Beyond its conventional role as an executor of fibrosis, resident fibroblasts display more pro-inflammatory phenotypes and contribute actively to driving inflammation during kidney injury.

Pathways leading to an immunological disease: systemic lupus erythematosus.

PubMed

Zharkova, Olga; Celhar, Teja; Cravens, Petra D; Satterthwaite, Anne B; Fairhurst, Anna-Marie; Davis, Laurie S

2017-04-01

SLE is a chronic autoimmune disease caused by perturbations of the immune system. The clinical presentation is heterogeneous, largely because of the multiple genetic and environmental factors that contribute to disease initiation and progression. Over the last 60 years, there have been a number of significant leaps in our understanding of the immunological mechanisms driving disease processes. We now know that multiple leucocyte subsets, together with inflammatory cytokines, chemokines and regulatory mediators that are normally involved in host protection from invading pathogens, contribute to the inflammatory events leading to tissue destruction and organ failure. In this broad overview, we discuss the main pathways involved in SLE and highlight new findings. We describe the immunological changes that characterize this form of autoimmunity. The major leucocytes that are essential for disease progression are discussed, together with key mediators that propagate the immune response and drive the inflammatory response in SLE. © The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology.

An Inflammation-Centric View of Neurological Disease: Beyond the Neuron

PubMed Central

Skaper, Stephen D.; Facci, Laura; Zusso, Morena; Giusti, Pietro

2018-01-01

Inflammation is a complex biological response fundamental to how the body deals with injury and infection to eliminate the initial cause of cell injury and effect repair. Unlike a normally beneficial acute inflammatory response, chronic inflammation can lead to tissue damage and ultimately its destruction, and often results from an inappropriate immune response. Inflammation in the nervous system (“neuroinflammation”), especially when prolonged, can be particularly injurious. While inflammation per se may not cause disease, it contributes importantly to disease pathogenesis across both the peripheral (neuropathic pain, fibromyalgia) and central [e.g., Alzheimer disease, Parkinson disease, multiple sclerosis, motor neuron disease, ischemia and traumatic brain injury, depression, and autism spectrum disorder] nervous systems. The existence of extensive lines of communication between the nervous system and immune system represents a fundamental principle underlying neuroinflammation. Immune cell-derived inflammatory molecules are critical for regulation of host responses to inflammation. Although these mediators can originate from various non-neuronal cells, important sources in the above neuropathologies appear to be microglia and mast cells, together with astrocytes and possibly also oligodendrocytes. Understanding neuroinflammation also requires an appreciation that non-neuronal cell—cell interactions, between both glia and mast cells and glia themselves, are an integral part of the inflammation process. Within this context the mast cell occupies a key niche in orchestrating the inflammatory process, from initiation to prolongation. This review will describe the current state of knowledge concerning the biology of neuroinflammation, emphasizing mast cell-glia and glia-glia interactions, then conclude with a consideration of how a cell's endogenous mechanisms might be leveraged to provide a therapeutic strategy to target neuroinflammation. PMID:29618972

Research Advances in the Intervention of Inflammation and Cancer by Active Ingredients of Traditional Chinese Medicine.

PubMed

Huang, Yinghong; Cai, Tiange; Xia, Xi; Cai, Y; Wu, Xiao Yu

2016-01-01

A large body of evidence has shown that inflammation and cancer are strongly related. Thus anti-inflammatory agents have been investigated for cancer prevention and treatment in preclinical and clinical studies, including the nonsteroidal anti-inflammatory drugs (NSAIDs) and traditional Chinese medicine (TCM). In TCM, there exist a wide range of biologically active substances, such as saponins, flavonoids, alkaloids, polysaccharides, polyphenols, phenylpropanoids, and quinones. Many of these active ingredients have been reported to inhibit inflammation, activate inflammatory immune response, and/or inhibit cancer cell proliferation and tumor growth. Given the potential role of inflammation in cancer initiation and progression, the inflammatory tumor microenvironment, the cross-talks between inflammatory and cancer cells, and multitargeting activities of some TCM compounds, we summarize the current knowledge on the anti-inflammatory and anti-cancer properties of ingredients of TCM together with their underlying mechanisms in an integrated way. We hope to provide a reliable basis and useful information for the development of new treatment strategies of inflammation and cancer comprehensively using TCM and their active ingredients.

Endogenous anti-inflammatory neuropeptides and pro-resolving lipid mediators: a new therapeutic approach for immune disorders

PubMed Central

Anderson, Per; Delgado, Mario

2008-01-01

Identification of the factors that regulate the immune tolerance and control the appearance of exacerbated inflammatory conditions is crucial for the development of new therapies of inflammatory and autoimmune diseases. Although much is known about the molecular basis of initiating signals and pro-inflammatory chemical mediators in inflammation, it has only recently become apparent that endogenous stop signals are critical at early checkpoints within the temporal events of inflammation. Some neuropeptides and lipid mediators that are produced during the ongoing inflammatory response have emerged as endogenous anti-inflammatory agents that participate in the regulation of the processes that ensure self-tolerance and/or inflammation resolution. Here we examine the latest research findings, which indicate that neuropeptides participate in maintaining immune tolerance in two distinct ways: by regulating the balance between pro-inflammatory and anti-inflammatory factors, and by inducing the emergence of regulatory T cells with suppressive activity against autoreactive T-cell effectors. On the other hand, we also focus on lipid mediators biosynthesized from ω-3 and ω-6 polyunsaturated fatty-acids in inflammatory exudates that promote the resolution phase of acute inflammation by regulating leucocyte influx to and efflux from local inflamed sites. Both anti-inflammatory neuropeptides and pro-resolving lipid mediators have shown therapeutic potential for a variety of inflammatory and autoimmune disorders and could be used as biotemplates for the development of novel pharmacologic agents. PMID:18554314

Impaired Resolution of Inflammation in Alzheimer's Disease: A Review.

PubMed

Whittington, Robert A; Planel, Emmanuel; Terrando, Niccolò

2017-01-01

Alzheimer's disease (AD) remains the leading cause of dementia worldwide, and over the last several decades, the role of inflammation in the pathogenesis of this neurodegenerative disorder has been increasingly elucidated. The initiation of the acute inflammatory response is counterbalanced by an active process termed resolution. This process is designed to restore homeostasis and promote tissue healing by the activation of neutrophilic apoptosis, promotion of neutrophil clearance by macrophages, and increasing anti-inflammatory cytokine levels, while concurrently leading to a diminution in pro-inflammatory mediators. The switch from the initiation to the resolution phase of inflammation is initially characterized by increased production of arachidonic acid-derived pro-resolving lipoxins and decreases in pro-inflammatory prostaglandin and leukotriene levels, subsequently followed by increases in specialized pro-resolving lipid mediators derived from omega-3 fatty acids (ω-3 FAs). There is mounting evidence that in AD, the resolution of inflammation is impaired, resulting in chronic inflammation and the exacerbation of the AD-related pathology. In this review, we examine preclinical and clinical evidence supporting the hypothesis that AD is a neurodegenerative disorder where the impairment or failure of resolution contributes to the disease process. Moreover, we review the literature supporting the potential therapeutic role of ω-3 FAs and specialized pro-resolving lipid mediators in the management of the disease. Lastly, we highlight areas that could strengthen the association of failed resolution to AD and should, therefore, be the focus of future scientific investigations in this research field.

Impaired Resolution of Inflammation in Alzheimer’s Disease: A Review

PubMed Central

Whittington, Robert A.; Planel, Emmanuel; Terrando, Niccolò

2017-01-01

Alzheimer’s disease (AD) remains the leading cause of dementia worldwide, and over the last several decades, the role of inflammation in the pathogenesis of this neurodegenerative disorder has been increasingly elucidated. The initiation of the acute inflammatory response is counterbalanced by an active process termed resolution. This process is designed to restore homeostasis and promote tissue healing by the activation of neutrophilic apoptosis, promotion of neutrophil clearance by macrophages, and increasing anti-inflammatory cytokine levels, while concurrently leading to a diminution in pro-inflammatory mediators. The switch from the initiation to the resolution phase of inflammation is initially characterized by increased production of arachidonic acid-derived pro-resolving lipoxins and decreases in pro-inflammatory prostaglandin and leukotriene levels, subsequently followed by increases in specialized pro-resolving lipid mediators derived from omega-3 fatty acids (ω-3 FAs). There is mounting evidence that in AD, the resolution of inflammation is impaired, resulting in chronic inflammation and the exacerbation of the AD-related pathology. In this review, we examine preclinical and clinical evidence supporting the hypothesis that AD is a neurodegenerative disorder where the impairment or failure of resolution contributes to the disease process. Moreover, we review the literature supporting the potential therapeutic role of ω-3 FAs and specialized pro-resolving lipid mediators in the management of the disease. Lastly, we highlight areas that could strengthen the association of failed resolution to AD and should, therefore, be the focus of future scientific investigations in this research field. PMID:29163531

Adoptively transferred dendritic cells restore primary cell-mediated inflammatory competence to acutely malnourished weanling mice.

PubMed

Hillyer, Lyn; Whitley, Charlene; Olver, Amy; Webster, Michelle; Steevels, Tessa; Woodward, Bill

2008-02-01

Immune depression associated with prepubescent malnutrition underlies a staggering burden of infection-related morbidity. This investigation centered on dendritic cells as potentially decisive in this phenomenon. C57BL/6J mice, initially 19 days old, had free access for 14 days to a complete diet or to a low-protein formulation that induced wasting deficits of protein and energy. Mice were sensitized by i.p. injection of sheep red blood cells on day 9, at which time one-half of the animals in each dietary group received a simultaneous injection of 10(6) syngeneic dendritic cells (JAWS II). All mice were challenged with the immunizing antigen in the right hind footpad on day 13, and the 24-hour delayed hypersensitivity response was assessed as percentage increase in footpad thickness. The low-protein diet reduced the inflammatory immune response, but JAWS cells, which exhibited immature phenotypic and functional characteristics, increased the response of both the malnourished group and the controls. By contrast, i.p. injection of 10(6) syngeneic T cells did not influence the inflammatory immune response of mice subjected to the low-protein protocol. Antigen-presenting cell numbers limited primary inflammatory cell-mediated competence in this model of wasting malnutrition, an outcome that challenges the prevailing multifactorial model of malnutrition-associated immune depression. Thus, a new dendritic cell-centered perspective emerges regarding the cellular mechanism underlying immune depression in acute pediatric protein and energy deficit.

In Vivo High-Content Evaluation of Three-Dimensional Scaffolds Biocompatibility

PubMed Central

Oliveira, Mariana B.; Ribeiro, Maximiano P.; Miguel, Sónia P.; Neto, Ana I.; Coutinho, Paula; Correia, Ilídio J.

2014-01-01

While developing tissue engineering strategies, inflammatory response caused by biomaterials is an unavoidable aspect to be taken into consideration, as it may be an early limiting step of tissue regeneration approaches. We demonstrate the application of flat and flexible films exhibiting patterned high-contrast wettability regions as implantable platforms for the high-content in vivo study of inflammatory response caused by biomaterials. Screening biomaterials by using high-throughput platforms is a powerful method to detect hit spots with promising properties and to exclude uninteresting conditions for targeted applications. High-content analysis of biomaterials has been mostly restricted to in vitro tests where crucial information is lost, as in vivo environment is highly complex. Conventional biomaterials implantation requires the use of high numbers of animals, leading to ethical questions and costly experimentation. Inflammatory response of biomaterials has also been highly neglected in high-throughput studies. We designed an array of 36 combinations of biomaterials based on an initial library of four polysaccharides. Biomaterials were dispensed onto biomimetic superhydrophobic platforms with wettable regions and processed as freeze-dried three-dimensional scaffolds with a high control of the array configuration. These chips were afterward implanted subcutaneously in Wistar rats. Lymphocyte recruitment and activated macrophages were studied on-chip, by performing immunocytochemistry in the miniaturized biomaterials after 24 h and 7 days of implantation. Histological cuts of the surrounding tissue of the implants were also analyzed. Localized and independent inflammatory responses were detected. The integration of these data with control data proved that these chips are robust platforms for the rapid screening of early-stage in vivo biomaterials' response. PMID:24568682

The Therapeutic Potential of Targeting Substance P/NK-1R Interactions in Inflammatory CNS Disorders

PubMed Central

Johnson, M. Brittany; Young, Ada D.; Marriott, Ian

2017-01-01

The inflammatory responses of resident central nervous system (CNS) cells are now known to play a critical role in the initiation and progression of an array of infectious and sterile neuroinflammatory disorders such as meningitis, encephalitis, Parkinson’s disease, Alzheimer’s disease and multiple sclerosis (MS). Regulating glial inflammatory responses in a timely manner is therefore critical in preserving normal CNS functions. The neuropeptide substance P is produced at high levels within the CNS and its selective receptor, the neurokinin 1 receptor (NK-1R), is abundantly expressed by neurons and is present on glial cell types including microglia and astrocytes. In addition to its functions as a neurotransmitter in the perception of pain and its essential role in gut motility, this tachykinin is widely recognized to exacerbate inflammation at peripheral sites including the skin, gastrointestinal tract and the lungs. Recently, a number of studies have identified a role for substance P and NK-1R interactions in neuroinflammation and described the ability of this neuropeptide to alter the immune functions of activated microglia and astrocytes. In this review article, we describe the expression of substance P and its receptor by resident CNS cells, and we discuss the ability of this neuropeptide to exacerbate the inflammatory responses of glia and immune cells that are recruited to the brain during neurodegenerative diseases. In addition, we discuss the available data indicating that the NK-1R-mediated augmentation of such responses appears to be detrimental during microbial infection and some sterile neurodegenerative disorders, and propose the repurposed use of NK-1R antagonists, of a type that are currently approved as anti-emetic and anti-anxiolytic agents, as an adjunct therapy to ameliorate the inflammatory CNS damage in these conditions. PMID:28101005

A parasitic helminth-derived peptide that targets the macrophage lysosome is a novel therapeutic option for autoimmune disease.

PubMed

Alvarado, Raquel; O'Brien, Bronwyn; Tanaka, Akane; Dalton, John P; Donnelly, Sheila

2015-02-01

Parasitic worms (helminths) reside in their mammalian hosts for many years. This is attributable, in part, to their ability to skew the host's immune system away from pro-inflammatory responses and towards anti-inflammatory or regulatory responses. This immune modulatory ability ensures helminth longevity within the host, while simultaneously minimises tissue destruction for the host. The molecules that the parasite releases clearly exert potent immune-modulatory actions, which could be exploited clinically, for example in the prophylactic and therapeutic treatment of pro-inflammatory and autoimmune diseases. We have identified a novel family of immune-modulatory proteins, termed helminth defence molecules (HDMs), which are secreted by several medically important helminth parasites. These HDMs share biochemical and structural characteristics with mammalian cathelicidin-like host defence peptides (HDPs), which are significant components of the innate immune system. Like their mammalian counterparts, parasite HDMs block the activation of macrophages via toll like receptor (TLR) 4 signalling, however HDMs are significantly less cytotoxic than HDPs. HDMs can traverse the cell membrane of macrophages and enter the endolysosomal system where they reduce the acidification of lysosomal compartments by inhibiting vacuolar (v)-ATPase activity. In doing this, HDMs can modulate critical cellular functions, such as cytokine secretion and antigen processing/presentation. Here, we review the role of macrophages, specifically their lysosomal mediated activities, in the initiation and perpetuation of pro-inflammatory immune responses. We also discuss the potential of helminth defence molecules (HDMs) as therapeutics to counteract the pro-inflammatory responses underlying autoimmune disease. Given the current lack of effective, non-cytotoxic treatment options to limit the progression of autoimmune pathologies, HDMs open novel treatment avenues. Crown Copyright © 2014. Published by Elsevier GmbH. All rights reserved.

A state of reversible compensated ventricular dysfunction precedes pathological remodelling in response to cardiomyocyte-specific activity of angiotensin II type-1 receptor in mice.

PubMed

Frentzou, Georgia A; Drinkhill, Mark J; Turner, Neil A; Ball, Stephen G; Ainscough, Justin F X

2015-08-01

Cardiac dysfunction is commonly associated with high-blood-pressure-induced cardiomyocyte hypertrophy, in response to aberrant renin-angiotensin system (RAS) activity. Ensuing pathological remodelling promotes cardiomyocyte death and cardiac fibroblast activation, leading to cardiac fibrosis. The initiating cellular mechanisms that underlie this progressive disease are poorly understood. We previously reported a conditional mouse model in which a human angiotensin II type-I receptor transgene (HART) was expressed in differentiated cardiomyocytes after they had fully matured, but not during development. Twelve-month-old HART mice exhibited ventricular dysfunction and cardiomyocyte hypertrophy with interstitial fibrosis following full receptor stimulation, without affecting blood pressure. Here, we show that chronic HART activity in young adult mice causes ventricular dysfunction without hypertrophy, fibrosis or cardiomyocyte death. Dysfunction correlated with reduced expression of pro-hypertrophy markers and increased expression of pro-angiogenic markers in the cardiomyocytes experiencing increased receptor load. This stimulates responsive changes in closely associated non-myocyte cells, including the downregulation of pro-angiogenic genes, a dampened inflammatory response and upregulation of Tgfβ. Importantly, this state of compensated dysfunction was reversible. Furthermore, increased stimulation of the receptors on the cardiomyocytes caused a switch in the secondary response from the non-myocyte cells. Progressive cardiac remodelling was stimulated through hypertrophy and death of individual cardiomyocytes, with infiltration, proliferation and activation of fibroblast and inflammatory cells, leading to increased angiogenic and inflammatory signalling. Together, these data demonstrate that a state of pre-hypertrophic compensated dysfunction can exist in affected individuals before common markers of heart disease are detectable. The data also suggest that there is an initial response from the housekeeping cells of the heart to signals emanating from distressed neighbouring cardiomyocytes to suppress those changes most commonly associated with progressive heart disease. We suggest that the reversible nature of this state of compensated dysfunction presents an ideal window of opportunity for personalised therapeutic intervention. © 2015. Published by The Company of Biologists Ltd.

Tissue response to intraperitoneal implants of polyethylene oxide-modified polyethylene terephthalate.

PubMed

Desai, N P; Hubbell, J A

1992-01-01

Polyethylene terephthalate films surface modified with polyethylene oxide of mol wt 18,500 g/mol (18.5 k) by a previously described technique, were implanted in the peritoneal cavity of mice, along with their respective untreated controls, for periods of 1-28 d. The implants were retrieved and examined for tissue reactivity and cellular adherence. The control polyethylene terephthalate surfaces showed an initial inflammatory reaction followed by an extensive fibrotic response with a mean thickness of 60 microns at 28 d. By contrast, polyethylene oxide-modified polyethylene terephthalate showed only a mild inflammatory response and no fibrotic encapsulation throughout the implantation period: at 28 d a cellular monolayer was observed. Apparently either the polyethylene oxide-modified surface was stimulating less inflammation, which was in turn stimulating less fibroblastic overgrowth, or the cellular adhesion to the polyethylene oxide-modified surface was too weak to support cellular multilayers.

The potential interactions between polyunsaturated fatty acids and colonic inflammatory processes

PubMed Central

Mills, SC; Windsor, AC; Knight, SC

2005-01-01

n-3 Polyunsaturated fatty acids (PUFAs) are recognized as having an anti-inflammatory effect, which is initiated and propagated via a number of mechanisms involving the cells of the immune system. These include: eicosanoid profiles, membrane fluidity and lipid rafts, signal transduction, gene expression and antigen presentation. The wide-range of mechanisms of action of n-3 PUFAs offer a number of potential therapeutic tools with which to treat inflammatory diseases. In this review we discuss the molecular, animal model and clinical evidence for manipulation of the immune profile by n-3 PUFAs with respect to inflammatory bowel disease. In addition to providing a potential therapy for inflammatory bowel disease there is also recent evidence that abnormalities in fatty acid profiles, both in the plasma phospholipid membrane and in perinodal adipose tissue, may be a key component in the multi-factorial aetiology of inflammatory bowel disease. Such abnormalities are likely to be the result of a genetic susceptibility to the changing ratios of n-3 : n-6 fatty acids in the western diet. Evidence that the fatty acid components of perinodal adipose are fuelling the pro- or anti-inflammatory bias of the immune response is also reviewed. PMID:16232207

FLT1 signaling in metastasis-associated macrophages activates an inflammatory signature that promotes breast cancer metastasis

PubMed Central

Zhang, Hui; Li, Jiufeng; He, Tianfang; Yeo, Eun-Jin; Soong, Daniel Y.H.; Carragher, Neil O.; Munro, Alison; Chang, Alvin; Bresnick, Anne R.; Lang, Richard A.

2015-01-01

Although the link between inflammation and cancer initiation is well established, its role in metastatic diseases, the primary cause of cancer deaths, has been poorly explored. Our previous studies identified a population of metastasis-associated macrophages (MAMs) recruited to the lung that promote tumor cell seeding and growth. Here we show that FMS-like tyrosine kinase 1 (Flt1, also known as VEGFR1) labels a subset of macrophages in human breast cancers that are significantly enriched in metastatic sites. In mouse models of breast cancer pulmonary metastasis, MAMs uniquely express FLT1. Using several genetic models, we show that macrophage FLT1 signaling is critical for metastasis. FLT1 inhibition does not affect MAM recruitment to metastatic lesions but regulates a set of inflammatory response genes, including colony-stimulating factor 1 (CSF1), a central regulator of macrophage biology. Using a gain-of-function approach, we show that CSF1-mediated autocrine signaling in MAMs is downstream of FLT1 and can restore the tumor-promoting activity of FLT1-inhibited MAMs. Thus, CSF1 is epistatic to FLT1, establishing a link between FLT1 and inflammatory responses within breast tumor metastases. Importantly, FLT1 inhibition reduces tumor metastatic efficiency even after initial seeding, suggesting that these pathways represent therapeutic targets in metastatic disease. PMID:26261265

Monitoring tissue inflammation and responses to drug treatments in early stages of mice bone fracture using 50 MHz ultrasound

PubMed Central

Chen, Yen-Chu; Lin, Yi-Hsun; Wang, Shyh-Hau; Lin, Shih-Ping; Shung, K. Kirk; Wu, Chia-Ching

2014-01-01

Bone fracture induces moderate inflammatory responses that are regulated by cyclooxygenase-2 (COX-2) or 5-lipoxygenase (5-LO) for initiating tissue repair and bone formation. Only a handful of non-invasive techniques focus on monitoring acute inflammation of injured bone currently exists. In the current study, we monitored in vivo inflammation levels during the initial 2 weeks of the inflammatory stage after mouse bone fracture utilizing 50 MHz ultrasound. The acquired ultrasonic images were correlated well with histological examinations. After the bone fracture in the tibia, dynamic changes in the soft tissue at the medial-posterior compartment near the fracture site were monitored by ultrasound on the days of 0, 2, 4, 7, and 14. The corresponding echogenicity increased on the 2nd, 4th, and 7th day, and subsequently declined to basal levels after the 14th day. An increase of cell death was identified by the positive staining of deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) assay and was consistent with ultrasound measurements. The increases of both COX-2 and Leukotriene B4 receptor 1 (BLT1, 5- LO-relative receptor), which are regulators for tissue inflammation, in the immunohistochemistry staining revealed their involvement in bone fracture injury. Monitoring the inflammatory response to various non-steroidal anti-inflammatory drugs (NSAIDs) treatments was investigated by treating injured mice with a daily oral intake of aspirin (Asp), indomethacin (IND), and a selective COX-2 inhibitor (SC-236). The Asp treatment significantly reduced fracture-increased echogenicity (hyperechogenicity, p < 0.05) in ultrasound images as well as inhibited cell death, and expression of COX-2 and BLT1. In contrast, treatment with IND or SC-236 did not reduce the hyperechogenicity, as confirmed by cell death (TUNEL) and expression levels of COX-2 or BLT1. Taken together, the current study reports the feasibility of a noninvasive ultrasound method capable of monitoring post-fracture tissue inflammation that positively correlates with histological findings. Results of this study also suggest that this approach may be further applied to elucidate the underlying mechanisms of inflammatory processes and to develop therapeutic strategies for facilitating fracture healing. PMID:23871514

Evidence of the impact of systemic inflammation on neuroinflammation from a non-bacterial endotoxin animal model.

PubMed

Huang, Chunxia; Irwin, Michael Garnet; Wong, Gordon Tin Chun; Chang, Raymond Chuen Chung

2018-05-17

Systemic inflammation induces neuroinflammation and cellular changes such as tau phosphorylation to impair cognitive function, including learning and memory. This study uses a single model, laparotomy without any pathogen, to characterize these changes and their responses to anti-inflammatory treatment in the intermediate term. In a two-part experiment, wild-type C57BL/6N mice (male, 3 month old, 25 ± 2 g) were subjected to sevoflurane anesthesia alone or to a laparotomy. Cognitive performance, systemic and neuroinflammatory responses, and tau phosphorylation were evaluated on postoperative days (POD) 1, 3, and 14. The effect of perioperative ibuprofen intervention (60 mg/kg) on these changes was then assessed. Mice in the laparotomy group displayed memory impairment up to POD 14 with initial high levels of inflammatory cytokines in the liver, frontal cortex (IL-1β, IL-6, and TNF-α), and hippocampus (IL-1β and IL-8). On POD 14, although most circulating and resident cytokine levels returned to normal, a significant number of microglia and astrocytes remained activated in the frontal cortex and microglia in the hippocampus, as well as abnormal tau phosphorylation in these two brain regions. Perioperative ibuprofen improved cognitive performance, attenuated systemic inflammation and glial activation, and suppressed the abnormal tau phosphorylation both in the frontal cortex and hippocampus. Our results suggest that (1) cognitive dysfunction is associated with an unbalanced pro-inflammatory and anti-inflammatory response, tauopathy, and gliosis; (2) cognitive dysfunction, gliosis, and tauopathy following laparotomy can persist well beyond the immediate postoperative period; and (3) anti-inflammatory drugs can act rapidly to attenuate inflammatory responses in the brain and negatively modulate neuropathological changes to improve cognition. These findings may have implications for the duration of therapeutic strategies aimed at curtaining cognitive dysfunction following surgery.

Essential oil of Artemisia argyi suppresses inflammatory responses by inhibiting JAK/STATs activation.

PubMed

Chen, Lin-Lin; Zhang, Hao-Jun; Chao, Jung; Liu, Jun-Feng

2017-05-23

Artemisia argyi is a herbal medicine traditionally used in Asia for the treatment of bronchitis, dermatitis and arthritis. Recent studies revealed the anti-inflammatory effect of essential oil in this plant. However, the mechanisms underlying the therapeutic potential have not been well elucidated. The present study is aimed to verify its anti-inflammatory effect and investigate the probable mechanisms. The essential oil from Artemisia argyi (AAEO) was initially tested against LPS-induced production of inflammatory mediators and cytokines in RAW264.7 macrophages. Protein and mRNA expressions of iNOS and COX-2 were determined by Western blotting and RT-PCR analysis, respectively. The effects on the activation of MAPK/NF-κB/AP-1 and JAK/STATs pathway were also investigated by western blot. Meanwhile, in vivo anti-inflammatory effect was examined by histologic and immunohistochemical analysis in TPA-induced mouse ear edema model. The results of in vitro experiments showed that AAEO dose-dependently suppressed the release of pro-inflammatory mediators (NO, PGE 2 and ROS) and cytokines (TNF-α, IL-6, IFN-β and MCP-1) in LPS-induced RAW264.7 macrophages. It down-regulated iNOS and COX-2 protein and mRNA expression but did not affect the activity of these two enzymes. AAEO significantly inhibited the phosphorylation of JAK2 and STAT1/3, but not the activation of MAPK and NF-κB cascades. In animal model, oral administration of AAEO significantly attenuated TPA-induced mouse ear edema and decreased the protein level of COX-2. AAEO suppresses inflammatory responses via down-regulation of the JAK/STATs signaling and ROS scavenging, which could contribute, at least in part, to the anti-inflammatory effect of AAEO. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

Pain intensity and duration can be enhanced by prior challenge: Initial evidence suggestive of a role of microglial priming

PubMed Central

Hains, Leah E.; Loram, Lisa C.; Weiseler, Julie L.; Frank, Matthew G.; Bloss, Erik B.; Sholar, Paige; Taylor, Frederick R; Harrison, Jacqueline A; Martin, Thomas J.; Eisenach, James C.; Maier, Steven F.; Watkins, Linda R.

2010-01-01

Activation of spinal microglia and consequent release of pro-inflammatory mediators facilitate pain. Under certain conditions, responses of activated microglia can become enhanced. Enhanced microglial production of pro-inflammatory products may result from priming (sensitization), similar to macrophage priming. We hypothesized that if spinal microglia were primed by an initial inflammatory challenge, subsequent challenges may create enhanced pain. Here, we used a "two-hit" paradigm using two successive challenges, which affect overlapping populations of spinal microglia, presented two weeks apart. Mechanical allodynia and/or activation of spinal glia were assessed. Initially, laparotomy preceded systemic lipopolysaccharide (LPS). Prior laparotomy caused prolonged microglial (not astrocyte) activation plus enhanced LPS-induced allodynia. In this “two-hit” paradigm, minocycline, a microglial activation inhibitor, significantly reduced later exaggerated pain induced by prior surgery when minocycline was administered intrathecally for 5 days starting either at the time of surgery or 5 days before LPS administration. To test generality of the priming effect, subcutaneous formalin preceded intrathecal HIV-1 gp120, which activates spinal microglia and causes robust allodynia. Prior formalin enhanced intrathecal gp120-induced allodynia, suggesting that microglial priming is not limited to laparotomy and again supporting a spinal site of action. Therefore, spinal microglial priming may increase vulnerability to pain enhancement. PMID:20434956

Host epithelial-viral interactions as cause and cure for asthma.

PubMed

Holtzman, Michael J; Patel, Dhara A; Zhang, Yong; Patel, Anand C

2011-08-01

Research on the pathogenesis of asthma has concentrated on initial stimuli, genetic susceptibilities, adaptive immune responses, and end-organ alterations (particularly in airway mucous cells and smooth muscle) as critical steps leading to disease. Recent evidence indicates that the innate immune cell response to respiratory viruses also contributes to the development of inflammatory airway disease. We further develop this concept by raising the issue that the interaction between host airway epithelial cells and respiratory viruses is another aspect of innate immunity that is also a critical determinant of asthma. We also introduce a rationale for how antiviral performance at the epithelial cell level might be improved to prevent acute infectious illness and chronic inflammatory disease caused by respiratory viruses. Copyright © 2011 Elsevier Ltd. All rights reserved.

Endothelial cells: From innocent bystanders to active participants in immune responses.

PubMed

Al-Soudi, A; Kaaij, M H; Tas, S W

2017-09-01

The endothelium is crucially important for the delivery of oxygen and nutrients throughout the body under homeostatic conditions. However, it also contributes to pathology, including the initiation and perpetuation of inflammation. Understanding the function of endothelial cells (ECs) in inflammatory diseases and molecular mechanisms involved may lead to novel approaches to dampen inflammation and restore homeostasis. In this article, we discuss the various functions of ECs in inflammation with a focus on pathological angiogenesis, attraction of immune cells, antigen presentation, immunoregulatory properties and endothelial-to-mesenchymal transition (EndMT). We also review the current literature on approaches to target these processes in ECs to modulate immune responses and advance anti-inflammatory therapies. Copyright © 2017 The Author(s). Published by Elsevier B.V. All rights reserved.

Nuclear DNA damage-triggered NLRP3 inflammasome activation promotes UVB-induced inflammatory responses in human keratinocytes

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

Hasegawa, Tatsuya, E-mail: tatsuya.hasegawa@to.shiseido.co.jp; Nakashima, Masaya; Suzuki, Yoshiharu

Ultraviolet (UV) radiation in sunlight can result in DNA damage and an inflammatory reaction of the skin commonly known as sunburn, which in turn can lead to cutaneous tissue disorders. However, little has been known about how UV-induced DNA damage mediates the release of inflammatory mediators from keratinocytes. Here, we show that UVB radiation intensity-dependently increases NLRP3 gene expression and IL-1β production in human keratinocytes. Knockdown of NLRP3 with siRNA suppresses UVB-induced production of not only IL-1β, but also other inflammatory mediators, including IL-1α, IL-6, TNF-α, and PGE{sub 2}. In addition, inhibition of DNA damage repair by knockdown of XPA,more » which is a major component of the nucleotide excision repair system, causes accumulation of cyclobutane pyrimidine dimer (CPD) and activation of NLRP3 inflammasome. In vivo immunofluorescence analysis confirmed that NLRP3 expression is also elevated in UV-irradiated human epidermis. Overall, our findings indicate that UVB-induced DNA damage initiates NLRP3 inflammasome activation, leading to release of various inflammatory mediators from human keratinocytes. - Highlights: • UVB radiation induces NLRP3 inflammasome activation in human keratinocytes. • NLRP3 knockdown suppresses production of UVB-induced inflammatory mediators. • UVB-induced DNA damage triggers NLRP3 inflammasome activation. • NLRP3 expression in human epidermis is elevated in response to UV radiation.« less

Time-dependent LXR/RXR pathway modulation characterizes capillary remodeling in inflammatory corneal neovascularization.

PubMed

Mukwaya, Anthony; Lennikov, Anton; Xeroudaki, Maria; Mirabelli, Pierfrancesco; Lachota, Mieszko; Jensen, Lasse; Peebo, Beatrice; Lagali, Neil

2018-05-01

Inflammation in the normally immune-privileged cornea can initiate a pathologic angiogenic response causing vision-threatening corneal neovascularization. Inflammatory pathways, however, are numerous, complex and are activated in a time-dependent manner. Effective resolution of inflammation and associated angiogenesis in the cornea requires knowledge of these pathways and their time dependence, which has, to date, remained largely unexplored. Here, using a model of endogenous resolution of inflammation-induced corneal angiogenesis, we investigate the time dependence of inflammatory genes in effecting capillary regression and the return of corneal transparency. Endogenous capillary regression was characterized by a progressive thinning and remodeling of angiogenic capillaries and inflammatory cell retreat in vivo in the rat cornea. By whole-genome longitudinal microarray analysis, early suppression of VEGF ligand-receptor signaling and inflammatory pathways preceded an unexpected later-phase preferential activation of LXR/RXR, PPARα/RXRα and STAT3 canonical pathways, with a concurrent attenuation of LPS/IL-1 inhibition of RXR function and Wnt/β-catenin signaling pathways. Potent downstream inflammatory cytokines such as Cxcl5, IL-1β, IL-6 and Ccl2 were concomitantly downregulated during the remodeling phase. Upstream regulators of the inflammatory pathways included Socs3, Sparc and ApoE. A complex and coordinated time-dependent interplay between pro- and anti-inflammatory signaling pathways highlights a potential anti-inflammatory role of LXR/RXR, PPARα/RXRα and STAT3 signaling pathways in resolving inflammatory corneal angiogenesis.

Systems-wide analyses of mucosal immune responses to Helicobacter pylori at the interface between pathogenicity and symbiosis

PubMed Central

Kronsteiner, Barbara; Bassaganya-Riera, Josep; Philipson, Casandra; Viladomiu, Monica; Carbo, Adria; Abedi, Vida; Hontecillas, Raquel

2016-01-01

Abstract Helicobacter pylori is the dominant member of the gastric microbiota in over half of the human population of which 5–15% develop gastritis or gastric malignancies. Immune responses to H. pylori are characterized by mixed T helper cell, cytotoxic T cell and NK cell responses. The presence of Tregs is essential for the control of gastritis and together with regulatory CX3CR1+ mononuclear phagocytes and immune-evasion strategies they enable life-long persistence of H. pylori. This H. pylori-induced regulatory environment might contribute to its cross-protective effect in inflammatory bowel disease and obesity. Here we review host-microbe interactions, the development of pro- and anti-inflammatory immune responses and how the latter contribute to H. pylori's role as beneficial member of the gut microbiota. Furthermore, we present the integration of existing and new data into a computational/mathematical model and its use for the investigation of immunological mechanisms underlying initiation, progression and outcomes of H. pylori infection. PMID:26939848

Innate and adaptive immune responses to cell death

PubMed Central

Rock, Kenneth L.; Lai, Jiann-Jyh; Kono, Hajime

2011-01-01

Summary The immune system plays an essential role in protecting the host against infections and to accomplish this task has evolved mechanisms to recognize microbes and destroy them. In addition, it monitors the health of cells and responds to ones that have been injured and die, even if this occurs under sterile conditions. This process is initiated when dying cells expose intracellular molecules that can be recognized by cells of the innate immune system. As a consequence of this recognition, dendritic cells are activated in ways that help to promote T-cell responses to antigens associated with the dying cells. In addition, macrophages are stimulated to produce the cytokine interleukin-1 that then acts on radioresistant parenchymal cells in the host in ways that drive a robust inflammatory response. In addition to dead cells, a number of other sterile particles and altered physiological states can similarly stimulate an inflammatory response and do so through common pathways involving the inflammasome and interleukin-1. These pathways underlie the pathogenesis of a number of diseases. PMID:21884177

Transient inflammatory response mediated by interleukin-1β is required for proper regeneration in zebrafish fin fold

PubMed Central

Hasegawa, Tomoya; Hall, Christopher J; Crosier, Philip S; Abe, Gembu; Kawakami, Koichi; Kudo, Akira; Kawakami, Atsushi

2017-01-01

Cellular responses to injury are crucial for complete tissue regeneration, but their underlying processes remain incompletely elucidated. We have previously reported that myeloid-defective zebrafish mutants display apoptosis of regenerative cells during fin fold regeneration. Here, we found that the apoptosis phenotype is induced by prolonged expression of interleukin 1 beta (il1b). Myeloid cells are considered to be the principal source of Il1b, but we show that epithelial cells express il1b in response to tissue injury and initiate the inflammatory response, and that its resolution by macrophages is necessary for survival of regenerative cells. We further show that Il1b plays an essential role in normal fin fold regeneration by regulating expression of regeneration-induced genes. Our study reveals that proper levels of Il1b signaling and tissue inflammation, which are tuned by macrophages, play a crucial role in tissue regeneration. DOI: http://dx.doi.org/10.7554/eLife.22716.001 PMID:28229859

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)

The Role of TLR and Chemokine in Wear Particle-Induced Aseptic Loosening

PubMed Central

Gu, Qiaoli; Shi, Qin; Yang, Huilin

2012-01-01

Wear particle-induced periprosthetic osteolysis remains the principal cause of aseptic loosening of orthopaedic implants. Monocytes/macrophages phagocytose wear particles and release cytokines that induce inflammatory response. This response promotes osteoclast differentiation and osteolysis. The precise mechanisms by which wear particles are recognized and induce the accumulation of inflammatory cells in the periprosthetic tissue have not been fully elucidated. Recent studies have shown that toll-like receptors (TLRs) contribute to the cellular interaction with wear particles. Wear particles are recognized by monocytes/macrophages through TLRs coupled with the adaptor protein MyD88. After the initial interaction, wear particles induce both local and systemic migration of monocytes/macrophages to the periprosthetic region. The cellular migration is mediated through chemokines including interleukin-8, macrophage chemotactic protein-1, and macrophage inhibitory protein-1 in the periprosthetic tissues. Interfering with chemokine-receptor axis can inhibit cellular migration and inflammatory response. This paper highlights recent advances in TLR, and chemokine participated in the pathogenesis of aseptic loosening. A comprehensive understanding of the recognition and migration mechanism is critical to the development of measures that prevent wear particle-induced aseptic loosening of orthopaedic implants. PMID:23193363

Sintered indium-tin oxide particles induce pro-inflammatory responses in vitro, in part through inflammasome activation.

PubMed

Badding, Melissa A; Schwegler-Berry, Diane; Park, Ju-Hyeong; Fix, Natalie R; Cummings, Kristin J; Leonard, Stephen S

2015-01-01

Indium-tin oxide (ITO) is used to make transparent conductive coatings for touch-screen and liquid crystal display electronics. As the demand for consumer electronics continues to increase, so does the concern for occupational exposures to particles containing these potentially toxic metal oxides. Indium-containing particles have been shown to be cytotoxic in cultured cells and pro-inflammatory in pulmonary animal models. In humans, pulmonary alveolar proteinosis and fibrotic interstitial lung disease have been observed in ITO facility workers. However, which ITO production materials may be the most toxic to workers and how they initiate pulmonary inflammation remain poorly understood. Here we examined four different particle samples collected from an ITO production facility for their ability to induce pro-inflammatory responses in vitro. Tin oxide, sintered ITO (SITO), and ventilation dust particles activated nuclear factor kappa B (NFκB) within 3 h of treatment. However, only SITO induced robust cytokine production (IL-1β, IL-6, TNFα, and IL-8) within 24 h in both RAW 264.7 mouse macrophages and BEAS-2B human bronchial epithelial cells. Our lab and others have previously demonstrated SITO-induced cytotoxicity as well. These findings suggest that SITO particles activate the NLRP3 inflammasome, which has been implicated in several immune-mediated diseases via its ability to induce IL-1β release and cause subsequent cell death. Inflammasome activation by SITO was confirmed, but it required the presence of endotoxin. Further, a phagocytosis assay revealed that pre-uptake of SITO or ventilation dust impaired proper macrophage phagocytosis of E. coli. Our results suggest that adverse inflammatory responses to SITO particles by both macrophage and epithelial cells may initiate and propagate indium lung disease. These findings will provide a better understanding of the molecular mechanisms behind an emerging occupational health issue.

Curcumin attenuates inflammatory response in IL-1beta-induced human synovial fibroblasts and collagen-induced arthritis in mouse model.

PubMed

Moon, Dong-Oh; Kim, Mun-Ok; Choi, Yung Hyun; Park, Yung-Min; Kim, Gi-Young

2010-05-01

Curcumin, a major component of turmeric, has been shown to exhibit anti-oxidant and anti-inflammatory activities. The present study was performed to determine whether curcumin is efficacious against both collagen-induced arthritis (CIA) in mice and IL-1beta-induced activation in fibroblast-like synoviocytes (FLSs). DBA/1 mice were immunized with bovine type II collagen (CII) and treated with curcumin every other day for 2weeks after the initial immunization. For arthritis, we evaluated the incidence of disease and used an arthritis index based on paw thickness. In vitro proliferation of CII- or concanavalin A-induced splenic T cells was examined using IFN-gamma production. Pro-inflammatory cytokines TNF-alpha and IL-1beta were examined in the mouse ankle joint and serum IgG1 and IgG2a isotypes were analyzed. The expression levels of prostaglandin E(2) (PGE(2)), cyclooxygenase-2 (COX-2), and matrix metalloproteinases (MMPs) in human FLSs were also determined. The results showed that compared with untreated CIA mice, curcumin-treated mice downregulated clinical arthritis score, the proliferation of splenic T cells, expression levels of TNF-alpha and IL-1beta in the ankle joint, and expression levels of IgG2a in serum. Additionally, by altering nuclear factor (NF)-kappaB transcription activity in FLSs, curcumin inhibited PGE(2) production, COX-2 expression, and MMP secretion. These results suggest that curcumin can effectively suppress inflammatory response by inhibiting pro-inflammatory mediators and regulating humoral and cellular immune responses. Copyright 2010 Elsevier B.V. All rights reserved.

Animal model of respiratory syncytial virus: CD8+ T cells cause a cytokine storm that is chemically tractable by sphingosine-1-phosphate 1 receptor agonist therapy.

PubMed

Walsh, Kevin B; Teijaro, John R; Brock, Linda G; Fremgen, Daniel M; Collins, Peter L; Rosen, Hugh; Oldstone, Michael B A

2014-06-01

The cytokine storm is an intensified, dysregulated, tissue-injurious inflammatory response driven by cytokine and immune cell components. The cytokine storm during influenza virus infection, whereby the amplified innate immune response is primarily responsible for pulmonary damage, has been well characterized. Now we describe a novel event where virus-specific T cells induce a cytokine storm. The paramyxovirus pneumonia virus of mice (PVM) is a model of human respiratory syncytial virus (hRSV). Unexpectedly, when C57BL/6 mice were infected with PVM, the innate inflammatory response was undetectable until day 5 postinfection, at which time CD8(+) T cells infiltrated into the lung, initiating a cytokine storm by their production of gamma interferon (IFN-γ) and tumor necrosis factor alpha (TNF-α). Administration of an immunomodulatory sphingosine-1-phosphate (S1P) receptor 1 (S1P1R) agonist significantly inhibited PVM-elicited cytokine storm by blunting the PVM-specific CD8(+) T cell response, resulting in diminished pulmonary disease and enhanced survival. A dysregulated overly exuberant immune response, termed a "cytokine storm," accompanies virus-induced acute respiratory diseases (VARV), is primarily responsible for the accompanying high morbidity and mortality, and can be controlled therapeutically in influenza virus infection of mice and ferrets by administration of sphingosine-1-phosphate 1 receptor (S1P1R) agonists. Here, two novel findings are recorded. First, in contrast to influenza infection, where the cytokine storm is initiated early by the innate immune system, for pneumonia virus of mice (PVM), a model of RSV, the cytokine storm is initiated late in infection by the adaptive immune response: specifically, by virus-specific CD8 T cells via their release of IFN-γ and TNF-α. Blockading these cytokines with neutralizing antibodies blunts the cytokine storm and protects the host. Second, PVM infection is controlled by administration of an S1P1R agonist.

KH-type splicing regulatory protein is regulated by nuclear factor-κB signaling to mediate innate immunity in Caco-2 cells infected by Salmonella enteritidis.

PubMed

Nie, Yuanyang; Cao, Mei; Wu, Daoyan; Li, Ningzhe; Peng, Jingshan; Yi, Sijun; Yang, Xiaofan; Zhang, Mao; Hu, Guoku; Zhao, Jian

2018-05-04

Salmonella enteritidis infection occurs in enterogenous diseases, such as gastroenteritis and parenteral focal infection, which often involve inflammation of intestinal epithelial cells. The nuclear factor kappa B (NF-κB) pathway participates in the innate immune response to many gram-negative pathogenic bacteria and initiates inflammation in epithelial cells. KH-type splicing regulatory protein (KSRP) is a multi-domain RNA-binding protein that recruits the exosome-containing mRNA degradation complex to mRNAs coding for inflammatory response factors. However, it remains unclear whether KSRP is regulated by NF-κB signaling pathway in response to S. enteritidis infection and affects the development of inflammation. Accordingly, in this study, we investigated the role of KSRP in mediating the response to S. enteritidis in Caco-2 cells. The data revealed that S. enteritidis infection decreased KSRP expression, which was suppressed by blocking the NF-κB pathway. Additionally, S. enteritidis infection significantly increased the expression of inducible nitric oxide synthase and cyclooxygenase-2. Overexpression of KSRP reduced the expression levels of inflammatory factors in Caco-2 cells. KSRP was regulated by the NF-κB signaling pathway and participated in mediating the innate immune response to S. enteritidis infection in Caco-2 cells, and KSRP acted as a negative regulator of inflammatory gene expression.

Time Courses of Inflammatory Markers after Aneurysmal Subarachnoid Hemorrhage and Their Possible Relevance for Future Studies.

PubMed

Höllig, Anke; Stoffel-Wagner, Birgit; Clusmann, Hans; Veldeman, Michael; Schubert, Gerrit A; Coburn, Mark

2017-01-01

Aneurysmal subarachnoid hemorrhage triggers an intense inflammatory response, which is suspected to increase the risk for secondary complications such as delayed cerebral ischemia (DCI). However, to date, the monitoring of the inflammatory response to detect secondary complications such as DCI has not become part of the clinical routine diagnostic. Here, we aim to illustrate the time courses of inflammatory parameters after aneurysmal subarachnoid hemorrhage (aSAH) and discuss the problems of inflammatory parameters as biomarkers but also their possible relevance for deeper understanding of the pathophysiology after aSAH and sophisticated planning of future studies. In this prospective cohort study, 109 patients with aSAH were initially included, n  = 28 patients had to be excluded. Serum and-if possible-cerebral spinal fluid samples ( n  = 48) were retrieved at days 1, 4, 7, 10, and 14 after aSAH. Samples were analyzed for leukocyte count and C-reactive protein (CRP) (serum samples only) as well as matrix metallopeptidase 9 (MMP9), intercellular adhesion molecule 1 (ICAM1), and leukemia inhibitory factor (LIF) [both serum and cerebrospinal fluid (CSF) samples]. Time courses of the inflammatory parameters were displayed and related to the occurrence of DCI. We illustrate the time courses of leukocyte count, CRP, MMP9, ICAM1, and LIF in patients' serum samples from the first until the 14th day after aSAH. Time courses of MMP9, ICAM1, and LIF in CSF samples are demonstrated. Furthermore, no significant difference was shown relating the time courses to the occurrence of DCI. We estimate that the wide range of the measured values hampers their interpretation and usage as a biomarker. However, understanding the inflammatory response after aSAH and generating a multicenter database may facilitate further studies: realistic sample size calculations on the basis of a multicenter database will increase the quality and clinical relevance of the acquired results.

Counterregulation between thymic stromal lymphopoietin- and IL-23-driven immune axes shapes skin inflammation in mice with epidermal barrier defects.

PubMed

Li, Jiagui; Leyva-Castillo, Juan Manuel; Hener, Pierre; Eisenmann, Aurelie; Zaafouri, Sarra; Jonca, Nathalie; Serre, Guy; Birling, Marie-Christine; Li, Mei

2016-07-01

Epidermal barrier dysfunction has been recognized as a critical factor in the initiation and exacerbation of skin inflammation, particularly in patients with atopic dermatitis (AD) and AD-like congenital disorders, including peeling skin syndrome type B. However, inflammatory responses developed in barrier-defective skin, as well as the underlying mechanisms, remained incompletely understood. We aimed to decipher inflammatory axes and the cytokine network in mouse skin on breakdown of epidermal stratum corneum barrier. We generated Cdsn(iep-/-) mice with corneodesmosin ablation in keratinocytes selectively in an inducible manner. We characterized inflammatory responses and cytokine expression by using histology, immunohistochemistry, ELISA, and quantitative PCR. We combined mouse genetic tools, antibody-mediated neutralization, signal-blocking reagents, and topical antibiotic treatment to explore the inflammatory axes. We show that on breakdown of the epidermal stratum corneum barrier, type 2 and type 17 inflammatory responses are developed simultaneously, driven by thymic stromal lymphopoietin (TSLP) and IL-23, respectively. Importantly, we reveal a counterregulation between these 2 inflammatory axes. Furthermore, we show that protease-activated receptor 2 signaling is involved in mediating the TSLP/type 2 axis, whereas skin bacteria are engaged in induction of the IL-23/type 17 axis. Moreover, we find that IL-1β is induced in skin of Cdsn(iep-/-) mice and that blockade of IL-1 signaling suppresses both TSLP and IL-23 expression and ameliorates skin inflammation. The inflammatory phenotype in barrier-defective skin is shaped by counterregulation between the TSLP/type 2 and IL-23/type 17 axes. Targeting IL-1 signaling could be a promising therapeutic option for controlling skin inflammation in patients with peeling skin syndrome type B and other diseases related to epidermal barrier dysfunction, including AD. Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Polysaccharide peptides from COV-1 strain of Coriolus versicolor induce hyperalgesia via inflammatory mediator release in the mouse.

PubMed

Chan, Siu-Lung; Yeung, John H K

2006-04-18

Polysaccharide peptide (PSP), isolated from Coriolus versicolor COV-1, has been widely used as an adjunct to cancer chemotherapy and as an immuno-stimulator in China. In this study, the anti-nociceptive effects of PSP were investigated in two different pain models in the mouse. In the acetic acid-induced writhing model, initial studies showed that PSP decreased the number of acetic acid-induced writhing by 92.9%, which, by definition, would constitute an analgesic effect. However, further studies showed that PSP itself induced a dose-dependent writhing response. Studies on inflammatory mediator release showed that PSP increased the release of prostaglandin E2, tumor necrosis factor-alpha, interleukin-1beta, and histamine in mouse peritoneal macrophages and mast cells both in vitro and in vivo. The role of inflammatory mediator release in PSP-induced writhing was confirmed when diclofenac and dexamethasone decreased the number of writhing responses by 54% and 58.5%, respectively. Diphenhydramine totally inhibited the PSP-induced writhing. In the hot-plate test, PSP dose-dependently shortened the hind paw withdrawal latency, indicative of a hyperalgesic effect. The hyperalgesic effect was reduced by pretreatment with the anti-inflammatory drugs. In conclusion, the PSP-induced hyperalgesia was related to activation of peritoneal resident cells and an increase in the release of inflammatory mediators.

Mitochondrial reactive oxygen species mediate the lipopolysaccharide-induced pro-inflammatory response in human gingival fibroblasts

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

Li, Xue; Wang, Xiaoxuan; Zheng, Ming, E-mail: zhengm@bjmu.edu.cn

Although periodontal diseases are initiated by bacteria that colonize the tooth surface and gingival sulcus, the host response is believed to play an essential role in the breakdown of connective tissue and bone. Mitochondrial reactive oxygen species (mtROS) have been proposed to regulate the activation of the inflammatory response by the innate immune system. However, the role of mtROS in modulating the response of human gingival fibroblasts (HGFs) to immune stimulation by lipopolysaccharides (LPS) has yet to be fully elucidated. Here, we showed that LPS from Porphyromonas gingivalis stimulated HGFs to increase mtROS production, which could be inhibited by treatmentmore » with a mitochondrial-targeted exogenous antioxidant (mito-TEMPO) or transfection with manganese superoxide dismutase (MnSOD). A time-course study revealed that an increase in the concentration of mtROS preceded the expression of inflammatory cytokines in HGFs. Mito-TEMPO treatment or MnSOD transfection also significantly prevented the LPS-induced increase of interleukin (IL)-1β, IL-6, and tumor necrosis factor-α. Furthermore, suppressing LPS-induced mtROS generation inhibited the activation of p38, c-Jun N-terminal kinase, and inhibitor of nuclear factor-κB kinase, as well as the nuclear localization of nuclear factor-κB. These results demonstrate that mtROS generation is a key signaling event in the LPS-induced pro-inflammatory response of HGFs. - Highlights: • Inflammation is thought to promote pathogenic changes in periodontitis. • We investigated mtROS as a regulator of inflammation in gingival fibroblasts. • Targeted antioxidants were used to inhibit mtROS production after LPS challenge. • Inhibiting mtROS generation suppressed the secretion of pro-inflammatory cytokines. • JNK, p38, IKK, and NF-κB were shown to act as transducers of mtROS signaling.« less

Transcriptomic responses to wounding: meta-analysis of gene expression microarray data.

PubMed

Sass, Piotr Andrzej; Dąbrowski, Michał; Charzyńska, Agata; Sachadyn, Paweł

2017-11-07

A vast amount of microarray data on transcriptomic response to injury has been collected so far. We designed the analysis in order to identify the genes displaying significant changes in expression after wounding in different organisms and tissues. This meta-analysis is the first study to compare gene expression profiles in response to wounding in as different tissues as heart, liver, skin, bones, and spinal cord, and species, including rat, mouse and human. We collected available microarray transcriptomic profiles obtained from different tissue injury experiments and selected the genes showing a minimum twofold change in expression in response to wounding in prevailing number of experiments for each of five wound healing stages we distinguished: haemostasis & early inflammation, inflammation, early repair, late repair and remodelling. During the initial phases after wounding, haemostasis & early inflammation and inflammation, the transcriptomic responses showed little consistency between different tissues and experiments. For the later phases, wound repair and remodelling, we identified a number of genes displaying similar transcriptional responses in all examined tissues. As revealed by ontological analyses, activation of certain pathways was rather specific for selected phases of wound healing, such as e.g. responses to vitamin D pronounced during inflammation. Conversely, we observed induction of genes encoding inflammatory agents and extracellular matrix proteins in all wound healing phases. Further, we selected several genes differentially upregulated throughout different stages of wound response, including established factors of wound healing in addition to those previously unreported  in this context such as PTPRC and AQP4. We found that transcriptomic responses to wounding showed similar traits in a diverse selection of tissues including skin, muscles, internal organs and nervous system. Notably, we distinguished transcriptional induction of inflammatory genes not only in the initial response to wounding, but also later, during wound repair and tissue remodelling.

Ultrafine particles from diesel vehicle emissions at different driving cycles induce differential vascular pro-inflammatory responses: Implication of chemical components and NF-κB signaling

PubMed Central

2010-01-01

Background Epidemiological evidence supports the association between exposure to ambient particulate matter (PM) and cardiovascular diseases. Chronic exposure to ultrafine particles (UFP; Dp <100 nm) is reported to promote atherosclerosis in ApoE knockout mice. Atherogenesis-prone factors induce endothelial dysfunction that contributes to the initiation and progression of atherosclerosis. We previously demonstrated that UFP induced oxidative stress via c-Jun N-terminal Kinases (JNK) activation in endothelial cells. In this study, we investigated pro-inflammatory responses of human aortic endothelial cells (HAEC) exposed to UFP emitted from a diesel truck under an idling mode (UFP1) and an urban dynamometer driving schedule (UFP2), respectively. We hypothesize that UFP1 and UFP2 with distinct chemical compositions induce differential pro-inflammatory responses in endothelial cells. Results UFP2 contained a higher level of redox active organic compounds and metals on a per PM mass basis than UFP1. While both UFP1 and UFP2 induced superoxide production and up-regulated stress response genes such as heme oxygenease-1 (HO-1), OKL38, and tissue factor (TF), only UFP2 induced the expression of pro-inflammatory genes such as IL-8 (2.8 ± 0.3-fold), MCP-1 (3.9 ± 0.4-fold), and VCAM (6.5 ± 1.1-fold) (n = 3, P < 0.05). UFP2-exposed HAEC also bound to a higher number of monocytes than UFP1-exposed HAEC (Control = 70 ± 7.5, UFP1 = 106.7 ± 12.5, UFP2 = 137.0 ± 8.0, n = 3, P < 0.05). Adenovirus NF-κB Luciferase reporter assays revealed that UFP2, but not UFP1, significantly induced NF-κB activities. NF-κB inhibitor, CAY10512, significantly abrogated UFP2-induced pro-inflammatory gene expression and monocyte binding. Conclusion While UFP1 induced higher level of oxidative stress and stress response gene expression, only UFP2, with higher levels of redox active organic compounds and metals, induced pro-inflammatory responses via NF-κB signaling. Thus, UFP with distinct chemical compositions caused differential response patterns in endothelial cells. PMID:20307321

Pharmacogenetics of steroid-responsive acute graft-versus-host disease.

PubMed

Arora, Mukta; Weisdorf, Daniel J; Shanley, Ryan M; Thyagarajan, Bharat

2017-05-01

Glucocorticoids are central to effective therapy of acute graft-versus-host disease (GVHD). However, only about half of the patients respond to steroids in initial therapy. Based on postulated mechanisms for anti-inflammatory effectiveness, we explored genetic variations in glucocorticoid receptor, co-chaperone proteins, membrane transporters, inflammatory mediators, and variants in the T-cell receptor complex in hematopoietic cell transplant recipients with acute GVHD requiring treatment with steroids and their donors toward response at day 28 after initiation of therapy. A total of 300 recipient and donor samples were analyzed. Twenty-three SNPs in 17 genes affecting glucocorticoid pathways were included in the analysis. In multiple regression analysis, donor SNP rs3192177 in the ZAP70 gene (O.R. 2.8, 95% CI: 1.3-6.0, P=.008) and donor SNP rs34471628 in the DUSPI gene (O.R. 0.3, 95% CI: 0.1-1.0, P=.048) were significantly associated with complete or partial response. However, after adjustment for multiple testing, these SNPs did not remain statistically significant. Our results, on this small, exploratory, hypothesis generating analysis suggest that common genetic variation in glucocorticoid pathways may help identify subjects with differential response to glucocorticoids. This needs further assessment in larger datasets and if validated could help identify subjects for alternative treatments and design targeted treatments to overcome steroid resistance. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Transcriptional Analysis of PRRSV-Infected Porcine Dendritic Cell Response to Streptococcus suis Infection Reveals Up-Regulation of Inflammatory-Related Genes Expression

PubMed Central

Auray, Gaël; Lachance, Claude; Wang, Yingchao; Gagnon, Carl A.; Segura, Mariela; Gottschalk, Marcelo

2016-01-01

The porcine reproductive and respiratory syndrome virus (PRRSV) is one of the most important swine pathogens and often serves as an entry door for other viral or bacterial pathogens, of which Streptococcus suis is one of the most common. Pre-infection with PRRSV leads to exacerbated disease caused by S. suis infection. Very few studies have assessed the immunological mechanisms underlying this higher susceptibility. Since antigen presenting cells play a major role in the initiation of the immune response, the in vitro transcriptional response of bone marrow-derived dendritic cells (BMDCs) and monocytes in the context of PRRSV and S. suis co-infection was investigated. BMDCs were found to be more permissive than monocytes to PRRSV infection; S. suis phagocytosis by PRRSV-infected BMDCs was found to be impaired, whereas no effect was found on bacterial intracellular survival. Transcription profile analysis, with a major focus on inflammatory genes, following S. suis infection, with and without pre-infection with PRRSV, was then performed. While PRRSV pre-infection had little effect on monocytes response to S. suis infection, a significant expression of several pro-inflammatory molecules was observed in BMDCs pre-infected with PRRSV after a subsequent infection with S. suis. While an additive effect could be observed for CCL4, CCL14, CCL20, and IL-15, a distinct synergistic up-regulatory effect was observed for IL-6, CCL5 and TNF-α after co-infection. This increased pro-inflammatory response by DCs could participate in the exacerbation of the disease observed during PRRSV and S. suis co-infection. PMID:27213692

HLA-DR expression, cytokines and bioactive lipids in sepsis

PubMed Central

2014-01-01

Sepsis accounts for more than 200,000 deaths annually in the USA alone. Both inflammatory and anti-inflammatory responses occur simultaneously in sepsis, the early phase dominated by the hyperinflammatory response and the late phase by immunosuppression. This late immunosuppression phase leads to loss of the delayed type hypersensitivity response, failure to clear the primary infection and development of secondary infections. Based on the available data, I hypothesize that failure to produce adequate amounts of inflammation resolving lipid mediators may be at the centre of both the hyperinflammatory response and late immunosuppression seen in sepsis. These proresolving lipids – lipoxins, resolvins and protectins – suppress exacerbated activation of leukocytes and macrophages, inhibit excess production of pro-inflammatory cytokines, initiate resolution of inappropriate inflammation, augment clearance of bacteria and other pathogens, and restore homeostasis. If true, this implies that administration of naturally occurring lipoxins, resolvins, protectins, maresins and nitrolipids by themselves or their more stable synthetic analogues such as 15-epi-16-(para-fluorophenoxy)-lipoxin A4-methyl ester, a synthetic analogue of 15-epi-lipoxin A4, and 15(R/S)-methyl-LXA4 may form a new approach in the prevention (in the high-risk subjects), management of sepsis and in resolving the imbalanced inflammatory process such that sepsis is ameliorated early. In addition, recent studies have suggested that nociceptin and cold inducible RNA binding protein (CIRBP) also have a role in the pathobiology of sepsis. It is suggested that both nociceptin and CIRBP inhibit the production of lipoxins, resolvins, protectins, maresins, and nitrolipids and thus play a role in sepsis and septic shock. PMID:24904669

Oral candidosis in relation to oral immunity.

PubMed

Feller, L; Khammissa, R A G; Chandran, R; Altini, M; Lemmer, J

2014-09-01

Symptomatic oral infection with Candida albicans is characterized by invasion of the oral epithelium by virulent hyphae that cause tissue damage releasing the inflammatory mediators that initiate and sustain local inflammation. Candida albicans triggers pattern-recognition receptors of keratinocytes, macrophages, monocytes and dendritic cells, stimulating the production of IL-1β, IL-6 and IL-23. These cytokines induce the differentiation of Th17 cells and the generation of IL-17- and/or IL-22-mediated antifungal protective immuno-inflammatory responses in infected mucosa. Some immune cells including NKT cells, γδ T cells and lymphoid cells that are innate to the oral mucosa have the capacity to produce large quantities of IL-17 in response to C. albicans, sufficient to mediate effective protective immunity against C. albicans. On the other hand, molecular structures of commensal C. albicans blastoconidia, although detected by pattern-recognition receptors, are avirulent, do not invade the oral epithelium, do not elicit inflammatory responses in a healthy host, but induce regulatory immune responses that maintain tissue tolerance to the commensal fungi. The type, specificity and sensitivity of the protective immune response towards C. albicans is determined by the outcome of the integrated interactions between the intracellular signalling pathways of specific combinations of activated pattern-recognition receptors (TLR2, TLR4, Dectin-1 and Dectin-2). IL-17-mediated protective immune response is essential for oral mucosal immunity to C. albicans infection. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

African Trypanosomes Undermine Humoral Responses and Vaccine Development: Link with Inflammatory Responses?

PubMed Central

Stijlemans, Benoit; Radwanska, Magdalena; De Trez, Carl; Magez, Stefan

2017-01-01

African trypanosomosis is a debilitating disease of great medical and socioeconomical importance. It is caused by strictly extracellular protozoan parasites capable of infecting all vertebrate classes including human, livestock, and game animals. To survive within their mammalian host, trypanosomes have evolved efficient immune escape mechanisms and manipulate the entire host immune response, including the humoral response. This report provides an overview of how trypanosomes initially trigger and subsequently undermine the development of an effective host antibody response. Indeed, results available to date obtained in both natural and experimental infection models show that trypanosomes impair homeostatic B-cell lymphopoiesis, B-cell maturation and survival and B-cell memory development. Data on B-cell dysfunctioning in correlation with parasite virulence and trypanosome-mediated inflammation will be discussed, as well as the impact of trypanosomosis on heterologous vaccine efficacy and diagnosis. Therefore, new strategies aiming at enhancing vaccination efficacy could benefit from a combination of (i) early parasite diagnosis, (ii) anti-trypanosome (drugs) treatment, and (iii) anti-inflammatory treatment that collectively might allow B-cell recovery and improve vaccination. PMID:28596768

Dynamic NF-κB and E2F interactions control the priority and timing of inflammatory signalling and cell proliferation

PubMed Central

Ankers, John M; Awais, Raheela; Jones, Nicholas A; Boyd, James; Ryan, Sheila; Adamson, Antony D; Harper, Claire V; Bridge, Lloyd; Spiller, David G; Jackson, Dean A; Paszek, Pawel; Sée, Violaine; White, Michael RH

2016-01-01

Dynamic cellular systems reprogram gene expression to ensure appropriate cellular fate responses to specific extracellular cues. Here we demonstrate that the dynamics of Nuclear Factor kappa B (NF-κB) signalling and the cell cycle are prioritised differently depending on the timing of an inflammatory signal. Using iterative experimental and computational analyses, we show physical and functional interactions between NF-κB and the E2 Factor 1 (E2F-1) and E2 Factor 4 (E2F-4) cell cycle regulators. These interactions modulate the NF-κB response. In S-phase, the NF-κB response was delayed or repressed, while cell cycle progression was unimpeded. By contrast, activation of NF-κB at the G1/S boundary resulted in a longer cell cycle and more synchronous initial NF-κB responses between cells. These data identify new mechanisms by which the cellular response to stress is differentially controlled at different stages of the cell cycle. DOI: http://dx.doi.org/10.7554/eLife.10473.001 PMID:27185527

Inhibition of CD23-mediated IgE transcytosis suppresses the initiation and development of airway allergic inflammation

USDA-ARS?s Scientific Manuscript database

The epithelium lining the airway tract and allergen-specific IgE are considered essential controllers of inflammatory responses to allergens. The human IgE receptor, CD23 (Fc'RII), is capable of transporting IgE or IgE-allergen complexes across the polarized human airway epithelial cell (AEC) monola...

Low-level laser therapy (LLLT) reduces inflammatory infiltrate and enhances skeletal muscle repair: Histomorphometric parameters

NASA Astrophysics Data System (ADS)

Paiva-Oliveira, E. L.; Lima, N. C.; Silva, P. H.; Sousa, N. T. A.; Barbosa, F. S.; Orsini, M.; Silva, J. G.

2012-09-01

Low level laser therapy (LLLT) has been suggested as an effective therapeutics in inflammatory processes modulation and tissue repairing. However, there is a lack of studies that analyze the anti-inflammatory effects of the infrared lasers in muscular skeletal injury. The aim of this study was to investigate the effects of low-level laser therapy 904 nm in the repair process of skeletal muscle tissue. Swiss mice were submitted to cryoinjury and divided in test (LLLT-treated) and control groups. Histological sections were stained with hematoxylin-eosin to assess general morphology and inflammatory influx, and Picrossirus to quantify collagen fibers deposition. Our results showed significant reduction in inflammatory infiltrated in irradiated mice after 4 days of treatment compared to control ( p = 0.01). After 8 days, the irradiated group showed high levels at regenerating myofibers with significant statistically differences in relation at control group ( p < 0.01). Collagen deposition was significantly increased in the final stages of regeneration at test group, when compared with control group ( p = 0.05). Our data suggests that LLLT reduces the inflammatory response in the initial stages of injury and accelerates the process of muscular tissue repair.

Inflammation, leukocytes and menstruation.

PubMed

Evans, Jemma; Salamonsen, Lois A

2012-12-01

Menstruation has many of the features of an inflammatory process. The complexity and sequence of inflammatory-type events leading to the final tissue breakdown and bleeding are slowly being unravelled. Progesterone has anti-inflammatory properties, and its rapidly declining levels (along with those of estrogen) in the late secretory phase of each non-conception cycle, initiates a sequence of interdependent events of an inflammatory nature involving local inter-cellular interactions within the endometrium. Intracellular responses to loss of progesterone (in decidualized stromal, vascular and epithelial cells) lead to decreased prostaglandin metabolism and loss of protection from reactive oxygen species (ROS). Increased ROS results in release of NFκB from suppression with activation of target gene transcription and increased synthesis of pro-inflammatory prostaglandins, cytokines, chemokines and matrix metalloproteinases (MMP). The resultant leukocyte recruitment, with changing phenotypes and activation, provide further degradative enzymes and MMP activators, which together with a hypoxic environment induced by prostaglandin actions, lead to the tissue breakdown and bleeding characteristic of menstruation. In parallel, at sites where shedding is complete, microenvironmentally-induced changes in phenotypes of neutrophils and macrophages from pro- to anti-inflammatory, in addition to induction of growth factors, contribute to the very rapid re-epithelialization and restoration of tissue integrity.

Effect of hemoadsorption during cardiopulmonary bypass surgery - a blinded, randomized, controlled pilot study using a novel adsorbent.

PubMed

Bernardi, Martin H; Rinoesl, Harald; Dragosits, Klaus; Ristl, Robin; Hoffelner, Friedrich; Opfermann, Philipp; Lamm, Christian; Preißing, Falk; Wiedemann, Dominik; Hiesmayr, Michael J; Spittler, Andreas

2016-04-09

Cardiopulmonary bypass (CPB) surgery initiates a systemic inflammatory response, which is associated with postoperative morbidity and mortality. Hemoadsorption (HA) of cytokines may suppress inflammatory responses and improve outcomes. We tested a new sorbent used for HA (CytoSorb™; CytoSorbents Europe GmbH, Berlin, Germany) installed in the CPB circuit on changes of pro- and anti-inflammatory cytokines levels, inflammation markers, and differences in patients' perioperative course. In this first pilot trial, 37 blinded patients were undergoing elective CPB surgery at the Medical University of Vienna and were randomly assigned to HA (n = 19) or control group (n = 18). The primary outcome was differences of cytokine levels (IL-1β, IL-6, IL-18, TNF-α, and IL-10) within the first five postoperative days. We also analyzed whether we can observe any differences in ex vivo lipopolysaccharide (LPS)-induced TNF-α production, a reduction of high-mobility box group 1 (HMGB1), or other inflammatory markers. Additionally, measurements for fluid components, blood products, catecholamine treatment, bioelectrical impedance analysis (BIA), and 30-day mortality were analyzed. We did not find differences in our primary outcome immediately following the HA treatment, although we observed differences for IL-10 24 hours after CPB (HA: median 0.3, interquartile range (IQR) 0-4.5; control: not traceable, P = 0.0347) and 48 hours after CPB (median 0, IQR 0-1.2 versus not traceable, P = 0.0185). We did not find any differences for IL-6 between both groups, and other cytokines were rarely expressed. We found differences in pretreatment levels of HMGB1 (HA: median 0, IQR 0-28.1; control: median 48.6, IQR 12.7-597.3, P = 0.02083) but no significant changes to post-treatment levels. No differences in inflammatory markers, fluid administration, blood substitution, catecholamines, BIA, or 30-day mortality were found. We did not find any reduction of the pro-inflammatory response in our patients and therefore no changes in their perioperative course. However, IL-10 showed a longer-lasting anti-inflammatory effect. The clinical impact of prolonged IL-10 needs further evaluation. We also observed strong inter-individual differences in cytokine levels; therefore, patients with an exaggerated inflammatory response to CPB need to be identified. The implementation of HA during CPB was feasible. ClinicalTrials.gov: NCT01879176, registration date: June 7, 2013.

Inflammatory Monocytes Orchestrate Innate Antifungal Immunity in the Lung

PubMed Central

Dutta, Orchi; Kasahara, Shinji; Donnelly, Robert; Du, Peicheng; Rosenfeld, Jeffrey; Leiner, Ingrid; Chen, Chiann-Chyi; Ron, Yacov; Hohl, Tobias M.; Rivera, Amariliz

2014-01-01

Aspergillus fumigatus is an environmental fungus that causes invasive aspergillosis (IA) in immunocompromised patients. Although -CC-chemokine receptor-2 (CCR2) and Ly6C-expressing inflammatory monocytes (CCR2+Mo) and their derivatives initiate adaptive pulmonary immune responses, their role in coordinating innate immune responses in the lung remain poorly defined. Using conditional and antibody-mediated cell ablation strategies, we found that CCR2+Mo and monocyte-derived dendritic cells (Mo-DCs) are essential for innate defense against inhaled conidia. By harnessing fluorescent Aspergillus reporter (FLARE) conidia that report fungal cell association and viability in vivo, we identify two mechanisms by which CCR2+Mo and Mo-DCs exert innate antifungal activity. First, CCR2+Mo and Mo-DCs condition the lung inflammatory milieu to augment neutrophil conidiacidal activity. Second, conidial uptake by CCR2+Mo temporally coincided with their differentiation into Mo-DCs, a process that resulted in direct conidial killing. Our findings illustrate both indirect and direct functions for CCR2+Mo and their derivatives in innate antifungal immunity in the lung. PMID:24586155

Innate inflammatory responses in stroke: mechanisms and potential therapeutic targets.

PubMed

Kim, J Y; Kawabori, M; Yenari, M A

2014-01-01

Stroke is a frequent cause of long-term disability and death worldwide. Ischemic stroke is more commonly encountered compared to hemorrhagic stroke, and leads to tissue death by ischemia due to occlusion of a cerebral artery. Inflammation is known to result as a result of ischemic injury, long thought to be involved in initiating the recovery and repair process. However, work over the past few decades indicates that aspects of this inflammatory response may in fact be detrimental to stroke outcome. Acutely, inflammation appears to have a detrimental effect, and anti-inflammatory treatments have been been studied as a potential therapeutic target. Chronically, reports suggest that post-ischemic inflammation is also essential for the tissue repairing and remodeling. The majority of the work in this area has centered around innate immune mechanisms, which will be the focus of this review. This review describes the different key players in neuroinflammation and their possible detrimental and protective effects in stroke. A better understanding of the roles of the different immune cells and their temporal profile of damage versus repair will help to clarify more effective modulation of inflammation post stroke.

Chronic Inflammatory Demyelinating Polyneuropathy Manifesting as Neuropathy With Liability to Pressure Palsies: A Case Report.

PubMed

Shah, Akshay; Rison, Richard A; Beydoun, Said R

2015-12-01

Chronic inflammatory demyelinating polyneuropathy (CIDP) is a progressive demyelinating neuropathy, which typically presents with proximal and distal neuropathic symptoms and is typically responsive to immunomodulatory therapies. Many variants have been subsequently described in the literature and have similarly shown to be responsive to immunotherapy. We present a case of a 43-year-old Middle Eastern/Arabic man presenting with symptoms of mixed sensorimotor neuropathy most evident at entrapment sites mimicking hereditary neuropathy with liability to pressure palsies. His electrodiagnostic study revealed features of acquired demyelinating neuropathy and a negative genetic workup. Alternative diagnosis of CIDP was considered in the context of symptomatic disease progression, negative genetic workup, and electrodiagnosis leading to initiation of immunotherapy with intravenous immunoglobulins. His neuropathy responded confirming our diagnosis of an inflammatory demyelinating polyneuropathy. We describe a previously unknown variant of CIDP with phenotypic characteristics of hereditary neuropathy with liability to pressure palsies and its potential for successful treatment with intravenous immunoglobulins. This case illustrates an unusual presentation of CIDP mimicking hereditary neuropathy with liability to pressure palsies.

Severe Vitamin E deficiency modulates airway allergic inflammatory responses in the murine asthma model

PubMed Central

LIM, YUNSOOK; VASU, VIHAS T.; VALACCHI, GIUSEPPE; LEONARD, SCOTT; AUNG, HNIN HNIN; SCHOCK, BETTINA C.; KENYON, NICHOLAS J.; LI, CHIN-SHANG; TRABER, MARET G.; CROSS, CARROLL E.

2009-01-01

Allergic asthma is a complex immunologically mediated disease associated with increased oxidative stress and altered antioxidant defenses. It was hypothesized that α-tocopherol (α-T) decreases oxidative stress and therefore its absence may influence allergic inflammatory process, a pathobiology known to be accompanied by oxidative stress. Therefore, selected parameters of allergic asthma sensitization and inflammation were evaluated following ovalbumin sensitization and re-challenge of α-T transfer protein (TTP) knock-out mice (TTP–/–) that have greatly reduced lung α-T levels (e.g. < 5%) compared to their litter mate controls (TTP+/+). Results showed that severe α-T deficiency result in a blunted lung expression of IL-5 mRNA and IL-5 protein and plasma IgE levels compared with TTP+/+ mice following immune sensitization and rechallenge, although lung lavage eosinophil levels were comparable in both genomic strains. It is concluded that the initial stimulation of immune responses by the TTP–/– mice were generally blunted compared to the TTP+/+ mice, thus diminishing some aspects of subsequent allergic inflammatory processes. PMID:18404538

Mechanisms of lymphocyte migration in autoimmune disease.

PubMed

Norman, M U; Hickey, M J

2005-09-01

The recruitment of leukocytes to inflamed tissues plays an essential role in combating infection and promoting wound healing. However, in autoimmune diseases such as multiple sclerosis and diabetes, leukocytes enter tissues and contribute to inappropriate inflammatory responses, which cause tissue injury and dysfunction. In diseases of this type, lymphocytes play critical roles in initiating and maintaining these aberrant inflammatory responses. The aim of this review is to examine the mechanisms whereby T-lymphocytes enter tissues in autoimmune diseases and to compare these mechanisms between various organs and diseases. An overview of the mechanisms of leukocyte recruitment and the techniques used to study leukocyte trafficking is provided, focusing on the use of intravital microscopy as a tool to assess the functional microvasculature in vivo. We also discuss the series of tissue homing events which allow naïve lymphocytes to first enter lymph nodes and undergo activation, then subsequently to home to the peripheral organ where their cognate antigen is present. Finally, we examine mechanisms of leukocyte recruitment in diseases such as multiple sclerosis, autoimmune diabetes, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease and asthma.

Genetic and Imaging Approaches Reveal Pro-Inflammatory and Immunoregulatory Roles of Mast Cells in Contact Hypersensitivity.

PubMed

Gaudenzio, Nicolas; Marichal, Thomas; Galli, Stephen J; Reber, Laurent L

2018-01-01

Contact hypersensitivity (CHS) is a common T cell-mediated skin disease induced by epicutaneous sensitization to haptens. Mast cells (MCs) are widely deployed in the skin and can be activated during CHS responses to secrete diverse products, including some with pro-inflammatory and anti-inflammatory functions. Conflicting results have been obtained regarding pathogenic versus protective roles of MCs in CHS, and this has been attributed in part to the limitations of certain models for studying MC functions in vivo . This review discusses recent advances in the development and analysis of mouse models to investigate the roles of MCs and MC-associated products in vivo . Notably, fluorescent avidin-based two-photon imaging approaches enable in vivo selective labeling and simultaneous tracking of MC secretory granules (e.g., during MC degranulation) and MC gene activation by real-time longitudinal intravital microscopy in living mice. The combination of such genetic and imaging tools has shed new light on the controversial role played by MCs in mouse models of CHS. On the one hand, they can amplify CHS responses of mild severity while, on the other hand, can limit the inflammation and tissue injury associated with more severe or chronic models, in part by representing an initial source of the anti-inflammatory cytokine IL-10.

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

Mechanisms underlying caloric restriction and life span regulation: implications for vascular aging

PubMed Central

Ungvari, Zoltan; Parrado-Fernandez, Cristina; Csiszar, Anna; de Cabo, Rafael

2008-01-01

This review focuses on the emerging evidence that attenuation of the production of reactive oxygen species (ROS) and inhibition of inflammatory pathways play a central role in the anti-aging cardiovascular effects of caloric restriction (CR). Particular emphasis is placed on the potential role of the plasma membrane redox system in CR-induced pathways responsible for sensing oxidative stress and increasing cellular oxidative stress resistance. We propose that CR increases bioavailability of NO, decreases vascular ROS generation, activates the Nrf2/ARE pathway inducing ROS detoxification systems, exerts anti-inflammatory effects and, thereby, suppresses initiation/progression of vascular disease that accompany aging. PMID:18340017

Folliculitis decalvans--response to rifampin.

PubMed

Brozena, S J; Cohen, L E; Fenske, N A

1988-12-01

Folliculitis decalvans is a rare follicular inflammatory disease of the scalp. It is characterized by initial perifollicular inflammatory changes followed by peripheral extension and eventual circumscribed patches of cicatricial alopecia. The disease is known for its resistance to treatment, resulting in an unfavorable prognosis. The cause of the disease is unknown, although a bacterial etiology is postulated. We report a classic case that was temporized with various antibiotics and only subsequently resolved after ten weeks of therapy with rifampin. The patient has remained free of disease for more than one year. We present a brief review of the cicatricial alopecias and discuss rifampin therapy for this condition.

Cyclophilin B attenuates the expression of TNF-α in lipopolysaccharide-stimulated macrophages through the induction of B cell lymphoma-3.

PubMed

Marcant, Adeline; Denys, Agnès; Melchior, Aurélie; Martinez, Pierre; Deligny, Audrey; Carpentier, Mathieu; Allain, Fabrice

2012-08-15

Extracellular cyclophilin A (CyPA) and CyPB have been well described as chemotactic factors for various leukocyte subsets, suggesting their contribution to inflammatory responses. Unlike CyPA, CyPB accumulates in extracellular matrixes, from which it is released by inflammatory proteases. Hence, we hypothesized that it could participate in tissue inflammation by regulating the activity of macrophages. In the current study, we confirmed that CyPB initiated in vitro migration of macrophages, but it did not induce production of proinflammatory cytokines. In contrast, pretreatment of macrophages with CyPB attenuated the expression of inflammatory mediators induced by LPS stimulation. The expression of TNF-α mRNA was strongly reduced after exposure to CyPB, but it was not accompanied by significant modification in LPS-induced activation of MAPK and NF-κB pathways. LPS activation of a reporter gene under the control of TNF-α gene promoter was also markedly decreased in cells treated with CyPB, suggesting a transcriptional mechanism of inhibition. Consistent with this hypothesis, we found that CyPB induced the expression of B cell lymphoma-3 (Bcl-3), which was accompanied by a decrease in the binding of NF-κB p65 to the TNF-α promoter. As expected, interfering with the expression of Bcl-3 restored cell responsiveness to LPS, thus confirming that CyPB acted by inhibiting initiation of TNF-α gene transcription. Finally, we found that CyPA was not efficient in attenuating the production of TNF-α from LPS-stimulated macrophages, which seemed to be due to a modest induction of Bcl-3 expression. Collectively, these findings suggest an unexpected role for CyPB in attenuation of the responses of proinflammatory macrophages.

Pure hemozoin is inflammatory in vivo and activates the NALP3 inflammasome via release of uric acid

PubMed Central

Griffith, Jason W.; Sun, Tiffany; McIntosh, Michael T.; Bucala, Richard

2013-01-01

The role of pro-inflammatory cytokine production in the pathogenesis of malaria is well established, but the identification of the parasite products that initiate inflammation is not complete. Hemozoin is a crystalline metabolite of hemoglobin digestion that is released during malaria infection. In the present study, we characterized the immunostimulatory activity of pure synthetic hemozoin (sHz) in vitro and in vivo. Stimulation of naïve murine macrophages with sHz results in the MyD88-independent activation of NF-κB and ERK, and the release of the chemokine MCP-1; these responses are augmented by IFN-γ. In macrophages pre-stimulated with IFN-γ, sHz also results in a MyD88-dependent release of TNF-α. Endothelial cells, which encounter hemozoin after schizont rupture, respond to sHz by releasing IL-6 and the chemokines MCP-1 and IL-8. In vivo, the introduction of sHz into the peritoneal cavity produces an inflammatory response characterized by neutrophil recruitment and the production of MCP-1, KC, IL-6, IL-1α and IL-1β. MCP-1 and KC are produced independently of MyD88, TLR 2/4 and 9, and components of the inflammasome, however neutrophil recruitment, the localized production of IL-1β, and the increase in circulating IL-6 require MyD88 signaling, the IL-1R pathway and the inflammasome components ICE, ASC and NALP3. Of note, inflammasome activation by sHz is reduced by allopurinol, which is an inhibitor of uric acid synthesis. This data suggests that uric acid is released during malaria infection and may serve to augment the initial host response to hemozoin via activation of the NALP3 inflammasome. PMID:19783673

Microglia of the Aged Brain: Primed to be Activated and Resistant to Regulation

PubMed Central

Norden, Diana M.; Godbout, Jonathan P.

2012-01-01

Innate immunity within the central nervous system (CNS) is primarily provided by resident microglia. Microglia are pivotal in immune surveillance and also facilitate the coordinated responses between the immune system and the brain. For example, microglia interpret and propagate inflammatory signals that are initiated in the periphery. This transient microglial activation helps mount the appropriate physiological and behavioral response following peripheral infection. With normal aging, however, microglia develop a more inflammatory phenotype. For instance, in several models of aging there are increased pro-inflammatory cytokines in the brain and increased expression of inflammatory receptors on microglia. This increased inflammatory status of microglia with aging is referred to as primed, reactive, or sensitized. A modest increase in the inflammatory profile of the CNS and altered microglial function in aging has behavioral and cognitive consequences. Nonetheless, there are major differences in microglial biology between young and old age when the immune system is challenged and microglia are activated. In this context, microglial activation is amplified and prolonged in the aged brain compared to adults. The cause of this amplified microglial activation may be related to impairments in several key regulatory systems with age that make it more difficult to resolve microglial activation. The consequences of impaired regulation and microglial hyper-activation following immune challenge are exaggerated neuroinflammation, sickness behavior, depressive-like behavior and cognitive deficits. Therefore the purpose of this review is to discuss the current understanding of age-associated microglial priming, consequences of priming and reactivity, and the impairments in regulatory systems that may underlie these age-related deficits. PMID:23039106

The Dynamic Duo–Inflammatory M1 macrophages and Th17 cells in Rheumatic Diseases

PubMed Central

Li, Jun; Hsu, Hui-Chen; Mountz, John D.

2014-01-01

The synovial tissue of Rheumatoid Arthritis (RA) patients is enriched with macrophages and T lymphocytes which are two central players in the pathogenesis of RA. Interaction between myeloid cells and T cells are essential for the initiation and progression of the inflammatory processes in the synovium. With the rapid evolution of our understanding of how these two cell types are involved in the regulation of immune responses, RA is emerging as an ideal disease model for investigating the cell-cell interactions and consequently introducing novel biologic agents that are designed to disrupt these processes. This review will discuss the bidirectional interaction between the IL-23+ inflammatory macrophages and IL-17+ GM-CSF+ CD4 T cells in rheumatic diseases as well as potential antirheumatic strategies via apoptosis induction in this context. PMID:25309946

Importance of asparagine on the conformational stability and chemical reactivity of selected anti-inflammatory peptides

NASA Astrophysics Data System (ADS)

Soriano-Correa, Catalina; Barrientos-Salcedo, Carolina; Campos-Fernández, Linda; Alvarado-Salazar, Andres; Esquivel, Rodolfo O.

2015-08-01

Inflammatory response events are initiated by a complex series of molecular reactions that generate chemical intermediaries. The structure and properties of peptides and proteins are determined by the charge distribution of their side chains, which play an essential role in its electronic structure and physicochemical properties, hence on its biological functionality. The aim of this study was to analyze the effect of changing one central amino acid, such as substituting asparagine for aspartic acid, from Cys-Asn-Ser in aqueous solution, by assessing the conformational stability, physicochemical properties, chemical reactivity and their relationship with anti-inflammatory activity; employing quantum-chemical descriptors at the M06-2X/6-311+G(d,p) level. Our results suggest that asparagine plays a more critical role than aspartic acid in the structural stability, physicochemical features, and chemical reactivity of these tripeptides. Substituent groups in the side chain cause significant changes on the conformational stability and chemical reactivity, and consequently on their anti-inflammatory activity.

In vivo modulation of foreign body response on polyurethane by surface entrapment technique.

PubMed

Khandwekar, Anand P; Patil, Deepak P; Hardikar, Anand A; Shouche, Yogesh S; Doble, Mukesh

2010-11-01

Implanted polymeric materials, such as medical devices, provoke the body to initiate an inflammatory reaction, known as the foreign body response (FBR), which causes several complications. In this study, polyurethane (Tecoflex®, PU) surface modified with the nonionic surfactant Tween80® (PU/T80) and the cell adhesive PLL-RGD peptide (PU/PLL-RGD) by a previously described entrapment technique were implanted in the peritoneal cavity of Wistar rats for 30 days. Implants were retrieved and examined for tissue reactivity and cellular adherence by various microscopic and analytical techniques. Surface-induced inflammatory response was assessed by real-time PCR based quantification of proinflammatory cytokine transcripts, namely, TNF-α and IL-1β, normalized to housekeeping gene GAPDH. Cellular adherence and their distribution profile were assessed by microscopic examination of H&E stained implant sections. It was observed that PU/PLL-RGD followed by the bare PU surface exhibited severe inflammatory and fibrotic response with an average mean thickness of 19 and 12 μm, respectively, in 30 days. In contrast, PU/T80 surface showed only a cellular monolayer of 2-3 μm in thickness, with a mild inflammatory response and no fibrotic encapsulation. The PU/PLL-RGD peptide-modified substrate promoted an enhanced rate of macrophage cell fusion to form foreign body giant cell (FBGCs), whereas FBGCs were rarely observed on Tween80®-modified substrate. The expression levels of proinflammatory cytokines (TNF-α and IL-1β) were upregulated on PU/PLL-RGD surface followed by bare PU, whereas the cytokine expressions were significantly suppressed on PU/T80 surface. Thus, our study highlights modulation of foreign body response on polyurethane surfaces through surface entrapment technique in the form of differential responses observed on PLL-RGD and Tween80® modified surfaces with the former effective in triggering tissue cell adhesion thereby fibrous encapsulation, while the later being mostly resistant to this phenomenon.

Mast Cell Interactions and Crosstalk in Regulating Allergic Inflammation.

PubMed

Velez, Tania E; Bryce, Paul J; Hulse, Kathryn E

2018-04-17

This review summarizes recent findings on mast cell biology with a focus on IgE-independent roles of mast cells in regulating allergic responses. Recent studies have described novel mast cell-derived molecules, both secreted and membrane-bound, that facilitate cross-talk with a variety of immune effector cells to mediate type 2 inflammatory responses. Mast cells are complex and dynamic cells that are persistent in allergy and are capable of providing signals that lead to the initiation and persistence of allergic mechanisms.

Characterization of the early pulmonary inflammatory response associated with PTFE fume exposure

NASA Technical Reports Server (NTRS)

Johnston, C. J.; Finkelstein, J. N.; Gelein, R.; Baggs, R.; Oberdorster, G.; Clarkson, T. W. (Principal Investigator)

1996-01-01

Heating of polytetrafluoroethylene (PTFE) has been described to release fumes containing ultrafine particles (approximately 18 nm diam). These fumes can be highly toxic in the respiratory tract inducing extensive pulmonary edema with hemorrhagic inflammation. Fischer-344 rats were exposed to PTFE fumes generated by temperatures ranging from 450 to 460 degrees C for 15 min at an exposure concentration of 5 x 10(5) particles/cm3, equivalent to approximately 50 micrograms/m3. Responses were examined 4 hr post-treatment when these rats demonstrated 60-85% neutrophils (PMNs) in their lung lavage. Increases in abundance for messages encoding the antioxidants manganese superoxide dismutase and metallothionein (MT) increased 15- and 40-fold, respectively. For messages encoding the pro- and anti-inflammatory cytokines: inducible nitric oxide synthase, interleukin 1 alpha, 1 beta, and 6 (IL-1 alpha, IL-1 beta, and IL-6), macrophage inflammatory protein-2, and tumor necrosis factor-alpha (TNF alpha) increases of 5-, 5-, 10-, 40-, 40-, and 15-fold were present. Vascular endothelial growth factor, which may play a role in the integrity of the endothelial barrier, was decreased to 20% of controls. In situ sections were hybridized with 33P cRNA probes encoding IL-6, MT, surfactant protein C, and TNF alpha. Increased mRNA abundance for MT and IL-6 was expressed around all airways and interstitial regions with MT and IL-6 demonstrating similar spatial distribution. Large numbers of activated PMNs expressed IL-6, MT, and TNF alpha. Additionally, pulmonary macrophages and epithelial cells were actively involved. These observations support the notion that PTFE fumes containing ultrafine particles initiate a severe inflammatory response at low inhaled particle mass concentrations, which is suggestive of an oxidative injury. Furthermore, PMNs may actively regulate the inflammatory process through cytokine and antioxidant expression.

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

The role of airway macrophages in apoptotic cell clearance following acute and chronic lung inflammation.

PubMed

Grabiec, Aleksander M; Hussell, Tracy

2016-07-01

Acute and chronic inflammatory responses in the lung are associated with the accumulation of large quantities of immune and structural cells undergoing apoptosis, which need to be engulfed by phagocytes in a process called 'efferocytosis'. Apoptotic cell recognition and removal from the lung is mediated predominantly by airway macrophages, though immature dendritic cells and non-professional phagocytes, such as epithelial cells and mesenchymal cells, can also display this function. Efficient clearance of apoptotic cells from the airways is essential for successful resolution of inflammation and the return to lung homeostasis. Disruption of this process leads to secondary necrosis of accumulating apoptotic cells, release of necrotic cell debris and subsequent uncontrolled inflammatory activation of the innate immune system by the released 'damage associated molecular patterns' (DAMPS). To control the duration of the immune response and prevent autoimmune reactions, anti-inflammatory signalling cascades are initiated in the phagocyte upon apoptotic cell uptake, mediated by a range of receptors that recognise specific phospholipids or proteins externalised on, or secreted by, the apoptotic cell. However, prolonged activation of apoptotic cell recognition receptors, such as the family of receptor tyrosine kinases Tyro3, Axl and MerTK (TAM), may delay or prevent inflammatory responses to subsequent infections. In this review, we will discuss recent advances in our understanding of the mechanism controlling apoptotic cell recognition and removal from the lung in homeostasis and during inflammation, the contribution of defective efferocytosis to chronic inflammatory lung diseases, such as chronic obstructive pulmonary disease, asthma and cystic fibrosis, and implications of the signals triggered by apoptotic cells in the susceptibility to pulmonary microbial infections.

Targeting pro-inflammatory cytokines following joint injury: acute intra-articular inhibition of interleukin-1 following knee injury prevents post-traumatic arthritis

PubMed Central

2014-01-01

Introduction Post-traumatic arthritis (PTA) is a progressive, degenerative response to joint injury, such as articular fracture. The pro-inflammatory cytokines, interleukin 1(IL-1) and tumor necrosis factor alpha (TNF-α), are acutely elevated following joint injury and remain elevated for prolonged periods post-injury. To investigate the role of local and systemic inflammation in the development of post-traumatic arthritis, we targeted both the initial acute local inflammatory response and a prolonged 4 week systemic inflammatory response by inhibiting IL-1 or TNF-α following articular fracture in the mouse knee. Methods Anti-cytokine agents, IL-1 receptor antagonist (IL-1Ra) or soluble TNF receptor II (sTNFRII), were administered either locally via an acute intra-articular injection or systemically for a prolonged 4 week period following articular fracture of the knee in C57BL/6 mice. The severity of arthritis was then assessed at 8 weeks post-injury in joint tissues via histology and micro computed tomography, and systemic and local biomarkers were assessed in serum and synovial fluid. Results Intra-articular inhibition of IL-1 significantly reduced cartilage degeneration, synovial inflammation, and did not alter bone morphology following articular fracture. However, systemic inhibition of IL-1, and local or systemic inhibition of TNF provided no benefit or conversely led to increased arthritic changes in the joint tissues. Conclusion These results show that intra-articular IL-1, rather than TNF-α, plays a critical role in the acute inflammatory phase of joint injury and can be inhibited locally to reduce post-traumatic arthritis following a closed articular fracture. Targeted local inhibition of IL-1 following joint injury may represent a novel treatment option for PTA. PMID:24964765

Eukaryotic Initiation Factor 4H Is under Transcriptional Control of p65/NF-κB

PubMed Central

Fiume, Giuseppe; Rossi, Annalisa; de Laurentiis, Annamaria; Falcone, Cristina; Pisano, Antonio; Vecchio, Eleonora; Pontoriero, Marilena; Scala, Iris; Scialdone, Annarita; Masci, Francesca Fasanella; Mimmi, Selena; Palmieri, Camillo; Scala, Giuseppe; Quinto, Ileana

2013-01-01

Protein synthesis is mainly regulated at the initiation step, allowing the fast, reversible and spatial control of gene expression. Initiation of protein synthesis requires at least 13 translation initiation factors to assemble the 80S ribosomal initiation complex. Loss of translation control may result in cell malignant transformation. Here, we asked whether translational initiation factors could be regulated by NF-κB transcription factor, a major regulator of genes involved in cell proliferation, survival, and inflammatory response. We show that the p65 subunit of NF-κB activates the transcription of eIF4H gene, which is the regulatory subunit of eIF4A, the most relevant RNA helicase in translation initiation. The p65-dependent transcriptional activation of eIF4H increased the eIF4H protein content augmenting the rate of global protein synthesis. In this context, our results provide novel insights into protein synthesis regulation in response to NF-κB activation signalling, suggesting a transcription-translation coupled mechanism of control. PMID:23776612

Mast Cells and Innate Lymphoid Cells: Underappreciated Players in CNS Autoimmune Demyelinating Disease.

PubMed

Brown, Melissa A; Weinberg, Rebecca B

2018-01-01

Multiple sclerosis (MS) and its mouse model, experimental autoimmune encephalomyelitis, are autoimmune CNS inflammatory diseases. As a result of a breakdown in the relatively impermeable blood-brain barrier (BBB) in affected individuals, myelin-specific CD4 + and CD8 + T cells gain entry into the immune privileged CNS and initiate myelin, oligodendrocyte, and nerve axon destruction. However, despite the absolute requirement for T cells, there is increasing evidence that innate immune cells also play critical amplifying roles in disease pathogenesis. By modulating the character and magnitude of the myelin-reactive T cell response and regulating BBB integrity, innate cells affect both disease initiation and progression. Two classes of innate cells, mast cells and innate lymphoid cells (ILCs), have been best studied in models of allergic and gastrointestinal inflammatory diseases. Yet, there is emerging evidence that these cell types also exert a profound influence in CNS inflammatory disease. Both cell types are residents within the meninges and can be activated early in disease to express a wide variety of disease-modifying cytokines and chemokines. In this review, we discuss how mast cells and ILCs can have either disease-promoting or -protecting effects on MS and other CNS inflammatory diseases and how sex hormones may influence this outcome. These observations suggest that targeting these cells and their unique mediators can be exploited therapeutically.

Immune response of Staphylococcus aureus strains in a mouse mastitis model is linked to adaptive capacity and genotypic profiles.

PubMed

Pereyra, Elizabet A L; Sacco, Sofía C; Duré, Andrea; Baravalle, Celina; Renna, María S; Andreotti, Carolina S; Monecke, Stefan; Calvinho, Luis F; Dallard, Bibiana E

2017-05-01

Staphylococcus aureus is one of the most frequently isolated major pathogens from intramammary infections (IMI) worldwide. The mechanisms by which S. aureus IMI are established and maintained in dairy cows involve both bacterial escape strategies and modulation of the host immune response. Moreover, it was shown that different S. aureus strains have varying effects on the immune response. The aim of this study was to investigate the immune response in a mouse mastitis model of two S. aureus strains isolated from bovine IMI with different clinical manifestation (persistent-P or non-persistent-NP), phenotypic and genotypic profile. Both strains were capable of establishing an IMI after 264h post inoculation (pi). Strain A (NP) showed a more aggressive behaviour than strain B (P) at early stages of IMI, while strain B multiplied initially at a lower rate but increased its replication capacity from 120h pi to the end of the study (264h pi). Strain A triggered a stronger initial inflammatory response compared with strain B inducing higher gene and protein expression of TLR2, NF-κB activation and higher gene expression of IL-1α at initial stage of IMI (6-12h pi) but inducing extensive mammary tissue damage. Immune cells response was different for each S. aureus strain throughout the course of infection, showing mammary glands inoculated with strain A greater initial immune cells stimulation compared with strain B and then a second immune cells stimulation (from 120 to 264h pi) represented by monocytes-macrophages, T and B lymphocytes, mainly stimulated by strain B, consistent with inflammatory process becoming chronic. Strain-specific pathogenicity observed underscores the importance of pathogen factors in the progression of the infectious process. These results contribute to increase the available information on host-pathogen interaction and point out for the need of further research to expand the knowledge about these interactions for developing new strategies to intervene in the IMI progress. Copyright © 2017 Elsevier B.V. All rights reserved.

HIV infection-induced transcriptional program in renal tubular epithelial cells activates a CXCR2-driven CD4+ T-cell chemotactic response.

PubMed

Chen, Ping; Yi, Zhengzi; Zhang, Weijia; Klotman, Mary E; Chen, Benjamin K

2016-07-31

Viral replication and interstitial inflammation play important roles in the pathogenesis of HIV-associated nephropathy. Cell-cell interactions between renal tubule epithelial cells (RTECs) and HIV-infected T cells can trigger efficient virus internalization and viral gene expression by RTEC. To understand how HIV replication initiates HIV-associated nephropathy, we studied the cellular response of RTECs to HIV, examining the transcriptional profiles of primary RTECs exposed to cell-free HIV or HIV-infected T cells. HIV-induced gene expression in hRTECs was examined in vitro by Illumina RNA deep sequencing and revealed an innate response to HIV, which was subclassified by gene ontology biological process terms. Chemokine responses were examined by CD4 T-cell chemotaxis assays. As compared with cell-free virus infection, exposure to HIV-infected T cells elicited a stronger upregulation of inflammatory and immune response genes. A major category of upregulated genes are chemokine/cytokine families involved in inflammation and immune response, including inflammatory cytokines CCL20, IL6 and IL8-related chemokines: IL8, CXCL1, CXCL2, CXCL3, CXCL5 and CXCL6. Supernatants from virus-exposed RTECs contained strong chemoattractant activity on primary CD4 T cells, which was potently blocked by a CXCR2 antagonist that antagonizes IL8-related chemokines. We observed a preferential migration of CXCR2-expressing, central memory CD4 T cells in response to HIV infection of RTECs. Interactions between primary RTECs and HIV-infected T cells result in potent induction of inflammatory response genes and release of cytokines/chemokines from RTECs that can attract additional T cells. Activation of these genes reflects an innate response to HIV by nonimmune cells.

Inhibition of phorbol ester-induced tumor promotion in mice by vitamin A analog and anti-inflammatory steroid

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

Weeks, C.E.; Slaga, T.J.; Hennings, H.

1979-08-01

The effects of a vitamin A analog, TMMP ethyl retinoate (abbreviated Ro 10-9359), and an anti-inflammatory steroid, fluocinoione acetonide (abbreviated FA), given alone or together were studied in a two-stage carcinogenesis system. the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) was used as the tumor promoter in a DMBA-initiated mouse skin system. Two stocks of female mice, which differ in their degrees of sensitivity to skin carcinogenesis, were used. A dose-dependent inhibition of carcinogenic expression, as determined by a decreased number of papillomas per animal, was observed in each mouse stock with the use of both FA and Ro 10-9359 were given alone.more » When FA and RO 10-9359 were given together, an enhanced effect on the lowering of tumor incidence was noted. FA effectively inhibited tumor formation in the sensitive mouse stock even when the steroid was given 1 day prior to TPA treatment under conditions of unusually high doses of initiator (DMBA) and/or promoter (TPA). These results suggest that both anti-inflammatory steroids and retinoids inhibit tumor promotion and can be effectively used as a combination regimen for increased chemopreventive response.« less

Aspergillus-Associated Airway Disease, Inflammation, and the Innate Immune Response

PubMed Central

Chotirmall, Sanjay H.; Al-Alawi, Mazen; Logan, P. Mark; Greene, Catherine M.; McElvaney, Noel G.

2013-01-01

Aspergillus moulds exist ubiquitously as spores that are inhaled in large numbers daily. Whilst most are removed by anatomical barriers, disease may occur in certain circumstances. Depending on the underlying state of the human immune system, clinical consequences can ensue ranging from an excessive immune response during allergic bronchopulmonary aspergillosis to the formation of an aspergilloma in the immunocompetent state. The severest infections occur in those who are immunocompromised where invasive pulmonary aspergillosis results in high mortality rates. The diagnosis of Aspergillus-associated pulmonary disease is based on clinical, radiological, and immunological testing. An understanding of the innate and inflammatory consequences of exposure to Aspergillus species is critical in accounting for disease manifestations and preventing sequelae. The major components of the innate immune system involved in recognition and removal of the fungus include phagocytosis, antimicrobial peptide production, and recognition by pattern recognition receptors. The cytokine response is also critical facilitating cell-to-cell communication and promoting the initiation, maintenance, and resolution of the host response. In the following review, we discuss the above areas with a focus on the innate and inflammatory response to airway Aspergillus exposure and how these responses may be modulated for therapeutic benefit. PMID:23971044

Macrophage Internalization of Fungal β-Glucans Is Not Necessary for Initiation of Related Inflammatory Responses

PubMed Central

McCann, Frances; Carmona, Eva; Puri, Vishwajeet; Pagano, Richard E.; Limper, Andrew H.

2005-01-01

Cell wall β-glucans are highly conserved structural components of fungi that potently trigger inflammatory responses in an infected host. Identification of molecular mechanisms responsible for internalization and signaling of fungal β-glucans should enhance our understanding of innate immune responses to fungi. In this study, we demonstrated that internalization of fungal β-glucan particles requires actin polymerization but not participation of components of caveolar uptake mechanisms. Using fluorescence microscopy, we observed that uptake of 5-([4,6-dichlorotriazin-2-yl] amino)-fluorescein hydrochloride-Celite complex-labeled Saccharomyces cerevisiae β-glucan by RAW macrophages was substantially reduced in the presence of cytochalasin D, which antagonizes actin-mediated internalization pathways, but not by treatment with nystatin, which blocks caveolar uptake. Interestingly, β-glucan-induced NF-κB translocation, which is necessary for inflammatory activation, and tumor necrosis factor alpha production were both normal in the presence of cytochalasin D, despite defective internalization of β-glucan particles following actin disruption. Dectin-1, a major β-glucan receptor on macrophages, colocalized to phagocytic cups on macrophages and exhibited tyrosine phosphorylation after challenge with β-glucan particles. Dectin-1 localization and other membrane markers were not affected by treatment with cytochalasin D. Furthermore, dectin-1 receptors rather than Toll-like receptor 2 receptors were shown to be necessary for both efficient internalization of β-glucan particles and cytokine release in response to the fungal cell wall component. PMID:16177305

Stress-evoked sterile inflammation, danger associated molecular patterns (DAMPs), microbial associated molecular patterns (MAMPs) and the inflammasome.

PubMed

Fleshner, Monika

2013-01-01

Since the inception of the field of psychoneuroimmunolology research, there has been an appreciation that the physiological response to stressors includes modulation of immune function. Investigators initially focused on the effect of stress on cellular migration and immunosuppression and the resultant decreases in tumor surveillance, anti-viral T cell immunity and antigen-specific antibody responses. More recently, it has become clear that exposure to stressors also potentiate innate immune processes. Stressor exposure, for example, can change the activation status of myeloid lineage cells such as monocytes, macrophages, neutrophils, and microglia, leading to a primed state. In addition, stressor exposure increases the synthesis and release of a vast cadre' of inflammatory proteins both in the blood and within tissues (i.e., spleen, liver, adipose, vasculature and brain). The mechanisms for stress-evoked innate immune 'arousal' remain unknown. The goals of this presidential address are the following: (1) offer a personalized, brief overview of stress and immunity with a focus on 'aroused' innate immunity; (2) describe sterile inflammatory processes and the role of the inflammasome; and (3) suggest that these same processes likely contribute to primed myeloid cells and inflammatory protein responses (systemic and tissue) produced by stress in the absence of pathogens. Copyright © 2012 Elsevier Inc. All rights reserved.

Inhibition of Na+/H+ exchanger 1 by cariporide reduces burn-induced intestinal barrier breakdown.

PubMed

Yang, Xuekang; Chen, Ji; Bai, Hua; Tao, Ke; Zhou, Qin; Hou, Hongyi; Hu, Dahai

2013-12-01

Severe burns initiate an inflammatory cascade within the gut, which leads to intestinal mucosal injury. Although Na(+)/H(+) exchanger 1 (NHE1) is recognised as a pivotal player in several inflammatory processes, its role in burn-induced intestinal injury is relatively unknown. We hypothesised that NHE1 might be involved in the increased intestinal permeability and barrier breakdown after severe burns. Thus, we here investigate whether the inhibition of NHE1 has a protective effect on burn-induced intestinal injury. Mice were subjected to a 30% total body surface area (TBSA) full-thickness steam burn. Cariporide was used to assess the function of NHE1 in mice with burn-induced intestinal injury by fluorescence spectrophotometry, Western blotting and enzyme linked immunosorbent assay (ELISA). We found that severe burn increased intestinal permeability, associated with the up-regulation of NHE1 and raised inflammatory cytokine levels. Mice treated with the NHE1 inhibitor cariporide had significantly attenuated burn-induced intestinal permeability and a reduced inflammatory response. NHE1 inhibition also reduced nuclear factor-κB (NF-κB) activation and attenuated p38 mitogen-activated protein kinase (MAPK) phosphorylation. Our study suggests that NHE1 plays an important role in burn-induced intestinal permeability through the regulation of the inflammatory response. Inhibition of NHE1 may be adopted as a potential therapeutic strategy for attenuating intestinal barrier breakdown. Copyright © 2013 Elsevier Ltd and ISBI. All rights reserved.

Chronic inflammatory demyelinating polyneuropathy-like neuropathy as an initial presentation of Crohn's disease.

PubMed

Kim, Suji; Kang, Seok-Jae; Oh, Ki-Wook; Ahn, Byung Kyu; Lee, Hang Lak; Han, Dong Soo; Jang, Kiseok; Kim, Young Seo

2015-03-28

Chronic inflammatory demyelinating polyneuropathy (CIDP) is a rare complication of Crohn's disease (CD), and it is uncertain whether it is associated with CD itself or with its treatment. We describe a case of CIDP-like neuropathy as an initial symptom of CD. The neurologic symptoms of the patient which responded partially to intravenous immunoglobulin (IVIG) recovered after resection of the appendiceal CD. A 17-year-old male had experienced three separate attacks of motor weakness and paresthesia of all four extremities over a period of 7 months. The electrophysiologic findings revealed a demyelinating sensory-motor polyneuropathy which was compatible with CIDP. However, repeated intravenous IVIG (2 g/kg) treatment gave only a partial response. Four days after the last discharge, he was diagnosed as appendiceal CD after surgical resection of a periappendiceal abscess. His neurologic symptoms and electrophysiologic findings recovered without any maintenance therapy. CIDP-like neuropathy can be an initial presentation of CD, and recovery of the CIDP symptoms may result from resection of the CD. Clinicians should be aware of the possibility of CD in patients with intractable CIDP symptoms.

The duration of hypotension before the initiation of antibiotic treatment is a critical determinant of survival in a murine model of Escherichia coli septic shock: association with serum lactate and inflammatory cytokine levels.

PubMed

Kumar, Anand; Haery, Cameron; Paladugu, Bhanu; Kumar, Aseem; Symeoneides, Simon; Taiberg, Leo; Osman, Jailan; Trenholme, Gordon; Opal, Steven M; Goldfarb, Roy; Parrillo, Joseph E

2006-01-15

This study was designed to examine the relationship between the timing of antibiotic treatment and both survival rates and hemodynamic/inflammatory correlates of survival in a murine model of Escherichia coli septic shock. Surgical implantation of an E. coli (O18:K1:H7)-laced, gelatin capsule-encased fibrinogen clot was used to generate a bacteremic model of murine septic shock. Survival duration, hemodynamic responses, and circulating serum tumor necrosis factor (TNF)-alpha , interleukin (IL)-6, and lactate levels were assessed in relation to increasing delays in or absence of antibiotic treatment. A critical inflection point with respect to survival occurred between 12 and 15 h after implantation. When initiated at or before 12 h, antibiotic treatment resulted in < or = 20% mortality, but, when initiated at or after 15 h, it resulted in >85% mortality. Physiologically relevant hypotension developed in untreated septic mice by 12 h after implantation. Values for heart rate differed between untreated septic mice and sham-infected control mice by 6 h after implantation, whereas values for cardiac output and stroke volume did not differ until at least 18-24 h after implantation. Antibiotic treatment initiated > or = 12 h after implantation was associated with persistence of increased circulating serum lactate, TNF- alpha , and IL-6 levels. The timing of antibiotic treatment relative to hypotension is closely associated with survival in this murine model of septic shock. Delay in antibiotic treatment results in the persistence of inflammatory/stress markers even after antibiotic treatment is initiated.

Histamine Induces Bovine Rumen Epithelial Cell Inflammatory Response via NF-κB Pathway.

PubMed

Sun, Xudong; Yuan, Xue; Chen, Liang; Wang, Tingting; Wang, Zhe; Sun, Guoquan; Li, Xiaobing; Li, Xinwei; Liu, Guowen

2017-01-01

Subacute ruminal acidosis (SARA) is a common disease in high-producing lactating cows. Rumenitis is the initial insult of SARA and is associated with the high concentrations of histamine produced in the rumen of dairy cows during SARA. However, the exact mechanism remains unclear. The objective of the current study is to investigate whether histamine induces inflammation of rumen epithelial cells and the underlying mechanism of this process. Bovine rumen epithelial cells were cultured and treated with different concentrations of histamine and pyrrolidine dithiocarbamate (PDTC, an NF-κB inhibitor) cultured in different pH medium (pH 7.2 or 5.5). qRT-PCR, Western-blotting, ELISA and immunocytofluorescence were used to evaluate whether histamine activated the NF-κB pathway and inflammatory cytokines. The results showed that histamine significantly increased the activity of IKK β and the phosphorylation levels of IκB α, as well as upregulated the mRNA and protein expression levels of NF-κB p65 in the rumen epithelial cells cultured in neutral (pH=7.2) and acidic (pH=5.5) medium. Furthermore, histamine treatment also significantly increased the transcriptional activity of NF-κB p65. High expression and transcriptional activity of NF-κB p65 significantly increased the mRNA expressions and concentrations of inflammatory cytokines, tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6) and interleukin 1 beta (IL-1β), thereby inducing the inflammatory response in bovine rumen epithelial cells. However, inhibition of NF-κB p65 by PDTC significantly decreased the expressions and concentrations of the inflammatory cytokines induced by histamine in the rumen epithelial cells cultured in the neutral and acidic medium. The present data indicate that histamine induces the inflammatory response of bovine rumen epithelial cells through the NF-κB pathway. © 2017 The Author(s). Published by S. Karger AG, Basel.

Human inflammatory and resolving lipid mediator responses to resistance exercise and ibuprofen treatment

PubMed Central

Markworth, James F.; Vella, Luke; Lingard, Benjamin S.; Tull, Dedreia L.; Rupasinghe, Thusitha W.; Sinclair, Andrew J.; Maddipati, Krishna Rao

2013-01-01

Classical proinflammatory eicosanoids, and more recently discovered lipid mediators with anti-inflammatory and proresolving bioactivity, exert a complex role in the initiation, control, and resolution of inflammation. Using a targeted lipidomics approach, we investigated circulating lipid mediator responses to resistance exercise and treatment with the NSAID ibuprofen. Human subjects undertook a single bout of unaccustomed resistance exercise (80% of one repetition maximum) following oral ingestion of ibuprofen (400 mg) or placebo control. Venous blood was collected during early recovery (0–3 h and 24 h postexercise), and serum lipid mediator composition was analyzed by LC-MS-based targeted lipidomics. Postexercise recovery was characterized by elevated levels of cyclooxygenase (COX)-1 and 2-derived prostanoids (TXB2, PGE2, PGD2, PGF2α, and PGI2), lipooxygenase (5-LOX, 12-LOX, and 15-LOX)-derived hydroxyeicosatetraenoic acids (HETEs), and leukotrienes (e.g., LTB4), and epoxygenase (CYP)-derived epoxy/dihydroxy eicosatrienoic acids (EpETrEs/DiHETrEs). Additionally, we detected elevated levels of bioactive lipid mediators with anti-inflammatory and proresolving properties, including arachidonic acid-derived lipoxins (LXA4 and LXB4), and the EPA (E-series) and DHA (D-series)-derived resolvins (RvD1 and RvE1), and protectins (PD1 isomer 10S, 17S-diHDoHE). Ibuprofen treatment blocked exercise-induced increases in COX-1 and COX-2-derived prostanoids but also resulted in off-target reductions in leukotriene biosynthesis, and a diminished proresolving lipid mediator response. CYP pathway product metabolism was also altered by ibuprofen treatment, as indicated by elevated postexercise serum 5,6-DiHETrE and 8,9-DiHETrE only in those receiving ibuprofen. These findings characterize the blood inflammatory lipid mediator response to unaccustomed resistance exercise in humans and show that acute proinflammatory signals are mechanistically linked to the induction of a biological active inflammatory resolution program, regulated by proresolving lipid mediators during postexercise recovery. PMID:24089379

The systemic inflammatory response syndrome.

PubMed

Robertson, Charles M; Coopersmith, Craig M

2006-04-01

The systemic inflammatory response syndrome (SIRS) is the body's response to an infectious or noninfectious insult. Although the definition of SIRS refers to it as an "inflammatory" response, it actually has pro- and anti-inflammatory components. This review outlines the pathophysiology of SIRS and highlights potential targets for future therapeutic intervention in patients with this complex entity.

Opposing effects of low molecular weight heparins on the release of inflammatory cytokines from peripheral blood mononuclear cells of asthmatics.

PubMed

Shastri, Madhur D; Stewart, Niall; Eapen, Mathew; Peterson, Gregory M; Zaidi, Syed Tabish R; Gueven, Nuri; Sohal, Sukhwinder Singh; Patel, Rahul P

2015-01-01

T-cell-mediated inflammatory cytokines, such as interleukin (IL)-4, IL-5, IL-13 and tumor necrosis factor-alpha (TNF-α), play an important role in the initiation and progression of inflammatory airways diseases. Low-molecular-weight heparins (LMWHs), widely used anticoagulants, possess anti-inflammatory properties making them potential treatment options for inflammatory diseases, including asthma. In the current study, we investigated the modulating effects of two LMWHs (enoxaparin and dalteparin) on the release of cytokines from stimulated peripheral blood mononuclear cells (PBMCs) of asthmatic subjects to identify the specific components responsible for the effects. PBMCs from asthmatic subjects (consist of ~75% of T-cells) were isolated from blood taken from ten asthmatic subjects. The PBMCs were pre-treated in the presence or absence of different concentrations of LMWHs, and were then stimulated by phytohaemagglutinin for the release of IL-4, IL-5, IL-13 and TNF-α. LMWHs were completely or selectively desulfated and their anticoagulant effect, as well as the ability to modulate cytokine release, was determined. LMWHs were chromatographically fractionated and each fraction was tested for molecular weight determination along with an assessment of anticoagulant potency and effect on cytokine release. Enoxaparin inhibited cytokine release by more than 48%, whereas dalteparin increased their release by more than 25%. The observed anti-inflammatory effects of enoxaparin were independent of their anticoagulant activities. Smaller fractions, in particular dp4 (four saccharide units), were responsible for the inhibitory effect of enoxaparin. Whereas, the larger fractions, in particular dp22 (twenty two saccharide units), were associated with the stimulatory effect of dalteparin. Enoxaparin and dalteparin demonstrated opposing effects on inflammatory markers. These observed effects could be due to the presence of structurally different components in the two LMWHs arising from different methods of depolymerisation. This study provides a platform for further studies investigating the usefulness of enoxaparin in various inflammatory diseases.

Training reduces catabolic and inflammatory response to a single practice in female volleyball players.

PubMed

Eliakim, Alon; Portal, Shawn; Zadik, Zvi; Meckel, Yoav; Nemet, Dan

2013-11-01

We examined the effect of training on hormonal and inflammatory response to a single volleyball practice in elite adolescent players. Thirteen female, national team level, Israeli volleyball players (age 16.0 ± 1.4 years, Tanner stage 4-5) participated in the study. Blood samples were collected before and immediately after a typical 60 minutes of volleyball practice, before and after 7 weeks of training during the initial phase of the season. Training involved tactic and technical drills (20% of time), power and speed drills (25% of time), interval sessions (25% of time), endurance-type training (15% of time), and resistance training (15% of time). To achieve greater training responses, the study was performed during the early phase (first 7 weeks) of the volleyball season. Hormonal measurements included the anabolic hormones growth hormone (GH), insulin-like growth factor-I (IGF-I) and IGF-binding protein-3, the catabolic hormone cortisol, the proinflammatory marker interleukin-6 (IL-6), and the anti-inflammatory marker IL-1 receptor antagonist. Training led to a significant improvement of vertical jump, anaerobic properties (peak and mean power by the Wingate Anaerobic Test), and predicted VO2max (by the 20-m shuttle run). Volleyball practice, both before and after the training intervention, was associated with a significant increase of serum lactate, GH, and IL-6. Training resulted in a significantly reduced cortisol response ([INCREMENT]cortisol: 4.2 ± 13.7 vs. -4.4 ± 12.3 ng · ml, before and after training, respectively; p < 0.02), and IL-6 response ([INCREMENT]IL-6: 1.3 ± 1.0 vs. 0.3 ± 0.4 pg · ml, before and after training, respectively; p < 0.01) to the same relative intensity volleyball practice. The results suggest that along with the improvement of power and anaerobic and aerobic characteristics, training reduces the catabolic and inflammatory response to exercise.

Natural Killer T Cells: An Ecological Evolutionary Developmental Biology Perspective

PubMed Central

Kumar, Amrendra; Suryadevara, Naveenchandra; Hill, Timothy M.; Bezbradica, Jelena S.; Van Kaer, Luc; Joyce, Sebastian

2017-01-01

Type I natural killer T (NKT) cells are innate-like T lymphocytes that recognize glycolipid antigens presented by the MHC class I-like protein CD1d. Agonistic activation of NKT cells leads to rapid pro-inflammatory and immune modulatory cytokine and chemokine responses. This property of NKT cells, in conjunction with their interactions with antigen-presenting cells, controls downstream innate and adaptive immune responses against cancers and infectious diseases, as well as in several inflammatory disorders. NKT cell properties are acquired during development in the thymus and by interactions with the host microbial consortium in the gut, the nature of which can be influenced by NKT cells. This latter property, together with the role of the host microbiota in cancer therapy, necessitates a new perspective. Hence, this review provides an initial approach to understanding NKT cells from an ecological evolutionary developmental biology (eco-evo-devo) perspective. PMID:29312339

C-reactive protein as a marker of periodontal disease.

PubMed

Kanaparthy, Rosaiah; Kanaparthy, Aruna; Mahendra, Muktishree

2012-01-01

Periodontal subgingival pathogens affect local and systemic immune and inflammatory response and cause the release of cytokines; this results in periodontal destruction and initiation of an acute phase systemic inflammatory response characterized by the release of C-reactive proteins (CRP). This study set out to evaluate the serum concentration of CRP that can be used as a marker of periodontal disease as well as a risk indicator for cardiovascular disease. Based on their periodontal status, 45 patients were divided into three groups. The following clinical parameters were recorded: plaque index, gingival index, bleeding index, probing pocket depth, and clinical attachment levels. Scoring was done on six tooth surfaces for all teeth. For the CRP assessment, blood samples were collected from subjects at the time of clinical examination. The results indicated an increase in serum CRP levels in patients with generalized aggressive periodontitis and chronic periodontitis as compared to controls.

Natural Killer T Cells: An Ecological Evolutionary Developmental Biology Perspective.

PubMed

Kumar, Amrendra; Suryadevara, Naveenchandra; Hill, Timothy M; Bezbradica, Jelena S; Van Kaer, Luc; Joyce, Sebastian

2017-01-01

Type I natural killer T (NKT) cells are innate-like T lymphocytes that recognize glycolipid antigens presented by the MHC class I-like protein CD1d. Agonistic activation of NKT cells leads to rapid pro-inflammatory and immune modulatory cytokine and chemokine responses. This property of NKT cells, in conjunction with their interactions with antigen-presenting cells, controls downstream innate and adaptive immune responses against cancers and infectious diseases, as well as in several inflammatory disorders. NKT cell properties are acquired during development in the thymus and by interactions with the host microbial consortium in the gut, the nature of which can be influenced by NKT cells. This latter property, together with the role of the host microbiota in cancer therapy, necessitates a new perspective. Hence, this review provides an initial approach to understanding NKT cells from an ecological evolutionary developmental biology (eco-evo-devo) perspective.

Vaccine antigens modulate the innate response of monocytes to Al(OH)3

PubMed Central

Brummelman, Jolanda; van Els, Cécile A. C. M.; Marino, Fabio; Heck, Albert J. R.; van Riet, Elly; Metz, Bernard; Kersten, Gideon F. A.; Pennings, Jeroen L. A.; Meiring, Hugo D.

2018-01-01

Aluminum-based adjuvants have widely been used in human vaccines since 1926. In the absence of antigens, aluminum-based adjuvants can initiate the inflammatory preparedness of innate cells, yet the impact of antigens on this response has not been investigated so far. In this study, we address the modulating effect of vaccine antigens on the monocyte-derived innate response by comparing processes initiated by Al(OH)3 and by Infanrix, an Al(OH)3-adjuvanted trivalent combination vaccine (DTaP), containing diphtheria toxoid (D), tetanus toxoid (T) and acellular pertussis (aP) vaccine antigens. A systems-wide analysis of stimulated monocytes was performed in which full proteome analysis was combined with targeted transcriptome analysis and cytokine analysis. This comprehensive study revealed four major differences in the monocyte response, between plain Al(OH)3 and DTaP stimulation conditions: (I) DTaP increased the anti-inflammatory cytokine IL-10, whereas Al(OH)3 did not; (II) Al(OH)3 increased the gene expression of IFNγ, IL-2 and IL-17a in contrast to the limited induction or even downregulation by DTaP; (III) increased expression of type I interferons-induced proteins was not observed upon DTaP stimulation, but was observed upon Al(OH)3 stimulation; (IV) opposing regulation of protein localization pathways was observed for Al(OH)3 and DTaP stimulation, related to the induction of exocytosis by Al(OH)3 alone. This study highlights that vaccine antigens can antagonize Al(OH)3-induced programming of the innate immune responses at the monocyte level. PMID:29813132

Blood-brain barrier hyperpermeability precedes demyelination in the cuprizone model.

PubMed

Berghoff, Stefan A; Düking, Tim; Spieth, Lena; Winchenbach, Jan; Stumpf, Sina K; Gerndt, Nina; Kusch, Kathrin; Ruhwedel, Torben; Möbius, Wiebke; Saher, Gesine

2017-12-01

In neuroinflammatory disorders such as multiple sclerosis, the physiological function of the blood-brain barrier (BBB) is perturbed, particularly in demyelinating lesions and supposedly secondary to acute demyelinating pathology. Using the toxic non-inflammatory cuprizone model of demyelination, we demonstrate, however, that the onset of persistent BBB impairment precedes demyelination. In addition to a direct effect of cuprizone on endothelial cells, a plethora of inflammatory mediators, which are mainly of astroglial origin during the initial disease phase, likely contribute to the destabilization of endothelial barrier function in vivo. Our study reveals that, at different time points of pathology and in different CNS regions, the level of gliosis correlates with the extent of BBB hyperpermeability and edema. Furthermore, in mutant mice with abolished type 3 CXC chemokine receptor (CXCR3) signaling, inflammatory responses are dampened and BBB dysfunction ameliorated. Together, these data have implications for understanding the role of BBB permeability in the pathogenesis of demyelinating disease.

Biocompatibility, Inflammatory Response, and Recannalization Characteristics of Nonradioactive Resin Microspheres: Histological Findings

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

Bilbao, Jose I., E-mail: Jibilbao@unav.e; Martino, Alba de; Luis, Esther de

2009-07-15

Intra-arterial radiotherapy with yttrium-90 microspheres (radioembolization) is a therapeutic procedure exclusively applied to the liver that allows the direct delivery of high-dose radiation to liver tumors, by means of endovascular catheters, selectively placed within the tumor vasculature. The aim of the study was to describe the distribution of spheres within the precapillaries, inflammatory response, and recannalization characteristics after embolization with nonradioactive resin microspheres in the kidney and liver. We performed a partial embolization of the liver and kidney vessels in nine white pigs. The left renal and left hepatic arteries were catheterized and filled with nonradioactive resin microspheres. Embolization wasmore » defined as the initiation of near-stasis of blood flow, rather than total occlusion of the vessels. The hepatic circulation was not isolated so that the effects of reflux of microspheres into stomach could be observed. Animals were sacrificed at 48 h, 4 weeks, and 8 weeks, and tissue samples from the kidney, liver, lung, and stomach evaluated. Microscopic evaluation revealed clusters of 10-30 microspheres (15-30 {mu}m in diameter) in the small vessels of the kidney (the arciform arteries, vasa recti, and glomerular afferent vessels) and liver. Aggregates were associated with focal ischemia and mild vascular wall damage. Occlusion of the small vessels was associated with a mild perivascular inflammatory reaction. After filling of the left hepatic artery with microspheres, there was some evidence of arteriovenous shunting into the lungs, and one case of cholecystitis and one case of marked gastritis and ulceration at the site of arterial occlusion due to the presence of clusters of microspheres. Beyond 48 h, microspheres were progressively integrated into the vascular wall by phagocytosis and the lumen recannalized. Eight-week evaluation found that the perivascular inflammatory reaction was mild. Liver cell damage, bile duct injury, and portal space fibrosis were not observed. In conclusion, resin microspheres (15-30 {mu}m diameter) trigger virtually no inflammatory response in target tissues (liver and kidney). Clusters rather than individual microspheres were associated with a mild to moderate perivascular inflammatory reaction. There was no evidence of either a prolonged inflammatory reaction or fibrosis in the liver parenchyma following recannalization.« less

Harnessing dendritic cells in inflammatory skin diseases

PubMed Central

Chu, Chung-Ching; Di Meglio, Paola; Nestle, Frank O.

2011-01-01

The skin immune system harbors a complex network of dendritic cells (DCs). Recent studies highlight a diverse functional specialization of skin DC subsets. In addition to generating cellular and humoral immunity against pathogens, skin DCs are involved in tolerogenic mechanisms to ensure the maintenance of immune homeostasis, as well as in pathogenesis of chronic inflammation in the skin when excessive immune responses are initiated and unrestrained. Harnessing DCs by directly targeting DC-derived molecules or selectively modulate DC subsets is a convincing strategy to tackle inflammatory skin diseases. In this review we discuss recent advances underlining the functional specialization of skin DCs and discuss the potential implication for future DC-based therapeutic strategies. PMID:21295490

Proprotein convertase furin/PCSK3 and atherosclerosis: New insights and potential therapeutic targets.

PubMed

Ren, Kun; Jiang, Ting; Zheng, Xi-Long; Zhao, Guo-Jun

2017-07-01

Furin, a member of the mammalian proprotein convertases family, can promote the proteolytic maturation of proproteins. It is known that furin is predominantly present in certain cell types of human atherosclerotic lesions and neointima in animal models, including vascular smooth muscle cells, endothelial cells and mononuclear inflammatory cells. Evidence suggests that furin participates in the initiation and progression of atherosclerosis through regulation of lipid and cholesterol metabolism, inflammatory response, blood pressure and the formation of atherosclerotic lesions. This review provides a panorama of the roles of furin in atherosclerosis and the insights into the prevention and treatment of atherosclerosis and cardiovascular disease. Copyright © 2017 Elsevier B.V. All rights reserved.

Edema: a silent but important factor.

PubMed

Villeco, June P

2012-01-01

Edema is a normal response to injury. Even the smallest injury is associated with some inflammation, and initial edema is part of the normal inflammatory process. However, edema becomes a concern when it persists beyond the inflammatory phase. Once we have progressed into the rebuilding, or fibroplastic phase of healing, edema will delay healing and contribute to complications such as pain and stiffness. Early prevention and management to prevent this progression are therefore critical. This article discusses edema in relation to stages of healing and presents the research behind techniques available to the clinician to manage localized extracellular upper extremity edema in the patient with an intact lymphatic system. Copyright © 2012 Hanley & Belfus. Published by Elsevier Inc. All rights reserved.

Contribution of vascular cell-derived cytokines to innate and inflammatory pathways in atherogenesis

PubMed Central

Loppnow, Harald; Buerke, Michael; Werdan, Karl; Rose-John, Stefan

2011-01-01

Abstract Inflammation is a central element of atherogenesis. Innate pathways contribute to vascular inflammation. However, the initial molecular process(es) starting atherogenesis remain elusive. The various risk factors, represented by particular compounds (activators), may cause altered cellular functions in the endothelium (e.g. vascular endothelial cell activation or -dysfunction), in invading cells (e.g. inflammatory mediator production) or in local vessel wall cells (e.g. inflammatory mediators, migration), thereby triggering the innate inflammatory process. The cellular components of innate immunology include granulocytes, natural killer cells and monocytes. Among the molecular innate constituents are innate molecules, such as the toll-like receptors or innate cytokines. Interleukin-1 (IL-1) and IL-6 are among the innate cytokines. Cytokines are potent activators of a great number of cellular functions relevant to maintain or commove homeostasis of the vessel wall. Within the vessel wall, vascular smooth muscle cells (SMCs) can significantly contribute to the cytokine-dependent inflammatory network by: (i) production of cytokines, (ii) response to cytokines and (iii) cytokine-mediated interaction with invading leucocytes. The cytokines IL-1 and IL-6 are involved in SMC-leucocyte interaction. The IL-6 effects are proposed to be mediated by trans-signalling. Dysregulated cellular functions resulting from dysregulated cytokine production may be the cause of cell accumulation, subsequent low-density lipoprotein accumulation and deposition of extracellular matrix (ECM). The deposition of ECM, increased accumulation of leucocytes and altered levels of inflammatory mediators may constitute an ‘innate-immunovascular-memory’ resulting in an ever-growing response to anew invasion. Thus, SMC-fostered inflammation, promoted by invading innate cells, may be a potent component for development and acceleration of atherosclerosis. PMID:21199323

Unraveling the Complex Relationship Triad between Lipids, Obesity, and Inflammation

PubMed Central

Khan, Shahida A.; Khan, Sarah A.; Zahran, Solafa A.; Damanhouri, Ghazi

2014-01-01

Obesity today stands at the intersection between inflammation and metabolic disorders causing an aberration of immune activity, and resulting in increased risk for diabetes, atherosclerosis, fatty liver, and pulmonary inflammation to name a few. Increases in mortality and morbidity in obesity related inflammation have initiated studies to explore different lipid mediated molecular pathways of attempting resolution that uncover newer therapeutic opportunities of anti-inflammatory components. Majorly the thromboxanes, prostaglandins, leukotrienes, lipoxins, and so forth form the group of lipid mediators influencing inflammation. Of special mention are the omega-6 and omega-3 fatty acids that regulate inflammatory mediators of interest in hepatocytes and adipocytes via the cyclooxygenase and lipoxygenase pathways. They also exhibit profound effects on eicosanoid production. The inflammatory cyclooxygenase pathway arising from arachidonic acid is a critical step in the progression of inflammatory responses. New oxygenated products of omega-3 metabolism, namely, resolvins and protectins, behave as endogenous mediators exhibiting powerful anti-inflammatory and immune-regulatory actions via the peroxisome proliferator-activated receptors (PPARs) and G protein coupled receptors (GPCRs). In this review we attempt to discuss the complex pathways and links between obesity and inflammation particularly in relation to different lipid mediators. PMID:25258478

Endogenous adenosine produced during hypoxia attenuates neutrophil accumulation: coordination by extracellular nucleotide metabolism.

PubMed

Eltzschig, Holger K; Thompson, Linda F; Karhausen, Jorn; Cotta, Richard J; Ibla, Juan C; Robson, Simon C; Colgan, Sean P

2004-12-15

Hypoxia is a well-documented inflammatory stimulus and results in tissue polymorphonuclear leukocyte (PMN) accumulation. Likewise, increased tissue adenosine levels are commonly associated with hypoxia, and given the anti-inflammatory properties of adenosine, we hypothesized that adenosine production via adenine nucleotide metabolism at the vascular surface triggers an endogenous anti-inflammatory response during hypoxia. Initial in vitro studies indicated that endogenously generated adenosine, through activation of PMN adenosine A(2A) and A(2B) receptors, functions as an antiadhesive signal for PMN binding to microvascular endothelia. Intravascular nucleotides released by inflammatory cells undergo phosphohydrolysis via hypoxia-induced CD39 ectoapyrase (CD39 converts adenosine triphosphate/adenosine diphosphate [ATP/ADP] to adenosine monophosphate [AMP]) and CD73 ecto-5'-nucleotidase (CD73 converts AMP to adenosine). Extensions of our in vitro findings using cd39- and cd73-null animals revealed that extracellular adenosine produced through adenine nucleotide metabolism during hypoxia is a potent anti-inflammatory signal for PMNs in vivo. These findings identify CD39 and CD73 as critical control points for endogenous adenosine generation and implicate this pathway as an innate mechanism to attenuate excessive tissue PMN accumulation.

Rheumatoid arthritis vaccine therapies: perspectives and lessons from therapeutic ligand epitope antigen presentation system vaccines for models of rheumatoid arthritis

PubMed Central

Rosenthal, Kenneth S.; Mikecz, Katalin; Steiner, Harold L.; Glant, Tibor T.; Finnegan, Alison; Carambula, Roy E.; Zimmerman, Daniel H.

2016-01-01

The current status of therapeutic vaccines for autoimmune diseases is reviewed with rheumatoid arthritis as the focus. Therapeutic vaccines for autoimmune diseases must regulate or subdue responses to common self-antigens. Ideally, such a vaccine would initiate an antigen-specific modulation of the T-cell immune response that drives the inflammatory disease. Appropriate animal models and types of T helper cells and signature cytokine responses that drive autoimmune disease are also discussed. Interpretation of these animal models must be done cautiously because the means of initiation, autoantigens, and even the signature cytokine and T helper cell (Th1 or Th17) responses that are involved in the disease may differ significantly from those in humans. We describe ligand epitope antigen presentation system vaccine modulation of T-cell autoimmune responses as a strategy for the design of therapeutic vaccines for rheumatoid arthritis, which may also be effective in other autoimmune conditions. PMID:25787143

Functional analysis of HPV-like particle-activated Langerhans cells in vitro.

PubMed

Yan, Lisa; Woodham, Andrew W; Da Silva, Diane M; Kast, W Martin

2015-01-01

Langerhans cells (LCs) are antigen-presenting cells responsible for initiating an immune response against human papillomaviruses (HPVs) entering the epithelial layer in vivo as they are the first immune cell that HPV comes into contact with. LCs become activated in response to foreign antigens, which causes internal signaling resulting in the increased expression of co-stimulatory molecules and the secretion of inflammatory cytokines. Functionally activated LCs are then capable of migrating to the lymph nodes where they interact with antigen-specific T cells and initiate an adaptive T-cell response in vivo. However, HPV has evolved in a manner that suppresses LC function, and thus the induction of antigen-specific T cells is hindered. While many methods exist to monitor the activity of LCs in vitro, the migration and induction of cytotoxic T cells is ultimately indicative of a functional immune response. Here, methods in analyzing functional migration and induction of antigen-specific T cells after stimulation of LCs with HPV virus-like particles in vitro are described.

Rheumatoid arthritis synovial fibroblasts produce a soluble form of the interleukin-7 receptor in response to pro-inflammatory cytokines

PubMed Central

Badot, V; Durez, P; Van den Eynde, BJ; Nzeusseu-Toukap, A; Houssiau, FA; Lauwerys, BR

2011-01-01

Abstract We previously demonstrated that baseline synovial overexpression of the interleukin-7 receptor α-chain (IL-7R) is associated with poor response to tumour necrosis factor (TNF) blockade in rheumatoid arthritis (RA). We found that IL-7R gene expression is induced in fibroblast-like synovial cells (FLS) by the addition of TNF-α, IL-1β and combinations of TNF-α+ IL-1β or TNF-α+ IL-17, thereby suggesting that these cytokines play a role in the resistance to TNF blockade in RA. Because FLS and CD4 T cells also produce a soluble form of IL-7R (sIL-7R), resulting from an alternative splicing of the full-length transcript, we wondered whether expression of sIL-7R is similarly regulated by pro-inflammatory cytokines. We also investigated whether sIL-7R is detectable in the serum of RA patients and associated with response to TNF blockade. RA FLS were cultured in the presence of pro-inflammatory cytokines and sIL-7R concentrations were measured in culture supernatants. Similarly, sIL-7R titres were measured in sera obtained from healthy individuals, early untreated RA patients with active disease and disease-modifying anti-rheumatic drug (DMARD)-resistant RA patients prior to initiation of TNF-blockade. Baseline serum sIL-7R titres were correlated with validated clinical measurements of disease activity. We found that exposure of RA FLS to pro-inflammatory cytokines (TNF-α, IL-1β and combinations of TNF-α and IL-1β or TNF-α and IL-17) induces sIL-7R secretion. Activated CD4 T cells also produce sIL-7R. sIL-7R serum levels are higher in RA patients as compared to controls. In DMARD-resistant patients, high sIL-7R serum concentrations are strongly associated with poor response to TNF-blockade. In conclusion, sIL-7R is induced by pro-inflammatory cytokines in RA FLS. sIL-7R could qualify as a new biomarker of response to therapy in RA. PMID:21129157

Multi-Walled Carbon Nanotubes Augment Allergic Airway Eosinophilic Inflammation by Promoting Cysteinyl Leukotriene Production.

PubMed

Carvalho, Sophia; Ferrini, Maria; Herritt, Lou; Holian, Andrij; Jaffar, Zeina; Roberts, Kevan

2018-01-01

Multi-walled carbon nanotubes (MWCNT) have been reported to promote lung inflammation and fibrosis. The commercial demand for nanoparticle-based materials has expanded rapidly and as demand for nanomaterials grows, so does the urgency of establishing an appreciation of the degree of health risk associated with their increased production and exposure. In this study, we examined whether MWCNT inhalation elicited pulmonary eosinophilic inflammation and influenced the development of allergic airway inflammatory responses. Our data revealed that instillation of FA21 MWCNT into the airways of mice resulted in a rapid increase, within 24 h, in the number of eosinophils present in the lungs. The inflammatory response elicited was also associated with an increase in the level of cysteinyl leukotrienes (cysLTs) present in the bronchoalveolar lavage fluid. CysLTs were implicated in the airway inflammatory response since pharmacological inhibition of their biosynthesis using the 5-lipoxygenase inhibitor Zileuton resulted in a marked reduction in the severity of inflammation observed. Moreover, FA21 MWCNT entering the airways of mice suffering from house dust mite (HDM)-elicited allergic lung inflammation markedly exacerbated the intensity of the airway inflammation. This response was characterized by a pulmonary eosinophilia, lymphocyte infiltration, and raised cysLT levels. The severity of pulmonary inflammation caused by either inhalation of MWCNT alone or in conjunction with HDM allergen correlated with the level of nickel present in the material, since preparations that contained higher levels of nickel (FA21, 5.54% Ni by weight) were extremely effective at eliciting or exacerbating inflammatory or allergic responses while preparations containing lower amounts of nickel (FA04, 2.54% Ni by weight) failed to initiate or exacerbate pulmonary inflammation. In summary, instillation of high nickel MWCNT into the lungs promoted eosinophilic inflammation and caused an intense exacerbation of pre-existing allergic airway inflammation by facilitating cysLT biosynthesis. These findings suggest that exposure to airborne MWCNT is likely to have adverse inflammatory effects in individuals suffering from atopic asthma and, in this context, further investigation of the therapeutic effects of pharmacological agents that block leukotriene synthesis is warranted.

The utility of fecal calprotectin in predicting the need for escalation of therapy in inflammatory bowel disease.

PubMed

Kwapisz, Lukasz; Gregor, Jamie; Chande, Nilesh; Yan, Brian; Ponich, Terry; Mosli, Mahmoud

2017-08-01

Fecal calprotectin is an important biomarker used in the evaluation of inflammatory bowel disease. It has proven to be an effective tool in initial screening as well monitoring response to therapy. The aim of this study is to examine the utility of fecal calprotectin both as a predictor for the escalation of therapy in established inflammatory bowel disease and as a predictor of de novo diagnosis. Patients with signs and symptoms concerning for inflammatory bowel disease presenting to outpatient clinics were recruited to provide fecal calprotectin stool samples prior to endoscopic evaluation. Patients were followed up for at least one year and monitored clinically for any change in symptomatology, escalation of therapy or development of IBD, confirmed endoscopically. A total of 126 patients, of whom 72 were known to have underlying inflammatory bowel disease, were included in the final analysis. Among the patients with elevated fecal calprotectin levels and known inflammatory bowel disease, 66% (33/50) went on to have escalation of therapy within 12 months compared to 18% (4/22) if the fecal calprotectin levels were in the normal range (p < .0001). For the remaining patients who at baseline did not have inflammatory bowel disease and a normal endoscopic evaluation, elevated fecal calprotectin resulted in no cases (0/17) of a new diagnosis in the next 12 months. Fecal calprotectin is a useful test for predicting escalation of therapy in established inflammatory bowel disease.

Mycobacterium abscessus-Induced Granuloma Formation Is Strictly Dependent on TNF Signaling and Neutrophil Trafficking

PubMed Central

Bernut, Audrey; Nguyen-Chi, Mai; Kremer, Laurent

2016-01-01

Mycobacterium abscessus is considered the most common respiratory pathogen among the rapidly growing non-tuberculous mycobacteria. Infections with M. abscessus are increasingly found in patients with chronic lung diseases, especially cystic fibrosis, and are often refractory to antibiotic therapy. M. abscessus has two morphotypes with distinct effects on host cells and biological responses. The smooth (S) variant is recognized as the initial airway colonizer while the rough (R) is known to be a potent inflammatory inducer associated with invasive disease, but the underlying immunopathological mechanisms of the infection remain unsolved. We conducted a comparative stepwise dissection of the inflammatory response in S and R pathogenesis by monitoring infected transparent zebrafish embryos. Loss of TNFR1 function resulted in increased mortality with both variants, and was associated with unrestricted intramacrophage bacterial growth and decreased bactericidal activity. The use of transgenic zebrafish lines harboring fluorescent macrophages and neutrophils revealed that neutrophils, like macrophages, interact with M. abscessus at the initial infection sites. Impaired TNF signaling disrupted the IL8-dependent neutrophil mobilization, and the defect in neutrophil trafficking led to the formation of aberrant granulomas, extensive mycobacterial cording, unrestricted bacterial growth and subsequent larval death. Our findings emphasize the central role of neutrophils for the establishment and maintenance of the protective M. abscessus granulomas. These results also suggest that the TNF/IL8 inflammatory axis is necessary for protective immunity against M. abscessus and may be of clinical relevance to explain why immunosuppressive TNF therapy leads to the exacerbation of M. abscessus infections. PMID:27806130

Does neuroinflammation drive the relationship between tau hyperphosphorylation and dementia development following traumatic brain injury?

PubMed

Collins-Praino, Lyndsey E; Corrigan, Frances

2017-02-01

A history of traumatic brain injury (TBI) is linked to an increased risk for the later development of dementia. This encompasses a variety of neurodegenerative diseases including Alzheimer's Disease (AD) and chronic traumatic encephalopathy (CTE), with AD linked to history of moderate-severe TBI and CTE to a history of repeated concussion. Of note, both AD and CTE are characterized by the abnormal accumulation of hyperphosphorylated tau aggregates, which are thought to play an important role in the development of neurodegeneration. Hyperphosphorylation of tau leads to destabilization of microtubules, interrupting axonal transport, whilst tau aggregates are associated with synaptic dysfunction. The exact mechanisms via which TBI may promote the later tauopathy and its role in the later development of dementia are yet to be fully determined. Following TBI, it is proposed that axonal injury may provide the initial perturbation of tau, by promoting its dissociation from microtubules, facilitating its phosphorylation and aggregation. Altered tau dynamics may then be exacerbated by the chronic persistent inflammatory response that has been shown to persist for decades following the initial impact. Importantly, immune activation has been shown to play a role in accelerating disease progression in other tauopathies, with pro-inflammatory cytokines, like IL-1β, shown to activate kinases that promote tau hyperphosphorylation. Thus, targeting the inflammatory response in the sub-acute phase following TBI may represent a promising target to halt the alterations in tau dynamics that may precede overt neurodegeneration and later development of dementia. Copyright © 2016 Elsevier Inc. All rights reserved.

Induction of Pro-Inflammatory Response via Activated Macrophage-Mediated NF-κB and STAT3 Pathways in Gastric Cancer Cells.

PubMed

Zhou, Yujuan; Xia, Longzheng; Liu, Qiang; Wang, Heran; Lin, Jingguan; Oyang, Linda; Chen, Xiaoyan; Luo, Xia; Tan, Shiming; Tian, Yutong; Su, Min; Wang, Ying; Chen, Pan; Wu, Yang; Wang, Hui; Liao, Qianjin

2018-06-19

Chronic inflammation plays an important role in the initiation and progression of gastric cancer (GC). However, the role and relationship of activated macrophages with gastric mucous epithelium cells in initiating and maintaining the inflammatory process during gastric carcinogenesis remains unclear. The tumour associated macrophages (TAMs) density of gastric cancer was characterized by immunohistochemistry, and the relationship between macrophages and gastric epithelium cells was analysed using an in vitro culture system that imitates the inflammatory microenvironment. The production of pro-inflammatory cytokines was detected by enzyme-linked immunosorbent assay (ELISA) and quantitative real-time PCR (qRT-PCR). MTT assays, Western blotting, qRT-PCR, and luciferase reporter assays were used to detect the effects of cell proliferation, as well as the NF-κB and STAT3 signalling pathways. TAMs infiltrated with a high intensity in GC and were significantly correlated with histology grade (P = 0.012), metastasis (P = 0.001), TNM stage (P = 0.002), and poor prognosis in patients (PFS, P = 0.005; OS, P = 0.028). In addition, IL-6 and IL-8 were elevated in the serum of GC patients and significantly promoted the growth of GC. The exposure of BGC823 gastric cancer cells to a conditioned medium from LPS-treated D-THP-1 cells significantly induced the production of TNF-α, IL-6, IL-1β and IL-8 (P< 0.01). LPS and LPS-treated D-THP-1-conditioned media promoted gastric cancer cell proliferation and triggered the significant activation of NF-κB and STAT3 with a concomitant degradation of IκBα and an increase in JAK2 phosphorylation (P < 0.05). Moreover, gastric cancer cells markedly expressed cell membrane LPS receptors, such as TLR1, TLR4, TLR6, CD14 and MD2. TAMs are closely associated with the growth of GC and prognosis in GC patients. GC cells may directly sustain and amplify the local pro-inflammatory response upon encountering activated macrophages and LPS via NF-κB and STAT3 signalling pathways, thereby promoting tumour progression. © 2018 The Author(s). Published by S. Karger AG, Basel.

Airway inflammation in cystic fibrosis: molecular mechanisms and clinical implications.

PubMed

Cohen-Cymberknoh, Malena; Kerem, Eitan; Ferkol, Thomas; Elizur, Arnon

2013-12-01

Airway epithelial cells and immune cells participate in the inflammatory process responsible for much of the pathology found in the lung of patients with cystic fibrosis (CF). Intense bronchial neutrophilic inflammation and release of proteases and oxygen radicals perpetuate the vicious cycle and progressively damage the airways. In vitro studies suggest that CF transmembrane conductance regulator (CFTR)-deficient airway epithelial cells display signalling abnormalities and aberrant intracellular processes which lead to transcription of inflammatory mediators. Several transcription factors, especially nuclear factor-κB, are activated. In addition, the accumulation of abnormally processed CFTR in the endoplasmic reticulum results in unfolded protein responses that trigger 'cell stress' and apoptosis leading to dysregulation of the epithelial cells and innate immune function in the lung, resulting in exaggerated and ineffective airway inflammation. Measuring airway inflammation is crucial for initiating treatment and monitoring its effect. No inflammatory biomarker predictive for the clinical course of CF lung disease is currently known, although neutrophil elastase seems to correlate with lung function decline. CF animal models mimicking human lung disease may provide an important insight into the pathogenesis of lung inflammation in CF and identify new therapeutic targets.

The role of microglia and myeloid immune cells in acute cerebral ischemia

PubMed Central

Benakis, Corinne; Garcia-Bonilla, Lidia; Iadecola, Costantino; Anrather, Josef

2015-01-01

The immune response to acute cerebral ischemia is a major contributor to stroke pathobiology. The inflammatory response is characterized by the participation of brain resident cells and peripheral leukocytes. Microglia in the brain and monocytes/neutrophils in the periphery have a prominent role in initiating, sustaining and resolving post-ischemic inflammation. In this review we aim to summarize recent literature concerning the origins, fate and role of microglia, monocytes and neutrophils in models of cerebral ischemia and to discuss their relevance for human stroke. PMID:25642168

Trauma-induced systemic inflammatory response versus exercise-induced immunomodulatory effects.

PubMed

Fehrenbach, Elvira; Schneider, Marion E

2006-01-01

Accidental trauma and heavy endurance exercise, both induce a kind of systemic inflammatory response, also called systemic inflammatory response syndrome (SIRS). Exercise-related SIRS is conditioned by hyperthermia and concomitant heat shock responses, whereas trauma-induced SIRS manifests concomitantly with tissue necrosis and immune activation, secondarily followed by fever. Inflammatory cytokines are common denominators in both trauma and exercise, although there are marked quantitative differences. Different anti-inflammatory cytokines may be involved in the control of inflammation in trauma- and exercise-induced stress. Exercise leads to a balanced equilibrium between inflammatory and anti-inflammatory responses. Intermittent states of rest, as well as anti-oxidant capacity, are lacking or minor in trauma but are high in exercising individuals. Regular training may enhance immune competence, whereas trauma-induced SIRS often paves the way for infectious complications, such as sepsis.

Protein kinase inhibitors in the treatment of inflammatory and autoimmune diseases

PubMed Central

Patterson, H; Nibbs, R; McInnes, I; Siebert, S

2014-01-01

Protein kinases mediate protein phosphorylation, which is a fundamental component of cell signalling, with crucial roles in most signal transduction cascades: from controlling cell growth and proliferation to the initiation and regulation of immunological responses. Aberrant kinase activity is implicated in an increasing number of diseases, with more than 400 human diseases now linked either directly or indirectly to protein kinases. Protein kinases are therefore regarded as highly important drug targets, and are the subject of intensive research activity. The success of small molecule kinase inhibitors in the treatment of cancer, coupled with a greater understanding of inflammatory signalling cascades, has led to kinase inhibitors taking centre stage in the pursuit for new anti-inflammatory agents for the treatment of immune-mediated diseases. Herein we discuss the main classes of kinase inhibitors; namely Janus kinase (JAK), mitogen-activated protein kinase (MAPK) and spleen tyrosine kinase (Syk) inhibitors. We provide a mechanistic insight into how these inhibitors interfere with kinase signalling pathways and discuss the clinical successes and failures in the implementation of kinase-directed therapeutics in the context of inflammatory and autoimmune disorders. PMID:24313320

Allergic rhinitis and inflammatory airway disease: interactions within the unified airspace.

PubMed

Marple, Bradley F

2010-01-01

Allergic rhinitis (AR), the most common chronic allergic condition in outpatient medicine, is associated with immense health care costs and socioeconomic consequences. AR's impact may be partly from interacting of respiratory conditions via allergic inflammation. This study was designed to review potential interactive mechanisms of AR and associated conditions and consider the relevance of a bidirectional "unified airway" respiratory inflammation model on diagnosis and treatment of inflammatory airway disease. MEDLINE was searched for pathophysiology and pathophysiological and epidemiologic links between AR and diseases of the sinuses, lungs, middle ear, and nasopharynx. Allergic-related inflammatory responses or neural and systemic processes fostering inflammatory changes distant from initial allergen provocation may link AR and comorbidities. Treating AR may benefit associated respiratory tract comorbidities. Besides improving AR outcomes, treatment inhibiting eosinophil recruitment and migration, normalizing cytokine profiles, and reducing asthma-associated health care use in atopic subjects would likely ameliorate other upper airway diseases such as acute rhinosinusitis, chronic rhinosinusitis (CRS) with nasal polyposis (NP), adenoidal hypertrophy, and otitis media with effusion. Epidemiological concordance of AR with several airway diseases conforms to a bidirectional "unified airway" respiratory inflammation model based on anatomic and histological upper and lower airway connections. Epidemiology and current understanding of inflammatory, humoral, and neural processes make links between AR and disorders including asthma, otitis media, NP, and CRS plausible. Combining AR with associated conditions increases disease burden; worsened associated illness may accompany worsened AR. AR pharmacotherapies include antihistamines, leukotriene antagonists, intranasal corticosteroids, and immunotherapy; treatments attenuating proinflammatory responses may also benefit associated conditions.

Innate immune response during Yersinia infection: critical modulation of cell death mechanisms through phagocyte activation.

PubMed

Bergsbaken, Tessa; Cookson, Brad T

2009-11-01

Yersinia pestis, the etiological agent of plague, is one of the most deadly pathogens on our planet. This organism shares important attributes with its ancestral progenitor, Yersinia pseudotuberculosis, including a 70-kb virulence plasmid, lymphotropism during growth in the mammalian host, and killing of host macrophages. Infections with both organisms are biphasic, where bacterial replication occurs initially with little inflammation, followed by phagocyte influx, inflammatory cytokine production, and tissue necrosis. During infection, plasmid-encoded attributes facilitate bacterial-induced macrophage death, which results from two distinct processes and corresponds to the inflammatory crescendo observed in vivo: Naïve cells die by apoptosis (noninflammatory), and later in infection, activated macrophages die by pyroptosis (inflammatory). The significance of this redirected cell death for the host is underscored by the importance of phagocyte activation for immunity to Yersinia and the protective role of pyroptosis during host responses to anthrax lethal toxin and infections with Francisella, Legionella, Pseudomonas, and Salmonella. The similarities of Y. pestis and Y. pseudotuberculosis, including conserved, plasmid-encoded functions inducing at least two distinct mechanisms of cell death, indicate that comparative studies are revealing about their critical pathogenic mechanism(s) and host innate immune responses during infection. Validation of this idea and evidence of similar interactions with the host immune system are provided by Y. pseudotuberculosis-priming, cross-protective immunity against Y. pestis. Despite these insights, additional studies indicate much remains to be understood concerning effective host responses against Yersinia, including chromosomally encoded attributes that also contribute to bacterial evasion and modulation of innate and adaptive immune responses.

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

Chronic inflammatory demyelinating polyneuropathy in children: a report of four patients with variable relapsing courses

PubMed Central

Chang, Soo Jin; Lee, Ji Hyun; Kim, Shin Hye; Lee, Joon Soo; Kim, Heung Dong; Kang, Joon Won; Lee, Young Mock

2015-01-01

Chronic inflammatory demyelinating polyneuropathy (CIDP) is a chronically progressive or relapsing symmetric sensorimotor disorder presumed to occur because of immunologic antibody-mediated reactions. To understand the clinical courses of CIDP, we report variable CIDP courses in children with respect to initial presentation, responsiveness to medical treatment, and recurrence interval. Four patients who were diagnosed with acute-onset and relapsing CIDP courses at Severance Children's Hospital, Seoul, Korea, were enrolled in this retrospective study. We diagnosed each patient on the basis of the CIDP diagnostic criteria developed in 2010 by the European Federation of Neurological Societies/Peripheral Nerve Society Guidelines. We present the cases of four pediatric patients diagnosed with CIDP to understand the variable clinical course of the disease in children. Our four patients were all between 8 and 12 years of age. Patients 1 and 2 were diagnosed with acute cerebellar ataxia or Guillain-Barré syndrome as initial symptoms. While patients 1 and 4 were given only intravenous dexamethasone (0.3 mg/kg/day) for 5 days at the first episode, Patients 2 and 3 were given a combination of intravenous immunoglobulin (2 g/kg) and dexamethasone (0.3 mg/kg/day). All patients were maintained with oral prednisolone at 30 mg/day, but their clinical courses were variable in both relapse intervals and severity. We experienced variable clinical courses of CIDP in children with respect to initial presentation, responsiveness to medical treatment, and recurrence interval. PMID:26124851

Food-grade TiO2 impairs intestinal and systemic immune homeostasis, initiates preneoplastic lesions and promotes aberrant crypt development in the rat colon.

PubMed

Bettini, Sarah; Boutet-Robinet, Elisa; Cartier, Christel; Coméra, Christine; Gaultier, Eric; Dupuy, Jacques; Naud, Nathalie; Taché, Sylviane; Grysan, Patrick; Reguer, Solenn; Thieriet, Nathalie; Réfrégiers, Matthieu; Thiaudière, Dominique; Cravedi, Jean-Pierre; Carrière, Marie; Audinot, Jean-Nicolas; Pierre, Fabrice H; Guzylack-Piriou, Laurence; Houdeau, Eric

2017-01-20

Food-grade titanium dioxide (TiO 2 ) containing a nanoscale particle fraction (TiO 2 -NPs) is approved as a white pigment (E171 in Europe) in common foodstuffs, including confectionary. There are growing concerns that daily oral TiO 2 -NP intake is associated with an increased risk of chronic intestinal inflammation and carcinogenesis. In rats orally exposed for one week to E171 at human relevant levels, titanium was detected in the immune cells of Peyer's patches (PP) as observed with the TiO 2 -NP model NM-105. Dendritic cell frequency increased in PP regardless of the TiO 2 treatment, while regulatory T cells involved in dampening inflammatory responses decreased with E171 only, an effect still observed after 100 days of treatment. In all TiO 2 -treated rats, stimulation of immune cells isolated from PP showed a decrease in Thelper (Th)-1 IFN-γ secretion, while splenic Th1/Th17 inflammatory responses sharply increased. E171 or NM-105 for one week did not initiate intestinal inflammation, while a 100-day E171 treatment promoted colon microinflammation and initiated preneoplastic lesions while also fostering the growth of aberrant crypt foci in a chemically induced carcinogenesis model. These data should be considered for risk assessments of the susceptibility to Th17-driven autoimmune diseases and to colorectal cancer in humans exposed to TiO 2 from dietary sources.

Food-grade TiO2 impairs intestinal and systemic immune homeostasis, initiates preneoplastic lesions and promotes aberrant crypt development in the rat colon

PubMed Central

Bettini, Sarah; Boutet-Robinet, Elisa; Cartier, Christel; Coméra, Christine; Gaultier, Eric; Dupuy, Jacques; Naud, Nathalie; Taché, Sylviane; Grysan, Patrick; Reguer, Solenn; Thieriet, Nathalie; Réfrégiers, Matthieu; Thiaudière, Dominique; Cravedi, Jean-Pierre; Carrière, Marie; Audinot, Jean-Nicolas; Pierre, Fabrice H.; Guzylack-Piriou, Laurence; Houdeau, Eric

2017-01-01

Food-grade titanium dioxide (TiO2) containing a nanoscale particle fraction (TiO2-NPs) is approved as a white pigment (E171 in Europe) in common foodstuffs, including confectionary. There are growing concerns that daily oral TiO2-NP intake is associated with an increased risk of chronic intestinal inflammation and carcinogenesis. In rats orally exposed for one week to E171 at human relevant levels, titanium was detected in the immune cells of Peyer’s patches (PP) as observed with the TiO2-NP model NM-105. Dendritic cell frequency increased in PP regardless of the TiO2 treatment, while regulatory T cells involved in dampening inflammatory responses decreased with E171 only, an effect still observed after 100 days of treatment. In all TiO2-treated rats, stimulation of immune cells isolated from PP showed a decrease in Thelper (Th)-1 IFN-γ secretion, while splenic Th1/Th17 inflammatory responses sharply increased. E171 or NM-105 for one week did not initiate intestinal inflammation, while a 100-day E171 treatment promoted colon microinflammation and initiated preneoplastic lesions while also fostering the growth of aberrant crypt foci in a chemically induced carcinogenesis model. These data should be considered for risk assessments of the susceptibility to Th17-driven autoimmune diseases and to colorectal cancer in humans exposed to TiO2 from dietary sources. PMID:28106049

Chronic inflammatory demyelinating polyneuropathy in children: a report of four patients with variable relapsing courses.

PubMed

Chang, Soo Jin; Lee, Ji Hyun; Kim, Shin Hye; Lee, Joon Soo; Kim, Heung Dong; Kang, Joon Won; Lee, Young Mock; Kang, Hoon-Chul

2015-05-01

Chronic inflammatory demyelinating polyneuropathy (CIDP) is a chronically progressive or relapsing symmetric sensorimotor disorder presumed to occur because of immunologic antibody-mediated reactions. To understand the clinical courses of CIDP, we report variable CIDP courses in children with respect to initial presentation, responsiveness to medical treatment, and recurrence interval. Four patients who were diagnosed with acute-onset and relapsing CIDP courses at Severance Children's Hospital, Seoul, Korea, were enrolled in this retrospective study. We diagnosed each patient on the basis of the CIDP diagnostic criteria developed in 2010 by the European Federation of Neurological Societies/Peripheral Nerve Society Guidelines. We present the cases of four pediatric patients diagnosed with CIDP to understand the variable clinical course of the disease in children. Our four patients were all between 8 and 12 years of age. Patients 1 and 2 were diagnosed with acute cerebellar ataxia or Guillain-Barré syndrome as initial symptoms. While patients 1 and 4 were given only intravenous dexamethasone (0.3 mg/kg/day) for 5 days at the first episode, Patients 2 and 3 were given a combination of intravenous immunoglobulin (2 g/kg) and dexamethasone (0.3 mg/kg/day). All patients were maintained with oral prednisolone at 30 mg/day, but their clinical courses were variable in both relapse intervals and severity. We experienced variable clinical courses of CIDP in children with respect to initial presentation, responsiveness to medical treatment, and recurrence interval.

Effects of heat stress and starvation on clonal odontoblast-like cells.

PubMed

Morotomi, Takahiko; Kitamura, Chiaki; Toyono, Takashi; Okinaga, Toshinori; Washio, Ayako; Saito, Noriko; Nishihara, Tatsuji; Terashita, Masamichi; Anan, Hisashi

2011-07-01

Heat stress during restorative procedures, particularly under severe starvation conditions, can trigger damage to dental pulp. In the present study, we examined effects of heat stress on odontoblastic activity and inflammatory responses in an odontoblast-like cell line (KN-3) under serum-starved conditions. Viability, nuclear structures, and inflammatory responses of KN-3 cells were examined in culture medium containing 10% or 1% serum after exposure to heat stress at 43°C for 45 minutes. Gene expression of extracellular matrices, alkaline phosphatase activity, and detection of extracellular calcium deposition in cells exposed to heat stress were also examined. Reduced viability and apoptosis were transiently induced in KN-3 cells during the initial phases after heat stress; thereafter, cells recovered their viability. The cytotoxic effects of heat stress were enhanced under serum-starved conditions. Heat stress also strongly up-regulated expression of heat shock protein 25 as well as transient expression of tumor necrosis factor-alpha, interleukin-6, and cyclooxygenase-2 in KN-3 cells. In contrast, expression of type-1 collagen, runt-related transcription factor 2, and dentin sialophosphoprotein were not inhibited by heat stress although starvation suppressed ALP activity and delayed progression of calcification. Odontoblast-like cells showed thermoresistance with transient inflammatory responses and without loss of calcification activity, and their thermoresistance and calcification activity were influenced by nutritional status. Copyright © 2011 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.

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

Mesenchymal Stem/Multipotent Stromal Cells from Human Decidua Basalis Reduce Endothelial Cell Activation.

PubMed

Alshabibi, Manal A; Al Huqail, Al Joharah; Khatlani, Tanvir; Abomaray, Fawaz M; Alaskar, Ahmed S; Alawad, Abdullah O; Kalionis, Bill; Abumaree, Mohamed Hassan

2017-09-15

Recently, we reported the isolation and characterization of mesenchymal stem cells from the decidua basalis of human placenta (DBMSCs). These cells express a unique combination of molecules involved in many important cellular functions, which make them good candidates for cell-based therapies. The endothelium is a highly specialized, metabolically active interface between blood and the underlying tissues. Inflammatory factors stimulate the endothelium to undergo a change to a proinflammatory and procoagulant state (ie, endothelial cell activation). An initial response to endothelial cell activation is monocyte adhesion. Activation typically involves increased proliferation and enhanced expression of adhesion and inflammatory markers by endothelial cells. Sustained endothelial cell activation leads to a type of damage to the body associated with inflammatory diseases, such as atherosclerosis. In this study, we examined the ability of DBMSCs to protect endothelial cells from activation through monocyte adhesion, by modulating endothelial proliferation, migration, adhesion, and inflammatory marker expression. Endothelial cells were cocultured with DBMSCs, monocytes, monocyte-pretreated with DBMSCs and DBMSC-pretreated with monocytes were also evaluated. Monocyte adhesion to endothelial cells was examined following treatment with DBMSCs. Expression of endothelial cell adhesion and inflammatory markers was also analyzed. The interaction between DBMSCs and monocytes reduced endothelial cell proliferation and monocyte adhesion to endothelial cells. In contrast, endothelial cell migration increased in response to DBMSCs and monocytes. Endothelial cell expression of adhesion and inflammatory molecules was reduced by DBMSCs and DBMSC-pretreated with monocytes. The mechanism of reduced endothelial proliferation involved enhanced phosphorylation of the tumor suppressor protein p53. Our study shows for the first time that DBMSCs protect endothelial cells from activation by inflammation triggered by monocyte adhesion and increased endothelial cell proliferation. These events are manifest in inflammatory diseases, such as atherosclerosis. Therefore, our results suggest that DBMSCs could be usefully employed as a therapeutic strategy for atherosclerosis.

Dendritic polyglycerol sulfates as multivalent inhibitors of inflammation.

PubMed

Dernedde, Jens; Rausch, Alexandra; Weinhart, Marie; Enders, Sven; Tauber, Rudolf; Licha, Kai; Schirner, Michael; Zügel, Ulrich; von Bonin, Arne; Haag, Rainer

2010-11-16

Adhesive interactions of leukocytes and endothelial cells initiate leukocyte migration to inflamed tissue and are important for immune surveillance. Acute and chronic inflammatory diseases show a dysregulated immune response and result in a massive efflux of leukocytes that contributes to further tissue damage. Therefore, targeting leukocyte trafficking may provide a potent form of anti-inflammatory therapy. Leukocyte migration is initiated by interactions of the cell adhesion molecules E-, L-, and P-selectin and their corresponding carbohydrate ligands. Compounds that efficiently address these interactions are therefore of high therapeutic interest. Based on this rationale we investigated synthetic dendritic polyglycerol sulfates (dPGS) as macromolecular inhibitors that operate via a multivalent binding mechanism mimicking naturally occurring ligands. dPGS inhibited both leukocytic L-selectin and endothelial P-selectin with high efficacy. Size and degree of sulfation of the polymer core determined selectin binding affinity. Administration of dPGS in a contact dermatitis mouse model dampened leukocyte extravasation as effectively as glucocorticoids did and edema formation was significantly reduced. In addition, dPGS interacted with the complement factors C3 and C5 as was shown in vitro and reduced C5a levels in a mouse model of complement activation. Thus, dPGS represent an innovative class of a fully synthetic polymer therapeutics that may be used for the treatment of inflammatory diseases.

Dendritic polyglycerol sulfates as multivalent inhibitors of inflammation

PubMed Central

Dernedde, Jens; Rausch, Alexandra; Weinhart, Marie; Enders, Sven; Tauber, Rudolf; Licha, Kai; Schirner, Michael; Zügel, Ulrich; von Bonin, Arne; Haag, Rainer

2010-01-01

Adhesive interactions of leukocytes and endothelial cells initiate leukocyte migration to inflamed tissue and are important for immune surveillance. Acute and chronic inflammatory diseases show a dysregulated immune response and result in a massive efflux of leukocytes that contributes to further tissue damage. Therefore, targeting leukocyte trafficking may provide a potent form of anti-inflammatory therapy. Leukocyte migration is initiated by interactions of the cell adhesion molecules E-, L-, and P-selectin and their corresponding carbohydrate ligands. Compounds that efficiently address these interactions are therefore of high therapeutic interest. Based on this rationale we investigated synthetic dendritic polyglycerol sulfates (dPGS) as macromolecular inhibitors that operate via a multivalent binding mechanism mimicking naturally occurring ligands. dPGS inhibited both leukocytic L-selectin and endothelial P-selectin with high efficacy. Size and degree of sulfation of the polymer core determined selectin binding affinity. Administration of dPGS in a contact dermatitis mouse model dampened leukocyte extravasation as effectively as glucocorticoids did and edema formation was significantly reduced. In addition, dPGS interacted with the complement factors C3 and C5 as was shown in vitro and reduced C5a levels in a mouse model of complement activation. Thus, dPGS represent an innovative class of a fully synthetic polymer therapeutics that may be used for the treatment of inflammatory diseases. PMID:21041668

A practical approach to vaccination of patients with autoimmune inflammatory rheumatic diseases in Australia.

PubMed

Wong, Peter K K; Bagga, Hanish; Barrett, Claire; Hanrahan, Paddy; Johnson, Doug; Katrib, Amel; Leder, Karin; Marabani, Mona; Pentony, Peta; Riordan, John; White, Ray; Young, Laurel

2017-05-01

Autoimmune inflammatory rheumatic diseases (AIIRD), such as rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis are often complicated by infection, which results in significant morbidity and mortality. The increased risk of infection is probably due to a combination of immunosuppressive effects of the AIIRD, comorbidities and the use of immunosuppressive conventional synthetic disease-modifying anti-rheumatic drugs (DMARDs) and more recently, targeted synthetic DMARDs and biologic DMARDs that block specific pro-inflammatory enzymes, cytokines or cell types. The use of these various DMARDs has revolutionised the treatment of AIIRD. This has led to a marked improvement in quality of life for AIIRD patients, who often now travel for prolonged periods. Many infections are preventable with vaccination. However, as protective immune responses induced by vaccination may be impaired by immunosuppression, where possible, vaccination may need to be performed prior to initiation of immunosuppression. Vaccination status should also be reviewed when planning overseas travel. Limited data regarding vaccine efficacy in patients with AIIRD make prescriptive guidelines difficult. However, a vaccination history should be part of the initial work-up in all AIIRD patients. Those caring for AIIRD patients should regularly consider vaccination to prevent infection within the practicalities of routine clinical practice. © 2017 Royal Australasian College of Physicians.

Reduced IFN-γ and IL-10 responses to paternal antigens during and after pregnancy in allergic women.

PubMed

Persson, Marie; Ekerfelt, Christina; Ernerudh, Jan; Matthiesen, Leif; Abelius, Martina Sandberg; Jonsson, Yvonne; Berg, Göran; Jenmalm, Maria C

2012-09-01

Normal pregnancy and allergy are both characterized by a T helper (Th) 2 deviation. In the current study, we hypothesized that paternal antigen-induced cytokine responses during pregnancy would be deviated toward Th2 and an anti-inflammatory profile, and that the Th2 deviation would be more pronounced in allergic pregnant women. Blood samples were collected longitudinally on three occasions during pregnancy and two occasions post partum (pp). Of the 86 women initially included, 54 women had a normal pregnancy and completed the sampling procedures. Twelve women fulfilled the criteria for allergy (allergic symptoms and circulating immunoglobulin [Ig] E antibodies to inhalant allergens) and 20 were non-allergic (nonsensitized without symptoms). The levels of Th1- and Th2-associated cytokines and chemokines, the Th17 cytokine IL-17 and the anti-inflammatory cytokine IL-10 of the groups were compared. Paternal antigen-induced IL-4 and IL-10 responses increased between the first and the third trimester. Allergy was associated with decreased paternal antigen-induced IFN-γ and CXCL10 secretion in the nonpregnant state (one year pp) and also decreased IFN-γ/IL-4 and IFN-γ/IL-13 ratios during pregnancy. We also observed a decreased paternal antigen-induced IL-10 response in allergic compared with non-allergic women during pregnancy, along with a decreased IL-10/IL-13 ratio. In conclusion, our findings support the hypothesis of lower Th1 responses toward paternal antigens in allergic than in non-allergic women, but also indicate that allergy is associated with a lower capacity to induce anti-inflammatory IL-10 responses after paternal antigen stimulation during pregnancy. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

DNFB-DNS hapten-induced colitis in mice should not be considered a model of inflammatory bowel disease.

PubMed

Bailón, Elvira; Cueto-Sola, Margarita; Utrilla, Pilar; Nieto, Ana; Garrido-Mesa, Natividad; Celada, Antonio; Zarzuelo, Antonio; Xaus, Jordi; Gálvez, Julio; Comalada, Mònica

2011-10-01

The dinitrofluorobenzene/dinitrosulfonic acid (DNFB/DNS) model was originally described as an experimental model of intestinal inflammation resembling human ulcerative colitis (UC). Due to the absence of acceptable UC experimental models for pharmacological preclinical assays, here we examine the immune response induced in this model. Balb/c mice were sensitized by skin application of DNFB on day 1, followed by an intrarectal challenge with DNS on day 5. We further expanded this model by administering a second DNS challenge on day 15. The features of colonic inflammation and immune response were evaluated. The changes observed in colonic tissue corresponded, in comparison to the trinitrobenzene sulfonic acid (TNBS) colitis model, to a mild mucosal effect in the colon, which spontaneously resolved in less than 5 days. Furthermore, the second hapten challenge did not exacerbate the inflammatory response. In contrast to other studies, we did not observe any clear involvement of tumor necrosis factor alpha (TNF-α) or other Th1 cytokines during the initial inflammatory response; however, we found that a more Th2-humoral response appeared to mediate the first contact with the hapten. An increased humoral response was detected during the second challenge, although an increased Th1/Th17-cytokine expression profile was also simultaneously observed. On the basis of these results, although the DNFB/DNS model can display some features found in human UC, it should be considered as a model for the study of the intestinal hypersensitivity seen, for example, during food allergy or irritable bowel syndrome but not intestinal inflammation per se. Copyright © 2010 Crohn's & Colitis Foundation of America, Inc.

Molecular Markers of Estrogen Metabolism and Progression From High-Grade Prostatic Intraepithelial Neoplasia (HGPIN) to Prostate Cancer

DTIC Science & Technology

2006-02-01

recruitment. Adipocytes (i.e., fat cells) regulate insulin sensitivity , steroid hormone metabolism, inflammatory responses , and release leptin and other...diabetes and insulin sensitivity on prostate cancer risk. • Less tangible, but no less significant, this study initiated a prostate cancer...proliferator-activated receptr alpha (PPARalpha) gene is associated with lower body mass index in patients with non- insulin -dependent diabetes mellitus

TRIF Licenses Caspase-11-Dependent NLRP3 Inflammasome Activation by Gram-Negative Bacteria

PubMed Central

Rathinam, Vijay A.K.; Vanaja, Sivapriya Kailasan; Waggoner, Lisa; Sokolovska, Anna; Becker, Christine; Stuart, Lynda M.; Leong, John M.; Fitzgerald, Katherine A.

2013-01-01

SUMMARY Systemic infections with Gram-negative bacteria are characterized by high mortality rates due to the “sepsis syndrome,” a widespread and uncontrolled inflammatory response. Though it is well recognized that the immune response during Gram-negative bacterial infection is initiated after the recognition of endotoxin by Toll-like receptor 4, the molecular mechanisms underlying the detrimental inflammatory response during Gram-negative bacteremia remain poorly defined. Here, we identify a TRIF pathway that licenses NLRP3 inflammasome activation by all Gram-negative bacteria. By engaging TRIF, Gram-negative bacteria activate caspase-11. TRIF activates caspase-11 via type I IFN signaling, an event that is both necessary and sufficient for caspase-11 induction and autoactivation. Caspase-11 subsequently synergizes with the assembled NLRP3 inflammasome to regulate caspase-1 activation and leads to caspase-1-independent cell death. These events occur specifically during infection with Gram-negative, but not Gram-positive, bacteria. The identification of TRIF as a regulator of caspase-11 underscores the importance of TLRs as master regulators of inflammasomes during Gram-negative bacterial infection. PMID:22819539

Inhibition of human dendritic cell activation by hydroethanolic but not lipophilic extracts of turmeric (Curcuma longa).

PubMed

Krasovsky, Joseph; Chang, David H; Deng, Gary; Yeung, Simon; Lee, Mavis; Leung, Ping Chung; Cunningham-Rundles, Susanna; Cassileth, Barrie; Dhodapkar, Madhav V

2009-03-01

Turmeric has been extensively utilized in Indian and Chinese medicine for its immune-modulatory properties. Dendritic cells (DCs) are antigen-presenting cells specialized to initiate and regulate immunity. The ability of DCs to initiate immunity is linked to their activation status. The effects of turmeric on human DCs have not been studied. Here we show that hydroethanolic (HEE) but not lipophilic "supercritical" extraction (SCE) of turmeric inhibits the activation of human DCs in response to inflammatory cytokines. Treatment of DCs with HEE also inhibits the ability of DCs to stimulate the mixed lymphocyte reaction (MLR). Importantly, the lipophilic fraction does not synergize with the hydroethanolic fraction for the ability of inhibiting DC maturation. Rather, culturing of DCs with the combination of HEE and SCE leads to partial abrogation of the effects of HEE on the MLR initiated by DCs. These data provide a mechanism for the anti-inflammatory properties of turmeric. However, they suggest that these extracts are not synergistic and may contain components with mutually antagonistic effects on human DCs. Harnessing the immune effects of turmeric may benefit from specifically targeting the active fractions.

Inhibition of Human Dendritic Cell Activation by Hydroethanolic But Not Lipophilic Extracts of Turmeric (Curcuma longa)

PubMed Central

Krasovsky, Joseph; Chang, David H.; Deng, Gary; Yeung, Simon; Lee, Mavis; Leung, Ping Chung; Cunningham-Rundles, Susanna; Cassileth, Barrie; Dhodapkar, Madhav V.

2015-01-01

Turmeric has been extensively utilized in Indian and Chinese medicine for its immune-modulatory properties. Dendritic cells (DCs) are antigen-presenting cells specialized to initiate and regulate immunity. The ability of DCs to initiate immunity is linked to their activation status. The effects of turmeric on human DCs have not been studied. Here we show that hydroethanolic (HEE) but not lipophilic “supercritical” extraction (SCE) of turmeric inhibits the activation of human DCs in response to inflammatory cytokines. Treatment of DCs with HEE also inhibits the ability of DCs to stimulate the mixed lymphocyte reaction (MLR). Importantly, the lipophilic fraction does not synergize with the hydroethanolic fraction for the ability of inhibiting DC maturation. Rather, culturing of DCs with the combination of HEE and SCE leads to partial abrogation of the effects of HEE on the MLR initiated by DCs. These data provide a mechanism for the anti-inflammatory properties of turmeric. However, they suggest that these extracts are not synergistic and may contain components with mutually antagonistic effects on human DCs. Harnessing the immune effects of turmeric may benefit from specifically targeting the active fractions. PMID:19034830

Role of inflammasomes in inflammatory autoimmune rheumatic diseases.

PubMed

Yi, Young-Su

2018-01-01

Inflammasomes are intracellular multiprotein complexes that coordinate anti-pathogenic host defense during inflammatory responses in myeloid cells, especially macrophages. Inflammasome activation leads to activation of caspase-1, resulting in the induction of pyroptosis and the secretion of pro-inflammatory cytokines including interleukin (IL)-1β and IL-18. Although the inflammatory response is an innate host defense mechanism, chronic inflammation is the main cause of rheumatic diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), ankylosing spondylitis (AS), and Sjögren's syndrome (SS). Since rheumatic diseases are inflammatory/autoimmune disorders, it is reasonable to hypothesize that inflammasomes activated during the inflammatory response play a pivotal role in development and progression of these diseases. Indeed, previous studies have provided important observations that inflammasomes are actively involved in the pathogenesis of inflammatory/autoimmune rheumatic diseases. In this review, we summarize the current knowledge on several types of inflammasomes during macrophage-mediated inflammatory responses and discuss recent research regarding the role of inflammasomes in the pathogenesis of inflammatory/autoimmune rheumatic diseases. This avenue of research could provide new insights for the development of promising therapeutics to treat inflammatory/autoimmune rheumatic diseases.

Harnessing dendritic cells in inflammatory skin diseases.

PubMed

Chu, Chung-Ching; Di Meglio, Paola; Nestle, Frank O

2011-02-01

The skin immune system harbors a complex network of dendritic cells (DCs). Recent studies highlight a diverse functional specialization of skin DC subsets. In addition to generating cellular and humoral immunity against pathogens, skin DCs are involved in tolerogenic mechanisms to ensure the maintenance of immune homeostasis, as well as in pathogenesis of chronic inflammation in the skin when excessive immune responses are initiated and unrestrained. Harnessing DCs by directly targeting DC-derived molecules or selectively modulate DC subsets is a convincing strategy to tackle inflammatory skin diseases. In this review we discuss recent advances underlining the functional specialization of skin DCs and discuss the potential implication for future DC-based therapeutic strategies. Copyright © 2011 Elsevier Ltd. All rights reserved.

Role of interleukins in obesity: implications for metabolic disease.

PubMed

Febbraio, Mark A

2014-06-01

It has been two decades since the discovery that pro-inflammatory cytokines are expressed in obesity. This initial work was the catalyst for the now-accepted paradigm that nutrient overload promotes inflammation and links the metabolic and immune systems, where inflammation may be pathological. However, inflammation is an adaptive and, importantly, an energy-consuming process. Indeed, the rapid mobilization of stored energy reserves by cytokines such as the interleukins, is critical to mounting any successful inflammatory response. Thus, the role of the interleukins in metabolism and energy homeostasis is more complex than first thought and recent evidence is mounting that, for several interleukins, although excess production is negative, blockade or insufficiency is equally undesirable. Copyright © 2014 Elsevier Ltd. All rights reserved.

Identification of a vesicular ATP release inhibitor for the treatment of neuropathic and inflammatory pain.

PubMed

Kato, Yuri; Hiasa, Miki; Ichikawa, Reiko; Hasuzawa, Nao; Kadowaki, Atsushi; Iwatsuki, Ken; Shima, Kazuhiro; Endo, Yasuo; Kitahara, Yoshiro; Inoue, Tsuyoshi; Nomura, Masatoshi; Omote, Hiroshi; Moriyama, Yoshinori; Miyaji, Takaaki

2017-07-18

Despite the high incidence of neuropathic and inflammatory pain worldwide, effective drugs with few side effects are currently unavailable for the treatment of chronic pain. Recently, researchers have proposed that inhibitors of purinergic chemical transmission, which plays a key role in the pathological pain response, may allow for targeted treatment of pathological neuropathic and inflammatory pain. However, such therapeutic analgesic agents have yet to be developed. In the present study, we demonstrated that clodronate, a first-generation bisphosphonate with comparatively fewer side effects than traditional treatments, significantly attenuates neuropathic and inflammatory pain unrelated to bone abnormalities via inhibition of vesicular nucleotide transporter (VNUT), a key molecule for the initiation of purinergic chemical transmission. In vitro analyses indicated that clodronate inhibits VNUT at a half-maximal inhibitory concentration of 15.6 nM without affecting other vesicular neurotransmitter transporters, acting as an allosteric modulator through competition with Cl - A low concentration of clodronate impaired vesicular ATP release from neurons, microglia, and immune cells. In vivo analyses revealed that clodronate is more effective than other therapeutic agents in attenuating neuropathic and inflammatory pain, as well as the accompanying inflammation, in wild-type but not VNUT -/- mice, without affecting basal nociception. These findings indicate that clodronate may represent a unique treatment strategy for chronic neuropathic and inflammatory pain via inhibition of vesicular ATP release.

Role of Peroxisome Proliferator-Activated Receptors in Inflammation Control

PubMed Central

Badr, Mostafa

2004-01-01

Peroxisome proliferator-activated receptors (PPARs) were discovered over a decade ago, and were classified as orphan members of the nuclear receptor superfamily. To date, three PPAR subtypes have been discovered and characterized (PPARα, β/δ, γ). Different PPAR subtypes have been shown to play crucial roles in important diseases and conditions such as obesity, diabetes, atherosclerosis, cancer, and fertility. Among the most studied roles of PPARs is their involvement in inflammatory processes. Numerous studies have revealed that agonists of PPARα and PPARγ exert anti-inflammatory effects both in vitro and in vivo. Using the carrageenan-induced paw edema model of inflammation, a recent study in our laboratories showed that these agonists hinder the initiation phase, but not the late phase of the inflammatory process. Furthermore, in the same experimental model, we recently also observed that activation of PPARδ exerted an anti-inflammatory effect. Despite the fact that exclusive dependence of these effects on PPARs has been questioned, the bulk of evidence suggests that all three PPAR subtypes, PPARα, δ, γ, play a significant role in controlling inflammatory responses. Whether these subtypes act via a common mechanism or are independent of each other remains to be elucidated. However, due to the intensity of research efforts in this area, it is anticipated that these efforts will result in the development of PPAR ligands as therapeutic agents for the treatment of inflammatory diseases. PMID:15292582

Dermal CD14(+) Dendritic Cell and Macrophage Infection by Dengue Virus Is Stimulated by Interleukin-4.

PubMed

Schaeffer, Evelyne; Flacher, Vincent; Papageorgiou, Vasiliki; Decossas, Marion; Fauny, Jean-Daniel; Krämer, Melanie; Mueller, Christopher G

2015-07-01

Dengue virus (DENV) is responsible for the most prevalent arthropod-borne viral infection in humans. Events decisive for disease development occur in the skin after virus inoculation by the mosquito. Yet, the role of human dermis-resident immune cells in dengue infection and disease remains elusive. Here we investigated how dermal dendritic cells (dDCs) and macrophages (dMs) react to DENV and impact on immunopathology. We show that both CD1c(+) and CD14(+) dDC subsets were infected, but viral load greatly increased in CD14(+) dDCs upon IL-4 stimulation, which correlated with upregulation of virus-binding lectins Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Nonintegrin (DC-SIGN/CD209) and mannose receptor (CD206). IL-4 also enhanced T-cell activation by dDCs, which was further increased upon dengue infection. dMs purified from digested dermis were initially poorly infected but actively replicated the virus and produced TNF-α upon lectin upregulation in response to IL-4. DC-SIGN(+) cells are abundant in inflammatory skin with scabies infection or Th2-type dermatitis, suggesting that skin reactions to mosquito bites heighten the risk of infection and subsequent immunopathology. Our data identify dDCs and dMs as primary arbovirus target cells in humans and suggest that dDCs initiate a potent virus-directed T-cell response, whereas dMs fuel the inflammatory cascade characteristic of dengue fever.

Inhibition of macrophage function prevents intestinal inflammation and postoperative ileus in rodents

PubMed Central

Wehner, Sven; Behrendt, Florian F; Lyutenski, Boris N; Lysson, Mariola; Bauer, Anthony J; Hirner, Andreas; Kalff, Jörg C

2007-01-01

Background Abdominal surgery results in a molecular and cellular inflammatory response in the intestine, leading to postoperative ileus. It was hypothesised that resident macrophages within the intestinal muscularis have an important role in this local inflammation. Aims To investigate whether chemical or genetic depletion of resident muscularis macrophages would lead to a reduction in the local inflammation and smooth‐muscle dysfunction. Methods Two rodent models were used to deplete and inactivate macrophages: (1) a rat model in which resident macrophages were depleted by chlodronate liposomes; (2) a model of mice with osteopetrosis mice, completely lacking the resident muscularis macrophages, used as an additional genetic approach. Animals with normal or altered intestinal macrophages underwent surgical intestinal manipulation. The inflammatory response was investigated by quantitative reverse transcriptase‐polymerase chain reaction for mRNA of MIP‐1α, interleukin (IL)1β, IL6, intracellular adhesion molecule 1 (ICAM‐1) and monocyte chemotractant protein 1 (MCP)‐1 in the isolated small bowel muscularis. In addition, muscularis whole mounts were used for histochemical and immunohistochemical analysis to quantify leucocyte infiltration and detect cytokine expression. Subsequently, in vitro muscle contractility and in vivo gastrointestinal transit were measured. Results Both models resulted in markedly decreased expression of MIP‐1α, IL1β, IL6, ICAM‐1 and MCP‐1 after manipulation compared with controls. In addition to this decrease in inflammatory mediators, recruitment of leucocytes into the muscularis was also diminished. Macrophage‐altered animals had near normal in vitro jejunal circular muscle function and gastrointestinal transit despite surgical manipulation. Conclusions Resident intestinal muscularis macrophages are initially involved in inflammatory responses resulting in postoperative ileus. Depletion and inactivation of the muscularis macrophage network prevents postoperative ileus. PMID:16809419

Airborne nitro-PAHs induce Nrf2/ARE defense system against oxidative stress and promote inflammatory process by activating PI3K/Akt pathway in A549 cells.

PubMed

Shang, Yu; Zhou, Qian; Wang, Tiantian; Jiang, Yuting; Zhong, Yufang; Qian, Guangren; Zhu, Tong; Qiu, Xinghua; An, Jing

2017-10-01

Ambient particulate matter (PM) is a worldwide health issue of concern. However, limited information is available regarding the toxic contributions of the nitro-derivatives of polycyclic aromatic hydrocarbons (nitro-PAHs). This study intend to examine whether 1-nitropyrene (1-NP) and 3-nitrofluoranthene (3-NF) could activate the nuclear factor-erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) antioxidant defense system, and whether the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) pathway participates in regulating pro-inflammatory responses in A549 cells. Firstly, 1-NP and 3-NF concentration-dependently induced cellular apoptosis, reactive oxygen species (ROS) generation, DNA damage, S phase cell cycle arrest and differential expression of related cytokine genes. Secondly, 1-NP and 3-NF activated the Nrf2/ARE defense system, as evidenced by increased protein expression levels and nuclear translocation of transcription factor Nrf2, elevated Nrf2/ARE binding activity, up-regulated expression of the target gene heme oxygenase-1 (HO-1). Significantly increased protein expression of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and phosphorylation level of Akt indicated that the PI3K/Akt pathway was activated during pro-inflammatory process. Further, both PI3K inhibitor (LY294002) and Akt inhibitor (MK-2206) reversed the elevated TNF-α expression to control level. Our results suggested that Nrf2/ARE pathway activation might cause an initiation step in cellular protection against oxidative stress caused by nitro-PAHs, and the PI3K/Akt pathway participated in regulating inflammatory responses. Copyright © 2017 Elsevier Ltd. All rights reserved.

Class II obese and healthy pregnant controls exhibit indistinguishable pro‐ and anti‐inflammatory immune responses to Caesarian section

PubMed Central

Graham, Caroline; Thorleifson, Mullein; Stefura, William P.; Funk, Duane J.

2017-01-01

Abstract Introduction Obesity during pregnancy is associated with meta‐inflammation and an increased likelihood of clinical complications. Surgery results in intense, acute inflammatory responses in any individual. Because obese individuals exhibit constitutive inflammatory responses and high rates of Caesarian section, it is important to understand the impact of surgery in such populations. Whether more pronounced pro‐inflammatory cytokine responses and/or counterbalancing changes in anti‐inflammatory immune modulators occurs is unknown. Here we investigated innate immune capacity in vivo and in vitro in non‐obese, term‐pregnant controls versus healthy, term‐pregnant obese women (Class II, BMI 35–40). Methods Systemic in vivo induction of eleven pro‐ and anti‐inflammatory biomarkers and acute phase proteins was assessed in plasma immediately prior to and again following Caesarian section surgery. Independently, innate immune capacity was examined by stimulating freshly isolated PBMC in vitro with a panel of defined PRR‐ligands for TLR4, TLR8, TLR3, and RLR 24 h post‐surgery. Results The kinetics and magnitude of the in vivo inflammatory responses examined were indistinguishable in the two populations across the broad range of biomarkers examined, despite the fact that obese women had higher baseline inflammatory status. Deliberate in vitro stimulation with a range of PRR ligands also elicited pro‐ and anti‐inflammatory cytokine responses that were indistinguishable between control and obese mothers. Conclusions Acute in vivo innate immune responses to C‐section, as well as subsequent in vitro stimulation with a panel of microbial mimics, are not detectably altered in Class II obese women. The data argue that while Class II obesity is undesirable, it has minimal impact on the in vivo inflammatory response, or innate immunomodulatory capacity, in women selecting C‐section. PMID:28544689

NleC, a type III secretion protease, compromises NF-κB activation by targeting p65/RelA.

PubMed

Yen, Hilo; Ooka, Tadasuke; Iguchi, Atsushi; Hayashi, Tetsuya; Sugimoto, Nakaba; Tobe, Toru

2010-12-16

The NF-κB signaling pathway is central to the innate and adaptive immune responses. Upon their detection of pathogen-associated molecular patterns, Toll-like receptors on the cell surface initiate signal transduction and activate the NF-κB pathway, leading to the production of a wide array of inflammatory cytokines, in attempt to eradicate the invaders. As a countermeasure, pathogens have evolved ways to subvert and manipulate this system to their advantage. Enteropathogenic and enterohemorrhagic Escherichia coli (EPEC and EHEC) are closely related bacteria responsible for major food-borne diseases worldwide. Via a needle-like protein complex called the type three secretion system (T3SS), these pathogens deliver virulence factors directly to host cells and modify cellular functions, including by suppressing the inflammatory response. Using gain- and loss-of-function screenings, we identified two bacterial effectors, NleC and NleE, that down-regulate the NF-κB signal upon being injected into a host cell via the T3SS. A recent report showed that NleE inhibits NF-κB activation, although an NleE-deficient pathogen was still immune-suppressive, indicating that other anti-inflammatory effectors are involved. In agreement, our present results showed that NleC was also required to inhibit inflammation. We found that NleC is a zinc protease that disrupts NF-κB activation by the direct cleavage of NF-κB's p65 subunit in the cytoplasm, thereby decreasing the available p65 and reducing the total nuclear entry of active p65. More importantly, we showed that a mutant EPEC/EHEC lacking both NleC and NleE (ΔnleC ΔnleE) caused greater inflammatory response than bacteria carrying ΔnleC or ΔnleE alone. This effect was similar to that of a T3SS-defective mutant. In conclusion, we found that NleC is an anti-inflammatory bacterial zinc protease, and that the cooperative function of NleE and NleC disrupts the NF-κB pathway and accounts for most of the immune suppression caused by EHEC/EPEC.

The Role of Inflammasome in Inflammatory Macrophage in Mycobacterium Avium Complex-lung Disease and Mycobacterium Abscessus-lung Disease

ClinicalTrials.gov

2014-06-27

To Investigate the Inflammasome Response of Inflammatory and Resting Macrophage; To Compare the Difference of Inflammasome Response of Inflammatory Macrophage; To Study the Diagnostic Aid From Immunological Markers in Inflammasome Response

Tolerance and Cross-Tolerance following Toll-Like Receptor (TLR)-4 and -9 Activation Are Mediated by IRAK-M and Modulated by IL-7 in Murine Splenocytes

PubMed Central

Julian, Mark W.; Strange, Heather R.; Ballinger, Megan N.; Hotchkiss, Richard S.; Papenfuss, Tracey L.; Crouser, Elliott D.

2015-01-01

Objective Immune suppression during critical illness predisposes to serious infections. We sought to determine the mechanisms regulating tolerance and cross-tolerance to common pro-inflammatory danger signals in a model that recapitulates the intact in vivo immune response. Materials and Methods Flt3-expanded splenocytes obtained from wild-type or matching IRAK-M knockout (IRAK-M-/-), C57BL/6, male mice (8–10 weeks old) were treated repeatedly or alternately with either LPS or CpGA DNA, agonists of Toll-like receptor (TLR)-4 and -9, respectively, over successive 24-hour periods. Supernatants were collected following each 24-hour period with cytokine release (ELISA) and splenocyte IRAK-M expression (Western blot) determined. Tolerance and cross-tolerance were assessed in the absence or presence of programmed death receptor (PD)-1 blocking antibody or IL-7 pre-treatment. Main Results Splenocytes notably exhibited both tolerance and cross-tolerance to subsequent treatments with either LPS or CpGA DNA. The character of tolerance and cross-tolerance in this model was distinct following initial LPS or CpGA treatment in that TNFα and IFNγ release (not IL-10) were suppressed following LPS; whereas, initial CpGA treatment suppressed TNFα, IFNγ and IL-10 release in response to subsequent stimulation (LPS or CpGA). Tolerance and cross-tolerance were unrelated to IL-10 release or PD-1 but were attenuated in IRAK-M-/- splenocytes. IL-7 significantly suppressed IRAK-M expression and restored TNFα and IFNγ production without influencing IL-10 release. Conclusions In summary, acute immune tolerance and cross-tolerance in response to LPS or CpGA were distinct in that LPS selectively suppressed pro-inflammatory cytokine responses; whereas, CpGA suppressed both pro- and anti-inflammatory responses. The induction of tolerance and cross-tolerance in response to common danger signals was mechanistically unrelated to IL-10 or PD-1 but was directly influenced by IRAK-M expression. IL-7 reduced IRAK-M expression and attenuated immune tolerance induced by either LPS or CpGA, and thus may be useful for reversal of immune tolerance in the setting of critical illness. PMID:26218271

Colonization with Heligmosomoides polygyrus suppresses mucosal IL-17 production

USDA-ARS?s Scientific Manuscript database

Helminth exposure appears to protect hosts from inappropriate inflammatory responses, such as those causing inflammatory bowel disease. A recently identified, strongly pro-inflammatory limb of the immune response is characterized by T cell IL-17 production. Many autoimmune-type inflammatory diseases...

Neurotrophins in healthy and diseased skin.

PubMed

Raap, U; Kapp, A

2010-04-01

Understanding the complex mechanism of allergic inflammatory skin diseases has been a main challenge of clinical and experimental research for years. It is well known that the inflammatory response is also controlled by tissue resident cells including neurons and structural cells. Thus, allergic inflammation triggers neuronal dysfunction and structural changes in diseased skin. Prime candidates for the interaction between immune, structural, and neuronal cells are presented by neurotrophins. Neurotrophins have initially been described for their neurotrophic capacity. However, recent evidence emerges that neurotrophins display bidirectional interaction pathways in activating structural cells, immune cells in addition to neurons. Neurotrophins including brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) are upregulated in allergic inflammatory skin diseases. Further, structural cells, neurons and tissue resident cells have not only been shown to be a target but also a source of neurotrophin. In this regard, eosinophil granulocytes which are key target effector cells in chronic inflammatory skin have been identified as a target of neurotrophins but are also capable of neurotrophin production. Thus, neuroimmune interaction mechanisms in allergic inflammatory skin display a novel pathophysiological aspect in which neurotrophins serve as prime candidates for bidirectional interaction mechanisms. In this review, we provide an actual overview of neurotrophins in healthy and diseased skin with special emphasis on atopic dermatitis and therapeutic implications.

Toll-like Receptors in the Vascular System: Sensing the Dangers Within

PubMed Central

McCarthy, Cameron G.; Webb, R. Clinton

2016-01-01

Toll-like receptors (TLRs) are components of the innate immune system that respond to exogenous infectious ligands (pathogen-associated molecular patterns, PAMPs) and endogenous molecules that are released during host tissue injury/death (damage-associated molecular patterns, DAMPs). Interaction of TLRs with their ligands leads to activation of downstream signaling pathways that induce an immune response by producing inflammatory cytokines, type I interferons (IFN), and other inflammatory mediators. TLR activation affects vascular function and remodeling, and these molecular events prime antigen-specific adaptive immune responses. Despite the presence of TLRs in vascular cells, the exact mechanisms whereby TLR signaling affects the function of vascular tissues are largely unknown. Cardiovascular diseases are considered chronic inflammatory conditions, and accumulating data show that TLRs and the innate immune system play a determinant role in the initiation and development of cardiovascular diseases. This evidence unfolds a possibility that targeting TLRs and the innate immune system may be a novel therapeutic goal for these conditions. TLR inhibitors and agonists are already in clinical trials for inflammatory conditions such as asthma, cancer, and autoimmune diseases, but their study in the context of cardiovascular diseases is in its infancy. In this article, we review the current knowledge of TLR signaling in the cardiovascular system with an emphasis on atherosclerosis, hypertension, and cerebrovascular injury. Furthermore, we address the therapeutic potential of TLR as pharmacological targets in cardiovascular disease and consider intriguing research questions for future study. PMID:26721702

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

Auger, Floriane; Gendron, Marie-Claude; Chamot, Christophe

Numerous epidemiological studies support the contention that ambient air pollution particles can adversely affect human health. To explain the acute inflammatory process in airways exposed to particles, a number of in vitro studies have been performed on cells grown submerged on plastic and poorly differentiated, and on cell lines, the physiology of which is somewhat different from that of well-differentiated cells. In order to obtain results using a model system in which epithelial cells are similar to those of the human airway in vivo, apical membranes of well-differentiated human nasal epithelial (HNE) cells cultured in an air-liquid interface (ALI) weremore » exposed for 24 h to diesel exhaust particles (DEP) and Paris urban air particles (PM{sub 2.5}). DEP and PM{sub 2.5} (10-80 {mu}g/cm{sup 2}) stimulated both IL-8 and amphiregulin (ligand of EGFR) secretion exclusively towards the basal compartment. In contrast, there was no IL-1{beta} secretion and only weak non-reproducible secretion of TNF-{alpha}. IL-6 and GM-CSF were consistently stimulated towards the apical compartment and only when cells were exposed to PM{sub 2.5}. ICAM-1 protein expression on cell surfaces remained low after particle exposure, although it increased after TNF-{alpha} treatment. Internalization of particles, which is believed to initiate oxidative stress and proinflammatory cytokine expression, was restricted to small nanoparticles ({<=} 40 nm). Production of reactive oxygen species (ROS) was detected, and DEP were more efficient than PM{sub 2.5}. Collectively, our results suggest that airway epithelial cells exposed to particles augment the local inflammatory response in the lung but cannot alone initiate a systemic inflammatory response.« less

Photodynamic therapy mediates innate immune responses via fibroblast-macrophage interactions.

PubMed

Zulaziz, N; Azhim, A; Himeno, N; Tanaka, M; Satoh, Y; Kinoshita, M; Miyazaki, H; Saitoh, D; Shinomiya, N; Morimoto, Y

2015-10-01

Antibacterial photodynamic therapy (PDT) has come to attract attention as an alternative therapy for drug-resistant bacteria. Recent reports revealed that antibacterial PDT induces innate immune response and stimulates abundant cytokine secretion as a part of inflammatory responses. However, the underlying mechanism how antibacterial PDT interacts with immune cells responsible for cytokine secretion has not been well outlined. In this study, we aimed to clarify the difference in gene expression and cytokine secretion between combined culture of fibroblasts and macrophages and their independent cultures. SCRC-1008, mouse fibroblast cell line and J774, mouse macrophage-like cell line were co-cultured and PDT treatments with different parameters were carried out. After various incubation periods (1-24 h), cells and culture medium were collected, and mRNA and protein levels for cytokines were measured using real-time PCR and ELISA, respectively. Our results showed that fibroblasts and macrophages interact with each other to mediate the immune response. We propose that fibroblasts initially respond to PDT by expressing Hspa1b, which regulates the NF-κB pathway via Tlr2 and Tlr4. Activation of the NF-κB pathway then results in an enhanced secretion of pro-inflammatory cytokines (TNF-α, IL-6 and IL-1β) and neutrophil chemoattractant MIP-2 and KC from macrophages.

Ubiquitination in Periodontal Disease: A Review.

PubMed

Tsuchida, Sachio; Satoh, Mamoru; Takiwaki, Masaki; Nomura, Fumio

2017-07-10

Periodontal disease (periodontitis) is a chronic inflammatory condition initiated by microbial infection that leads to gingival tissue destruction and alveolar bone resorption. The periodontal tissue's response to dental plaque is characterized by the accumulation of polymorphonuclear leukocytes, macrophages, and lymphocytes, all of which release inflammatory mediators and cytokines to orchestrate the immunopathogenesis of periodontal disease. Ubiquitination is achieved by a mechanism that involves a number of factors, including an ubiquitin-activating enzyme, ubiquitin-conjugating enzyme, and ubiquitin-protein ligase. Ubiquitination is a post-translational modification restricted to eukaryotes that are involved in essential host processes. The ubiquitin system has been implicated in the immune response, development, and programmed cell death. Increasing numbers of recent reports have provided evidence that many approaches are delivering promising reports for discovering the relationship between ubiquitination and periodontal disease. The scope of this review was to investigate recent progress in the discovery of ubiquitinated protein in diseased periodontium and to discuss the ubiquitination process in periodontal diseases.

Ubiquitination in Periodontal Disease: A Review

PubMed Central

Tsuchida, Sachio; Satoh, Mamoru; Takiwaki, Masaki; Nomura, Fumio

2017-01-01

Periodontal disease (periodontitis) is a chronic inflammatory condition initiated by microbial infection that leads to gingival tissue destruction and alveolar bone resorption. The periodontal tissue’s response to dental plaque is characterized by the accumulation of polymorphonuclear leukocytes, macrophages, and lymphocytes, all of which release inflammatory mediators and cytokines to orchestrate the immunopathogenesis of periodontal disease. Ubiquitination is achieved by a mechanism that involves a number of factors, including an ubiquitin-activating enzyme, ubiquitin-conjugating enzyme, and ubiquitin–protein ligase. Ubiquitination is a post-translational modification restricted to eukaryotes that are involved in essential host processes. The ubiquitin system has been implicated in the immune response, development, and programmed cell death. Increasing numbers of recent reports have provided evidence that many approaches are delivering promising reports for discovering the relationship between ubiquitination and periodontal disease. The scope of this review was to investigate recent progress in the discovery of ubiquitinated protein in diseased periodontium and to discuss the ubiquitination process in periodontal diseases. PMID:28698506

LRP1 integrates murine macrophage cholesterol homeostasis and inflammatory responses in atherosclerosis

PubMed Central

Zhou, Li; Plattner, Florian; Liu, Mingxia; Parks, John S; Hammer, Robert E; Boucher, Philippe; Tsai, Shirling

2017-01-01

Low-density lipoprotein receptor-related protein 1 (LRP1) is a multifunctional cell surface receptor with diverse physiological roles, ranging from cellular uptake of lipoproteins and other cargo by endocytosis to sensor of the extracellular environment and integrator of a wide range of signaling mechanisms. As a chylomicron remnant receptor, LRP1 controls systemic lipid metabolism in concert with the LDL receptor in the liver, whereas in smooth muscle cells (SMC) LRP1 functions as a co-receptor for TGFβ and PDGFRβ in reverse cholesterol transport and the maintenance of vascular wall integrity. Here we used a knockin mouse model to uncover a novel atheroprotective role for LRP1 in macrophages where tyrosine phosphorylation of an NPxY motif in its intracellular domain initiates a signaling cascade along an LRP1/SHC1/PI3K/AKT/PPARγ/LXR axis to regulate and integrate cellular cholesterol homeostasis through the expression of the major cholesterol exporter ABCA1 with apoptotic cell removal and inflammatory responses. PMID:29144234

Podocytes Are Nonhematopoietic Professional Antigen-Presenting Cells

PubMed Central

Burkard, Miriam; Ölke, Martha; Daniel, Christoph; Amann, Kerstin; Hugo, Christian; Kurts, Christian; Steinkasserer, Alexander; Gessner, André

2013-01-01

Podocytes are essential to the structure and function of the glomerular filtration barrier; however, they also exhibit increased expression of MHC class II molecules under inflammatory conditions, and they remove Ig and immune complexes from the glomerular basement membrane (GBM). This finding suggests that podocytes may act as antigen-presenting cells, taking up and processing antigens to initiate specific T cell responses, similar to professional hematopoietic cells such as dendritic cells or macrophages. Here, MHC–antigen complexes expressed exclusively on podocytes of transgenic mice were sufficient to activate CD8+ T cells in vivo. In addition, deleting MHC class II exclusively on podocytes prevented the induction of experimental anti-GBM nephritis. Podocytes ingested soluble and particulate antigens, activated CD4+ T cells, and crosspresented exogenous antigen on MHC class I molecules to CD8+ T cells. In conclusion, podocytes participate in the antigen-specific activation of adaptive immune responses, providing a potential target for immunotherapies of inflammatory kidney diseases and transplant rejection. PMID:23539760

Early identification of ‘acute-onset’ chronic inflammatory demyelinating polyneuropathy

PubMed Central

Sung, Jia-Ying; Tani, Jowy; Park, Susanna B.; Kiernan, Matthew C.

2014-01-01

Distinguishing patients with acute-onset chronic inflammatory demyelinating polyneuropathy from acute inflammatory demyelinating polyneuropathy prior to relapse is often challenging at the onset of their clinical presentation. In the present study, nerve excitability tests were used in conjunction with the clinical phenotype and disease staging, to differentiate between patients with acute-onset chronic inflammatory demyelinating polyneuropathy and patients with acute inflammatory demyelinating polyneuropathy at an early stage, with the aim to better guide treatment. Clinical assessment, staging and nerve excitability tests were undertaken on patients initially fulfilling the diagnostic criteria of acute inflammatory demyelinating polyneuropathy soon after symptom onset and their initial presentation. Patients were subsequently followed up for minimum of 12 months to determine if their clinical presentations were more consistent with acute-onset chronic inflammatory demyelinating polyneuropathy. Clinical severity as evaluated by Medical Research Council sum score and Hughes functional grading scale were not significantly different between the two cohorts. There was no difference between the time of onset of initial symptoms and nerve excitability test assessment between the two cohorts nor were there significant differences in conventional nerve conduction study parameters. However, nerve excitability test profiles obtained from patients with acute inflammatory demyelinating polyneuropathy demonstrated abnormalities in the recovery cycle of excitability, including significantly reduced superexcitability (P < 0.001) and prolonged relative refractory period (P < 0.01), without changes in threshold electrotonus. In contrast, in patients with acute-onset chronic inflammatory demyelinating polyneuropathy, a different pattern occurred with the recovery cycle shifted downward (increased superexcitability, P < 0.05; decreased subexcitability, P < 0.05) and increased threshold change in threshold electrotonus in both hyperpolarizing and depolarizing directions [depolarizing threshold electrotonus (90–100 ms) P < 0.005, hyperpolarizing threshold electrotonus (10–20 ms), P < 0.01, hyperpolarizing threshold electrotonus (90–100 ms), P < 0.05], perhaps suggesting early hyperpolarization. In addition, using excitability parameters superexcitability, subexcitability and hyperpolarizing threshold electrotonus (10–20 ms), the patients with acute inflammatory demyelinating polyneuropathy and acute-onset chronic inflammatory demyelinating polyneuropathy could be clearly separated into two non-overlapping groups. Studies of nerve excitability may be able to differentiate acute from acute-onset chronic inflammatory demyelinating polyneuropathy at an early stage. Characteristic nerve excitability parameter changes occur in early acute-onset chronic inflammatory demyelinating polyneuropathy, to match the clinical phenotype. Importantly, this pattern of change was strikingly different to that shown by patients with acute inflammatory demyelinating polyneuropathy, suggesting that nerve excitability techniques may be useful in distinguishing acute-onset chronic inflammatory demyelinating polyneuropathy from acute inflammatory demyelinating polyneuropathy at the initial stage. PMID:24983276

Parenchymal and Stromal Cells Contribute to Pro-Inflammatory Myocardial Environment at Early Stages of Diabetes: Protective Role of Resveratrol.

PubMed

Savi, Monia; Bocchi, Leonardo; Sala, Roberto; Frati, Caterina; Lagrasta, Costanza; Madeddu, Denise; Falco, Angela; Pollino, Serena; Bresciani, Letizia; Miragoli, Michele; Zaniboni, Massimiliano; Quaini, Federico; Del Rio, Daniele; Stilli, Donatella

2016-11-16

Background: Little information is currently available concerning the relative contribution of cardiac parenchymal and stromal cells in the activation of the pro-inflammatory signal cascade, at the initial stages of diabetes. Similarly, the effects of early resveratrol (RSV) treatment on the negative impact of diabetes on the different myocardial cell compartments remain to be defined. Methods: In vitro challenge of neonatal cardiomyocytes and fibroblasts to high glucose and in vivo/ex vivo experiments on a rat model of Streptozotocin-induced diabetes were used to specifically address these issues. Results: In vitro data indicated that, besides cardiomyocytes, neonatal fibroblasts contribute to generating initial changes in the myocardial environment, in terms of pro-inflammatory cytokine expression. These findings were mostly confirmed at the myocardial tissue level in diabetic rats, after three weeks of hyperglycemia. Specifically, monocyte chemoattractant protein-1 and Fractalkine were up-regulated and initial abnormalities in cardiomyocyte contractility occurred. At later stages of diabetes, a selective enhancement of pro-inflammatory macrophage M1 phenotype and a parallel reduction of anti-inflammatory macrophage M2 phenotype were associated with a marked disorganization of cardiomyocyte ultrastructural properties. RSV treatment inhibited pro-inflammatory cytokine production, leading to a recovery of cardiomyocyte contractile efficiency and a reduced inflammatory cell recruitment. Conclusion: Early RSV administration could inhibit the pro-inflammatory diabetic milieu sustained by different cardiac cell types.

Antimicrobial aspects of inflammatory resolution in the mucosa: A role for pro-resolving mediators1

PubMed Central

Campbell, Eric L.; Serhan, Charles N.; Colgan, Sean P.

2011-01-01

Mucosal surfaces function as selectively permeable barriers between the host and the outside world. Given their close proximity to microbial antigens, mucosal surfaces have evolved sophisticated mechanisms for maintaining homeostasis and preventing excessive acute inflammatory reactions. The role attributed to epithelial cells was historically limited to serving as a selective barrier, in recent years numerous findings implicate an active role of the epithelium with pro-resolving mediators in the maintenance of immunological equilibrium. In this brief review, we highlight new evidence that the epithelium actively contributes to coordination and resolution of inflammation, principally through the generation of anti-inflammatory and pro-resolution lipid mediators. These autacoids, derived from ω-6 and ω-3 polyunsaturated fatty acids, are implicated in the initiation, progression and resolution of acute inflammation and display specific, epithelial-directed actions focused on mucosalhomeostasis. We also summarize present knowledge of mechanisms for resolution via regulation of epithelial-derived antimicrobial peptides in response to pro-resolving lipid mediators. PMID:21934099

Gene-specific mechanisms direct glucocorticoid-receptor-driven repression of inflammatory response genes in macrophages

PubMed Central

Sacta, Maria A; Tharmalingam, Bowranigan; Coppo, Maddalena; Rollins, David A; Deochand, Dinesh K; Benjamin, Bradley; Yu, Li; Zhang, Bin; Hu, Xiaoyu; Li, Rong; Chinenov, Yurii

2018-01-01

The glucocorticoid receptor (GR) potently represses macrophage-elicited inflammation, however, the underlying mechanisms remain obscure. Our genome-wide analysis in mouse macrophages reveals that pro-inflammatory paused genes, activated via global negative elongation factor (NELF) dissociation and RNA Polymerase (Pol)2 release from early elongation arrest, and non-paused genes, induced by de novo Pol2 recruitment, are equally susceptible to acute glucocorticoid repression. Moreover, in both cases the dominant mechanism involves rapid GR tethering to p65 at NF-kB-binding sites. Yet, specifically at paused genes, GR activation triggers widespread promoter accumulation of NELF, with myeloid cell-specific NELF deletion conferring glucocorticoid resistance. Conversely, at non-paused genes, GR attenuates the recruitment of p300 and histone acetylation, leading to a failure to assemble BRD4 and Mediator at promoters and enhancers, ultimately blocking Pol2 initiation. Thus, GR displays no preference for a specific pro-inflammatory gene class; however, it effects repression by targeting distinct temporal events and components of transcriptional machinery. PMID:29424686

Photoaging and skin cancer: Is the inflammasome the missing link?

PubMed

Awad, Fawaz; Assrawi, Eman; Louvrier, Camille; Jumeau, Claire; Giurgea, Irina; Amselem, Serge; Karabina, Sonia-Athina

2018-03-12

Photoaging and epithelial skin tumorigenesis are complex processes triggered mainly by UV radiation from chronic sun exposure. This leads to DNA damage and reactive oxygen species (ROS) production, which initiate an inflammatory response that alters cell structure and function. Changes in cell homeostasis and ROS production activate intracellular multiprotein platforms called inflammasomes. Inflammasomes nucleate around cytoplasmic receptors mainly of the NLR (nucleotide-binding domain and leucine-rich repeat) family and regulate caspase-1-dependant secretion of pro-inflammatory interleukin (IL)1β and IL18 cytokines, and an inflammatory form of death named pyroptosis. NLRP1 inflammasomes have taken centre stage in skin biology, as mutations in NLRP1 underlie the genetic etiology of dermatological diseases and increase the susceptibility to skin cancer. Targeting inflammasome(s) might be an important approach to improve skin inflammation, photoaging and reduce the risk of epithelial skin tumorigenesis. In this context, we discuss the potential implication of NLRP1 and NLRP3 inflammasomes. Copyright © 2018 Elsevier B.V. All rights reserved.

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

Tsou, Tsui-Chun, E-mail: tctsou@nhri.org.tw; Liou, Saou-Hsing; Yeh, Szu-Ching

Our previous studies indicated that zinc induced inflammatory response in both vascular endothelial cells and promonocytes. Here, we asked if other metals could cause the similar effect on vascular endothelial cells and tried to determine its underlying mechanism. Following screening of fifteen metals, zinc and nickel were identified with a marked proinflammatory effect, as determined by ICAM-1 and IL-8 induction, on human umbilical vein endothelial cells (HUVECs). Inhibiting protein expression of myeloid differentiation primary response protein-88 (MyD88), a Toll-like receptor (TLR) adaptor acting as a TLR-signaling transducer, significantly attenuated the zinc/nickel-induced inflammatory response, suggesting the critical roles of TLRs inmore » the inflammatory response. Blockage of TLR-4 signaling by CLI-095, a TLR-4 inhibitor, completely inhibited the nickel-induced ICAM-1 and IL-8 expression and NFκB activation. The same CLI-095 treatment significantly blocked the zinc-induced IL-8 expression, however with no significant effect on the ICAM-1 expression and a minor inhibitory effect on the NFκB activation. The finding demonstrated the differential role of TLR-4 in regulation of the zinc/nickel-induced inflammatory response, where TLR-4 played a dominant role in NFκB activation by nickel, but not by zinc. Moreover, inhibition of NFκB by adenovirus-mediated IκBα expression and Bay 11-7025, an inhibitor of cytokine-induced IκB-α phosphorylation, significantly attenuated the zinc/nickel-induced inflammatory responses, indicating the critical of NFκB in the process. The study demonstrates the crucial role of TLRs in the zinc/nickel-induced inflammatory response in vascular endothelial cells and herein deciphers a potential important difference in NFκB activation via TLRs. The study provides a molecular basis for linkage between zinc/nickel exposure and pathogenesis of the metal-related inflammatory vascular disease. - Highlights: • Both zinc and nickel cause ICAM-1/IL‑8 expression in endothelial cells via TLRs. • Nickel induces the inflammatory responses via a TLR-4/NF-κB pathway. • Zinc causes the inflammatory responses via a broader TLRs/NF-κB signaling. • Nickel shows a significantly higher inflammatory effect than zinc. • NF-κB activation is the primary mechanism involved in the inflammatory responses.« less

Extracorporeal photopheresis: Review of technical aspects.

PubMed

Arora, Satyam; Setia, Rasika

2017-01-01

Extracorporeal photochemotherapy (ECP) is considered as an immune modulating therapy majorly targeting the T cells of the Immune system. ECP induces an anti-inflammatory condition with tolerogenic responses without inducing a global immunosuppression state which is a typical feature of other therapeutic options such as steroids. Clinical indication of ECP has grown over time since its initial applications. Our review discusses the technical aspects of the concept of photopheresis with the available methods for its clinical applications.

Transcriptional and Chromatin Dynamics of Muscle Regeneration After Severe Trauma

DTIC Science & Technology

2016-10-12

performed pathway analysis of the time-clustered RNA- Seq data16 and showed an initial burst of pro-inflammatory and immune-response transcripts in the...143 showed dynamic behavior (See Methods) and analysis of the dynamic miRNAs reinforced many of the results observed from the RNA-Seq datasets...excellent agreement was viewed. Hierarchical clustering of the datasets through time revealed 5 clusters, and gene ontology (GO) analysis of the

Decoding cell death signals in liver inflammation.

PubMed

Brenner, Catherine; Galluzzi, Lorenzo; Kepp, Oliver; Kroemer, Guido

2013-09-01

Inflammation can be either beneficial or detrimental to the liver, depending on multiple factors. Mild (i.e., limited in intensity and destined to resolve) inflammatory responses have indeed been shown to exert consistent hepatoprotective effects, contributing to tissue repair and promoting the re-establishment of homeostasis. Conversely, excessive (i.e., disproportionate in intensity and permanent) inflammation may induce a massive loss of hepatocytes and hence exacerbate the severity of various hepatic conditions, including ischemia-reperfusion injury, systemic metabolic alterations (e.g., obesity, diabetes, non-alcoholic fatty liver disorders), alcoholic hepatitis, intoxication by xenobiotics and infection, de facto being associated with irreversible liver damage, fibrosis, and carcinogenesis. Both liver-resident cells (e.g., Kupffer cells, hepatic stellate cells, sinusoidal endothelial cells) and cells that are recruited in response to injury (e.g., monocytes, macrophages, dendritic cells, natural killer cells) emit pro-inflammatory signals including - but not limited to - cytokines, chemokines, lipid messengers, and reactive oxygen species that contribute to the apoptotic or necrotic demise of hepatocytes. In turn, dying hepatocytes release damage-associated molecular patterns that-upon binding to evolutionary conserved pattern recognition receptors-activate cells of the innate immune system to further stimulate inflammatory responses, hence establishing a highly hepatotoxic feedforward cycle of inflammation and cell death. In this review, we discuss the cellular and molecular mechanisms that account for the most deleterious effect of hepatic inflammation at the cellular level, that is, the initiation of a massive cell death response among hepatocytes. Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

NAD+-dependent sirtuin 1 and 6 proteins coordinate a switch from glucose to fatty acid oxidation during the acute inflammatory response.

PubMed

Liu, Tie Fu; Vachharajani, Vidula T; Yoza, Barbara K; McCall, Charles E

2012-07-27

The early initiation phase of acute inflammation is anabolic and primarily requires glycolysis with reduced mitochondrial glucose oxidation for energy, whereas the later adaptation phase is catabolic and primarily requires fatty acid oxidation for energy. We reported previously that switching from the early to the late acute inflammatory response following TLR4 stimulation depends on NAD(+) activation of deacetylase sirtuin 1 (SirT1). Here, we tested whether NAD(+) sensing by sirtuins couples metabolic polarity with the acute inflammatory response. We found in TLR4-stimulated THP-1 promonocytes that SirT1 and SirT 6 support a switch from increased glycolysis to increased fatty acid oxidation as early inflammation converts to late inflammation. Glycolysis enhancement required hypoxia-inducing factor-1α to up-regulate glucose transporter Glut1, phospho-fructose kinase, and pyruvate dehydrogenase kinase 1, which interrupted pyruvate dehydrogenase and reduced mitochondrial glucose oxidation. The shift to late acute inflammation and elevated fatty acid oxidation required peroxisome proliferator-activated receptor γ coactivators PGC-1α and β to increase external membrane CD36 and fatty acid mitochondrial transporter carnitine palmitoyl transferase 1. Metabolic coupling between early and late responses also required NAD(+) production from nicotinamide phosphoryltransferase (Nampt) and activation of SirT6 to reduce glycolysis and SirT1 to increase fatty oxidation. We confirmed similar shifts in metabolic polarity during the late immunosuppressed stage of human sepsis blood leukocytes and murine sepsis splenocytes. We conclude that NAD(+)-dependent bioenergy shifts link metabolism with the early and late stages of acute inflammation.

Agmatine Reverses Sub-chronic Stress induced Nod-like Receptor Protein 3 (NLRP3) Activation and Cytokine Response in Rats.

PubMed

Sahin, Ceren; Albayrak, Ozgur; Akdeniz, Tuğba F; Akbulut, Zeynep; Yanikkaya Demirel, Gulderen; Aricioglu, Feyza

2016-10-01

The activation of Nod-like receptor protein 3 (NLRP3) has lately been implicated in stress and depression as an initiator mechanism required for the production of interleukin (IL)-1β and IL-18. Agmatine, an endogenous polyamine widely distributed in mammalian brain, is a novel neurotransmitter/neuromodulator, with antistress, anxiolytic and antidepressant-like effects. In this study, we examined the effect of exogenously administered agmatine on NLRP3 inflammasome pathway/cytokine responses in rats exposed to restraint stress for 7 days. The rats were divided into three groups: stress, stress+agmatine (40 mg/kg; i.p.) and control groups. Agmatine significantly down-regulated the gene expressions of all stress-induced NLRP3 inflammasome components (NLRP3, NF-κB, PYCARD, caspase-1, IL-1β and IL-18) in the hippocampus and prefrontal cortex (PFC) and reduced pro-inflammatory cytokine levels not only in both brain regions, but also in serum. Stress-reduced levels of IL-4 and IL-10, two major anti-inflammatory cytokines, were restored back to normal by agmatine treatment in the PFC. The findings of the present study suggest that stress-activated NLRP3 inflammasome and cytokine responses are reversed by an acute administration of agmatine. Whether antidepressant-like effect of agmatine can somehow, at least partially, be mediated by the inhibition of NLRP3 inflammasome cascade and relevant inflammatory responses requires further studies in animal models of depression. © 2016 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

The α-MSH analogue AP214 attenuates rise in pulmonary pressure and fall in ejection fraction in lipopolysaccharide-induced systemic inflammatory response syndrome in pigs.

PubMed

Kristensen, Jens; Jonassen, Thomas E N; Rehling, Michael; Tønnesen, Else; Sloth, Erik; Nielsen, Søren; Frøkiaer, Jørgen

2011-01-01

The effect of an α-melanocyte stimulating hormone (α-MSH) analogue (AP214) on experimentally endotoxin-induced systemic inflammatory response syndrome (SIRS) was studied, because α-MSH in rodent models has shown promise in attenuating inflammatory response markers and associated organ damage in SIRS. SIRS is associated with considerable morbidity and mortality. Consequently, new treatment modalities are still warranted to address the different aspects of the pathophysiological process. SIRS was induced by lipopolysaccharide (LPS) (Escherichia coli endotoxin) infusion in anaesthetized Danish Landrace pigs (20-25 kg). The pigs received an α-MSH analogue (AP214) or saline as a bolus at the initiation of the LPS infusion. The hemodynamic response was registered as well as echocardiographic indices of left ventricular function. The cardiovascular response was recorded together with echocardiographic indices of left ventricular function in control and in intervention animals. AP214 reduced the early peak in pulmonary pressure and pulmonary vascular resistance by approximately 33%. Furthermore, AP214 prevented the decline in left ventricular fractional shortening as observed in the control group. Mean change and standard deviation in fractional shortening (ΔFS) in control group: - 7·3 (4·7), AP214 (low dose): 0·9 (8·2) and AP214 (high dose) 4·1 (6·0), P < 0·05 for both intervention groups versus control. In the porcine model, the peak increase in pulmonary pressure was attenuated, and the LPS-induced decline in left ventricular function was prevented. © 2010 The Authors. Clinical Physiology and Functional Imaging © 2010 Scandinavian Society of Clinical Physiology and Nuclear Medicine.

The antiprotease SPINK7 serves as an inhibitory checkpoint for esophageal epithelial inflammatory responses.

PubMed

Azouz, Nurit P; Ynga-Durand, Mario A; Caldwell, Julie M; Jain, Ayushi; Rochman, Mark; Fischesser, Demetria M; Ray, Leanne M; Bedard, Mary C; Mingler, Melissa K; Forney, Carmy; Eilerman, Matthew; Kuhl, Jonathan T; He, Hua; Biagini Myers, Jocelyn M; Mukkada, Vincent A; Putnam, Philip E; Khurana Hershey, Gurjit K; Kottyan, Leah C; Wen, Ting; Martin, Lisa J; Rothenberg, Marc E

2018-06-06

Loss of barrier integrity has an important role in eliciting type 2 immune responses, yet the molecular events that initiate and connect this with allergic inflammation remain unclear. We reveal an endogenous, homeostatic mechanism that controls barrier function and inflammatory responses in esophageal allergic inflammation. We show that a serine protease inhibitor, SPINK7 (serine peptidase inhibitor, kazal type 7), is part of the differentiation program of human esophageal epithelium and that SPINK7 depletion occurs in a human allergic, esophageal condition termed eosinophilic esophagitis. Experimental manipulation strategies reducing SPINK7 in an esophageal epithelial progenitor cell line and primary esophageal epithelial cells were sufficient to induce barrier dysfunction and transcriptional changes characterized by loss of cellular differentiation and altered gene expression known to stimulate allergic responses (for example, FLG and SPINK5 ). Epithelial silencing of SPINK7 promoted production of proinflammatory cytokines including thymic stromal lymphopoietin (TSLP). Loss of SPINK7 increased the activity of urokinase plasminogen-type activator (uPA), which in turn had the capacity to promote uPA receptor-dependent eosinophil activation. Treatment of epithelial cells with the broad-spectrum antiserine protease, α1 antitrypsin, reversed the pathologic features associated with SPINK7 silencing. The relevance of this pathway in vivo was supported by finding genetic epistasis between variants in TSLP and the uPA-encoding gene, PLAU We propose that the endogenous balance between SPINK7 and its target proteases is a key checkpoint in regulating mucosal differentiation, barrier function, and inflammatory responses and that protein replacement with antiproteases may be therapeutic for select allergic diseases. Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Composite ganglioside autoantibodies and immune treatment response in MMN and MADSAM.

PubMed

Martinez-Thompson, Jennifer M; Snyder, Melissa R; Ettore, Michael; McKeon, Andrew; Pittock, Sean J; Roforth, Matthew M; Mandrekar, Jay; Mauermann, Michelle L; Taylor, Bruce V; Dyck, P James B; Windebank, Anthony J; Klein, Christopher J

2018-06-01

Multifocal motor neuropathy (MMN) is a motor only, asymmetric onset neuropathy that is relatively treatment-refractory compared with classic chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and multifocal acquired demyelinating sensory and motor (MADSAM) neuropathy. We reviewed 35 patients seropositive for GM1 (monosialo-asialo [immunoglobulin M, IgM; immunoglobulin G, IgG]) and/or GD1b (disialo [IgG, IgM]) autoantibodies having MMN, classic CIDP, or MADSAM. Immune-treatment responsiveness and clinical course was compared with antibody negative disease controls. Seventy-nine percent of seropositives with an initial diagnosis of MMN were immunotherapy responsive compared with 46% of seronegatives (P = 0.045). Eight ganglioside antibody positive MMN patients of 19 (42%) developed sensory findings consistent with MADSAM compared with 3 of 41 (7%) seronegative MMN patients (P = 0.003). MMN and MADSAM patients with ganglioside antibody positivity had more sustained treatment responses (P = 0.03). Patients initially diagnosed with MMN seropositive for diverse GM1 autoantibodies appear more likely to have sustained treatment response and evolution to MADSAM. Muscle Nerve 57: 1000-1005, 2018. © 2017 Wiley Periodicals, Inc.

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

Toll-like receptors in the inflammatory response during open and laparoscopic colectomy for colorectal cancer.

PubMed

Tsimogiannis, Konstantinos E; Tellis, Constantinos C; Tselepis, Alexandros D; Pappas-Gogos, George K; Tsimoyiannis, Evangelos C; Basdanis, George

2012-02-01

Surgical interventions activate a cascade of reactions that result in an aseptic inflammatory reaction. This inflammatory response initiates the organism's innate immunity. Laparoscopic surgery reduces the trauma, and patients benefit from diminished surgical trauma and maintained immune function. Cytokine levels and C-reactive protein (CRP) are related to the magnitude of surgical trauma and surgical stress. Toll-like receptors (TLRs) 2 and 4 are the first sensor-recognition receptors of the invading pathogens for the innate immune response. This study aimed to compare the inflammatory response and then the stress response during laparoscopic and open colectomy for cancer by calculating TLR-2 and TLR-4 as the first sensor-recognition receptors together with interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and high-sensitivity CRP (hsCRP). A total 40 patients with colorectal cancer were randomized in two groups: group A (open colectomy, n = 20) and group B (laparoscopic colectomy, n = 20). An epidural catheter was placed in all patients 1 h preoperatively. Rupivocaine was administered perioperatively and 48 h postoperatively. Blood samples were taken for calculation of IL-6, TNF-α, hsCRP, TLR-2, and TLR-4 preoperatively and 5 min after deflation of pneumoperitoneum (group B) or 5 min after division of the colon (group A), then 6 and 24 h postoperatively. The mean operative time was 115 for group A and 142 min for group B. The mean blood loss was respectively 240 and 105 ml (P < 0.001), and the mean hospital stay was respectively 8 and 5 days (P < 0.05). The IL-6 level was significant higher in group A than in group B at 6 and 24 h postoperatively (P < 0.0001), and the hsCRP level was significant higher in group A than in group B at 24 h postoperatively (P < 0.001). The TNF-α values did not differ between the two groups. The TLR-2 level was significantly higher in group A than in group B at 5 min (P = 0.013) and 24 h (P = 0.007) postoperatively. The TLR-4 level was significant higher in group A than in group B at 5 min postoperatively (P = 0.03). The inflammatory response and the resultant stress response are significantly less during laparoscopic colectomy than during open colectomy for colorectal cancer. This is an obvious short-term clinical benefit for the patient, providing tinder for further study to investigate the long-term results of laparoscopic colectomy versus open colectomy for colorectal cancer.

A New Human 3D-Liver Model Unravels the Role of Galectins in Liver Infection by the Parasite Entamoeba histolytica

PubMed Central

Petropolis, Debora B.; Faust, Daniela M.; Deep Jhingan, Gagan; Guillen, Nancy

2014-01-01

Investigations of human parasitic diseases depend on the availability of appropriate in vivo animal models and ex vivo experimental systems, and are particularly difficult for pathogens whose exclusive natural hosts are humans, such as Entamoeba histolytica, the protozoan parasite responsible for amoebiasis. This common infectious human disease affects the intestine and liver. In the liver sinusoids E. histolytica crosses the endothelium and penetrates into the parenchyma, with the concomitant initiation of inflammatory foci and subsequent abscess formation. Studying factors responsible for human liver infection is hampered by the complexity of the hepatic environment and by the restrictions inherent to the use of human samples. Therefore, we built a human 3D-liver in vitro model composed of cultured liver sinusoidal endothelial cells and hepatocytes in a 3D collagen-I matrix sandwich. We determined the presence of important hepatic markers and demonstrated that the cell layers function as a biological barrier. E. histolytica invasion was assessed using wild-type strains and amoebae with altered virulence or different adhesive properties. We showed for the first time the dependence of endothelium crossing upon amoebic Gal/GalNAc lectin. The 3D-liver model enabled the molecular analysis of human cell responses, suggesting for the first time a crucial role of human galectins in parasite adhesion to the endothelial cells, which was confirmed by siRNA knockdown of galectin-1. Levels of several pro-inflammatory cytokines, including galectin-1 and -3, were highly increased upon contact of E. histolytica with the 3D-liver model. The presence of galectin-1 and -3 in the extracellular medium stimulated pro-inflammatory cytokine release, suggesting a further role for human galectins in the onset of the hepatic inflammatory response. These new findings are relevant for a better understanding of human liver infection by E. histolytica. PMID:25211477

Lycopene mitigates β-amyloid induced inflammatory response and inhibits NF-κB signaling at the choroid plexus in early stages of Alzheimer's disease rats.

PubMed

Liu, Chong-Bin; Wang, Rui; Yi, Yan-Feng; Gao, Zhen; Chen, Yi-Zhu

2018-03-01

The choroid plexus is able to modulate the cognitive function, through changes in the neuroinflammatory response and in brain immune surveillance. However, whether lycopene is involved in inflammatory responses at the choroid plexus in the early stages of Alzheimer's disease, and its molecular underpinnings are elusive. In this rat study, lycopene was used to investigate its protective effects on inflammation caused by β-amyloid. We characterized the learning and memory abilities, cytokine profiles of circulating TNF-α, IL-1β and IL-6β in the serum and the expressions of Toll like receptor 4 and nuclear factor-κB p65 mRNA and protein at the choroid plexus. The results showed that functional deficits of learning and memory in lycopene treatment groups were significantly improved compared to the control group without lycopene treatment in water maze test. The levels of serum TNF-α, IL-1β and IL-6β were significantly increased, and the expressions of TLR4 and NF-κB p65 mRNA and protein at the choroid plexus were up-regulated, indicating inflammation response was initiated following administration of Aβ 1-42 . After intragastric pretreatment with lycopene, inflammatory cytokines were significantly reduced and lycopene also reversed the Aβ 1-42 induced up-regulation of TLR4 and NF-κB p65 mRNA and protein expressions at the choroid plexus. These results provided a novel evidence that lycopene significantly improved cognitive deficits and were accompanied by the attenuation of inflammatory injury via blocking the activation of NF-κB p65 and TLR4 expressions and production of cytokines, thereby endorsing its usefulness for diminishing β-amyloid deposition in the hippocampus tissues. Copyright © 2017 Elsevier Inc. All rights reserved.

Effectiveness of anti-tumour necrosis factor-α therapy in Danish patients with inflammatory bowel diseases.

PubMed

Bank, Steffen; Andersen, Paal Skytt; Burisch, Johan; Pedersen, Natalia; Roug, Stine; Galsgaard, Julie; Turino, Stine Ydegaard; Brodersen, Jacob Broder; Rashid, Shaista; Avlund, Sara; Olesen, Thomas Bastholm; Green, Anders; Hoffmann, Hans Jürgen; Thomsen, Marianne Kragh; Thomsen, Vibeke Østergaard; Nexø, Bjørn Andersen; Vogel, Ulla; Andersen, Vibeke

2015-03-01

The objective of this study was to evaluate the outcome of anti-tumour necrosis factor-α (anti-TNF) treatment in a large cohort of patients with inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC) in clinical practice and to establish a cohort for future studies of genetic markers associated with treatment response. A national, clinically based cohort of previously naïve anti-TNF treated patients from 18 medical departments was established. The patients were screened for tuberculosis prior to treatment initiation. By combining the unique personal identification number of Danish citizens (the CPR number) from blood samples with data from the National Patient Registry, patients with International Classification of Diseases, Version 10 (ICD-10) codes K50-K63 were identified. Treatment efficacy reflected the maximum response within 22 weeks. Among 492 patients with CD and 267 patients with UC, 74%/13%/14% and 65%/12%/24% were responders, partial responders and non-responders to anti-TNF therapy, respectively. More patients with UC than with CD were non-responders (odds ratio (OR) = 1.96, 95% confidence interval (CI): 1.34-2.87, p = 0.001). Young age was associated with a beneficial response (p = 0.03), whereas smoking ≥ 10 cigarettes/day was associated with non-response among patients with CD (OR = 2.33, 95% CI: 1.13-4.81, p = 0.03). In this clinically based cohort of Danish patients with IBD treated with anti-TNF, high response rates were found. Heavy smoking was associated with non-response, whereas young age at treatment initiation was associated with a beneficial response among patients with CD. Thus, the results obtained in this cohort recruited from clinical practice were similar to those previously obtained in clinical trials. The work was funded by Health Research Fund of Central Denmark Region, Colitis-Crohn Foreningen and the University of Aarhus (PhD grant). Clinicaltrials NCT02322008.

Th17 involvement in nonalcoholic fatty liver disease progression to non-alcoholic steatohepatitis.

PubMed

Chackelevicius, Carla Melisa; Gambaro, Sabrina Eliana; Tiribelli, Claudio; Rosso, Natalia

2016-11-07

The nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome. NAFLD encompasses a wide histological spectrum ranging from benign simple steatosis to non-alcoholic steatohepatitis (NASH). Sustained inflammation in the liver is critical in this process. Hepatic macrophages, including liver resident macropaghes (Kupffer cells), monocytes infiltrating the injured liver, as well as specific lymphocytes subsets play a pivotal role in the initiation and perpetuation of the inflammatory response, with a major deleterious impact on the progression of fatty liver to fibrosis. During the last years, Th17 cells have been involved in the development of inflammation not only in liver but also in other organs, such as adipose tissue or lung. Differentiation of a naïve T cell into a Th17 cell leads to pro-inflammatory cytokine and chemokine production with subsequent myeloid cell recruitment to the inflamed tissue. Th17 response can be mitigated by T regulatory cells that secrete anti-inflammatory cytokines. Both T cell subsets need TGF-β for their differentiation and a characteristic plasticity in their phenotype may render them new therapeutic targets. In this review, we discuss the role of the Th17 pathway in NAFLD progression to NASH and to liver fibrosis analyzing different animal models of liver injury and human studies.

3,4-dichloropropionaniline suppresses normal macrophage function.

PubMed

Ustyugova, Irina V; Frost, Laura L; Van Dyke, Knox; Brundage, Kathleen M; Schafer, Rosana; Barnett, John B

2007-06-01

Macrophages are a critical part of the innate immune response and natural surveillance mechanisms. As such, proper macrophage function is crucial for engulfing bacterial pathogens through phagocytosis and destroying them by generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS). The production of a number of cytokines by macrophages, such as tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta, and IL-6, plays an important role in the initiation of the acquired immune response creating an inflammatory environment favorable for fighting a bacterial infection. 3,4-Dichloropropionaniline (DCPA) suppresses several inflammatory parameters, including TNF-alpha production through a mechanism where nuclear factor-kappaB (NF-kappaB)-DNA binding is inhibited but not entirely abrogated. The goal of the present study was to evaluate the effects of DCPA on the inflammatory mediators of macrophages, including ROS and RNS in both murine peritoneal exudate cells and the human monocytic cell line, THP-1. The ability to perform phagocytosis and directly kill Listeria monocytogenes was also assessed. The results indicate that DCPA decreases the ability of both types of macrophages to phagocytize beads and generate both types of reactive species, which was correlated with a decrement in listericidal activity. These results demonstrate that DCPA has profound effects on macrophage function and provide insight into the potential mechanisms of immunosuppression by DCPA.

Innate inflammatory responses in stroke: mechanisms and potential therapeutic targets

PubMed Central

Kim, Jong Youl; Kawabori, Masahito; Yenari, Midori A.

2014-01-01

Stroke is a frequent cause of long-term disability and death worldwide. Ischemic stroke is more commonly encountered compared to hemorrhagic stroke, and leads to tissue death by ischemia due to occlusion of a cerebral artery. Inflammation is known to result as a result of ischemic injury, long thought to be involved in initiating the recovery and repair process. However, work over the past few decades indicates that aspects of this inflammatory response may in fact be detrimental to stroke outcome. Acutely, inflammation appears to have a detrimental effect, and anti-inflammatory treatments have been been studied as a potential therapeutic target. Chronically, reports suggest that post-ischemic inflammation is also essential for the tissue repairing and remodeling. The majority of the work in this area has centered around innate immune mechanisms, which will be the focus of this review. This review describes the different key players in neuroinflammation and their possible detrimental and protective effects in stroke. A better understanding of the roles of the different immune cells and their temporal profile of damage versus repair will help to clarify more effective modulation of inflammation post stroke. Introduction Stroke refers to conditions caused by occlusion and/or rupture of blood vessels in the brain, and is a leading cause of death and disability in the industrialized world. PMID:24372209

Nitric Oxide Donors as Neuroprotective Agents after an Ischemic Stroke-Related Inflammatory Reaction

PubMed Central

Rojas-Mayorquín, Argelia E.; Ortuño-Sahagún, Daniel

2013-01-01

Cerebral ischemia initiates a cascade of detrimental events including glutamate-associated excitotoxicity, intracellular calcium accumulation, formation of Reactive oxygen species (ROS), membrane lipid degradation, and DNA damage, which lead to the disruption of cellular homeostasis and structural damage of ischemic brain tissue. Cerebral ischemia also triggers acute inflammation, which exacerbates primary brain damage. Therefore, reducing oxidative stress (OS) and downregulating the inflammatory response are options that merit consideration as potential therapeutic targets for ischemic stroke. Consequently, agents capable of modulating both elements will constitute promising therapeutic solutions because clinically effective neuroprotectants have not yet been discovered and no specific therapy for stroke is available to date. Because of their ability to modulate both oxidative stress and the inflammatory response, much attention has been focused on the role of nitric oxide donors (NOD) as neuroprotective agents in the pathophysiology of cerebral ischemia-reperfusion injury. Given their short therapeutic window, NOD appears to be appropriate for use during neurosurgical procedures involving transient arterial occlusions, or in very early treatment of acute ischemic stroke, and also possibly as complementary treatment for neurodegenerative diseases such as Parkinson or Alzheimer, where oxidative stress is an important promoter of damage. In the present paper, we focus on the role of NOD as possible neuroprotective therapeutic agents for ischemia/reperfusion treatment. PMID:23691263

Allergen-specific immunotherapy: update on immunological mechanisms.

PubMed

Alvaro, M; Sancha, J; Larramona, H; Lucas, J M; Mesa, M; Tabar, A I; Martinez-Cañavate, A

2013-01-01

Immunotherapy selectively modulates the allergen-specific immune response. It involves the gradual administration of increasing amounts of allergen for the purpose of inducing protective immunological changes and it is the only curative approach for specific type I allergy. Description of the allergic inflammation.- Comprehension of the early cellular changes after specific immunotherapy has been initiated. Exposure of the mechanisms involved in tolerance induction by regulatory T cells (Treg) with the inhibition of the Th2 responses. Comprehension of IL-10 and transforming growth factor (TGF- ) roles. Explanation of specific IgE, IgG and IgA changes. Description of the suppression of inflammatory responses during immunotherapy. Copyright © 2012 SEICAP. Published by Elsevier Espana. All rights reserved.

Cytokines and the Inception of CD8 T Cell Responses

PubMed Central

Cox, Maureen A.; Harrington, Laurie E.; Zajac, Allan J.

2011-01-01

The activation and differentiation of CD8 T cells is a necessary first step that endows these cells with the phenotypic and functional properties required for the control of intracellular pathogens. The induction of the CD8 T cell responses typically results in the development of a massive overall population of effector cells, comprised of both highly functional but short-lived terminally differentiated cells, as well as a smaller subset of precursors that are predisposed to survive and transition into the memory T cell pool. In this article we discuss how inflammatory cytokines and IL-2 bias the initial response towards short-lived effector generation and also highlight the potential counterbalancing role of IL-21. PMID:21371940

Cutaneous immunology: basics and new concepts.

PubMed

Yazdi, Amir S; Röcken, Martin; Ghoreschi, Kamran

2016-01-01

As one of the largest organs, the skin forms a mechanical and immunological barrier to the environment. The skin immune system harbors cells of the innate immune system and cells of the adaptive immune system. Signals of the innate immune system typically initiate skin immune responses, while cells and cytokines of the adaptive immune system perpetuate the inflammation. Skin immune responses ensure effective host defense against pathogens but can also cause inflammatory skin diseases. An extensive crosstalk between the different cell types of the immune system, tissue cells, and pathogens is responsible for the complexity of skin immune reactions. Here we summarize the major cellular and molecular components of the innate and adaptive skin immune system.

Status epilepticus does not induce acute brain inflammatory response in the Amazon rodent Proechimys, an animal model resistant to epileptogenesis.

PubMed

Scorza, Carla A; Marques, Marcia J G; Gomes da Silva, Sérgio; Naffah-Mazzacoratti, Maria da Graça; Scorza, Fulvio A; Cavalheiro, Esper A

2018-03-06

Mesial temporal lobe epilepsy is a serious brain disorder in adults that is often preceded by an initial brain insult, such as status epilepticus (SE), that after a latent period leads to recurrent seizures. Post-SE models are widely used for studies on epileptogenic processes. Previous findings of our laboratory suggested that the Neotropical rodents Proechimys exhibit endogenous antiepileptogenic mechanisms in post-SE models. Strong body of research supports that SE triggers a rapid and dramatic upregulation of inflammatory mediators and vascular endothelial growth factor (VEGF). In this work we found that, in the epilepsy-resistant Proechimys, hippocampal and cortical levels of inflammatory cytokines (IL-1β, IL-6, IL-10, TNF-α) and VEGF remained unchanged 24h after SE, strongly contrasting to the high levels of post-SE changes observed in Wistar rats. Furthermore, substantial differences in the brain baseline levels of these proteins were encountered between animal species studied. Since inflammatory cytokines and VEGF have been recognized as major orchestrators of the epileptogenic process, our results suggest their role in the antiepileptogenic mechanisms previously described in Proechimys. Copyright © 2017 Elsevier B.V. All rights reserved.

Dendritic cell reprogramming by endogenously produced lactic acid.

PubMed

Nasi, Aikaterini; Fekete, Tünde; Krishnamurthy, Akilan; Snowden, Stuart; Rajnavölgyi, Eva; Catrina, Anca I; Wheelock, Craig E; Vivar, Nancy; Rethi, Bence

2013-09-15

The demand for controlling T cell responses via dendritic cell (DC) vaccines initiated a quest for reliable and feasible DC modulatory strategies that would facilitate cytotoxicity against tumors or tolerance in autoimmunity. We studied endogenous mechanisms in developing monocyte-derived DCs (MoDCs) that can induce inflammatory or suppressor programs during differentiation, and we identified a powerful autocrine pathway that, in a cell concentration-dependent manner, strongly interferes with inflammatory DC differentiation. MoDCs developing at low cell culture density have superior ability to produce inflammatory cytokines, to induce Th1 polarization, and to migrate toward the lymphoid tissue chemokine CCL19. On the contrary, MoDCs originated from dense cultures produce IL-10 but no inflammatory cytokines upon activation. DCs from high-density cultures maintained more differentiation plasticity and can develop to osteoclasts. The cell concentration-dependent pathway was independent of peroxisome proliferator-activated receptor γ (PPARγ), a known endogenous regulator of MoDC differentiation. Instead, it acted through lactic acid, which accumulated in dense cultures and induced an early and long-lasting reprogramming of MoDC differentiation. Our results suggest that the lactic acid-mediated inhibitory pathway could be efficiently manipulated in developing MoDCs to influence the immunogenicity of DC vaccines.

Anti-inflammatory activity of soy and tea in prostate cancer prevention

PubMed Central

Hsu, Anna; Bray, Tammy M; Ho, Emily

2014-01-01

Prostate cancer is the leading cancer-related cause of death for men in the USA. Prostate cancer risk is significantly lower in Asian countries compared with the USA, which has prompted interest in the potential chemo-preventive action of soyand green teathat are more predominant in Asian diets. It has been proposed that chronic inflammation is a major risk factor of prostate cancer, acting as both an initiator and promoter. Specifically, the nuclear factor-kappa B (NF-κB) pathway has been implicated as an important mediator between chronic inflammation, cell proliferation and prostate cancer. Dietary factors that inhibit inflammation and NF-κB may serve as effective chemo-preventive agents. Recent studies have demonstrated that soy and green tea have anti-inflammatory properties, and may have the potential to block the inflammatory response during cancer progression. This minireview discusses the relationship between chronic inflammation and prostate cancer, emphasizing on the significance of NF-κB, and further explores the anti-inflammatory effects of soy and green tea. Finally, we propose that dietary strategies that incorporate these bioactive food components as whole foods may be a more effective means to target pathways that contribute to prostate cancer development. PMID:20511670

Epigenetics, microbiota, and intraocular inflammation: New paradigms of immune regulation in the eye.

PubMed

Wen, Xiaofeng; Hu, Xiao; Miao, Li; Ge, Xiaofei; Deng, Yuhua; Bible, Paul W; Wei, Lai

2018-05-01

Sight threatening immune responses that damage the eye characterize intraocular inflammatory diseases. These diseases including uveitis and age-related macular degeneration are worryingly common and quality of life shattering. Genetic studies in past decades significantly advanced our understanding of the etiology of these devastating diseases. Unfortunately, patient genetics alone failed to adequately explain disease origin, susceptibility, and progression. Non-genetic factors such as the epigenetic regulation of ocular diseases and the environmental factors triggering intraocular inflammation offer new insight into intraocular inflammatory disorders. Importantly, mounting evidence is signaling that dysbiosis of human microbiota leads to rapid epigenomic reprograming of host cells and results in the onset of many diseases. In this review, we discuss how epigenetic mechanisms and microbiota may cooperate to initiate and perpetuate ocular inflammation. Lastly, we propose that the discovery of intraocular microbiota presents a significant shift in thought affecting current approaches to the diagnosis, treatment, and prevention of intraocular inflammatory diseases such as uveitis and age-related macular degeneration. The geographical and genetic background difference in both disease presentation and genetic association of intraocular inflammatory diseases may be due to the variation of intraocular microbiota. Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

Extracorporeal membrane oxygenation and cytokine adsorption

PubMed Central

Träger, Karl

2018-01-01

Extracorporeal membrane oxygenation (ECMO) is an increasingly used technology for mechanical support of respiratory and cardio-circulatory failure. Excessive systemic inflammatory response is observed during sepsis and after cardiopulmonary bypass (CPB) with similar clinical features. The overwhelming inflammatory response is characterized by highly elevated pro- and anti-inflammatory cytokine levels. The excessive cytokine release during the overwhelming inflammatory response may result in multiple organ damage and failure. During ECMO therapy activation of complement and contact systems occur which may be followed by cytokine release. Controlling excessively increased cytokines may be considered as a valuable treatment option. Hemoadsorption therapy may be used to decrease cytokine levels in case of excessive inflammatory response and due to its unspecific adsorptive characteristics also substances like myoglobin, free hemoglobin or bilirubin. Controlling pro-inflammatory response with hemoadsorption may have positive impact on the endothelial glycocalix and also may be advantageous for maintenance of the vascular barrier function which plays a pivotal role in the development of tissue edema and oxygen mismatch. Hemoadsorption therapy seems to offer a promising new option for the treatment of patients with overwhelming inflammatory response leading to faster hemodynamic and metabolic stabilization finally resulting in preserved organ functions. PMID:29732183

Extracorporeal membrane oxygenation and cytokine adsorption.

PubMed

Datzmann, Thomas; Träger, Karl

2018-03-01

Extracorporeal membrane oxygenation (ECMO) is an increasingly used technology for mechanical support of respiratory and cardio-circulatory failure. Excessive systemic inflammatory response is observed during sepsis and after cardiopulmonary bypass (CPB) with similar clinical features. The overwhelming inflammatory response is characterized by highly elevated pro- and anti-inflammatory cytokine levels. The excessive cytokine release during the overwhelming inflammatory response may result in multiple organ damage and failure. During ECMO therapy activation of complement and contact systems occur which may be followed by cytokine release. Controlling excessively increased cytokines may be considered as a valuable treatment option. Hemoadsorption therapy may be used to decrease cytokine levels in case of excessive inflammatory response and due to its unspecific adsorptive characteristics also substances like myoglobin, free hemoglobin or bilirubin. Controlling pro-inflammatory response with hemoadsorption may have positive impact on the endothelial glycocalix and also may be advantageous for maintenance of the vascular barrier function which plays a pivotal role in the development of tissue edema and oxygen mismatch. Hemoadsorption therapy seems to offer a promising new option for the treatment of patients with overwhelming inflammatory response leading to faster hemodynamic and metabolic stabilization finally resulting in preserved organ functions.

Targeted Overexpression of Inducible 6-Phosphofructo-2-kinase in Adipose Tissue Increases Fat Deposition but Protects against Diet-induced Insulin Resistance and Inflammatory Responses*

PubMed Central

Huo, Yuqing; Guo, Xin; Li, Honggui; Xu, Hang; Halim, Vera; Zhang, Weiyu; Wang, Huan; Fan, Yang-Yi; Ong, Kuok Teong; Woo, Shih-Lung; Chapkin, Robert S.; Mashek, Douglas G.; Chen, Yanming; Dong, Hui; Lu, Fuer; Wei, Lai; Wu, Chaodong

2012-01-01

Increasing evidence demonstrates the dissociation of fat deposition, the inflammatory response, and insulin resistance in the development of obesity-related metabolic diseases. As a regulatory enzyme of glycolysis, inducible 6-phosphofructo-2-kinase (iPFK2, encoded by PFKFB3) protects against diet-induced adipose tissue inflammatory response and systemic insulin resistance independently of adiposity. Using aP2-PFKFB3 transgenic (Tg) mice, we explored the ability of targeted adipocyte PFKFB3/iPFK2 overexpression to modulate diet-induced inflammatory responses and insulin resistance arising from fat deposition in both adipose and liver tissues. Compared with wild-type littermates (controls) on a high fat diet (HFD), Tg mice exhibited increased adiposity, decreased adipose inflammatory response, and improved insulin sensitivity. In a parallel pattern, HFD-fed Tg mice showed increased hepatic steatosis, decreased liver inflammatory response, and improved liver insulin sensitivity compared with controls. In both adipose and liver tissues, increased fat deposition was associated with lipid profile alterations characterized by an increase in palmitoleate. Additionally, plasma lipid profiles also displayed an increase in palmitoleate in HFD-Tg mice compared with controls. In cultured 3T3-L1 adipocytes, overexpression of PFKFB3/iPFK2 recapitulated metabolic and inflammatory changes observed in adipose tissue of Tg mice. Upon treatment with conditioned medium from iPFK2-overexpressing adipocytes, mouse primary hepatocytes displayed metabolic and inflammatory responses that were similar to those observed in livers of Tg mice. Together, these data demonstrate a unique role for PFKFB3/iPFK2 in adipocytes with regard to diet-induced inflammatory responses in both adipose and liver tissues. PMID:22556414

Differential Alteration in Intestinal Epithelial Cell Expression of Toll-Like Receptor 3 (TLR3) and TLR4 in Inflammatory Bowel Disease

PubMed Central

Cario, Elke; Podolsky, Daniel K.

2000-01-01

Initiation and perpetuation of the inflammatory intestinal responses in inflammatory bowel disease (IBD) may result from an exaggerated host defense reaction of the intestinal epithelium to endogenous lumenal bacterial flora. Intestinal epithelial cell lines constitutively express several functional Toll-like receptors (TLRs) which appear to be key regulators of the innate response system. The aim of this study was to characterize the expression pattern of TLR2, TLR3, TLR4, and TLR5 in primary intestinal epithelial cells from patients with IBD. Small intestinal and colonic biopsy specimens were collected from patients with IBD (Crohn's disease [CD], ulcerative colitis [UC]) and controls. Non-IBD specimens were assessed by immunofluorescence histochemistry using polyclonal antibodies specific for TLR2, TLR3, TLR4, and TLR5. Primary intestinal epithelial cells (IEC) of normal mucosa constitutively expressed TLR3 and TLR5, while TLR2 and TLR4 were only barely detectable. In active IBD, the expression of TLR3 and TLR4 was differentially modulated in the intestinal epithelium. TLR3 was significantly downregulated in IEC in active CD but not in UC. In contrast, TLR4 was strongly upregulated in both UC and CD. TLR2 and TLR5 expression remained unchanged in IBD. These data suggest that IBD may be associated with distinctive changes in selective TLR expression in the intestinal epithelium, implying that alterations in the innate response system may contribute to the pathogenesis of these disorders. PMID:11083826

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

Lee, Jeong Eun; Hanyang Biomedical Research Institute, Seoul; Park, Jae Hyeon

Oxidative stress can lead to expression of inflammatory transcription factors, which are important regulatory elements in the induction of inflammatory responses. One of the transcription factors, nuclear transcription factor kappa-B (NF-κB) plays a significant role in the inflammation regulatory process. Inflammatory cell death has been implicated in neuronal cell death in some neurodegenerative disorders such as Parkinson's disease (PD). In this study, we investigated the molecular mechanisms underlying apoptosis initiated by chlorpyrifos (CPF)-mediated oxidative stress. Based on the cytotoxic mechanism of CPF, we examined the neuroprotective effects of rosiglitazone (RGZ), a peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist, against CPF-induced neuronalmore » cell death. The treatment of SH-SY5Y cells with CPF induced oxidative stress. In addition, CPF activated the p38, JNK and ERK mitogen-activated protein kinases (MAPKs), and induced increases in the inflammatory genes such as COX-2 and TNF-α. CPF also induced nuclear translocation of NF-κB and inhibitors of NF-κB abolished the CPF-induced COX-2 expression. Pretreatment with RGZ significantly reduced ROS generation and enhanced HO-1 expression in CPF-exposed cells. RGZ blocked the activation of both p38 and JNK signaling, while ERK activation was strengthened. RGZ also attenuated CPF-induced cell death through the reduction of NF-κB-mediated proinflammatory factors. Results from this study suggest that RGZ may exert an anti-apoptotic effect against CPF-induced cytotoxicity by attenuation of oxidative stress as well as inhibition of the inflammatory cascade via inactivation of signaling by p38 and JNK, and NF-κB. - Highlights: • CPF induces apoptotic cell death in SH-SY5Y cells • ROS involved in CPF-mediated apoptotic cell death • Inflammation involved in CPF-mediated apoptotic cell death • Rosiglitazone modulates ROS and inflammatory response in CPF-treated cells.« less

Chagas disease: modulation of the inflammatory response by acetylcholinesterase in hematological cells and brain tissue.

PubMed

Silva, Aniélen D; Bottari, Nathieli B; do Carmo, Guilherme M; Baldissera, Matheus D; Souza, Carine F; Machado, Vanessa S; Morsch, Vera M; Schetinger, Maria Rosa C; Mendes, Ricardo E; Monteiro, Silvia G; Da Silva, Aleksandro S

2018-01-01

Chagas disease is an acute or chronic illness that causes severe inflammatory response, and consequently, it may activate the inflammatory cholinergic pathway, which is regulated by cholinesterases, including the acetylcholinesterase. This enzyme is responsible for the regulation of acetylcholine levels, an anti-inflammatory molecule linked to the inflammatory response during parasitic diseases. Thus, the aim of this study was to investigate whether Trypanosoma cruzi infection can alter the activity of acetylcholinesterase and acetylcholine levels in mice, and whether these alterations are linked to the inflammatory cholinergic signaling pathway. Twenty-four mice were divided into two groups: uninfected (control group, n = 12) and infected by T. cruzi, Y strain (n = 12). The animals developed acute disease with a peak of parasitemia on day 7 post-infection (PI). Blood, lymphocytes, and brain were analyzed on days 6 and 12 post-infection. In the brain, acetylcholine and nitric oxide levels, myeloperoxidase activity, and histopathology were analyzed. In total blood and brain, acetylcholinesterase activity decreased at both times. On the other hand, acetylcholinesterase activity in lymphocytes increased on day 6 PI compared with the control group. Infection by T. cruzi increased acetylcholine and nitric oxide levels and histopathological damage in the brain of mice associated to increased myeloperoxidase activity. Therefore, an intense inflammatory response in mice with acute Chagas disease in the central nervous system caused an anti-inflammatory response by the activation of the cholinergic inflammatory pathway.

The Impact of Therapeutic Antibodies on the Management of Digestive Diseases: History, Current Practice, and Future Directions.

PubMed

Sofia, M Anthony; Rubin, David T

2017-04-01

The development of therapeutic antibodies represents a revolutionary change in medical therapy for digestive diseases. Beginning with the initial studies that confirmed the pathogenicity of cytokines in inflammatory bowel disease, the development and application of therapeutic antibodies brought challenges and insights into their potential and optimal use. Infliximab was the first biological drug approved for use in Crohn's disease and ulcerative colitis. The lessons learned from infliximab include the importance of immunogenicity and the influence of pharmacokinetics on disease response and outcomes. Building on this foundation, other therapeutic antibodies achieved approval for inflammatory bowel disease and many more are in development for several digestive diseases. In this review, we reflect on the history of therapeutic antibodies and discuss current practice and future directions for the field.

Seronegative inflammations of the ankle and foot: diagnostic challenges

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

Capen, D.; Scheck, M.

Seronegative inflammatory disease was diagnosed in seven patients who had pain, swelling, and redness of the foot and/or ankle. Since the clinical findings mimicked infection, tendinitis, fasciitis, or chronic strain, the initial diagnosis was erroneous and treatment ineffective. In addition to the test for the HLA-B27 antigen, technetium-99m-diphosphonate scintigraphy and magnification roentgenograms have proved valuable tools. Increased isotope uptake was found in all involved extremities, and magnification roentgenograms helped to detect early and subtle lesions of bone. The lesions comprised cortical erosion, increased intracortical absorption of bone, periosteal reactions, and osteoporosis. The response to anti-inflammatory drugs was good in allmore » seven patients. Limited and preliminary follow-up data, including repeat bone scans, suggest that the inflammation may be of a transient nature.« less

Patient characteristics associated with response to NSAID monotherapy in children with systemic juvenile idiopathic arthritis.

PubMed

Sura, Anjali; Failing, Christopher; Sturza, Julie; Stannard, Jasmine; Riebschleger, Meredith

2018-01-05

Systemic juvenile idiopathic arthritis (sJIA) is an auto-inflammatory disease characterized by fever, arthritis, and ≥1 of rash, generalized lymphadenopathy, hepato/splenomegaly, and serositis. Non-steroidal anti-inflammatory drugs (NSAIDs) are among the initial treatments of sJIA, but there is currently no evidence indicating which children should undergo a trial of NSAID monotherapy and which should not. Our objective is to identify presentation characteristics which are associated with response and lack of response to a trial of NSAID monotherapy. This is a retrospective single-center cohort study of children diagnosed with sJIA from 2000 to 2014. Patient demographics and disease characteristics were investigated to identify predictors of response to NSAID monotherapy. Eighty-seven children were newly diagnosed with sJIA 2000-2014. Thirteen of the 51 children who received NSAID monotherapy achieved clinically inactive disease (CID) without other medications. Age at presentation (≤8 years old), initial joint count (≤5), and C-reactive protein (CRP) (≤13 mg/dL) at diagnosis were associated with achievement of CID on NSAIDs alone. Physicians were less likely to trial NSAID monotherapy if the patient had either serositis or macrophage activation syndrome (MAS) at diagnosis. Ultimate achievement of CID and time to CID were not significantly affected by whether the patient received a trial of NSAID monotherapy. While a subset of children with sJIA can achieve CID with NSAID monotherapy, we recommend against a trial in patients who are >8 years old, with >5 joints involved, or with CRP > 13 mg/dL. Patients who undergo a trial of NSAID monotherapy should follow up within 2-4 weeks to evaluate for possible need for drug escalation. Clinical trials are necessary to confirm these findings.

A neuro-immune model of Myalgic Encephalomyelitis/Chronic fatigue syndrome.

PubMed

Morris, Gerwyn; Maes, Michael

2013-12-01

This paper proposes a neuro-immune model for Myalgic Encephalomyelitis/Chronic fatigue syndrome (ME/CFS). A wide range of immunological and neurological abnormalities have been reported in people suffering from ME/CFS. They include abnormalities in proinflammatory cytokines, raised production of nuclear factor-κB, mitochondrial dysfunctions, autoimmune responses, autonomic disturbances and brain pathology. Raised levels of oxidative and nitrosative stress (O&NS), together with reduced levels of antioxidants are indicative of an immuno-inflammatory pathology. A number of different pathogens have been reported either as triggering or maintaining factors. Our model proposes that initial infection and immune activation caused by a number of possible pathogens leads to a state of chronic peripheral immune activation driven by activated O&NS pathways that lead to progressive damage of self epitopes even when the initial infection has been cleared. Subsequent activation of autoreactive T cells conspiring with O&NS pathways cause further damage and provoke chronic activation of immuno-inflammatory pathways. The subsequent upregulation of proinflammatory compounds may activate microglia via the vagus nerve. Elevated proinflammatory cytokines together with raised O&NS conspire to produce mitochondrial damage. The subsequent ATP deficit together with inflammation and O&NS are responsible for the landmark symptoms of ME/CFS, including post-exertional malaise. Raised levels of O&NS subsequently cause progressive elevation of autoimmune activity facilitated by molecular mimicry, bystander activation or epitope spreading. These processes provoke central nervous system (CNS) activation in an attempt to restore immune homeostatsis. This model proposes that the antagonistic activities of the CNS response to peripheral inflammation, O&NS and chronic immune activation are responsible for the remitting-relapsing nature of ME/CFS. Leads for future research are suggested based on this neuro-immune model.

Phytochemicals and their impact on adipose tissue inflammation and diabetes.

PubMed

Leiherer, Andreas; Mündlein, Axel; Drexel, Heinz

2013-01-01

Type 2 diabetes mellitus is an inflammatory disease and the mechanisms that underlie this disease, although still incompletely understood, take place in the adipose tissue of obese subjects. Concurrently, the prevalence of obesity caused by Western diet's excessive energy intake and the lack of exercise escalates, and is believed to be causative for the chronic inflammatory state in adipose tissue. Overnutrition itself as an overload of energy may induce the adipocytes to secrete chemokines activating and attracting immune cells to adipose tissue. But also inflammation-mediating food ingredients like saturated fatty acids are believed to directly initiate the inflammatory cascade. In addition, hypoxia in adipose tissue as a direct consequence of obesity, and its effect on gene expression in adipocytes and surrounding cells in fat tissue of obese subjects appears to play a central role in this inflammatory response too. In contrast, revisiting diet all over the world, there are also some natural food products and beverages which are associated with curative effects on human health. Several natural compounds known as spices such as curcumin, capsaicin, and gingerol, or secondary plant metabolites catechin, resveratrol, genistein, and quercetin have been reported to provide an improved health status to their consumers, especially with regard to diabetes, and therefore have been investigated for their anti-inflammatory effect. In this review, we will give an overview about these phytochemicals and their role to interfere with inflammatory cascades in adipose tissue and their potential for fighting against inflammatory diseases like diabetes as investigated in vivo. Copyright © 2012 Elsevier Inc. All rights reserved.

The enduring importance of animal modelsin understanding periodontal disease

PubMed Central

Hajishengallis, George; Lamont, Richard J; Graves, Dana T

2015-01-01

Whereas no single animal model can reproduce the complexity of periodontitis, different aspects of the disease can be addressed by distinct models. Despite their limitations, animal models are essential for testing the biological significance of in vitro findings and for establishing cause-and-effect relationships relevant to clinical observations, which are typically correlative. We provide evidence that animal-based studies have generated a durable framework for dissecting the mechanistic basis of periodontitis. These studies have solidified the etiologic role of bacteria in initiating the inflammatory response that leads to periodontal bone loss and have identified key mediators (IL-1, TNF, prostaglandins, complement, RANKL) that induce inflammatory breakdown. Moreover, animal studies suggest that dysbiosis, rather than individual bacterial species, are important in initiating periodontal bone loss and have introduced the concept that organisms previously considered commensals can play important roles as accessory pathogens or pathobionts. These studies have also provided insight as to how systemic conditions, such as diabetes or leukocyte adhesion deficiency, contribute to tissue destruction. In addition, animal studies have identified and been useful in testing therapeutic targets. PMID:25574929

Immunoexcitatory mechanisms in glioma proliferation, invasion and occasional metastasis

PubMed Central

Blaylock, Russell L.

2013-01-01

There is increasing evidence of an interaction between inflammatory cytokines and glutamate receptors among a number of neurological diseases including traumatic brain injuries, neurodegenerative diseases and central nervous system (CNS) infections. A number of recent studies have now suggested a strong relation between inflammatory mechanisms and excitatory cascades and these may play a role in glioma invasiveness and proliferation. Chronic inflammation appears to be a major initiating mechanism in most human cancers, involving cell-signaling pathways, which are responsible for cell cycling, cancer cell migration, invasion, tumor aggressiveness, and angiogenesis. It is less well appreciated that glutamate receptors also play a significant role in both proliferation and especially glioma invasion. There is some evidence that sustained elevations in glutamate may play a role in initiating certain cancers and new studies demonstrate an interaction between inflammation and glutamate receptors that may enhance tumor invasion and metastasis by affecting a number of cell-signaling mechanisms. These mechanisms are discussed in this paper as well as novel treatment options for reducing immune-glutamate promotion of cancer growth and invasion. PMID:23493580

The DNA Inflammasome in Human Myeloid Cells Is Initiated by a STING-Cell Death Program Upstream of NLRP3

PubMed Central

Gaidt, Moritz M.; Ebert, Thomas S.; Chauhan, Dhruv; Ramshorn, Katharina; Pinci, Francesca; Zuber, Sarah; O’Duill, Fionan; Schmid-Burgk, Jonathan L.; Hoss, Florian; Buhmann, Raymund; Wittmann, Georg; Latz, Eicke; Subklewe, Marion; Hornung, Veit

2018-01-01

Summary Detection of cytosolic DNA constitutes a central event in the context of numerous infectious and sterile inflammatory conditions. Recent studies have uncovered a bipartite mode of cytosolic DNA recognition, in which the cGAS-STING axis triggers antiviral immunity, whereas AIM2 triggers inflammasome activation. Here, we show that AIM2 is dispensable for DNA-mediated inflammasome activation in human myeloid cells. Instead, detection of cytosolic DNA by the cGAS-STING axis induces a cell death program initiating potassium efflux upstream of NLRP3. Forward genetics identified regulators of lysosomal trafficking to modulate this cell death program, and subsequent studies revealed that activated STING traffics to the lysosome, where it triggers membrane permeabilization and thus lysosomal cell death (LCD). Importantly, the cGAS-STING-NLRP3 pathway constitutes the default inflammasome response during viral and bacterial infections in human myeloid cells. We conclude that targeting the cGAS-STING-LCD-NLRP3 pathway will ameliorate pathology in inflammatory conditions that are associated with cytosolic DNA sensing. PMID:29033128

Aggregatibacter actinomycetemcomitans, a potent immunoregulator of the periodontal host defense system and alveolar bone homeostasis

PubMed Central

Herbert, Bethany A.; Novince, Chad M.; Kirkwood, Keith L.

2015-01-01

Summary Aggregatibacter actinomycetemcomitans is a perio-pathogenic bacteria that has long been associated with localized aggressive periodontitis. The mechanisms of its pathogenicity have been studied in humans and pre-clinical experimental models. Although different serotypes of A. actinomycetemcomitans have differential virulence factor expression, A. actinomycetemcomitans cytolethal distending toxin (CDT), leukotoxin, and lipopolysaccharide (LPS) have been most extensively studied in the context of modulating the host immune response. Following colonization and attachment in the oral cavity, A. actinomycetemcomitans employs CDT, leukotoxin, and LPS to evade host innate defense mechanisms and drive a pathophysiologic inflammatory response. This supra-physiologic immune response state perturbs normal periodontal tissue remodeling/turnover and ultimately has catabolic effects on periodontal tissue homeostasis. In this review, we have divided the host response into two systems: non-hematopoietic and hematopoietic. Non-hematopoietic barriers include epithelium and fibroblasts that initiate the innate immune host response. The hematopoietic system contains lymphoid and myeloid-derived cell lineages that are responsible for expanding the immune response and driving the pathophysiologic inflammatory state in the local periodontal microenvironment. Effector systems and signaling transduction pathways activated and utilized in response to A. actinomycetemcomitans will be discussed to further delineate immune cell mechanisms during A. actinomycetemcomitans infection. Finally, we will discuss the osteo-immunomodulatory effects induced by A. actinomycetemcomitans and dissect the catabolic disruption of balanced osteoclast-osteoblast mediated bone remodeling, which subsequently leads to net alveolar bone loss. PMID:26197893

Innate immune responses following Kawasaki disease and toxic shock syndrome

PubMed Central

Messina, Nicole; Germano, Susie; Bonnici, Rhian; Freyne, Bridget; Cheung, Michael; Goldsmith, Greta; Kollmann, Tobias R.; Levin, Michael; Burgner, David; Curtis, Nigel

2018-01-01

The pathogenesis of Kawasaki disease (KD) remains unknown and there is accumulating evidence for the importance of the innate immune system in initiating and mediating the host inflammatory response. We compared innate immune responses in KD and toxic shock syndrome (TSS) participants more than two years after their acute illness with control participants to investigate differences in their immune phenotype. Toxic shock syndrome shares many clinical features with KD; by including both disease groups we endeavoured to explore changes in innate immune responses following acute inflammatory illnesses more broadly. We measured the in vitro production of interferon (IFN)-γ, tumour necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, IL-1 receptor antagonist (IL-1ra), and IL-10 following whole blood stimulation with toll-like receptor and inflammasome ligands in 52 KD, 20 TSS, and 53 control participants in a case-control study. Analyses were adjusted for age, sex, and unstimulated cytokine concentrations. Compared to controls, KD participants have reduced IL-1ra production in response to stimulation with double stranded RNA (geometric mean ratio (GMR) 0.37, 95% CI 0.15, 0.89, p = 0.03) and increased IL-6 production in response to incubation with Lyovec™ (GMR 5.48, 95% CI 1.77, 16.98, p = 0.004). Compared to controls, TSS participants have increased IFN-γ production in response to peptidoglycan (GMR 4.07, 95% CI 1.82, 9.11, p = 0.001), increased IL-1β production to lipopolysaccharide (GMR 1.64, 95% CI 1.13, 2.38, p = 0.01) and peptidoglycan (GMR 1.61, 95% CI 1.11, 2.33, p = 0.01), and increased IL-6 production to peptidoglycan (GMR 1.45, 95% CI 1.10, 1.92, p = 0.01). Years following the acute illness, individuals with previous KD or TSS exhibit a pro-inflammatory innate immune phenotype suggesting a possible underlying immunological susceptibility or innate immune memory. PMID:29447181

Cytokines and metabolic patterns in pediatric patients with critical illness.

PubMed

Briassoulis, George; Venkataraman, Shekhar; Thompson, Ann

2010-01-01

It is not known if cytokines, which are cell-derived mediators released during the host immune response to stress, affect metabolic response to stress during critical illness. The aim of this prospective study was to determine whether the metabolic response to stress is related to the inflammatory interleukin-6 (IL-6), 10 (IL-10), and other stress mediators' responses and to assess their relationships with different feeding patterns, nutritional markers, the severity of illness as assessed by the Multiple Organ System Failure (MOSF), the Pediatric Risk of Mortality Score (PRISM), systemic inflammatory response syndrome (SIRS), and mortality in critically ill children. Patients were classified as hypermetabolic, normometabolic, and hypometabolic when the measured resting energy expenditures (REE) were >110%, 90-110% and, <90% of the predicted basal metabolic rate, respectively. The initial predominance of the hypometabolic pattern (48.6%) declined within 1 week of acute stress (20%), and the hypermetabolic patterns dominated only after 2 weeks (60%). Only oxygen consumption (VO(2)) and carbon dioxide production (VCO(2)) (P < .0001) but none of the cytokines and nutritional markers, were independently associated with a hypometabolic pattern. REE correlated with the IL-10 but not PRISM. In the presence of SIRS or sepsis, CRP, IL-6, IL-10, Prognostic Inflammatory and Nutritional Index (NI), and triglycerides--but not glucose, VO(2), or VCO(2) increased significantly. High IL-10 levels (P = .0000) and low measured REE (P = .0000) were independently associated with mortality (11.7%), which was higher in the hypometabolic compared to other metabolic patterns (P < .005). Our results showed that only VO(2) and VCO(2), but not IL-6 or IL-10, were associated with a hypometabolic pattern which predominated the acute phase of stress, and was associated with increased mortality. Although in SIRS or sepsis, the cytokine response was reliably reflected by increases in NI and triglycerides, it was different from the metabolic (VO(2), VCO(2)) or glucose response.

Cytokines and Metabolic Patterns in Pediatric Patients with Critical Illness

PubMed Central

Briassoulis, George; Venkataraman, Shekhar; Thompson, Ann

2010-01-01

It is not known if cytokines, which are cell-derived mediators released during the host immune response to stress, affect metabolic response to stress during critical illness. The aim of this prospective study was to determine whether the metabolic response to stress is related to the inflammatory interleukin-6 (IL-6), 10 (IL-10), and other stress mediators' responses and to assess their relationships with different feeding patterns, nutritional markers, the severity of illness as assessed by the Multiple Organ System Failure (MOSF), the Pediatric Risk of Mortality Score (PRISM), systemic inflammatory response syndrome (SIRS), and mortality in critically ill children. Patients were classified as hypermetabolic, normometabolic, and hypometabolic when the measured resting energy expenditures (REE) were >110%, 90–110% and, <90% of the predicted basal metabolic rate, respectively. The initial predominance of the hypometabolic pattern (48.6%) declined within 1 week of acute stress (20%), and the hypermetabolic patterns dominated only after 2 weeks (60%). Only oxygen consumption (VO2) and carbon dioxide production (VCO2) (P < .0001) but none of the cytokines and nutritional markers, were independently associated with a hypometabolic pattern. REE correlated with the IL-10 but not PRISM. In the presence of SIRS or sepsis, CRP, IL-6, IL-10, Prognostic Inflammatory and Nutritional Index (NI), and triglycerides—but not glucose, VO2, or VCO2 increased significantly. High IL-10 levels (P = .0000) and low measured REE (P = .0000) were independently associated with mortality (11.7%), which was higher in the hypometabolic compared to other metabolic patterns (P < .005). Our results showed that only VO2 and VCO2, but not IL-6 or IL-10, were associated with a hypometabolic pattern which predominated the acute phase of stress, and was associated with increased mortality. Although in SIRS or sepsis, the cytokine response was reliably reflected by increases in NI and triglycerides, it was different from the metabolic (VO2, VCO2) or glucose response. PMID:20490277

Innate immune responses following Kawasaki disease and toxic shock syndrome.

PubMed

Chen, Katherine Y H; Messina, Nicole; Germano, Susie; Bonnici, Rhian; Freyne, Bridget; Cheung, Michael; Goldsmith, Greta; Kollmann, Tobias R; Levin, Michael; Burgner, David; Curtis, Nigel

2018-01-01

The pathogenesis of Kawasaki disease (KD) remains unknown and there is accumulating evidence for the importance of the innate immune system in initiating and mediating the host inflammatory response. We compared innate immune responses in KD and toxic shock syndrome (TSS) participants more than two years after their acute illness with control participants to investigate differences in their immune phenotype. Toxic shock syndrome shares many clinical features with KD; by including both disease groups we endeavoured to explore changes in innate immune responses following acute inflammatory illnesses more broadly. We measured the in vitro production of interferon (IFN)-γ, tumour necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, IL-1 receptor antagonist (IL-1ra), and IL-10 following whole blood stimulation with toll-like receptor and inflammasome ligands in 52 KD, 20 TSS, and 53 control participants in a case-control study. Analyses were adjusted for age, sex, and unstimulated cytokine concentrations. Compared to controls, KD participants have reduced IL-1ra production in response to stimulation with double stranded RNA (geometric mean ratio (GMR) 0.37, 95% CI 0.15, 0.89, p = 0.03) and increased IL-6 production in response to incubation with Lyovec™ (GMR 5.48, 95% CI 1.77, 16.98, p = 0.004). Compared to controls, TSS participants have increased IFN-γ production in response to peptidoglycan (GMR 4.07, 95% CI 1.82, 9.11, p = 0.001), increased IL-1β production to lipopolysaccharide (GMR 1.64, 95% CI 1.13, 2.38, p = 0.01) and peptidoglycan (GMR 1.61, 95% CI 1.11, 2.33, p = 0.01), and increased IL-6 production to peptidoglycan (GMR 1.45, 95% CI 1.10, 1.92, p = 0.01). Years following the acute illness, individuals with previous KD or TSS exhibit a pro-inflammatory innate immune phenotype suggesting a possible underlying immunological susceptibility or innate immune memory.

Micro124-mediated AHR expression regulates the inflammatory response of chronic rhinosinusitis (CRS) with nasal polyps.

PubMed

Liu, C C; Xia, M; Zhang, Y J; Jin, P; Zhao, L; Zhang, J; Li, T; Zhou, X M; Tu, Y Y; Kong, F; Sun, C; Shi, L; Zhao, M Q

2018-06-02

MicroRNAs represent a component of the innate immune responses that can restrain inflammatory signaling, miR124 is an important member of inflammation-associated miRNAs, and abnormal miR124 expression is observed in many inflammatory diseases and immune disorders. However, the role and signaling pathways of miR124 in chronic rhinosinusitis with nasal polyps (CRSwNPs) have not been studied in detail. The aryl hydrocarbon receptor (AHR) is a ligand-inducible transcription factor that is highly conserved in evolution and plays important roles in the inflammatory response process. In our study, we describe the role of miR124 in the inflammatory response of CRS with nasal polyps. We found that the expression of miR124 was decreased in nasal polyps, and negatively correlated with the expression of AHR. MiR124 can inhibit AHR expression by directly target 3' untranslated region (3'-UTR) of AHR. To further investigate the relationship between miR124, AHR and CRS inflammatory response, we transfect HNEpC cells with miR124 mimic, miR124 inhibitors or siRNA of AHR, then all the results showed that miR124 could regulates cellular inflammatory response through negatively regulating AHR expression. This study demonstrated that the regulation of AHR expression by miR124 is critical to the development of inflammatory response in CRSwNPs. Copyright © 2018. Published by Elsevier Inc.

Role of muscarinic receptors in the regulation of immune and inflammatory responses

PubMed Central

Razani-Boroujerdi, Seddigheh; Behl, Muskaan; Hahn, Fletcher F.; Pena-Philippides, Juan Carlos; Hutt, Julie; Sopori, Mohan L.

2008-01-01

Leukocytes contain both nicotinic and muscarinic receptors, and while activation of nicotinic receptors suppresses immune/inflammatory responses, the role of muscarinic receptors in immunity is unclear. We examined the effects of a muscarinic receptor antagonist (atropine) and agonist (oxotremorine), administered chronically through miniosmotic pumps, on immune/inflammatory responses in the rat. Results show that while oxotremorine stimulated, atropine inhibited the antibody and T-cell proliferative responses. Moreover, atropine also suppressed the turpentine-induced leukocytic infiltration and tissue injury, and inhibited chemotaxis of leukocytes toward neutrophil and monocyte/lymphocyte chemoattractants. Thus, activation of nicotinic and muscarinic receptors has opposite effects on the immune/inflammatory responses. PMID:18190972

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.

NF-kappaB Activity in Macrophages Determines Metastatic Potential of Breast Tumor Cells

DTIC Science & Technology

2011-08-01

Cheng DS, Chodosh LA, Blackwell TS, Yull FE: Activation of nuclear factor kappa B in mammary epithelium promotes milk loss during mammary... microbial products (15, 16). To date, the potential role of macrophages in the fetal lung innate immune response has not been closely examined. Studies...In this model, microbial products initially activate NF-kB in lung macrophages. The release of inflammatory mediators, particularly IL-1b and/or TNF-a

Pulmonary Inflammatory Responses to Acute Meteorite Dust Exposures - Implications for Human Space Exploration

NASA Technical Reports Server (NTRS)

Harrington, A. D.; McCubbin, F. M.; Vander Kaaden, K. E.; Kaur, J.; Smirnov, A.; Galdanes, K.; Schoonen, M. A. A.; Chen, L. C.; Tsirka, S. E.; Gordon, T.

2018-01-01

New initiatives to send humans to Mars within the next few decades are illustrative of the resurgence of interest in space travel. However, as with all exploration, there are risks. The Human Research Roadmap developed by NASA identifies the Risk of Adverse Health and Performance Effects of Celestial Dust Exposure as an area of concern. Extended human exploration will further increase the probability of inadvertent and repeated exposures to celestial dusts.

Nonsteroidal Anti-Inflammatory Drugs Quickly Resolve Symptoms Associated with EBV-Induced Infectious Mononucleosis in Patients with Atopic Predispositions.

PubMed

Kazama, Itsuro; Miura, Chieko; Nakajima, Toshiyuki

2016-02-14

Infectious mononucleosis is a clinical syndrome most commonly associated with primary Epstein-Barr virus (EBV) infection. In adults, the symptoms can often be severe and prolonged, sometimes causing serious complications. Analgesic or antipyretic drugs are normally used to relieve the symptoms. However, there is no causal treatment for the disease. Two cases of adult patients with atopic predispositions developed nocturnal fever, general fatigue, pharyngitis and lymphadenopathy after an exacerbation of atopic symptoms or those of allergic rhinitis. Due to the positive results for EBV viral-capsid antigen (VCA) IgM and negative results for EBV nuclear antigen (EBNA) IgG, diagnoses of infectious mononucleosis induced by EBV were made in both cases. Although oral antibiotics or acetaminophen alone did not improve the deteriorating symptoms, including fever, headache and general fatigue, nonsteroidal anti-inflammatory drugs (NSAIDs), such as tiaramide or loxoprofen, completely improved the symptoms quickly after the initiation. In these cases, given the atopic predispositions of the patients, an enhanced immunological response was likely to be mainly responsible for the pathogenesis of the symptoms. In such cases, NSAIDs, that are known to reduce the activity of EBV, may dramatically improve the deteriorating symptoms quickly after the initiation. In the present cases, the immunosuppressive property of these drugs was considered to suppress the activity of lymphocytes and thus provide the rapid and persistent remission of the disease.

Airway Fibrinogenolysis and the Initiation of Allergic Inflammation

PubMed Central

Millien, Valentine Ongeri; Lu, Wen; Mak, Garbo; Yuan, Xiaoyi; Knight, J. Morgan; Porter, Paul; Kheradmand, Farrah

2014-01-01

The past 15 years of allergic disease research have produced extraordinary improvements in our understanding of the pathogenesis of airway allergic diseases such as asthma. Whereas it was previously viewed as largely an immunoglobulin E-mediated process, the gradual recognition that T cells, especially Type 2 T helper (Th2) cells and Th17 cells, play a major role in asthma and related afflictions has inspired clinical trials targeting cytokine-based inflammatory pathways that show great promise. What has yet to be clarified about the pathogenesis of allergic inflammatory disorders, however, are the fundamental initiating factors, both exogenous and endogenous, that drive and sustain B- and T-cell responses that underlie the expression of chronic disease. Here we review how proteinases derived from diverse sources drive allergic responses. A central discovery supporting the proteinase hypothesis of allergic disease pathophysiology is the role played by airway fibrinogen, which in part appears to serve as a sensor of unregulated proteinase activity and which, when cleaved, both participates in a novel allergic signaling pathway through Toll-like receptor 4 and forms fibrin clots that contribute to airway obstruction. Unresolved at present is the ultimate source of airway allergenic proteinases. From among many potential candidates, perhaps the most intriguing is the possibility such enzymes derive from airway fungi. Together, these new findings expand both our knowledge of allergic disease pathophysiology and options for therapeutic intervention. PMID:25525732

Nutritional Approaches for Managing Obesity-Associated Metabolic Diseases

PubMed Central

Botchlett, Rachel; Woo, Shih-Lung; Liu, Mengyang; Pei, Ya; Guo, Xin; Li, Honggui; Wu, Chaodong

2017-01-01

Obesity is an ongoing pandemic and serves as a causal factor of a wide spectrum of metabolic diseases including diabetes, fatty liver disease, and cardiovascular disease. Much evidence has demonstrated that nutrient overload/overnutrition initiates or exacerbates inflammatory responses in tissues/organs involved in the regulation of systemic metabolic homeostasis. This obesity-associated inflammation is usually at a low-grade and viewed as metabolic inflammation. When it exists continuously, inflammation inappropriately alters metabolic pathways and impairs insulin signaling cascades in peripheral tissues/organs such as adipose tissue, the liver and skeletal muscle, resulting in local fat deposition and insulin resistance and systemic metabolic dysregulation. In addition, inflammatory mediators, e.g., proinflammatory cytokines, and excessive nutrients, e.g., glucose and fatty acids, act together to aggravate local insulin resistance and form a vicious cycle to further disturb local metabolic pathways and exacerbate systemic metabolic dysregulation. Owing to the critical role of nutrient metabolism in the control of the initiation and progression of inflammation and insulin resistance, nutritional approaches have been implicated as effective tools for managing obesity and obesity-associated metabolic diseases. Based on the mounting evidence generated from both basic and clinical research, nutritional approaches are commonly used for suppressing inflammation, improving insulin sensitivity, and/or decreasing fat deposition. Consequently, the combined effects are responsible for improvement of systemic insulin sensitivity and metabolic homeostasis. PMID:28400405

The Acute Exercise-Induced Inflammatory Response: A Comparison of Young-Adult Smokers and Nonsmokers

ERIC Educational Resources Information Center

Kastelein, Tegan E.; Donges, Cheyne E.; Mendham, Amy E.; Duffield, Rob

2017-01-01

Purpose: This study examined postexercise inflammatory and leukocyte responses in smokers and nonsmokers, as well as the effects of cigarette smoking on the acute postexercise inflammatory and leukocyte response in habitual smokers. Method: Eleven recreationally active male smokers and 11 nonsmokers matched for age and aerobic fitness were…

Streptococcus pneumoniae and Pseudomonas aeruginosa pneumonia induce distinct host responses.

PubMed

McConnell, Kevin W; McDunn, Jonathan E; Clark, Andrew T; Dunne, W Michael; Dixon, David J; Turnbull, Isaiah R; Dipasco, Peter J; Osberghaus, William F; Sherman, Benjamin; Martin, James R; Walter, Michael J; Cobb, J Perren; Buchman, Timothy G; Hotchkiss, Richard S; Coopersmith, Craig M

2010-01-01

Pathogens that cause pneumonia may be treated in a targeted fashion by antibiotics, but if this therapy fails, then treatment involves only nonspecific supportive measures, independent of the inciting infection. The purpose of this study was to determine whether host response is similar after disparate infections with similar mortalities. Prospective, randomized controlled study. Animal laboratory in a university medical center. Pneumonia was induced in FVB/N mice by either Streptococcus pneumoniae or two different concentrations of Pseudomonas aeruginosa. Plasma and bronchoalveolar lavage fluid from septic animals was assayed by a microarray immunoassay measuring 18 inflammatory mediators at multiple time points. The host response was dependent on the causative organism as well as kinetics of mortality, but the pro-inflammatory and anti-inflammatory responses were independent of inoculum concentration or degree of bacteremia. Pneumonia caused by different concentrations of the same bacteria, Pseudomonas aeruginosa, also yielded distinct inflammatory responses; however, inflammatory mediator expression did not directly track the severity of infection. For all infections, the host response was compartmentalized, with markedly different concentrations of inflammatory mediators in the systemic circulation and the lungs. Hierarchical clustering analysis resulted in the identification of five distinct clusters of the host response to bacterial infection. Principal components analysis correlated pulmonary macrophage inflammatory peptide-2 and interleukin-10 with progression of infection, whereas elevated plasma tumor necrosis factor sr2 and macrophage chemotactic peptide-1 were indicative of fulminant disease with >90% mortality within 48 hrs. Septic mice have distinct local and systemic responses to Streptococcus pneumoniae and Pseudomonas aeruginosa pneumonia. Targeting specific host inflammatory responses induced by distinct bacterial infections could represent a potential therapeutic approach in the treatment of sepsis.

Growth and Development Symposium: Inflammation: Role in the etiology and pathophysiology of clinical mastitis in dairy cows.

PubMed

Ballou, M A

2012-05-01

Genetic selection for increased milk production in dairy cattle was not associated with an attenuated inflammatory response. The systemic and local inflammatory responses contribute to altered metabolism, reduced production performance, and increased cull rate of lactating dairy cows with clinical mastitis. More aggressive inflammatory responses were observed during the peripartum period when compared with cows in late lactation after an intramammary challenge with purified lipopolysaccharide. The epidemiology of clinical mastitis indicates that the greatest incidence is observed during the peripartum period; therefore, an enhanced inflammatory response with concomitant suppression in other immune responses may be involved in the etiology and severity of the clinical mastitis observed in peripartum cows. Milk production losses and compositional changes are observed among all mammary quarters from a cow with clinical mastitis, but the responses are more severe and sustained among infected quarters. The infected mammary quarters reflect both the systemic and local reactions, whereas uninfected quarters represent only the systemic response. The systemic effects of the inflammatory response include reduced DMI, hyperthermia, and changes in whole-body nutrient partitioning affecting mammary epithelial substrate availability, whereas local inflammatory effects include energetic requirements of the increased inflammatory leukocyte pool, decreased synthetic capacity of mammary epithelium independent of substrate availability, and paracellular leakage of milk components from the alveolar lumen into the extracellular fluid. Research has focused on improving host immunological defenses, attenuating the inflammatory response, or improving the resolution of the disease state to limit the deleterious effects during clinical mastitis. This paper highlights the role inflammation plays in the etiology and pathophysiology of clinical mastitis as well as potential management strategies to reduce or prevent those losses.

Early identification of 'acute-onset' chronic inflammatory demyelinating polyneuropathy.

PubMed

Sung, Jia-Ying; Tani, Jowy; Park, Susanna B; Kiernan, Matthew C; Lin, Cindy Shin-Yi

2014-08-01

Distinguishing patients with acute-onset chronic inflammatory demyelinating polyneuropathy from acute inflammatory demyelinating polyneuropathy prior to relapse is often challenging at the onset of their clinical presentation. In the present study, nerve excitability tests were used in conjunction with the clinical phenotype and disease staging, to differentiate between patients with acute-onset chronic inflammatory demyelinating polyneuropathy and patients with acute inflammatory demyelinating polyneuropathy at an early stage, with the aim to better guide treatment. Clinical assessment, staging and nerve excitability tests were undertaken on patients initially fulfilling the diagnostic criteria of acute inflammatory demyelinating polyneuropathy soon after symptom onset and their initial presentation. Patients were subsequently followed up for minimum of 12 months to determine if their clinical presentations were more consistent with acute-onset chronic inflammatory demyelinating polyneuropathy. Clinical severity as evaluated by Medical Research Council sum score and Hughes functional grading scale were not significantly different between the two cohorts. There was no difference between the time of onset of initial symptoms and nerve excitability test assessment between the two cohorts nor were there significant differences in conventional nerve conduction study parameters. However, nerve excitability test profiles obtained from patients with acute inflammatory demyelinating polyneuropathy demonstrated abnormalities in the recovery cycle of excitability, including significantly reduced superexcitability (P < 0.001) and prolonged relative refractory period (P < 0.01), without changes in threshold electrotonus. In contrast, in patients with acute-onset chronic inflammatory demyelinating polyneuropathy, a different pattern occurred with the recovery cycle shifted downward (increased superexcitability, P < 0.05; decreased subexcitability, P < 0.05) and increased threshold change in threshold electrotonus in both hyperpolarizing and depolarizing directions [depolarizing threshold electrotonus (90-100 ms) P < 0.005, hyperpolarizing threshold electrotonus (10-20 ms), P < 0.01, hyperpolarizing threshold electrotonus (90-100 ms), P < 0.05], perhaps suggesting early hyperpolarization. In addition, using excitability parameters superexcitability, subexcitability and hyperpolarizing threshold electrotonus (10-20 ms), the patients with acute inflammatory demyelinating polyneuropathy and acute-onset chronic inflammatory demyelinating polyneuropathy could be clearly separated into two non-overlapping groups. Studies of nerve excitability may be able to differentiate acute from acute-onset chronic inflammatory demyelinating polyneuropathy at an early stage. Characteristic nerve excitability parameter changes occur in early acute-onset chronic inflammatory demyelinating polyneuropathy, to match the clinical phenotype. Importantly, this pattern of change was strikingly different to that shown by patients with acute inflammatory demyelinating polyneuropathy, suggesting that nerve excitability techniques may be useful in distinguishing acute-onset chronic inflammatory demyelinating polyneuropathy from acute inflammatory demyelinating polyneuropathy at the initial stage. © The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Use of CytoSorb in Traumatic Amputation of the Forearm and Severe Septic Shock

PubMed Central

Grieb, Alexander; Mostafa, Karim; Berger, Reinhard

2017-01-01

Severe trauma associated with later disability and mortality still constitutes a major health and socioeconomic problem throughout the world. While primary morbidity and mortality are mostly related to initial injuries and early complications, secondary lethality is strongly linked to the development of systemic inflammatory response syndrome, sepsis, and ultimately multiple organ dysfunction syndrome. We herein report on a 49-year-old male patient who was admitted to the hospital after a traumatic amputation of his right forearm that was cut off while working on a landfill. After initial treatment for shock, he received immediate replantation and was transferred to the ICU. Due to the anticipated risk of a complex infection, continuous renal replacement therapy in combination with CytoSorb was initiated. During the course of the combined treatment, a rapid improvement in hemodynamics was noticed, as well as a significant reduction of IL-6 and lactate levels. Despite a recurring septic episode and the necessity for amputation, the patient clinically stabilized and underwent complete recovery. The early treatment with a combination of CVVHDF and CytoSorb was accompanied by an attenuation of the systemic inflammatory reaction, which subsided without major or permanent organ damage, despite the impressive pathogen spectrum and the pronounced local damage. PMID:29423323

Use of CytoSorb in Traumatic Amputation of the Forearm and Severe Septic Shock.

PubMed

Steltzer, Heinz; Grieb, Alexander; Mostafa, Karim; Berger, Reinhard

2017-01-01

Severe trauma associated with later disability and mortality still constitutes a major health and socioeconomic problem throughout the world. While primary morbidity and mortality are mostly related to initial injuries and early complications, secondary lethality is strongly linked to the development of systemic inflammatory response syndrome, sepsis, and ultimately multiple organ dysfunction syndrome. We herein report on a 49-year-old male patient who was admitted to the hospital after a traumatic amputation of his right forearm that was cut off while working on a landfill. After initial treatment for shock, he received immediate replantation and was transferred to the ICU. Due to the anticipated risk of a complex infection, continuous renal replacement therapy in combination with CytoSorb was initiated. During the course of the combined treatment, a rapid improvement in hemodynamics was noticed, as well as a significant reduction of IL-6 and lactate levels. Despite a recurring septic episode and the necessity for amputation, the patient clinically stabilized and underwent complete recovery. The early treatment with a combination of CVVHDF and CytoSorb was accompanied by an attenuation of the systemic inflammatory reaction, which subsided without major or permanent organ damage, despite the impressive pathogen spectrum and the pronounced local damage.

Genomic responses in rat cerebral cortex after traumatic brain injury

PubMed Central

von Gertten, Christina; Morales, Amilcar Flores; Holmin, Staffan; Mathiesen, Tiit; Nordqvist, Ann-Christin Sandberg

2005-01-01

Background Traumatic brain injury (TBI) initiates a complex sequence of destructive and neuroprotective cellular responses. The initial mechanical injury is followed by an extended time period of secondary brain damage. Due to the complicated pathological picture a better understanding of the molecular events occurring during this secondary phase of injury is needed. This study was aimed at analysing gene expression patterns following cerebral cortical contusion in rat using high throughput microarray technology with the goal of identifying genes involved in an early and in a more delayed phase of trauma, as genomic responses behind secondary mechanisms likely are time-dependent. Results Among the upregulated genes 1 day post injury, were transcription factors and genes involved in metabolism, e.g. STAT-3, C/EBP-δ and cytochrome p450. At 4 days post injury we observed increased gene expression of inflammatory factors, proteases and their inhibitors, like cathepsins, α-2-macroglobulin and C1q. Notably, genes with biological function clustered to immune response were significantly upregulated 4 days after injury, which was not found following 1 day. Osteopontin and one of its receptors, CD-44, were both upregulated showing a local mRNA- and immunoreactivity pattern in and around the injury site. Fewer genes had decreased expression both 1 and 4 days post injury and included genes implicated in transport, metabolism, signalling, and extra cellular matrix formation, e.g. vitronectin, neuroserpin and angiotensinogen. Conclusion The different patterns of gene expression, with little overlap in genes, 1 and 4 days post injury showed time dependence in genomic responses to trauma. An early induction of factors involved in transcription could lead to the later inflammatory response with strongly upregulated CD-44 and osteopontin expression. An increased knowledge of genes regulating the pathological mechanisms in trauma will help to find future treatment targets. Since trauma is a risk factor for development of neurodegenerative disease, this knowledge may also reduce late negative effects. PMID:16318630

Differing House Finch Cytokine Expression Responses to Original and Evolved Isolates of Mycoplasma gallisepticum.

PubMed

Vinkler, Michal; Leon, Ariel E; Kirkpatrick, Laila; Dalloul, Rami A; Hawley, Dana M

2018-01-01

The recent emergence of the poultry bacterial pathogen Mycoplasma gallisepticum (MG) in free-living house finches ( Haemorhous mexicanus ), which causes mycoplasmal conjunctivitis in this passerine bird species, resulted in a rapid coevolutionary arms-race between MG and its novel avian host. Despite extensive research on the ecological and evolutionary dynamics of this host-pathogen system over the past two decades, the immunological responses of house finches to MG infection remain poorly understood. We developed seven new probe-based one-step quantitative reverse transcription polymerase chain reaction assays to investigate mRNA expression of house finch cytokine genes ( IL1B, IL6, IL10, IL18, TGFB2, TNFSF15 , and CXCLi2 , syn. IL8L ). These assays were then used to describe cytokine transcription profiles in a panel of 15 house finch tissues collected at three distinct time points during MG infection. Based on initial screening that indicated strong pro-inflammatory cytokine expression during MG infection at the periorbital sites in particular, we selected two key house finch tissues for further characterization: the nictitating membrane, i.e., the internal eyelid in direct contact with MG, and the Harderian gland, the secondary lymphoid tissue responsible for regulation of periorbital immunity. We characterized cytokine responses in these two tissues for 60 house finches experimentally inoculated either with media alone (sham) or one of two MG isolates: the earliest known pathogen isolate from house finches (VA1994) or an evolutionarily more derived isolate collected in 2006 (NC2006), which is known to be more virulent. We show that the more derived and virulent isolate NC2006, relative to VA1994, triggers stronger local inflammatory cytokine signaling, with peak cytokine expression generally occurring 3-6 days following MG inoculation. We also found that the extent of pro-inflammatory interleukin 1 beta signaling was correlated with conjunctival MG loads and the extent of clinical signs of conjunctivitis, the main pathological effect of MG in house finches. These results suggest that the pathogenicity caused by MG infection in house finches is largely mediated by host pro-inflammatory immune responses, with important implications for the dynamics of host-pathogen coevolution.

Fenspiride inhibits histamine-induced responses in a lung epithelial cell line.

PubMed

Quartulli, F; Pinelli, E; Broué-Chabbert, A; Gossart, S; Girard, V; Pipy, B

1998-05-08

Using the human lung epithelial WI26VA4 cell line, we investigated the capacity of fenspiride, an anti-inflammatory drug with anti-bronchoconstrictor properties, to interfere with histamine-induced intracellular Ca2+ increase and eicosanoid formation. Histamine and a histamine H1 receptor agonist elicited a rapid and transient intracellular Ca2+ increase (0-60 s) in fluo 3-loaded WI26VA4 cells. This response was antagonized by the histamine H1 receptor antagonist, diphenhydramine, the histamine H2 receptor antagonist, cimetidine, having no effect. Fenspiride (10(-7)-10(-5) M) inhibited the histamine H1 receptor-induced Ca2+ increase. In addition, histamine induced a biphasic increase in arachidonic acid release. The initial rise (0-30 s), a rapid and transient arachidonic acid release, was responsible for the histamine-induced intracellular Ca2+ increase. In the second phase release (15-60 min), a sustained arachidonic acid release appeared to be associated with the formation of cyclooxygenase and lipoxygenase metabolites. Fenspiride (10(-5) M) abolished both phases of histamine-induced arachidonic acid release. These results suggest that anti-inflammatory and antibronchoconstrictor properties of fenspiride may result from the inhibition of these effects of histamine.

In vitro and in vivo acute response towards injectable thermosensitive chitosan/TEMPO-oxidized cellulose nanofiber hydrogel.

PubMed

Nguyen, Trang Ho Minh; Abueva, Celine; Ho, Hai Van; Lee, Sun-Young; Lee, Byong-Taek

2018-01-15

TEMPO-oxidized cellulose nanofiber (TOCNF) is a natural material with many promising properties, including biocompatibility and degradability. In this study, we integrated TOCNF at different concentrations (0.2, 0.4, 0.6, 0.8% w/v) with chitosan (CS) and created a thermosensitive injectable hydrogel intended for biomedical applications. These hydrogels can undergo sol-gel transition at body temperature through interactions between chitosan and β-glycerophosphate. The addition of TOCNF resulted in faster gelation time and increased porosity. These hydrogels with TOCNF showed improved biocompatibility both in vitro and in vivo compared to CS hydrogel. Both MC3T3-E1 pre-osteoblast cells and L929 fibroblast cells showed biocompatibility towards CS/TOCNF 0.4. After 7days of implantation, initial inflammatory response to CS/TOCNF 0.4 was found. Such response was significantly subsided within 14days. Cell infiltration within the hydrogel was also prominent, showing anti-inflammatory or wound healing (M2) macrophage at 14days after implantation. These results showed that the addition of TOCNF could significantly improve the biocompatibility of CS hydrogel as a biomaterial for biomedical application. Copyright © 2017 Elsevier Ltd. All rights reserved.

The case for immunomodulatory approaches in treating HSV encephalitis

PubMed Central

Ramakrishna, Chandran; Openshaw, Harry; Cantin, Edouard M

2013-01-01

HSV encephalitis (HSE) is the most prevalent sporadic viral encephalitis. Although safe and effective antiviral therapies and greatly improved noninvasive diagnostic procedures have significantly improved outcomes, mortality (~20%) and debilitating neurological sequelae in survivors remain unacceptably high. An encouraging new development is that the focus is now shifting away from the virus exclusively, to include consideration of the host immune response to infection in the pathology underlying development of HSE. In this article, the authors discuss results from recent studies in experimental mouse models, as well as clinical reports that demonstrate a role for exaggerated host inflammatory responses in the brain in the development of HSE that is motivating researchers and clinicians to consider new therapeutic approaches for treating HSE. The authors also discuss results from a few studies that have shown that immunomodulatory drugs can be highly protective against HSE, which supports a role for deleterious host inflammatory responses in HSE. The impressive outcomes of some immunomodulatory approaches in mouse models of HSE emphasize the urgent need for clinical trials to rigorously evaluate combination antiviral and immunomodulatory therapy in comparison with standard antiviral therapy for treatment of HSE, and support for such an initiative is gaining momentum. PMID:23956785

Similar Metabolic, Innate Immunity, and Adipokine Profiles in Adult and Pediatric Sepsis Versus Systemic Inflammatory Response Syndrome-A Pilot Study.

PubMed

Tavladaki, Theonymfi; Spanaki, Anna Maria; Dimitriou, Helen; Kondili, Efmorfia; Choulaki, Christianna; Georgopoulos, Dimitris; Briassoulis, George

2017-11-01

To examine whether the septic profiles of heat shock protein 72, heat shock protein 90α, resistin, adiponectin, oxygen consumption, CO2 production, energy expenditure, and metabolic pattern, along with illness severity, nutritional, and inflammatory indices, differ between adult and pediatric patients compared with systemic inflammatory response syndrome and healthy controls. To evaluate whether these biomolecules may discriminate sepsis from systemic inflammatory response syndrome in adult and pediatric patients. Prospective cohort study. University ICU and PICU. Seventy-eight adults (sepsis/23; systemic inflammatory response syndrome/23; healthy controls/33), 67 children (sepsis/18; systemic inflammatory response syndrome/23; controls/27), mechanically ventilated. None. Flow cytometry determined mean fluorescence intensity for monocyte or neutrophil heat shock protein expression. Resistin, adiponectin, and extracellular heat shock proteins were measured using enzyme-linked immunosorbent assay; energy expenditure by E-COVX (GE Healthcare). Genomic DNA was extracted with PureLink Genomic DNA kit (Invitrogen, Carlsbad, CA) to detect heat shock protein 72 single nucleotide polymorphisms. Similarly, in adult and pediatric patients, Acute Physiology and Chronic Evaluation-II/Acute Physiology and Pediatric Risk of Mortality-III, Simplified Acute Physiology Score-III, C-reactive protein, lactate, and resistin were higher and myocardial contractility, monocyte heat shock protein 72, oxygen consumption, CO2 production, energy expenditure, metabolic pattern, glucose, and albumin lower in sepsis compared with systemic inflammatory response syndrome or controls (p < 0.05). For discriminating sepsis from systemic inflammatory response syndrome, resistin, extracellular heat shock protein 90α, and lactate achieved a receiver operating characteristic curve greater than 0.80 in children and greater than 0.75 in adults (p < 0.05). In both, adults and children, genotype heat shock protein 72 analysis did not disclose any diagnosis or mortality group differences regarding either rs6457452 or rs1061581 haplotypes. Sepsis presents with similar profiles in adult and pediatric patients, characterized by enhanced inflammatory hormonal response and by repressed innate immunity, metabolism, and myocardial contractility. These features early distinguish sepsis from systemic inflammatory response syndrome across all age groups.

Human Corneal Limbal-Epithelial Cell Response to Varying Silk Film Geometric Topography In Vitro

PubMed Central

Lawrence, Brian D.; Pan, Zhi; Liu, Aihong; Kaplan, David L.; Rosenblatt, Mark I.

2012-01-01

Silk fibroin films are a promising class of biomaterials that have a number of advantages for use in ophthalmic applications due to their transparent nature, mechanical properties and minimal inflammatory response upon implantation. Freestanding silk films with parallel line and concentric ring topographies were generated for in vitro characterization of human corneal limbal-epithelial (HCLE) cell response upon differing geometric patterned surfaces. Results indicated that silk film topography significantly affected initial HCLE culture substrate attachment, cellular alignment, cell-to-cell contact formation, actin cytoskeleton alignment, and focal adhesion (FA) localization. Most notably, parallel line patterned surfaces displayed a 36%–54% increase on average in initial cell attachment, which corresponded to an over 2-fold increase in FA localization when compared to other silk film surfaces and controls. In addition, distinct localization of FA formation was observed along the edges for all patterned silk film topographies. In conclusion, silk film feature topography appears to help direct corneal epithelial cell response and cytoskeleton development, especially in regards to FA distribution, in vitro. PMID:22705042

Helminths in the hygiene hypothesis: sooner or later?

PubMed Central

Maizels, R M; McSorley, H J; Smyth, D J

2014-01-01

There is increasing recognition that exposures to infectious agents evoke fundamental effects on the development and behaviour of the immune system. Moreover, where infections (especially parasitic infections) have declined, immune responses appear to be increasingly prone to hyperactivity. For example, epidemiological studies of parasite-endemic areas indicate that prenatal or early-life experience of infections can imprint an individual's immunological reactivity. However, the ability of helminths to dampen pathology in established inflammatory diseases implies that they can have therapeutic effects even if the immune system has developed in a low-infection setting. With recent investigations of how parasites are able to modulate host immune pathology at the level of individual parasite molecules and host cell populations, we are now able to dissect the nature of the host–parasite interaction at both the initiation and recall phases of the immune response. Thus the question remains – is the influence of parasites on immunity one that acts primarily in early life, and at initiation of the immune response, or in adulthood and when recall responses occur? In short, parasite immunosuppression – sooner or later? PMID:24749722

Fatty acid-binding protein 5 limits the anti-inflammatory response in murine macrophages.

PubMed

Moore, Sherri M; Holt, Vivian V; Malpass, Lillie R; Hines, Ian N; Wheeler, Michael D

2015-10-01

The beginning stages of liver damage induced by various etiologies (i.e. high fat diet, alcohol consumption, toxin exposure) are characterized by abnormal accumulation of lipid in liver. Alterations in intracellular lipid transport, storage, and metabolism accompanied by cellular insult within the liver play an important role in the pathogenesis of liver disease, often involving a sustained inflammatory response. The intracellular lipid transporter, fatty acid binding protein 5 (FABP5), is highly expressed in macrophages and may play an important role in the hepatic inflammatory response after endotoxin exposure in mice. This study tested the hypothesis that FABP5 regulates macrophage response to LPS in male C57bl/6 (wild type) and FABP5 knockout mice, both in vitro and in vivo. Treatment with LPS revealed that loss of FABP5 enhances the number of hepatic F4/80(+) macrophages in the liver despite limited liver injury. Conversely, FABP5 knock out mice display higher mRNA levels of anti-inflammatory cytokines IL-10, arginase, YM-1, and Fizz-1 in liver compared to wild type mice. Bone marrow derived macrophages stimulated with inflammatory (LPS and IFN-γ) or anti-inflammatory (IL-4) mediators also showed significantly higher expression of anti-inflammatory/regulatory factors. These findings reveal a regulatory role of FABP5 in the acute inflammatory response to LPS-induced liver injury, which is consistent with the principle finding that FABP5 is a regulator of macrophage phenotype. Specifically, these findings demonstrate that loss of FABP5 promotes a more anti-inflammatory response. Copyright © 2015 Elsevier Ltd. All rights reserved.

[Antioxidant and anti-inflammatory activities of Moroccan Erica arborea L].

PubMed

Amezouar, F; Badri, W; Hsaine, M; Bourhim, N; Fougrach, H

2013-12-01

The present study was carried out to evaluate the antioxidant and anti-inflammatory capacity, and acute toxicity of Moroccan Erica arborea leaves. Antioxidant capacity was assessed by diphenyle-picryl-hydrazyl (DPPH), phosphomolybdate (PPM) and ferric reducing antioxidant power (FRAP) tests and anti-inflammatory capacity was evaluated by hind paw oedema model using carrageenan-induced inflammation in rat. The acute toxicity was evaluated using mice. Acute toxicity of ethanolic extract of E. arborea showed no sign of toxicity at dose of 5 g/kg B.W. Our extracts have important antioxidant properties. The efficient concentration of the ethanolic extract (10.22 μg/ml) required for decreasing initial DPPH concentration by 50% was comparable to that of standard solution butyl-hydroxy-toluene (BHT) (8.87 μg/ml). The administration of ethanolic extract at doses of 200 and 400mg/kg B.W. was able to prevent plantar oedema and exhibited a significant inhibition against carrageenan-induced inflammation when compared to the control group (NaCl 0.9%) but comparable to those of diclofenac (reference drug). Our results show that the leaves of E. arborea may contain some bioactive compounds which are responsible for the antioxidant and anti-inflammatory activities observed here. Our finding may indicate the possibility of using the extracts of this plant to prevent the antioxidant and inflammatory processes. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

Control of cellular influx in lung and its role in pulmonary toxicology.

PubMed Central

Lynn, W S

1984-01-01

The pulmonary influx of cytotoxic inflammatory cells, normally, in response to external toxins, is now thought to be etiologic in many of the disease syndromes of man, such as bronchitis and emphysema. Many types of effector inflammatory cells are involved, e.g., eosinophils, neutrophils, T-lymphocytes, monocytes. The diseases are characterized either by tissue destruction or by tissue hyperplasia. Agents which initiate the influx and cytotoxic secretions by these cells are legion and in general are not cell-specific. They include agents, such as phorbol esters, formyl peptides-complement fragments, elastin fragments, fatty acids (leukotrienes) as well as many uncharacterized excretions of inflammatory cells themselves, which react with specific receptors on the inflammatory cells, and secreted proteins such as fibronectin. Other agents, such as linoleic acid, digitonin and hydroxy fatty acids which are not bound by specific receptors also activate motility of inflammatory cells. The precise role of the above multiple cytotoxins in specific cellular fluxes in most pulmonary disease remains undefined. Similarly, the mechanism of cytotoxicity used by specific invading cells in specific pulmonary syndromes remains unclear. In general, macrophages are thought to destroy using specific proteases, neutrophils use oxidant radicals and proteases and eosinophils use basic surface active peptides. T-cells kill by unknown mechanisms. However, in specific clinical syndromes, it is usually not clear which cell is the cytotoxic culprit, nor is the mechanism of destruction usually known. PMID:6376103

Pathophysiology of NASH: perspectives for a targeted treatment

PubMed Central

Marra, Fabio; Lotersztajn, Sophie

2013-01-01

Non alcoholic steatohepatitis (NASH) is the more severe form of nonalcoholic fatty liver disease. In NASH, fatty liver, hepatic inflammation, hepatocyte injury and fibrogenesis are associated, and thi condition may eventually lead to cirrhosis. Current treatment of NASH relies on the reduction of body weight and increase in physical activity, but there is no pharmacologic treatment approved as yet. Emerging data indicate that NASH progression results from parallel events originating from the liver as well as from the adipose tissue, the gut and the gastrointestinal tract. Thus, dysfunction of the adipose tissue through enhanced flow of free fatty acids and release of adipocytokines, and alterations in the gut microbiome generate proinflammatory signals that underly NASH progression. Additional ‘extrahepatic hits’ include dietary factors and gastrointestinal hormones. Within the liver, hepatocyte apoptosis, ER stress and oxidative stress are key contributors to hepatocellular injury. In addition, lipotoxic mediators and danger signals activate Kupffer cells which initiate and perpetuate the inflammatory response by releasing inflammatory mediators that contribute to inflammatory cell recruitment and development of fibrosis. Inflammatory and fibrogenic mediators include chemokines, the cannabinoid system, the inflammasome and activation of pattern-recognition receptors. Here we review the major mechanisms leading to appearance and progression of NASH, focusing on both extrahepatic signals and local inflammatory mechanisms, in an effort to identify the most promising molecular targets for the treatment of this condition. PMID:23394092

Clots Are Potent Triggers of Inflammatory Cell Gene Expression: Indications for Timely Fibrinolysis.

PubMed

Campbell, Robert A; Vieira-de-Abreu, Adriana; Rowley, Jesse W; Franks, Zechariah G; Manne, Bhanu Kanth; Rondina, Matthew T; Kraiss, Larry W; Majersik, Jennifer J; Zimmerman, Guy A; Weyrich, Andrew S

2017-10-01

Blood vessel wall damage often results in the formation of a fibrin clot that traps inflammatory cells, including monocytes. The effect of clot formation and subsequent lysis on the expression of monocyte-derived genes involved in the development and progression of ischemic stroke and other vascular diseases, however, is unknown. Determine whether clot formation and lysis regulates the expression of human monocyte-derived genes that modulate vascular diseases. We performed next-generation RNA sequencing on monocytes extracted from whole blood clots and using a purified plasma clot system. Numerous mRNAs were differentially expressed by monocytes embedded in clots compared with unclotted controls, and IL-8 (interleukin 8) and MCP-1 (monocyte chemoattractant protein-1) were among the upregulated transcripts in both models. Clotted plasma also increased expression of IL-8 and MCP-1, which far exceeded responses observed in lipopolysaccharide-stimulated monocytes. Upregulation of IL-8 and MCP-1 occurred in a thrombin-independent but fibrin-dependent manner. Fibrinolysis initiated shortly after plasma clot formation (ie, 1-2 hours) reduced the synthesis of IL-8 and MCP-1, whereas delayed fibrinolysis was far less effective. Consistent with these in vitro models, monocytes embedded in unresolved thrombi from patients undergoing thrombectomy stained positively for IL-8 and MCP-1. These findings demonstrate that clots are potent inducers of monocyte gene expression and that timely fibrinolysis attenuates inflammatory responses, specifically IL-8 and MCP-1. Dampening of inflammatory gene expression by timely clot lysis may contribute to the clinically proven efficacy of fibrinolytic drug treatment within hours of stroke onset. © 2017 American Heart Association, Inc.

Possible role of glial cells in the onset and progression of Lyme neuroborreliosis

PubMed Central

Ramesh, Geeta; Borda, Juan T; Gill, Amy; Ribka, Erin P; Morici, Lisa A; Mottram, Peter; Martin, Dale S; Jacobs, Mary B; Didier, Peter J; Philipp, Mario T

2009-01-01

Background Lyme neuroborreliosis (LNB) may present as meningitis, cranial neuropathy, acute radiculoneuropathy or, rarely, as encephalomyelitis. We hypothesized that glia, upon exposure to Borrelia burgdorferi, the Lyme disease agent, produce inflammatory mediators that promote the acute cellular infiltration of early LNB. This inflammatory context could potentiate glial and neuronal apoptosis. Methods We inoculated live B. burgdorferi into the cisterna magna of rhesus macaques and examined the inflammatory changes induced in the central nervous system (CNS), and dorsal root nerves and ganglia (DRG). Results ELISA of the cerebrospinal fluid (CSF) showed elevated IL-6, IL-8, CCL2, and CXCL13 as early as one week post-inoculation, accompanied by primarily lymphocytic and monocytic pleocytosis. In contrast, onset of the acquired immune response, evidenced by anti-B. burgdorferi C6 serum antibodies, was first detectable after 3 weeks post-inoculation. CSF cell pellets and CNS tissues were culture-positive for B. burgdorferi. Histopathology revealed signs of acute LNB: severe multifocal leptomeningitis, radiculitis, and DRG inflammatory lesions. Immunofluorescence staining and confocal microscopy detected B. burgdorferi antigen in the CNS and DRG. IL-6 was observed in astrocytes and neurons in the spinal cord, and in neurons in the DRG of infected animals. CCL2 and CXCL13 were found in microglia as well as in endothelial cells, macrophages and T cells. Importantly, the DRG of infected animals showed significant satellite cell and neuronal apoptosis. Conclusion Our results support the notion that innate responses of glia to B. burgdorferi initiate/mediate the inflammation seen in acute LNB, and show that neuronal apoptosis occurs in this context. PMID:19706181

Ceramic modifications of porous titanium: effects on macrophage activation.

PubMed

Scislowska-Czarnecka, A; Menaszek, E; Szaraniec, B; Kolaczkowska, E

2012-12-01

Porous titanium is one of the most widely used implant materials because of its mechanical properties, however, it is also characterised by low bioactivity. To improve the above parameter we prepared three modifications of the porous (30 wt%) titanium (Ti) surface by covering it with bioactive hydroxyapatite (HA), bioglass (BG) and calcium silicate (CS). Subsequently we tested the impact of the modifications on macrophages directing the inflammatory response that might compromise the implant bioactivity. In the study we investigated the in vitro effects of the materials on murine cell line RAW 264.7 macrophage adherence, morphology and activation (production/release of metalloproteinase MMP-9 and pro- and anti-inflammatory cytokines). CS Ti decreased the macrophage adherence and up-regulated the release of several pro-inflammatory mediators, including TNF-α, IL-6, IL-12. Also HA Ti reduced the cell adherence but other parameters were generally not increased, except of TNF-α. In contrast, BG Ti improved macrophage adherence and either decreased production of multiple mediators (MMP-9, TNF-α, IFN-γ, MCP-1) or did not change it in comparison to the porous titanium. We can conclude that analyzing the effects on the inflammatory response initiated by macrophages in vitro, calcium silicate did not improve the biological properties of the porous titanium. The improved bioactivity of titanium was, however, achieved by the application of the hydroxyapatite and bioglass layers. The present in vitro results suggest that these materials, HA Ti and especially BG Ti, may be suitable for in vivo application and thus justify their further investigation. Copyright © 2012 Elsevier Ltd. All rights reserved.

Evaluating the effects of protective ventilation on organ-specific cytokine production in porcine experimental postoperative sepsis.

PubMed

Sperber, Jesper; Lipcsey, Miklós; Larsson, Anders; Larsson, Anders; Sjölin, Jan; Castegren, Markus

2015-05-10

Protective ventilation with lower tidal volume (VT) and higher positive end-expiratory pressure (PEEP) reduces the negative additive effects of mechanical ventilation during systemic inflammatory response syndrome. We hypothesised that protective ventilation during surgery would affect the organ-specific immune response in an experimental animal model of endotoxin-induced sepsis-like syndrome. 30 pigs were laparotomised for 2 hours (h), after which a continuous endotoxin infusion was started at 0.25 micrograms × kg(-1) × h(-1) for 5 h. Catheters were placed in the carotid artery, hepatic vein, portal vein and jugular bulb. Animals were randomised to two protective ventilation groups (n = 10 each): one group was ventilated with VT 6 mL × kg(-1) during the whole experiment while the other group was ventilated during the surgical phase with VT of 10 mL × kg(-1). In both groups PEEP was 5 cmH2O during surgery and increased to 10 cmH2O at the start of endotoxin infusion. A control group (n = 10) was ventilated with VT of 10 mL × kg(-1) and PEEP 5 cm H20 throughout the experiment. In four sample locations we a) simultaneously compared cytokine levels, b) studied the effect of protective ventilation initiated before and during endotoxemia and c) evaluated protective ventilation on organ-specific cytokine levels. TNF-alpha levels were highest in the hepatic vein, IL-6 levels highest in the artery and jugular bulb and IL-10 levels lowest in the artery. Protective ventilation initiated before and during endotoxemia did not differ in organ-specific cytokine levels. Protective ventilation led to lower levels of TNF-alpha in the hepatic vein compared with the control group, whereas no significant differences were seen in the artery, portal vein or jugular bulb. Variation between organs in cytokine output was observed during experimental sepsis. We see no implication from cytokine levels for initiating protective ventilation before endotoxemia. However, during endotoxemia protective ventilation attenuates hepatic inflammatory cytokine output contributing to a reduced total inflammatory burden.

The Host Response to a Clinical MDR Mycobacterial Strain Cultured in a Detergent-Free Environment: A Global Transcriptomics Approach.

PubMed

Leisching, Gina; Pietersen, Ray-Dean; Mpongoshe, Vuyiseka; van Heerden, Carel; van Helden, Paul; Wiid, Ian; Baker, Bienyameen

2016-01-01

During Mycobacterium tuberculosis (M.tb) infection, the initial interactions between the pathogen and the host cell determines internalization and innate immune response events. It is established that detergents such as Tween alter the mycobacterial cell wall and solubilize various lipids and proteins. The implication of this is significant since induced changes on the cell wall affect macrophage uptake and the immune response to M.tb. Importantly, during transmission between hosts, aerosolized M.tb enters the host in its native form, i.e. in a detergent-free environment, thus in vitro and in vivo studies should mimic this as closely as possible. To this end, we have optimized a procedure for growing and processing detergent-free M.tb and assessed the response of murine macrophages (BMDM) infected with multi drug-resistant M.tb (R179 Beijing 220 clinical isolate) using RNAseq. We compared the effects of the host response to M.tb cultured under standard laboratory conditions (Tween 80 containing medium -R179T), or in detergent-free medium (R179NT). RNAseq comparisons reveal 2651 differentially expressed genes in BMDMs infected with R179T M.tb vs. BMDMs infected with R179NT M.tb. A range of differentially expressed genes involved in BMDM receptor interaction with M.tb (Mrc1, Ifngr1, Tlr9, Fpr1 and Itgax) and pro-inflammatory cytokines/chemokines (Il6, Il1b, Tnf, Ccl5 and Cxcl14) were selected for analysis through qPCR. BMDMs infected with R179NT stimulate a robust inflammatory response. Interestingly, R179NT M.tb induce transcription of Fpr1, a receptor which detects bacterial formyl peptides and initiates a myriad of immune responses. Additionally we show that the host components Cxcl14, with an unknown role in M.tb infection, and Tlr9, an emerging role player, are only stimulated by infection with R179NT M.tb. Taken together, our results suggest that the host response differs significantly in response to Tween 80 cultured M.tb and should therefore not be used in infection experiments.

Purinergic signaling modulates the cerebral inflammatory response in experimentally infected fish with Streptococcus agalactiae: an attempt to improve the immune response.

PubMed

Souza, Carine F; Baldissera, Matheus D; Bottari, Nathiele B; Moreira, Karen L S; da Rocha, Maria Izabel U M; da Veiga, Marcelo L; Santos, Roberto C V; Baldisserotto, Bernardo

2018-06-01

Appropriate control of the immune response is a critical determinant of fish health, and the purinergic cascade has an important role in the immune and inflammatory responses. This cascade regulates the levels of adenosine triphosphate (ATP), adenosine diphosphate, adenosine monophosphate and adenosine (Ado), molecules involved in physiological or pathological events as inflammatory and anti-inflammatory mediators. Thus, the aim of this study was to evaluate whether purinergic signaling, through the activities of nucleoside triphosphate diphosphohydrolase (NTPDase), 5'-nucleotidase, and adenosine deaminase (ADA), is capable of modulating the cerebral immune and inflammatory responses in silver catfish that is experimentally infected with Streptococcus agalactiae. Cerebral NTPDase (with ATP as substrate) and 5'-nucleotidase activities increased, while ADA activity decreased in silver catfish that is experimentally infected with S. agalactiae, compared to the control group. Moreover, the cerebral levels of ATP and Ado increased in infected animals compared to the uninfected control group. Brain histopathology in infected animals revealed inflammatory demyelination (the presence of occasional bubbly collections), increased cellular density in the area near to pia-mater and intercellular edema. Based on this evidence, the modulation of the purinergic cascade by the enzymes NTPDase, 5'-nucleotidase, and ADA exerts an anti-inflammatory profile due to the regulation of ATP and Ado levels. This suggests involvement of purinergic enzymes on streptococcosis pathogenesis, through regulating cerebral ATP and Ado levels, molecules known to participate in physiological or pathological events as inflammatory and anti-inflammatory mediators, respectively. In summary, the modulation of the cerebral purinergic cascade exerts an anti-inflammatory profile in an attempt to reduce inflammatory damage.

The Systemic and Pulmonary Immune Response to Staphylococcal Enterotoxins

PubMed Central

Kumar, Sanjeev; Ménoret, Antoine; Ngoi, Soo-Mun; Vella, Anthony T.

2010-01-01

In response to environmental cues the human pathogen Staphylococcus aureus synthesizes and releases proteinaceous enterotoxins. These enterotoxins are natural etiologic entities of severe food poisoning, toxic shock syndrome, and acute diseases. Staphylococcal enterotoxins are currently listed as Category B Bioterrorism Agents by the Center for Disease Control and Prevention. They are associated with respiratory illnesses, and may contribute to exacerbation of pulmonary disease. This likely stems from the ability of Staphylococcal enterotoxins to elicit powerful episodes of T cell stimulation resulting in release of pro-inflammatory cytokines. Here, we discuss the role of the immune system and potential mechanisms of disease initiation and progression. PMID:22069664

[Defibrotide therapy for patients with sinusoidal obstruction syndrome after hematopoietic stem cell transplantation].

PubMed

Yakushijin, Kimikazu; Okamura, Atsuo; Ono, Kanako; Kawano, Yuko; Kawano, Hiroki; Funakoshi, Yohei; Kawamori, Yuriko; Nishikawa, Shinichiro; Minagawa, Kentaro; Sada, Akiko; Shimoyama, Manabu; Yamamoto, Katsuya; Katayama, Yoshio; Matsui, Toshimitsu

2009-01-01

Sinusoidal obstruction syndrome (SOS) is one of the life-threatening complications caused by endothelial damage to the hepatic sinusoids after hematopoietic stem cell transplantation. However, a satisfactory treatment for SOS has not yet been established. Defibrotide has anti-thrombotic, anti-ischemic, anti-inflammatory, and thrombolytic properties without systemic anticoagulant effects. We treated eight post-transplant SOS patients with defibrotide. Three patients responded to the therapy and the initial response was observed within a week. In addition to the improvement of liver function, rapid recovery of response to diuretic drugs followed by the improvement of renal function was observed. All of the five patients with respiratory dysfunction died despite administration of defibrotide, suggesting that early treatment might lead to better outcomes. There were no severe adverse effects directly due to defibrotide administration. Defibrotide seems to be a promising treatment for SOS, and the initiation of a clinical study in Japan would be important.

Immunological and inflammatory mapping of vascularized composite allograft rejection processes in a rat model

PubMed Central

Friedman, Or; Carmel, Narin; Sela, Meirav; Abu Jabal, Ameen; Inbal, Amir; Ben Hamou, Moshe; Krelin, Yakov; Gur, Eyal

2017-01-01

Background Hand and face vascularized composite allotransplantation (VCA) is an evolving and challenging field with great opportunities. During VCA, massive surgical damage is inflicted on both donor and recipient tissues, which may contribute to the high VCA rejection rates. To segregate between the damage-induced and rejection phase of post-VCA responses, we compared responses occurring up to 5 days following syngeneic versus allogeneic vascularized groin flap transplantations, culminating in transplant acceptance or rejection, respectively. Methods The immune response elicited upon transplantation of a syngeneic versus allogeneic vascularized groin flap was compared at Post-operative days 2 or 5 by histology, immunohistochemistry and by broad-scope gene and protein analyses using quantitative real-time PCR and Multiplex respectively. Results Immune cell infiltration began at the donor-recipient interface and paralleled expression of a large group of wound healing-associated genes in both allografts and syngrafts. By day 5 post-transplantation, cell infiltration spread over the entire allograft but remained confined to the wound site in the syngraft. This shift correlated with upregulation of IL-18, INFg, CXCL9, 10 and 11, CCL2, CCL5, CX3CL1 and IL-10 in the allograft only, suggesting their role in the induction of the anti-alloantigen adaptive immune response. Conclusions High resemblance between the cues governing VCA and solid organ rejection was observed. Despite this high resemblance we describe also, for the first time, a damage induced inflammatory component in VCA rejection as immune cell infiltration into the graft initiated at the surgical damage site spreading to the entire allograft only at late stage rejection. We speculate that the highly inflammatory setting created by the unique surgical damage during VCA may enhance acute allograft rejection. PMID:28746417

The exaggerated inflammatory response in Behçet's syndrome: identification of dysfunctional post-transcriptional regulation of the IFN-γ/CXCL10 IP-10 pathway

PubMed Central

Ambrose, N; Khan, E; Ravindran, R; Lightstone, L; Abraham, S; Botto, M; Johns, M; Haskard, D O

2015-01-01

The mechanisms underlying the exaggerated inflammatory response in Behçet's syndrome (BS) remain poorly understood. We investigated the response of CD14+ blood monocytes to interferon (IFN)-γ, focusing on the chemokine CXCL10. Chemokine synthesis and release were analysed at a protein and mRNA level following stimulation with IFN-γ. Findings in BS patients were compared with 25 healthy controls (HC), 15 rheumatoid arthritis (RA) and 15 systemic lupus erythematosus (SLE) disease control patients. BS monocytes produced significantly more CXCL10 protein than HC monocytes from 2 h following IFN-γ stimulation, despite equivalent quantities of mRNA, suggesting more efficient translation. This was significantly more pronounced in BS with high disease activity and in those with ocular and neurological clinical manifestations. The imbalance between CXCL10 protein and mRNA expression was not observed in either RA or SLE patients, and was not seen with other chemokines studied (CXCL9, CXCL11 and CCL2). Furthermore, BS monocytes treated with an alternative stimulant (LPS) did not show abnormal tumour necrosis factor (TNF)-α release. Sucrose density gradients to segregate monocyte CXCL10 mRNA into free RNA or polysome-associated RNA showed equal proportions in BS and HC samples, suggesting that the difference between BS and HC may be due to reduced negative control of CXCL10 translation in BS at a post-initiation level. We conclude that BS monocytes have dysfunctional post-transcriptional regulation of CXCL10 mRNA, resulting in over-expression of CXCL10 protein upon IFN-γ stimulation. As CXCL10 is a chemokine that recruits mononuclear cells, this abnormality may contribute to the exaggerated inflammatory responses that characterizes BS. PMID:25982097

The exaggerated inflammatory response in Behçet's syndrome: identification of dysfunctional post-transcriptional regulation of the IFN-γ/CXCL10 IP-10 pathway.

PubMed

Ambrose, N; Khan, E; Ravindran, R; Lightstone, L; Abraham, S; Botto, M; Johns, M; Haskard, D O

2015-09-01

The mechanisms underlying the exaggerated inflammatory response in Behçet's syndrome (BS) remain poorly understood. We investigated the response of CD14(+) blood monocytes to interferon (IFN)-γ, focusing on the chemokine CXCL10. Chemokine synthesis and release were analysed at a protein and mRNA level following stimulation with IFN-γ. Findings in BS patients were compared with 25 healthy controls (HC), 15 rheumatoid arthritis (RA) and 15 systemic lupus erythematosus (SLE) disease control patients. BS monocytes produced significantly more CXCL10 protein than HC monocytes from 2 h following IFN-γ stimulation, despite equivalent quantities of mRNA, suggesting more efficient translation. This was significantly more pronounced in BS with high disease activity and in those with ocular and neurological clinical manifestations. The imbalance between CXCL10 protein and mRNA expression was not observed in either RA or SLE patients, and was not seen with other chemokines studied (CXCL9, CXCL11 and CCL2). Furthermore, BS monocytes treated with an alternative stimulant (LPS) did not show abnormal tumour necrosis factor (TNF)-α release. Sucrose density gradients to segregate monocyte CXCL10 mRNA into free RNA or polysome-associated RNA showed equal proportions in BS and HC samples, suggesting that the difference between BS and HC may be due to reduced negative control of CXCL10 translation in BS at a post-initiation level. We conclude that BS monocytes have dysfunctional post-transcriptional regulation of CXCL10 mRNA, resulting in over-expression of CXCL10 protein upon IFN-γ stimulation. As CXCL10 is a chemokine that recruits mononuclear cells, this abnormality may contribute to the exaggerated inflammatory responses that characterizes BS. © 2015 British Society for Immunology.

Passive therapy with humanized anti-staphylococcal enterotoxin B antibodies attenuates systemic inflammatory response and protects from lethal pneumonia caused by staphylococcal enterotoxin B-producing Staphylococcus aureus.

PubMed

Karau, Melissa J; Tilahun, Mulualem E; Krogman, Ashton; Osborne, Barbara A; Goldsby, Richard A; David, Chella S; Mandrekar, Jayawant N; Patel, Robin; Rajagopalan, Govindarajan

2017-10-03

Drugs such as linezolid that inhibit bacterial protein synthesis may be beneficial in treating infections caused by toxigenic Staphylococcus aureus. As protein synthesis inhibitors have no effect on preformed toxins, neutralization of pathogenic exotoxins with anti-toxin antibodies may be beneficial in conjunction with antibacterial therapy. Herein, we evaluated the efficacy of human-mouse chimeric high-affinity neutralizing anti-staphylococcal enterotoxin B (SEB) antibodies in the treatment of experimental pneumonia caused by SEB-producing S. aureus. Since HLA class II transgenic mice mount a stronger systemic immune response following challenge with SEB and are more susceptible to SEB-induced lethal toxic shock than conventional mice strains, HLA-DR3 transgenic mice were used. Lethal pneumonia caused by SEB-producing S. aureus in HLA-DR3 transgenic mice was characterized by robust T cell activation and elevated systemic levels of several pro-inflammatory cytokines and chemokines. Prophylactic administration of a single dose of linezolid 30 min prior to the onset of infection attenuated the systemic inflammatory response and protected from mortality whereas linezolid administered 60 min after the onset of infection failed to confer significant protection. Human-mouse chimeric high-affinity neutralizing anti-SEB antibodies alone, but not polyclonal human IgG, mitigated this response and protected from death when administered immediately after initiation of infection. Further, anti-SEB antibodies as well as intact polyclonal human IgG, but not its Fab or Fc fragments, protected from lethal pneumonia when followed with linezolid therapy 60 min later. In conclusion, neutralization of superantigens with high-affinity antibodies may have beneficial effects in pneumonia.

pH-Responsive Hydrogel With an Anti-Glycation Agent for Modulating Experimental Periodontitis.

PubMed

Yu, Min-Chen; Chang, Chih-Yeun; Chao, Yi-Chi; Jheng, Yi-Han; Yang, Connie; Lee, Ning; Yu, Shan-Huey; Yu, Xin-Hong; Liu, Dean-Mo; Chang, Po-Chun

2016-06-01

Stimulus-responsive devices have emerged as a novel approach for local drug delivery. This study investigates the feasibility of a novel chitosan-based, pH-responsive hydrogel loaded with N-phenacylthiazolium bromide (PTB), which cleaves the crosslinks of advanced glycation end products on the extracellular matrix. A chitosan-based hydrogel loaded with PTB was fabricated, and the in vitro release profile was evaluated within pH 5.5 to 7.4. BALB/cJ mice and Sprague-Dawley rats were used to evaluate the effects during the induction and recovery phases of periodontitis, respectively, and animals in each phase were divided into four groups: 1) no periodontitis induction; 2) ligature-induced experimental periodontitis (group PR); 3) experimental periodontitis plus hydrogel without PTB (group PH); and 4) experimental periodontitis plus hydrogel with PTB (group PP). The therapeutic effects were evaluated by microcomputed tomographic imaging of periodontal bone level (PBL) loss and histomorphometry for inflammatory cell infiltration and collagen density. PTB was released faster at pH 5.5 to 6.5 and consistently slower at pH 7.4. In the induction phase, PBL and inflammatory cell infiltration were significantly reduced in group PP relative to group PR, and the loss of collagen matrix was significantly reduced relative to that observed in group PH. In the recovery phase, PBL and inflammatory cell infiltration were significantly reduced, and significantly greater collagen deposition was noted in group PP relative to groups PR and PH at 4 and 14 days after silk removal. Chitosan-based, pH-responsive hydrogels loaded with PTB can retard the initiation of and facilitate the recovery from experimental periodontitis.

High and low molecular weight hyaluronic acid differentially influence macrophage activation

PubMed Central

Rayahin, Jamie E.; Buhrman, Jason S.; Zhang, Yu; Koh, Timothy J.; Gemeinhart, Richard A.

2015-01-01

Macrophages exhibit phenotypic diversity permitting wide-ranging roles in maintaining physiologic homeostasis. Hyaluronic acid, a major glycosaminoglycan of the extracellular matrix, has been shown to have differential signaling based on its molecular weight. With this in mind, the main objective of this study was to elucidate the role of hyaluronic acid molecular weight on macrophage activation and reprogramming. Changes in macrophage activation were assessed by activation state selective marker measurement, specifically quantitative real time polymerase chain reaction, and cytokine enzyme-linked immunoassays, after macrophage treatment with differing molecular weights of hyaluronic acid under four conditions: the resting state, concurrent with classical activation, and following inflammation involving either classically or alternatively activated macrophages. Regardless of initial polarization state, low molecular weight hyaluronic acid induced a classically activated-like state, confirmed by up-regulation of pro-inflammatory genes, including nos2, tnf, il12b, and cd80, and enhanced secretion of nitric oxide and TNF-α. High molecular weight hyaluronic acid promoted an alternatively activated-like state, confirmed by up regulation of pro-resolving gene transcription, including arg1, il10, and mrc1, and enhanced arginase activity. Overall, our observations suggest that macrophages undergo phenotypic changes dependent on molecular weight of hyaluronan that correspond to either (1) pro-inflammatory response for low molecular weight HA or (2) pro-resolving response for high molecular weight HA. These observations bring significant further understanding of the influence of extracellular matrix polymers, hyaluronic acid in particular, on regulating the inflammatory response of macrophages. This knowledge can be used to guide the design of HA-containing biomaterials to better utilize the natural response to HAs. PMID:26280020

S100a8/a9 released by CD11b+Gr1+ neutrophils activates cardiac fibroblasts to initiate angiotensin II-Induced cardiac inflammation and injury.

PubMed

Wu, Yina; Li, Yulin; Zhang, Congcong; A, Xi; Wang, Yueli; Cui, Wei; Li, Huihua; Du, Jie

2014-06-01

Angiotensin II induces cardiovascular injury, in part, by activating inflammatory response; however, the initial factors that trigger the inflammatory cascade remain unclear. Microarray analysis of cardiac tissue exposed to systemic angiotensin II infusion revealed that extracellular heterodimeric proteins S100a8/a9 were highly upregulated. The increase in S100a8/a9 mRNA of CD11b(+)Gr1(+) neutrophils isolated from both the peripheral blood and heart was highest on day 1 of angiotensin II infusion and decreased to baseline at day 7. Immunostaining showed that S100a8/a9 was primarily present in infiltrating CD11b(+)Gr1(+) neutrophils in the heart. The receptor for advanced glycation end products, an S100a8/a9 receptor, was expressed in cardiac fibroblasts (CFs). Microarray analysis and Bio-Plex protein array showed that treatment of CFs with recombinant S100a8/a9 activated multiple chemokine and cytokines released. Luciferase reporter assay indicated S100a8/a9-activated nuclear factor-κ B pathway in CFs. Consequently, recombinant S100a8/a9-treated CFs promoted migration of monocytes and CFs, whereas neutralizing S100a9 antibody blocked S100a9 or receptor for advanced glycation end products-suppressed cellular migration. Finally, administration of a neutralizing S100a9 antibody prevented angiotensin II infusion-induced nuclear factor-κ B activation, inflammatory cell infiltration, cytokine production, subsequent perivascular and interstitial fibrosis, and hypertrophy in heart. Our findings identify neutrophil-produced S100a8/a9 as an initial proinflammatory factor needed to trigger inflammation and cardiac injury during acute hypertension.

Modulation of immunity and inflammatory gene expression in the gut, in inflammatory diseases of the gut and in the liver by probiotics

PubMed Central

Plaza-Diaz, Julio; Gomez-Llorente, Carolina; Fontana, Luis; Gil, Angel

2014-01-01

The potential for the positive manipulation of the gut microbiome through the introduction of beneficial microbes, as also known as probiotics, is currently an active area of investigation. The FAO/WHO define probiotics as live microorganisms that confer a health benefit to the host when administered in adequate amounts. However, dead bacteria and bacterial molecular components may also exhibit probiotic properties. The results of clinical studies have demonstrated the clinical potential of probiotics in many pathologies, such as allergic diseases, diarrhea, inflammatory bowel disease and viral infection. Several mechanisms have been proposed to explain the beneficial effects of probiotics, most of which involve gene expression regulation in specific tissues, particularly the intestine and liver. Therefore, the modulation of gene expression mediated by probiotics is an important issue that warrants further investigation. In the present paper, we performed a systematic review of the probiotic-mediated modulation of gene expression that is associated with the immune system and inflammation. Between January 1990 to February 2014, PubMed was searched for articles that were published in English using the MeSH terms “probiotics" and "gene expression" combined with “intestines", "liver", "enterocytes", "antigen-presenting cells", "dendritic cells", "immune system", and "inflammation". Two hundred and five original articles matching these criteria were initially selected, although only those articles that included specific gene expression results (77) were later considered for this review and separated into three major topics: the regulation of immunity and inflammatory gene expression in the gut, in inflammatory diseases of the gut and in the liver. Particular strains of Bifidobacteria, Lactobacilli, Escherichia coli, Propionibacterium, Bacillus and Saccharomyces influence the gene expression of mucins, Toll-like receptors, caspases, nuclear factor-κB, and interleukins and lead mainly to an anti-inflammatory response in cultured enterocytes. In addition, the interaction of commensal bacteria and probiotics with the surface of antigen-presenting cells in vitro results in the downregulation of pro-inflammatory genes that are linked to inflammatory signaling pathways, whereas other anti-inflammatory genes are upregulated. The effects of probiotics have been extensively investigated in animal models ranging from fish to mice, rats and piglets. These bacteria induce a tolerogenic and hyporesponsive immune response in which many genes that are related to the immune system, in particular those genes expressing anti-inflammatory cytokines, are upregulated. By contrast, information related to gene expression in human intestinal cells mediated by the action of probiotics is scarce. There is a need for further clinical studies that evaluate the mechanism of action of probiotics both in healthy humans and in patients with chronic diseases. These types of clinical studies are necessary for addressing the influence of these microorganisms in gene expression for different pathways, particularly those that are associated with the immune response, and to better understand the role that probiotics might have in the prevention and treatment of disease. PMID:25400447

Systemic inflammatory response syndrome (SIRS)

PubMed Central

Balk, Robert A

2014-01-01

The concept of a systemic inflammatory response syndrome (SIRS) to describe the complex pathophysiologic response to an insult such as infection, trauma, burns, pancreatitis, or a variety of other injuries came from a 1991 consensus conference charged with the task of developing an easy-to-apply set of clinical parameters to aid in the early identification of potential candidates to enter into clinical trials to evaluate new treatments for sepsis. There was recognition that a diverse group of injuries produced a common inflammatory response in the host and provided attractive targets for new anti-inflammatory molecules designed to prevent further propagation and/or provide specific treatment. Effective application of these new anti-inflammatory strategies necessitated identification of early clinical markers that could be assessed in real-time and were likely to define a population of patients that would have a beneficial response to the targeted intervention. It was felt that early clinical manifestations might be more readily available to clinicians than more sophisticated and specific assays for inflammatory substances that were systemically released by the network of injurious inflammatory events. Therefore, the early definition of a systemic inflammatory response syndrome (SIRS) was built upon a foundation of basic clinical and laboratory abnormalities that were readily available in almost all clinical settings. With further refinement, it was hoped, that this definition would have a high degree of sensitivity, coupled with a reasonable degree of specificity. This manuscript reviews the derivation, application, utilization, potential benefits, and speculation regarding the future of the SIRS definition. PMID:24280933

Sex differences in the pro-inflammatory cytokine response to endotoxin unfold in vivo but not ex vivo in healthy humans.

PubMed

Wegner, Alexander; Benson, Sven; Rebernik, Laura; Spreitzer, Ingo; Jäger, Marcus; Schedlowski, Manfred; Elsenbruch, Sigrid; Engler, Harald

2017-07-01

Clinical data indicate that inflammatory responses differ across sexes, but the mechanisms remain elusive. Herein, we assessed in vivo and ex vivo cytokine responses to bacterial endotoxin in healthy men and women to elucidate the role of systemic and cellular factors underlying sex differences in inflammatory responses. Participants received an i.v. injection of low-dose endotoxin (0.4 ng/kg body mass), and plasma TNF-α and IL-6 responses were analyzed over a period of 6 h. In parallel, ex vivo cytokine production was measured in endotoxin-stimulated blood samples obtained immediately before in vivo endotoxin administration. As glucocorticoids (GCs) play an important role in the negative feedback regulation of the inflammatory response, we additionally analyzed plasma cortisol concentrations and ex vivo GC sensitivity of cytokine production. Results revealed greater in vivo pro-inflammatory responses in women compared with men, with significantly higher increases in plasma TNF-α and IL-6 concentrations. In addition, the endotoxin-induced rise in plasma cortisol was more pronounced in women. In contrast, no sex differences in ex vivo cytokine production and GC sensitivity were observed. Together, these findings demonstrate major differences in in vivo and ex vivo responses to endotoxin and underscore the importance of systemic factors underlying sex differences in the inflammatory response.

Differences in innate cytokine responses between European and African children.

PubMed

Labuda, Lucja A; de Jong, Sanne E; Meurs, Lynn; Amoah, Abena S; Mbow, Moustapha; Ateba-Ngoa, Ulysse; van der Ham, Alwin J; Knulst, André C; Yazdanbakhsh, Maria; Adegnika, Ayola A

2014-01-01

Although differences in immunological responses between populations have been found in terms of vaccine efficacy, immune responses to infections and prevalence of chronic inflammatory diseases, the mechanisms responsible for these differences are not well understood. Therefore, innate cytokine responses mediated by various classes of pattern-recognition receptors including Toll-like receptors (TLR), C-type lectin receptors (CLRs) and nucleotide-binding oligomerisation domain-like receptors (NLRs) were compared between Dutch (European), semi-urban and rural Gabonese (African) children. Whole blood was stimulated for 24 hours and the pro-inflammatory tumor necrosis factor (TNF) and the anti-inflammatory/regulatory interleukin-10 (IL-10) cytokines in culture supernatant were measured by enzyme-linked immunosorbent assay (ELISA). Gabonese children had a lower pro-inflammatory response to poly(I:C) (TLR3 ligand), but a higher pro-inflammatory response to FSL-1 (TLR2/6 ligand), Pam3 (TLR2/1 ligand) and LPS (TLR4 ligand) compared to Dutch children. Anti-inflammatory responses to Pam3 were also higher in Gabonese children. Non-TLR ligands did not induce substantial cytokine production on their own. Interaction between various TLR and non-TLR receptors was further assessed, but no differences were found between the three populations. In conclusion, using a field applicable assay, significant differences were observed in cytokine responses between European and African children to TLR ligands, but not to non-TLR ligands.

Inflammatory Bowel Disease in Primary Immunodeficiencies.

PubMed

Kelsen, Judith R; Sullivan, Kathleen E

2017-08-01

Inflammatory bowel disease is most often a polygenic disorder with contributions from the intestinal microbiome, defects in barrier function, and dysregulated host responses to microbial stimulation. There is, however, increasing recognition of single gene defects that underlie a subset of patients with inflammatory bowel disease, particularly those with early-onset disease, and this review focuses on the primary immunodeficiencies associated with early-onset inflammatory bowel disease. The advent of next-generation sequencing has led to an improved recognition of single gene defects underlying some cases of inflammatory bowel disease. Among single gene defects, immune response genes are the most frequent category identified. This is also true of common genetic variants associated with inflammatory bowel disease, supporting a pivotal role for host responses in the pathogenesis. This review focuses on practical aspects related to diagnosis and management of children with inflammatory bowel disease who have underlying primary immunodeficiencies.

Novel insights for systemic inflammation in sepsis and hemorrhage.

PubMed

Cai, Bolin; Deitch, Edwin A; Ulloa, Luis

2010-01-01

The inflammatory responses in sepsis and hemorrhage remain a major cause of death. Clinically, it is generally accepted that shock in sepsis or hemorrhage differs in its mechanisms. However, the recognition of inflammatory cytokines as a common lethal pathway has become consent. Proinflammatory cytokines such as tumor necrosis factor (TNF) or high-mobility group box1 (HMGB1) are fanatically released and cause lethal multiorgan dysfunction. Inhibition of these cytokines can prevent the inflammatory responses and organ damage. In seeking potential anti-inflammatory strategies, we reported that ethyl pyruvate and alpha7 nicotinic acetylcholine receptor (alpha7nAChR) agonists effectively restrained cytokine production to provide therapeutic benefits in both experimental sepsis and hemorrhage. Here, we review the inflammatory responses and the anti-inflammatory strategies in experimental models of sepsis and hemorrhage, as they may have a consistent inflammatory pathway in spite of their different pathophysiological processes.

The PI3K/Akt pathway is required for LPS activation of microglial cells.

PubMed

Saponaro, Concetta; Cianciulli, Antonia; Calvello, Rosa; Dragone, Teresa; Iacobazzi, Francesco; Panaro, Maria Antonietta

2012-10-01

Upregulation of inflammatory responses in the brain is associated with a number of neurodegenerative diseases. Microglia are activated in neurodegenerative diseases, producing pro-inflammatory mediators. Critically, lipopolysaccharide (LPS)-induced microglial activation causes dopaminergic neurodegeneration in vitro and in vivo. The signaling mechanisms triggered by LPS to stimulate the release of pro-inflammatory mediators in microglial cells are still incompletely understood. To further explore the mechanisms of LPS-mediated inflammatory response of microglial cells, we studied the role of phosphatidylinositol 3-kinase (PI3K)/Akt signal transduction pathways known to be activated by toll-like receptor-4 signaling through LPS. In the current study, we report that the activation profile of LPS-induced pAkt activation preceded those of LPS-induced NF-κB activation, suggesting a role for PI3K/Akt in the pathway activation of NF-κB-dependent inflammatory responses of activated microglia. These results, providing the first evidence that PI3K dependent signaling is involved in the inflammatory responses of microglial cells following LPS stimulation, may be useful in preventing inflammatory based neurodegenerative processes.

Bilateral sclerosing orbital pseudotumour in an adult

PubMed Central

Sripathi, Smiti; Shenoy, Poonam Mohan; Ayachit, Anurag; Kadavigere, Rajagopal

2014-01-01

Sclerosing pseudotumour of the orbit is a rare idiopathic chronic inflammatory process, which greatly mimics neoplasms both clinically and on imaging studies. It is therefore important to differentiate this entity from true neoplasms and to rule out any systemic associations. We present a rare case of sclerosing orbital pseudotumour in an adult man with no systemic illnesses who presented with painless progressive proptosis of both eyes and showed a gradual initial response to steroid therapy but relapsed after a 2-year interval. PMID:24876210

Bilateral sclerosing orbital pseudotumour in an adult.

PubMed

Sripathi, Smiti; Shenoy, Poonam Mohan; Ayachit, Anurag; Kadavigere, Rajagopal

2014-05-29

Sclerosing pseudotumour of the orbit is a rare idiopathic chronic inflammatory process, which greatly mimics neoplasms both clinically and on imaging studies. It is therefore important to differentiate this entity from true neoplasms and to rule out any systemic associations. We present a rare case of sclerosing orbital pseudotumour in an adult man with no systemic illnesses who presented with painless progressive proptosis of both eyes and showed a gradual initial response to steroid therapy but relapsed after a 2-year interval. 2014 BMJ Publishing Group Ltd.

Yoga, Meditation and Mind-Body Health: Increased BDNF, Cortisol Awakening Response, and Altered Inflammatory Marker Expression after a 3-Month Yoga and Meditation Retreat.

PubMed

Cahn, B Rael; Goodman, Matthew S; Peterson, Christine T; Maturi, Raj; Mills, Paul J

2017-01-01

Thirty-eight individuals (mean age: 34.8 years old) participating in a 3-month yoga and meditation retreat were assessed before and after the intervention for psychometric measures, brain derived neurotrophic factor (BDNF), circadian salivary cortisol levels, and pro- and anti-inflammatory cytokines. Participation in the retreat was found to be associated with decreases in self-reported anxiety and depression as well as increases in mindfulness. As hypothesized, increases in the plasma levels of BDNF and increases in the magnitude of the cortisol awakening response (CAR) were also observed. The normalized change in BDNF levels was inversely correlated with BSI-18 anxiety scores at both the pre-retreat ( r = 0.40, p < 0.05) and post-retreat ( r = 0.52, p < 0.005) such that those with greater anxiety scores tended to exhibit smaller pre- to post-retreat increases in plasma BDNF levels. In line with a hypothesized decrease in inflammatory processes resulting from the yoga and meditation practices, we found that the plasma level of the anti-inflammatory cytokine Interleukin-10 was increased and the pro-inflammatory cytokine Interleukin-12 was reduced after the retreat. Contrary to our initial hypotheses, plasma levels of other pro-inflammatory cytokines, including Interferon Gamma (IFN-γ), Tumor Necrosis Factor (TNF-α), Interleukin-1β (IL-1β), Interleukin-6 (IL-6), and Interleukin-8 (IL-8) were increased after the retreat. Given evidence from previous studies of the positive effects of meditative practices on mental fitness, autonomic homeostasis and inflammatory status, we hypothesize that these findings are related to the meditative practices throughout the retreat; however, some of the observed changes may also be related to other aspects of the retreat such as physical exercise-related components of the yoga practice and diet. We hypothesize that the patterns of change observed here reflect mind-body integration and well-being. The increased BDNF levels observed is a potential mediator between meditative practices and brain health, the increased CAR is likely a reflection of increased dynamic physiological arousal, and the relationship of the dual enhancement of pro- and anti-inflammatory cytokine changes to healthy immunologic functioning is discussed.

Adenosine monophosphate-activated protein kinase activation and suppression of inflammatory response by cell stretching in rabbit synovial fibroblasts.

PubMed

Kunanusornchai, Wanlop; Muanprasat, Chatchai; Chatsudthipong, Varanuj

2016-12-01

Joint mobilization is known to be beneficial in osteoarthritis (OA) patients. This study aimed to investigate the effect of stretching on adenosine monophosphate-activated protein kinase (AMPK) activity and its role in modulating inflammation in rabbit synovial fibroblasts. Uniaxial stretching of isolated rabbit synovial fibroblasts for ten min was performed. Stretching-induced AMPK activation, its underlying mechanism, and its anti-inflammatory effect were investigated using Western blot. Static stretching at 20 % of initial length resulted in AMPK activation characterized by expression of phosphorylated AMPK and phosphorylated acetyl-Co A carboxylase. AMP-activated protein kinase phosphorylation peaked 1 h after stretching and declined toward resting activity. Using cell viability assays, static stretching did not appear to cause cellular damage. Activation of AMPK involves Ca 2+ influx via a mechanosensitive L-type Ca 2+ channel, which subsequently raises intracellular Ca 2+ and activates AMPK via Ca 2+ /calmodulin-dependent protein kinase kinase β (CaMKKβ). Interestingly, stretching suppressed TNFα-induced expression of COX-2, iNOS, and phosphorylated NF-κB. These effects were prevented by pretreatment with compound C, an AMPK inhibitor. These results suggest that mechanical stretching suppressed inflammatory responses in synovial fibroblasts via a L-type Ca 2+ -channel-CaMKKβ-AMPK-dependent pathway which may underlie joint mobilization's ability to alleviate OA symptoms.

Antihyperglycemic effect of Sesbania grandiflora seed decoction on streptozotocin-induced diabetic mice: Inflammatory status and the role of interleukin-10

NASA Astrophysics Data System (ADS)

Zamroni, Ahmad; Widjanarko, Simon B.; Rifa'i, Muhaimin; Zubaidah, Elok

2017-05-01

Diabetes is one of the fastest growing diseases in the world: its prevalence is estimated to reach 642 million people, or one-tenth of adults will have diabetes by 2040. Traditional herbal exploration and investigation are needed in order to discover medicines that have potential anti-diabetic activity, with no or lower side effects than the medicines clinically used today. In this research, we investigated the anti-hyperglycemic activity of an aqueous decoction of Sesbania grandiflora seeds in streptozotocin-induced diabetic mice, and analyzed the immune responses that occurred during the counter balance process to reach blood glucose homeostasis. Our results revealed that administration of the aqueous decoction (2.5 g/kg BW) could lower the blood glucose levels of diabetic mice from an initial blood glucose level of 435 mg/dl to 213 mg/dl within 18 days of treatment. Analysis of inflammatory markers showed that there was no significant difference in the relative amounts of CD4+CD62L-, CD8+CD62L-, TNF-α or IFN-γ between the experimental groups, which revealed that there were no pro-inflammatory responses involved either in hyperglycemia or in the blood glucose lowering process. On the other hand, an increased amount of interleukin-10 in diabetic mice treated with an S. grandiflora seed decoction indicated a role for IL-10 in maintaining blood glucose homeostasis.

Multiple levels of regulation determine the role of the receptor for AGE (RAGE) as common soil in inflammation, immune responses and diabetes mellitus and its complications.

PubMed

Bierhaus, A; Nawroth, P P

2009-11-01

The pattern recognition receptor or receptor for AGE (RAGE) is constitutionally expressed in a few cell types only. However in almost all cells studied so far it is induced by reactions known to initiate inflammation. Its biological activity seems to be mainly dependent on the presence of its various ligands, including AGE, S100-calcium binding protein/calgranulins, high-mobility group protein 1, amyloid-beta-peptides and the family of beta-sheet fibrils, all known to be elevated in chronic metabolic, malignant and inflammatory diseases. The RAGE pathway interacts with cytokine-, lipopolysaccharide-, oxidised LDL- and glucose-triggered cellular reactions by turning a short-lasting inflammatory response into a sustained change of cellular function driven by perpetuated activation of the proinflammatory transcription factor, nuclear factor kappa-B. RAGE-mediated persistent cell activation is of pivotal importance in various experimental and clinical settings, including diabetes and its complications, neurodegeneration, ageing, tumour growth, and autoimmune and infectious inflammatory disease. Due to RAGE's central role in maintaining perpetuated cell activation, various therapeutic attempts to block RAGE or its ligands are currently under investigation. Despite broad experimental evidence for the role of RAGE in chronic disease, knowledge of its physiological function is still missing, limiting predictions about safety of long-term inhibition of RAGE x ligand interaction in chronic diseases.

Changing the threshold-Signals and mechanisms of mast cell priming.

PubMed

Halova, Ivana; Rönnberg, Elin; Draberova, Lubica; Vliagoftis, Harissios; Nilsson, Gunnar P; Draber, Petr

2018-03-01

Mast cells play a key role in allergy and other inflammatory diseases involving engagement of multivalent antigen with IgE bound to high-affinity IgE receptors (FcεRIs). Aggregation of FcεRIs on mast cells initiates a cascade of signaling events that eventually lead to degranulation, secretion of leukotrienes and prostaglandins, and cytokine and chemokine production contributing to the inflammatory response. Exposure to pro-inflammatory cytokines, chemokines, bacterial and viral products, as well as some other biological products and drugs, induces mast cell transition from the basal state into a primed one, which leads to enhanced response to IgE-antigen complexes. Mast cell priming changes the threshold for antigen-mediated activation by various mechanisms, depending on the priming agent used, which alone usually do not induce mast cell degranulation. In this review, we describe the priming processes induced in mast cells by various cytokines (stem cell factor, interleukins-4, -6 and -33), chemokines, other agents acting through G protein-coupled receptors (adenosine, prostaglandin E 2 , sphingosine-1-phosphate, and β-2-adrenergic receptor agonists), toll-like receptors, and various drugs affecting the cytoskeleton. We will review the current knowledge about the molecular mechanisms behind priming of mast cells leading to degranulation and cytokine production and discuss the biological effects of mast cell priming induced by several cytokines. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Ultraviolet-radiation-induced inflammation promotes angiotropism and metastasis in melanoma

NASA Astrophysics Data System (ADS)

Bald, Tobias; Quast, Thomas; Landsberg, Jennifer; Rogava, Meri; Glodde, Nicole; Lopez-Ramos, Dorys; Kohlmeyer, Judith; Riesenberg, Stefanie; van den Boorn-Konijnenberg, Debby; Hömig-Hölzel, Cornelia; Reuten, Raphael; Schadow, Benjamin; Weighardt, Heike; Wenzel, Daniela; Helfrich, Iris; Schadendorf, Dirk; Bloch, Wilhelm; Bianchi, Marco E.; Lugassy, Claire; Barnhill, Raymond L.; Koch, Manuel; Fleischmann, Bernd K.; Förster, Irmgard; Kastenmüller, Wolfgang; Kolanus, Waldemar; Hölzel, Michael; Gaffal, Evelyn; Tüting, Thomas

2014-03-01

Intermittent intense ultraviolet (UV) exposure represents an important aetiological factor in the development of malignant melanoma. The ability of UV radiation to cause tumour-initiating DNA mutations in melanocytes is now firmly established, but how the microenvironmental effects of UV radiation influence melanoma pathogenesis is not fully understood. Here we report that repetitive UV exposure of primary cutaneous melanomas in a genetically engineered mouse model promotes metastatic progression, independent of its tumour-initiating effects. UV irradiation enhanced the expansion of tumour cells along abluminal blood vessel surfaces and increased the number of lung metastases. This effect depended on the recruitment and activation of neutrophils, initiated by the release of high mobility group box 1 (HMGB1) from UV-damaged epidermal keratinocytes and driven by Toll-like receptor 4 (TLR4). The UV-induced neutrophilic inflammatory response stimulated angiogenesis and promoted the ability of melanoma cells to migrate towards endothelial cells and use selective motility cues on their surfaces. Our results not only reveal how UV irradiation of epidermal keratinocytes is sensed by the innate immune system, but also show that the resulting inflammatory response catalyses reciprocal melanoma-endothelial cell interactions leading to perivascular invasion, a phenomenon originally described as angiotropism in human melanomas by histopathologists. Angiotropism represents a hitherto underappreciated mechanism of metastasis that also increases the likelihood of intravasation and haematogenous dissemination. Consistent with our findings, ulcerated primary human melanomas with abundant neutrophils and reactive angiogenesis frequently show angiotropism and a high risk for metastases. Our work indicates that targeting the inflammation-induced phenotypic plasticity of melanoma cells and their association with endothelial cells represent rational strategies to specifically interfere with metastatic progression.

Inflammation in Alzheimer's disease: amyloid-beta oligomers trigger innate immunity defence via pattern recognition receptors.

PubMed

Salminen, Antero; Ojala, Johanna; Kauppinen, Anu; Kaarniranta, Kai; Suuronen, Tiina

2009-02-01

The inflammatory process has a fundamental role in the pathogenesis of Alzheimer's disease (AD). Recent studies indicate that inflammation is not merely a bystander in neurodegeneration but a powerful pathogenetic force in the disease process. Increased production of amyloid-beta peptide species can activate the innate immunity system via pattern recognition receptors (PRRs) and evoke Alzheimer's pathology. We will focus on the role of innate immunity system of brain in the initiation and the propagation of inflammatory process in AD. We examine here in detail the significance of amyloid-beta oligomers and fibrils as danger-associated molecular patterns (DAMPs) in the activation of a wide array of PRRs in glial cells and neurons, such as Toll-like, NOD-like, formyl peptide, RAGE and scavenger receptors along with complement and pentraxin systems. We also characterize the signaling pathways triggered by different PRRs in evoking inflammatory responses. In addition, we will discuss whether AD pathology could be the outcome of chronic activation of the innate immunity defence in the brain of AD patients.

Polymer: bioceramic composites optimization by tetracycline addition.

PubMed

Pataro, André L; Oliveira, Michele F; Teixeira, Karina I R; Turchetti-Maia, Regina M M; Lopes, Miriam T P; Wykrota, Francisco H L; Sinisterra, Rubén D; Cortés, Maria E

2007-05-04

The aim of this study was to evaluate the biocompatibility of composites of poly-lactic acid polymer (PLA) and copolymer of lactic and glycolic acid (PLGA), dispersed in a bioceramic matrix, Osteosynt (BC), to which tetracycline (TC) was added. The in vitro test used direct contact test (ASTM F-813) and elution test (USP-XXIII, ISO 10993-5), and in vivo evaluation was performed after subcutaneous implantation in outbread Swiss mice. The 0.01% (w/w) TC addition did not affect composite cytotoxicity in vitro. The macroscopic and histologic evaluation in vivo after 1, 7, 13, 21, 28 and 56 days showed an initial intense infiltrate of inflammatory cells for most of the groups. The tissue showed normal pattern after 21 days for all the groups. TC addition exhibited significantly larger reduction of inflammation signs (Mann-Whitney test, p<0.05) in the critical period of the resolution of the inflammatory process. Angiogenesis, cellular adsorption and fibrous deposit were observed on SEM evaluation. In conclusion, TC addition optimized composites polymer/bioceramic biocompatibility, contributing to anti-inflammatory response during the early phases of the wound healing process.

Regulation of Nlrp3 inflammasome by dietary metabolites

PubMed Central

Camell, Christina; Goldberg, Emily; Dixit, Vishwa Deep

2015-01-01

The bidirectional communication between innate immune cells and energy metabolism is now widely appreciated to regulate homeostasis as well as chronic diseases that emerge from dysregulated inflammation. Macronutrients-derived from diet or endogenous pathways that generate and divert metabolites into energetic or biosynthetic pathways-regulate the initiation, duration and cessation of the inflammatory response. The NLRP3 inflammasome is an important innate sensor of structurally diverse metabolic damage-associated molecular patterns (DAMPs) that has been implicated in a wide range of inflammatory disorders associated with caloric excess, adiposity and aging. Understanding the regulators of immune-metabolic interactions and their contribution towards chronic disease mechanisms, therefore, has the potential to reduce disease pathology, improve quality of life in elderly and promote the extension of healthspan. Just as specialized subsets of immune cells dampen inflammation through the production of negative regulatory cytokines; specific immunoregulatory metabolites can deactivate inflammasome-mediated immune activation. Here, we highlight the role of energy substrates, alternative fuels and metabolic DAMPs in the regulation of the NLRP3 inflammasome and discuss potential dietary interventions that may impact sterile inflammatory disease. PMID:26776831

RIG-I Like Receptors and Their Signaling Crosstalk in the Regulation of Antiviral Immunity

PubMed Central

Ramos, Hilario J; Gale, Michael

2011-01-01

During virus infection, multiple immune signaling pathways are triggered, both within the host cell and bystander cells of an infected tissue. These pathways act in concert to mediate innate antiviral immunity and to initiate the inflammatory response against infection. The RIG-I-like receptor (RLR) family of pattern recognition receptors (PRRs) is a group of cytosolic RNA helicase proteins that can identify viral RNA as nonself via binding to pathogen associated molecular patter (PAMP) motifs within RNA ligands that accumulate during virus infection. This interaction then leads to triggering of an innate antiviral response within the infected cells through RLR induction of downstream effector molecules such as type I interferon (IFN) and other pro-inflammatory cytokines that serve to induce antiviral and inflammatory gene expression within the local tissue. Cellular regulation of RLR signaling is a critical process that can direct the outcome of infection and is essential for governance of the overall immune response and avoidance of immune toxicity. Mechanisms of positive and negative regulation of RLR signaling have been identified that include signaling crosstalk between RLR pathways and Nuclear Oligomerization Domain (NOD)-Like Receptor (NLR) pathways and Caspase networks. Furthermore, many viruses have evolved mechanisms to target these pathways to promote enhanced replication and spread within the host. These virus-host interactions therefore carry important consequences for host immunity and viral pathogenesis. Understanding the pivotal role of RLRs in immune regulation and signaling crosstalk in antiviral immunity may provide new insights into therapeutic strategies for the control of virus infection and immunity. PMID:21949557

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.

The Early Innate Response of Chickens to Salmonella enterica Is Dependent on the Presence of O-Antigen but Not on Serovar Classification

PubMed Central

Varmuzova, Karolina; Matulova, Marta Elsheimer; Sebkova, Alena; Sekelova, Zuzana; Havlickova, Hana; Sisak, Frantisek; Babak, Vladimir; Rychlik, Ivan

2014-01-01

Salmonella vaccines used in poultry in the EU are based on attenuated strains of either Salmonella serovar Enteritidis or Typhimurium which results in a decrease in S. Enteritidis and S. Typhimurium but may allow other Salmonella serovars to fill an empty ecological niche. In this study we were therefore interested in the early interactions of chicken immune system with S. Infantis compared to S. Enteritidis and S. Typhimurium, and a role of O-antigen in these interactions. To reach this aim, we orally infected newly hatched chickens with 7 wild type strains of Salmonella serovars Enteritidis, Typhimurium and Infantis as well as with their rfaL mutants and characterized the early Salmonella-chicken interactions. Inflammation was characterized in the cecum 4 days post-infection by measuring expression of 43 different genes. All wild type strains stimulated a greater inflammatory response than any of the rfaL mutants. However, there were large differences in chicken responses to different wild type strains not reflecting their serovar classification. The initial interaction between newly-hatched chickens and Salmonella was found to be dependent on the presence of O-antigen but not on its structure, i.e. not on serovar classification. In addition, we observed that the expression of calbindin or aquaporin 8 in the cecum did not change if inflammatory gene expression remained within a 10 fold fluctuation, indicating the buffering capacity of the cecum, preserving normal gut functions even in the presence of minor inflammatory stimuli. PMID:24763249

Characterization of the early local immune response to Ixodes ricinus tick bites in human skin.

PubMed

Glatz, Martin; Means, Terry; Haas, Josef; Steere, Allen C; Müllegger, Robert R

2017-03-01

Little is known about the immunomodulation by tick saliva during a natural tick bite in human skin, the site of the tick-host interaction. We examined the expression of chemokines, cytokines and leucocyte markers on the mRNA levels and histopathologic changes in human skin biopsies of tick bites (n=37) compared to unaffected skin (n=9). Early tick-bite skin lesions (<24 hours of tick attachment) were characterized by a predominance of macrophages and dendritic cells, elevated mRNA levels of macrophage chemoattractants (CCL2, CCL3, CCL4) and neutrophil chemoattractants (CXCL1, CXCL8), of the pro-inflammatory cytokine, IL-1β, and the anti-inflammatory cytokine, IL-5. In contrast, the numbers of lymphocytes and mRNA levels of lymphocyte cell markers (CD4, CD8, CD19), lymphocyte chemoattractants (CXCL9, CXCL10, CXCL11, CXCL13, CCL1, CCL22), dendritic cell chemoattractants (CCL20), and other pro- (IL-6, IL-12p40, IFN-γ, TNF-α) and anti-inflammatory cytokines (IL-4, IL-10, TGF-β) did not differ from normal skin. With longer tick attachment (>24 hours), the numbers of innate immune cells and mediators (not significantly) declined, whereas the numbers of lymphocytes (not significantly) increased. Natural tick bites by Ixodes ricinus ticks initially elicit a strong local innate immune response in human skin. Beyond 24 hours of tick attachment, this response usually becomes less, perhaps because of immunomodulation by tick saliva. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Impact of graft composition on the systemic inflammatory response after an elective repair of an abdominal aortic aneurysm

PubMed Central

Baek, Jong Kwan; Kwon, Hyunwook; Ko, Gi-Young; Kim, Min Joo; Han, Youngjin; Chung, Young Soo; Park, Hojong; Kwon, Tae-Won

2015-01-01

Purpose The present study aimed to evaluate the risk factors and the role of graft material in the development of an acute phase systemic inflammatory response, and the clinical outcome in patients who undergo endovascular aneurysm repair (EVAR) or open surgical repair (OSR) of an abdominal aortic aneurysm (AAA). Methods We retrospectively evaluated the risk factors and the role of graft material in an increased risk of developing systemic inflammatory response syndrome (SIRS), and the clinical outcome in patients who underwent EVAR or OSR of an AAA. Results A total of 308 consecutive patients who underwent AAA repair were included; 178 received EVAR and 130 received OSR. There was no significant difference in the incidence of SIRS between EVAR patients and OSR patients. Regardless of treatment modality, SIRS was observed more frequently in patients treated with woven polyester grafts. Postoperative hospitalization was significantly prolonged in patients that experienced SIRS. In multivariate analyses, the initial white blood cell count (P = 0.001) and the use of woven polyester grafts (P = 0.005) were significantly associated with an increased risk of developing SIRS in patients who underwent EVAR. By contrast, the use of woven polyester grafts was the only factor associated with an increased risk of developing SIRS in patients who underwent OSR, although this was not statistically significant (P = 0.052). Conclusion The current study shows that the graft composition plays a primordial role in the development of SIRS, and it leads to prolonged hospitalization in both EVAR and OSR patients. PMID:25553321

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

Effect of rottlerin, a PKC-{delta} inhibitor, on TLR-4-dependent activation of murine microglia

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

Kim, Dong-Chan; Division of Research and Development, Neuronex, Inc., San31, Hyoja-dong, Nam-gu, Pohang 790-784; Kim, Sun-Hee

2005-11-11

In microglia, Toll-like receptors have been shown to recognize pathogen-associated molecular patterns and initiate innate immune responses upon interaction with infectious agents. The effect of rottlerin, a PKC-{delta} specific inhibitor, on TLR-4-mediated signaling was investigated in murine microglia stimulated with lipopolysaccharide and taxol. Pretreatment of microglia cells with rottlerin decreased LPS- and taxol-induced nitric oxide production in a concentration-dependent manner (IC{sub 50} = 99.1 {+-} 1.5 nM). Through MTT and FACS analysis, we found that the inhibition effect of rottlerin was not due to microglial cell death. Rottlerin pretreatment also attenuated LPS-induced phosphorylation of I{kappa}B-{alpha}, nuclear translocation of NF-{kappa}B, andmore » expression of type II nitric oxide synthase. In addition, microglial phagocytosis in response to TLR-4 activation was diminished in which rottlerin was pretreated. Together, these data raise the possibility that certain PKC-{delta} specific inhibitors can modulate TLR-4-derived signaling and inflammatory target gene expression, and can alter susceptibility to microbial infection and chronic inflammatory diseases in central nervous system.« less

Modifiable risk factors in periodontitis: at the intersection of aging and disease.

PubMed

Reynolds, Mark A

2014-02-01

Chronic inflammation is a prominent feature of aging and of common age-related diseases, including atherosclerosis, cancer and periodontitis. This volume examines modifiable risk factors for periodontitis and other chronic inflammatory diseases. Oral bacterial communities and viral infections, particularly with cytomegalovirus and other herpesviruses, elicit distinct immune responses and are central in the initiation of periodontal diseases. Risk of disease is dynamic and changes in response to complex interactions of genetic, environmental and stochastic factors over the lifespan. Many modifiable risk factors, such as smoking and excess caloric intake, contribute to increases in systemic markers of inflammation and can modify gene regulation through a variety of biologic mechanisms (e.g. epigenetic modifications). Periodontitis and other common chronic inflammatory diseases share multiple modifiable risk factors, such as tobacco smoking, psychological stress and depression, alcohol consumption, obesity, diabetes, metabolic syndrome and osteoporosis. Interventions that target modifiable risk factors have the potential to improve risk profiles for periodontitis as well as for other common chronic diseases. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Oxidative Stress and Antioxidant System in Periodontitis

PubMed Central

Wang, Yue; Andrukhov, Oleh; Rausch-Fan, Xiaohui

2017-01-01

Periodontitis is a common inflammatory disease, which is initiated by bacterial infection and subsequently progressed by aberrant host response. It can result in the destruction of teeth supporting tissues and have an influence on systemic health. When periodontitis occurs, reactive oxygen species, which are overproduced mostly by hyperactive neutrophils, could not be balanced by antioxidant defense system and cause tissues damage. This is characterized by increased metabolites of lipid peroxidation, DNA damage and protein damage. Local and systemic activities of antioxidants can also be influenced by periodontitis. Total antioxidant capacity, total oxidant status and oxidative stress index have been used to evaluate the oxidative stress associated with periodontitis. Studies have confirmed that inflammatory response in periodontitis is associated with an increased local and systemic oxidative stress and compromised antioxidant capacity. Our review focuses on increased oxidative stress in periodontal disease, specifically, on the relationship between the local and systemic biomarkers of oxidative stress and periodontitis and their association with the pathogenesis of periodontitis. Also, the relationship between periodontitis and systemic inflammation, and the effects of periodontal therapy on oxidative stress parameters will be discussed. PMID:29180965

Life-Threatening Atypical Case of Acute Generalized Exanthematous Pustulosis.

PubMed

Tajmir-Riahi, Azadeh; Wörl, Petra; Harrer, Thomas; Schliep, Stefan; Schuler, Gerold; Simon, Miklos

2017-01-01

Antibiotics are known to cause severe cutaneous adverse reactions, such as the rare acute generalized exanthematous pustulosis (AGEP). Unlike Stevens-Johnson syndrome or toxic epidermal necrolysis, AGEP is rarely life-threatening. Systemic involvement is not typical, and if present usually coincides with a mild elevation of the hepatic enzymes and a decrease in renal function. Hence, AGEP is known to have a good prognosis and to be life-threatening only in elderly patients or patients with chronic diseases. Herein, we report a case of AGEP in a young healthy male leading to systemic inflammatory response syndrome and to treatment in an intensive care unit after being treated with 5 different antibiotics. Initial symptoms were not indicative for AGEP and the patient's course of disease led promptly to critical cardiorespiratory symptoms and systemic inflammatory response syndrome. We assume that the administration of the 5 different antibiotics resulted in type IV allergy as well as secondary infection with Enterococcus faecium and Staphylococcus aureus, while the underlying periodontitis also contributed to the severity of this case. © 2017 S. Karger AG, Basel.

Plasmacytoid Dendritic Cells Die by the CD8 T Cell-Dependent Perforin Pathway during Acute Nonviral Inflammation.

PubMed

Mossu, Adrien; Daoui, Anna; Bonnefoy, Francis; Aubergeon, Lucie; Saas, Philippe; Perruche, Sylvain

2016-09-01

Regulation of the inflammatory response involves the control of dendritic cell survival. To our knowledge, nothing is known about the survival of plasmacytoid dendritic cells (pDC) in such situation. pDC are specialized in type I IFN (IFN-I) secretion to control viral infections, and IFN-I also negatively regulate pDC survival during the course of viral infections. In this study, we asked about pDC behavior in the setting of virus-free inflammation. We report that pDC survival was profoundly reduced during different nonviral inflammatory situations in the mouse, through a mechanism independent of IFN-I and TLR signaling. Indeed, we demonstrated that during inflammation, CD8(+) T cells induced pDC apoptosis through the perforin pathway. The data suggest, therefore, that pDC have to be turned down during ongoing acute inflammation to not initiate autoimmunity. Manipulating CD8(+) T cell response may therefore represent a new therapeutic opportunity for the treatment of pDC-associated autoimmune diseases, such as lupus or psoriasis. Copyright © 2016 by The American Association of Immunologists, Inc.

Leptin in the interplay of inflammation, metabolism and immune system disorders.

PubMed

Abella, Vanessa; Scotece, Morena; Conde, Javier; Pino, Jesús; Gonzalez-Gay, Miguel Angel; Gómez-Reino, Juan J; Mera, Antonio; Lago, Francisca; Gómez, Rodolfo; Gualillo, Oreste

2017-02-01

Leptin is one of the most relevant factors secreted by adipose tissue and the forerunner of a class of molecules collectively called adipokines. Initially discovered in 1994, its crucial role as a central regulator in energy homeostasis has been largely described during the past 20 years. Once secreted into the circulation, leptin reaches the central and peripheral nervous systems and acts by binding and activating the long form of leptin receptor (LEPR), regulating appetite and food intake, bone mass, basal metabolism, reproductive function and insulin secretion, among other processes. Research on the regulation of different adipose tissues has provided important insights into the intricate network that links nutrition, metabolism and immune homeostasis. The neuroendocrine and immune systems communicate bi-directionally through common ligands and receptors during stress responses and inflammation, and control cellular immune responses in several pathological situations including immune-inflammatory rheumatic diseases. This Review discusses the latest findings regarding the role of leptin in the immune system and metabolism, with particular emphasis on its effect on autoimmune and/or inflammatory rheumatic diseases, such as rheumatoid arthritis and osteoarthritis.

Prediction of inflammatory responses induced by biomaterials in contact with human blood using protein fingerprint from plasma.

PubMed

Engberg, Anna E; Nilsson, Per H; Huang, Shan; Fromell, Karin; Hamad, Osama A; Mollnes, Tom Eirik; Rosengren-Holmberg, Jenny P; Sandholm, Kerstin; Teramura, Yuji; Nicholls, Ian A; Nilsson, Bo; Ekdahl, Kristina N

2015-01-01

Inappropriate complement activation is often responsible for incompatibility reactions that occur when biomaterials are used. Complement activation is therefore a criterion included in legislation regarding biomaterials testing. However, no consensus is yet available regarding appropriate complement-activation-related test parameters. We examined protein adsorption in plasma and complement activation/cytokine release in whole blood incubated with well-characterized polymers. Strong correlations were found between the ratio of C4 to its inhibitor C4BP and generation of 10 (mainly pro-inflammatory) cytokines, including IL-17, IFN-γ, and IL-6. The levels of complement activation products correlated weakly (C3a) or not at all (C5a, sC5b-9), confirming their poor predictive values. We have demonstrated a direct correlation between downstream biological effects and the proteins initially adhering to an artificial surface after contact with blood. Consequently, we propose the C4/C4BP ratio as a robust, predictor of biocompatibility with superior specificity and sensitivity over the current gold standard. Copyright © 2014 Elsevier Ltd. All rights reserved.

Inflammation and cancer: advances and new agents.

PubMed

Crusz, Shanthini M; Balkwill, Frances R

2015-10-01

Tumour-promoting inflammation is considered one of the enabling characteristics of cancer development. Chronic inflammatory disease increases the risk of some cancers, and strong epidemiological evidence exists that NSAIDs, particularly aspirin, are powerful chemopreventive agents. Tumour microenvironments contain many different inflammatory cells and mediators; targeting these factors in genetic, transplantable and inducible murine models of cancer substantially reduces the development, growth and spread of disease. Thus, this complex network of inflammation offers targets for prevention and treatment of malignant disease. Much potential exists in this area for novel cancer prevention and treatment strategies, although clinical research to support targeting of cancer-related inflammation and innate immunity in patients with advanced-stage cancer remains in its infancy. Following the initial successes of immunotherapies that modulate the adaptive immune system, we assert that inflammation and innate immunity are important targets in patients with cancer on the basis of extensive preclinical and epidemiological data. The adaptive immune response is heavily dependent on innate immunity, therefore, inhibiting some of the tumour-promoting immunosuppressive actions of the innate immune system might enhance the potential of immunotherapies that activate a nascent antitumour response.

Inflammatory Mechanisms Linking Periodontal Diseases to Cardiovascular Diseases

PubMed Central

Schenkein, Harvey A.; Loos, Bruno G.

2015-01-01

Aims In this paper, inflammatory mechanisms that link periodontal diseases to cardiovascular diseases (CVD) are reviewed. Materials and Methods and Results This paper is a literature review. Studies in the literature implicate a number of possible mechanisms that could be responsible for increased inflammatory responses in atheromatous lesions due to periodontal infections. These include increased systemic levels of inflammatory mediators stimulated by bacteria and their products at sites distant from the oral cavity, elevated thrombotic and hemostatic markers that promote a prothrombotic state and inflammation, cross-reactive systemic antibodies that promote inflammation and interact with the atheroma, promotion of dyslipidemia with consequent increases in proinflammatory lipid classes and subclasses, and common genetic susceptibility factors present in both disease leading to increased inflammatory responses. Conclusions Such mechanisms may be thought to act in concert to increase systemic inflammation in periodontal disease and to promote or exacerbate atherogenesis. However, proof that the increase in systemic inflammation attributable to periodontitis impacts inflammatory responses during atheroma development, thrombotic events, or myocardial infarction or stroke is lacking. PMID:23627334

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

Indicaxanthin inhibits NADPH oxidase (NOX)-1 activation and NF-κB-dependent release of inflammatory mediators and prevents the increase of epithelial permeability in IL-1β-exposed Caco-2 cells.

PubMed

Tesoriere, L; Attanzio, A; Allegra, M; Gentile, C; Livrea, M A

2014-02-01

Dietary redox-active/antioxidant phytochemicals may help control or mitigate the inflammatory response in chronic inflammatory bowel disease (IBD). In the present study, the anti-inflammatory activity of indicaxanthin (Ind), a pigment from the edible fruit of cactus pear (Opuntia ficus-indica, L.), was shown in an IBD model consisting of a human intestinal epithelial cell line (Caco-2 cells) stimulated by IL-1β, a cytokine known to play a major role in the initiation and amplification of inflammatory activity in IBD. The exposure of Caco-2 cells to IL-1β brought about the activation of NADPH oxidase (NOX-1) and the generation of reactive oxygen species (ROS) to activate intracellular signalling leading to the activation of NF-κB, with the over-expression of inflammatory enzymes and release of pro-inflammatory mediators. The co-incubation of the cells with Ind, at a nutritionally relevant concentration (5-25 μM), and IL-1β prevented the release of the pro-inflammatory cytokines IL-6 and IL-8, PGE2 and NO, the formation of ROS and the loss of thiols in a dose-dependent manner. The co-incubation of the cells with Ind and IL-1β also prevented the IL-1β-induced increase of epithelial permeability. It was also shown that the activation of NOX-1 and NF-κB was prevented by Ind and the expression of COX-2 and inducible NO synthase was reduced. The uptake of Ind in Caco-2 cell monolayers appeared to be unaffected by the inflamed state of the cells. In conclusion, our findings suggest that the dietary pigment Ind may have the potential to modulate inflammatory processes at the intestinal level.

Inflammatory responses of stromal fibroblasts to inflammatory epithelial cells are involved in the pathogenesis of bovine mastitis

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

Zhang, Wenyao; Li, Xuezhong; Xu, Tong

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 proliferationmore » 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. - Highlights: • Inflammatory BMEs affect the properties of BMFs during mastitis. • BMEs inhibited the proliferation and promoted the migration of BMFs. • BMEs enhanced secretion of inflammatory mediators and deposition of ECM in BMFs. • Changes of the properties of BMFs were mediated by specific signal molecules.« less

Clinicopathological correlates in HIV seropositive tuberculosis cases presenting with jaundice after initiating antiretroviral therapy with a structured review of the literature.

PubMed

Barr, David A; Ramdial, Pravistadevi K

2012-10-14

The development of jaundice after initiation of HAART in HIV-TB co-infected patients is a challenging presentation in resource constrained settings, and is often attributed to drug induced liver injury (DILI).Some investigators have described hepatic tuberculosis Immune Reconstitution Inflammatory Syndrome (TB-IRIS) as a cause of liver disease in patients initiating HAART, which could also cause jaundice. We report the clinical and histopathological features of five HIV-TB co-infected patients presenting with a syndrome of jaundice, tender hepatomegaly, bile canalicular enzyme rise and return of constitutional symptoms within 8 weeks of initiation of highly active antiretroviral therapy (HAART) for advanced HIV infection at a rural clinic in KwaZulu Natal, South Africa.All five patients had been diagnosed with tuberculosis infection prior to HAART initiation and were on antituberculous medication at time of developing jaundice. There was evidence of multiple aetiologies of liver injury in all patients. However, based on clinical course and pathological findings, predominant hepatic injury was thought to be drug induced in one case and hepatic tuberculosis associated immune reconstitution inflammatory syndrome (TB-IRIS) in the other four.In these later 4 patients, liver biopsy findings included necrotising and non-necrotising granulomatous inflammation in the lobules and portal tracts. The granulomas demonstrated - in addition to epithelioid histiocytes and Langhans giant cells - neutrophils, plasma cells and large numbers of lymphocytes, which are not features of a conventional untreated tuberculous response. In this high TB prevalent, low resource setting, TB-IRIS may be an important cause of jaundice post-HAART initiation. Clinicopathological correlation is essential for optimal diagnosis. Further multi-organ based histopathological studies in the context of immune reconstitution would be useful to clinicians in low resource settings dealing with this challenging presentation.

Nitro-oleic acid inhibits vascular endothelial inflammatory responses and the endothelial-mesenchymal transition.

PubMed

Ambrozova, Gabriela; Fidlerova, Tana; Verescakova, Hana; Koudelka, Adolf; Rudolph, Tanja K; Woodcock, Steven R; Freeman, Bruce A; Kubala, Lukas; Pekarova, Michaela

2016-11-01

Inflammatory-mediated pathological processes in the endothelium arise as a consequence of the dysregulation of vascular homeostasis. Of particular importance are mediators produced by stimulated monocytes/macrophages inducing activation of endothelial cells (ECs). This is manifested by excessive soluble pro-inflammatory mediator production and cell surface adhesion molecule expression. Nitro-fatty acids are endogenous products of metabolic and inflammatory reactions that display immuno-regulatory potential and may represent a novel therapeutic strategy to treat inflammatory diseases. The purpose of our study was to characterize the effects of nitro-oleic acid (OA-NO2) on inflammatory responses and the endothelial-mesenchymal transition (EndMT) in ECs that is a consequence of the altered healing phase of the immune response. The effect of OA-NO2 on inflammatory responses and EndMT was determined in murine macrophages and murine and human ECs using Western blotting, ELISA, immunostaining, and functional assays. OA-NO2 limited the activation of macrophages and ECs by reducing pro-inflammatory cytokine production and adhesion molecule expression through its modulation of STAT, MAPK and NF-κB-regulated signaling. OA-NO2 also decreased transforming growth factor-β-stimulated EndMT and pro-fibrotic phenotype of ECs. These effects are related to the downregulation of Smad2/3. The study shows the pleiotropic effect of OA-NO2 on regulating EC-macrophage interactions during the immune response and suggests a role for OA-NO2 in the regulation of vascular endothelial immune and fibrotic responses arising during chronic inflammation. These findings propose the OA-NO2 may be useful as a novel therapeutic agent for treatment of cardiovascular disorders associated with dysregulation of the endothelial immune response. Copyright © 2016 Elsevier B.V. All rights reserved.

Tricyclic antidepressants for management of residual symptoms in inflammatory bowel disease.

PubMed

Iskandar, Heba N; Cassell, Benjamin; Kanuri, Navya; Gyawali, C Prakash; Gutierrez, Alexandra; Dassopoulos, Themistocles; Ciorba, Matthew A; Sayuk, Gregory S

2014-01-01

Tricyclic antidepressants (TCAs) have efficacy in treating irritable bowel syndrome (IBS). Some clinicians use TCAs to treat residual symptoms in inflammatory bowel disease (IBD) patients already on decisive IBD therapy or with quiescent inflammation, although this strategy has not been formally studied. The aim of this study was to examine the efficacy of TCA therapy in IBD patients with residual symptoms, despite controlled inflammation, in a retrospective cohort study. Inclusion required initiation of TCA for persistent gastrointestinal symptoms. IBD patients had inactive or mildly active disease with persistent symptoms despite adequate IBD therapy as determined by their physician. Symptom response was compared with IBS patients. Established Likert scales were used to score baseline symptom severity (0=no symptoms, 3=severe symptoms) and TCA response (0=no improvement; 3=complete satisfaction). Eighty-one IBD [41.3±1.7 y, 56F; 58 Crohn's disease/23 ulcerative colitis (UC)] and 77 IBS (46.2±1.7 y, 60F) patients were initiated on a TCA therapy. Baseline symptom scores (IBD, 2.06±0.03; IBS, 2.12±0.04; P=0.15) and symptom response to TCA therapy (IBD, 1.46±0.09; IBS, 1.30±0.09; P=0.2) were similar in both the groups. At least moderate improvement (Likert score ≥2) on TCA was achieved by comparable proportions of patients (59.3% IBD vs. 46% IBS; P=0.09). Within IBD, response was better with UC than Crohn's disease (1.86±0.13 vs. 1.26±0.11, respectively, P=0.003). In a clinical practice setting, TCA use led to moderate improvement of residual gastrointestinal symptoms in IBD patients for whom escalation of IBD therapy was not planned. UC patients demonstrated higher therapeutic success. IBD symptom responses were similar to IBS patients.

Keratinocyte p38δ loss inhibits Ras-induced tumor formation, while systemic p38δ loss enhances skin inflammation in the early phase of chemical carcinogenesis in mouse skin.

PubMed

Kiss, Alexi; Koppel, Aaron C; Anders, Joanna; Cataisson, Christophe; Yuspa, Stuart H; Blumenberg, Miroslav; Efimova, Tatiana

2016-05-01

p38δ expression and/or activity are increased in human cutaneous malignancies, including invasive squamous cell carcinoma (SCC) and head and neck SCC, but the role of p38δ in cutaneous carcinogenesis has not been well-defined. We have reported that mice with germline loss of p38δ exhibited a reduced susceptibility to skin tumor development compared with wild-type mice in the two-stage 7,12-dimethylbenz(a)anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA) chemical skin carcinogenesis model. Here, we report that p38δ gene ablation inhibited the growth of tumors generated from v-ras(Ha) -transformed keratinocytes in skin orthografts to nude mice, indicating that keratinocyte-intrinsic p38δ is required for Ras-induced tumorigenesis. Gene expression profiling of v-ras(Ha) -transformed p38δ-null keratinocytes revealed transcriptional changes associated with cellular responses linked to tumor suppression, such as reduced proliferation and increased differentiation, cell adhesion, and cell communications. Notably, a short-term DMBA/TPA challenge, modeling the initial stages of chemical skin carcinogenesis treatment, elicited an enhanced inflammation in p38δ-null skin compared with skin of wild-type mice, as assessed by measuring the expression of pro-inflammatory cytokines, including IL-1β, IL-6, IL-17, and TNFα. Additionally, p38δ-null skin and p38δ-null keratinocytes exhibited increased p38α activation and signaling in response to acute inflammatory challenges, suggesting a role for p38α in stimulating the elevated inflammatory response in p38δ-null skin during the initial phases of the DMBA/TPA treatment compared with similarly treated p38δ(+/+) skin. Altogether, our results indicate that p38δ signaling regulates skin carcinogenesis not only by keratinocyte cell-autonomous mechanisms, but also by influencing the interaction between between the epithelial compartment of the developing skin tumor and its stromal microenvironment. © 2015 Wiley Periodicals, Inc.

Evidence of the Anti-Inflammatory Effects of Probiotics and Synbiotics in Intestinal Chronic Diseases.

PubMed

Plaza-Díaz, Julio; Ruiz-Ojeda, Francisco Javier; Vilchez-Padial, Laura Maria; Gil, Angel

2017-05-28

Probiotics and synbiotics are used to treat chronic diseases, principally due to their role in immune system modulation and the anti-inflammatory response. The present study reviewed the effects of probiotics and synbiotics on intestinal chronic diseases in in vitro, animal, and human studies, particularly in randomized clinical trials. The selected probiotics exhibit in vitro anti-inflammatory properties. Probiotic strains and cell-free supernatants reduced the expression of pro-inflammatory cytokines via action that is principally mediated by toll-like receptors. Probiotic administration improved the clinical symptoms, histological alterations, and mucus production in most of the evaluated animal studies, but some results suggest that caution should be taken when administering these agents in the relapse stages of IBD. In addition, no effects on chronic enteropathies were reported. Probiotic supplementation appears to be potentially well tolerated, effective, and safe in patients with IBD, in both CD and UC. Indeed, probiotics such as Bifidobacterium longum 536 improved the clinical symptoms in patients with mild to moderate active UC. Although it has been proposed that probiotics can provide benefits in certain conditions, the risks and benefits should be carefully assessed before initiating any therapy in patients with IBD. For this reason, further studies are required to understand the precise mechanism by which probiotics and synbiotics affect these diseases.

Evidence of the Anti-Inflammatory Effects of Probiotics and Synbiotics in Intestinal Chronic Diseases

PubMed Central

Plaza-Díaz, Julio; Ruiz-Ojeda, Francisco Javier; Vilchez-Padial, Laura Maria; Gil, Angel

2017-01-01

Probiotics and synbiotics are used to treat chronic diseases, principally due to their role in immune system modulation and the anti-inflammatory response. The present study reviewed the effects of probiotics and synbiotics on intestinal chronic diseases in in vitro, animal, and human studies, particularly in randomized clinical trials. The selected probiotics exhibit in vitro anti-inflammatory properties. Probiotic strains and cell-free supernatants reduced the expression of pro-inflammatory cytokines via action that is principally mediated by toll-like receptors. Probiotic administration improved the clinical symptoms, histological alterations, and mucus production in most of the evaluated animal studies, but some results suggest that caution should be taken when administering these agents in the relapse stages of IBD. In addition, no effects on chronic enteropathies were reported. Probiotic supplementation appears to be potentially well tolerated, effective, and safe in patients with IBD, in both CD and UC. Indeed, probiotics such as Bifidobacterium longum 536 improved the clinical symptoms in patients with mild to moderate active UC. Although it has been proposed that probiotics can provide benefits in certain conditions, the risks and benefits should be carefully assessed before initiating any therapy in patients with IBD. For this reason, further studies are required to understand the precise mechanism by which probiotics and synbiotics affect these diseases. PMID:28555037

The anti-inflammatory effect of TR6 on LPS-induced mastitis in mice.

PubMed

Hu, Xiaoyu; Fu, Yunhe; Tian, Yuan; Zhang, Zecai; Zhang, Wenlong; Gao, Xuejiao; Lu, Xiaojie; Cao, Yongguo; Zhang, Naisheng

2016-01-01

[TRIAP]-derived decoy peptides have anti-inflammatory properties. In this study, we synthesized a TRIAP-derived decoy peptide (TR6) containing, the N-terminal portion of the third helical region of the [TIRAP] TIR domain (sequence "N"-RQIKIWFQNRRMKWK and -KPGFLRDPWCKYQML-"C"). We evaluated the effects of TR6 on lipopolysaccharide-induced mastitis in mice. In vivo, the mastitis model was induced by LPS administration for 24h, and TR6 treatment was initiated 1h before or after induction of LPS. In vitro, primary mouse mammary epithelial cells and neutrophils were used to investigate the effects of TR6 on LPS-induced inflammatory responses. The results showed that TR6 significantly inhibited mammary gland hisopathologic changes, MPO activity, and LPS-induced production of TNF-α, IL-1β and IL-6. In vitro, TR6 significantly inhibited LPS-induced TNF-α and IL-6 production and phosphorylation of NF-κB and MAPKs. In conclusion, this study demonstrated that the anti-inflammatory effect of TR6 against LPS-induced mastitis may be due to its ability to inhibit TLR4-mediated NF-κB and MAPK signaling pathways. TR6 may be a promising therapeutic reagent for mastitis treatment. Copyright © 2015. Published by Elsevier B.V.

Short-Term and Long-Term Effects of Orthopedic Biodegradable Implants

PubMed Central

Amini, Ami R.; Wallace, James S.; Nukavarapu, Syam P.

2012-01-01

Presently, orthopedic and oral/maxillofacial implants represent a combined $2.8 billion market, a figure expected to experience significant and continued growth. Although traditional permanent implants have been proved clinically efficacious, they are also associated with several drawbacks, including secondary revision and removal surgeries. Non-permanent, biodegradable implants offer a promising alternative for patients, as they provide temporary support and degrade at a rate matching tissue formation, and thus, eliminate the need for secondary surgeries. These implants have been in clinical use for nearly 25 years, competing directly with, or maybe even exceeding, the performance of permanent implants. The initial implantation of biodegradable materials, as with permanent materials, mounts an acute host inflammatory response. Over time, the implant degradation profile and possible degradation product toxicity mediate long-term biodegradable implant-induced inflammation. However, unlike permanent implants, this inflammation is likely to cease once the material disappears. Implant-mediated inflammation is a critical determinant for implant success. Thus, for the development of a proactive biodegradable implant that has the ability to promote optimal bone regeneration and minimal detrimental inflammation, a thorough understanding of short- and long-term inflammatory events is required. Here, we discuss an array of biodegradable orthopedic implants, their associated short- and long- term inflammatory effects, and methods to mediate these inflammatory events. PMID:22043969

Possible contribution of chronic inflammation in the induction of cancer in rheumatic diseases.

PubMed

Cutolo, Maurizio; Paolino, Sabrina; Pizzorni, Carmen

2014-01-01

Several chronic inflammatory conditions and autoimmune diseases involving different organs and tissues have been found at risk of progression to cancer. A wide array of proinflammatory cytokines, prostaglandins, nitric oxide products, and matricellular proteins are closely involved in premalignant and malignant transition of cells almost always in a background of chronic inflammation. Interestingly, epigenetic perturbations (i.e. miRNA aberrations, altered DNA methylation) together with important steroid hormone metabolic changes (i.e. oestrogens), or the altered vitamin D concentrations that may unbalance the immune / inflammatory response, have been found linked to the risk and severity in several chronic inflammatory conditions, as well as in cancer. In particular, it is evident, that not only the parent oestrogen but also oestrogen metabolites should be taken into account when this process is evaluated, specially the formation of catecholoestrogen metabolites, that are capable of forming either stable or depurinating DNA adducts, which can cause extensive DNA damage. It is interesting that today the successful treatment of several chronic immune/inflammatory rheumatic diseases is obtained also by using medications initially developed for their use in oncology. The circadian increase of growth factors, specially during the late night, in both chronic inflammation and in cancer patients, as well as the presence of oestrogen-regulated circadian mechanisms, suggests further important links.

Effect of detonation nanodiamonds on phagocyte activity.

PubMed

Karpukhin, Alexey V; Avkhacheva, Nadezhda V; Yakovlev, Ruslan Yu; Kulakova, Inna I; Yashin, Valeriy A; Lisichkin, Georgiy V; Safronova, Valentina G

2011-07-01

Detonation ND (nanodiamond) holds much promise for biological studies and medical applications. Properties like size of particles, inclination for modification of their surface and unambiguous biocompatibility are crucial. Of prime importance is interaction between ND and immune cells, which supervise foreign intrusion into an organism and eliminate it. Neutrophils are more reactive in inflammatory response implementing cytotoxical arsenal including ROS (reactive oxygen species). The aim of the work was to estimate the ability of two ND samples (produced by Diamond Center and PlasmaChem) to keep the vitality of neutrophils from the inflammatory site. The ability of cells to generate ROS in the presence of ND particles is considered as indicating their biocompatibility. IR spectra and size of particles in the samples were characterized. Acid modification of ND was carried out to get the luminescent form. In the biological aspect, ND demonstrated up or down action, depending on the concentration, time and conditions of activation of cells. Weak action of ND in whole blood was obtained possibly owing to the ND adsorbed plasma proteins, which mask active functional groups to interact with the cell membrane. ND did not influence the viability of isolated inflammatory neutrophils in low and moderate concentrations and suppressed it in high concentrations (≥1 g/l). Addition of ND to the cell suspension initiated concentration-dependent reaction to produce ROS similar to respiratory burst. ND up-regulated response to bacterial formylpeptide, but up- and down-modified (low or high concentrations, accordingly) response to such bacterial agents as OZ (opsonized zymosan), which neutrophils swallow up by oxygen-dependent phagocytosis. Localization of the particles on the cell surface as into the cells was identified by monitoring the intrinsic fluorescence of oxidized ND. The various mechanisms that could account for penetration of ND particles into the cell are discussed. Common conclusion concerns compatibility of ND with living neutrophils from inflammatory site and their normal functioning for infection safeguard.

New Insights into the Immunobiology of Mononuclear Phagocytic Cells and Their Relevance to the Pathogenesis of Cardiovascular Diseases

PubMed Central

Sanmarco, Liliana Maria; Eberhardt, Natalia; Ponce, Nicolás Eric; Cano, Roxana Carolina; Bonacci, Gustavo; Aoki, Maria Pilar

2018-01-01

Macrophages are the primary immune cells that reside within the myocardium, suggesting that these mononuclear phagocytes are essential in the orchestration of cardiac immunity and homeostasis. Independent of the nature of the injury, the heart triggers leukocyte activation and recruitment. However, inflammation is harmful to this vital terminally differentiated organ with extremely poor regenerative capacity. As such, cardiac tissue has evolved particular strategies to increase the stress tolerance and minimize the impact of inflammation. In this sense, growing evidences show that mononuclear phagocytic cells are particularly dynamic during cardiac inflammation or infection and would actively participate in tissue repair and functional recovery. They respond to soluble mediators such as metabolites or cytokines, which play central roles in the timing of the intrinsic cardiac stress response. During myocardial infarction two distinct phases of monocyte influx have been identified. Upon infarction, the heart modulates its chemokine expression profile that sequentially and actively recruits inflammatory monocytes, first, and healing monocytes, later. In the same way, a sudden switch from inflammatory macrophages (with microbicidal effectors) toward anti-inflammatory macrophages occurs within the myocardium very shortly after infection with Trypanosoma cruzi, the causal agent of Chagas cardiomyopathy. While in sterile injury, healing response is necessary to stop tissue damage; during an intracellular infection, the anti-inflammatory milieu in infected hearts would promote microbial persistence. The balance of mononuclear phagocytic cells seems to be also dynamic in atherosclerosis influencing plaque initiation and fate. This review summarizes the participation of mononuclear phagocyte system in cardiovascular diseases, keeping in mind that the immune system evolved to promote the reestablishment of tissue homeostasis following infection/injury, and that the effects of different mediators could modulate the magnitude and quality of the immune response. The knowledge of the effects triggered by diverse mediators would serve to identify new therapeutic targets in different cardiovascular pathologies. PMID:29375564

New Insights into the Immunobiology of Mononuclear Phagocytic Cells and Their Relevance to the Pathogenesis of Cardiovascular Diseases.

PubMed

Sanmarco, Liliana Maria; Eberhardt, Natalia; Ponce, Nicolás Eric; Cano, Roxana Carolina; Bonacci, Gustavo; Aoki, Maria Pilar

2017-01-01

Macrophages are the primary immune cells that reside within the myocardium, suggesting that these mononuclear phagocytes are essential in the orchestration of cardiac immunity and homeostasis. Independent of the nature of the injury, the heart triggers leukocyte activation and recruitment. However, inflammation is harmful to this vital terminally differentiated organ with extremely poor regenerative capacity. As such, cardiac tissue has evolved particular strategies to increase the stress tolerance and minimize the impact of inflammation. In this sense, growing evidences show that mononuclear phagocytic cells are particularly dynamic during cardiac inflammation or infection and would actively participate in tissue repair and functional recovery. They respond to soluble mediators such as metabolites or cytokines, which play central roles in the timing of the intrinsic cardiac stress response. During myocardial infarction two distinct phases of monocyte influx have been identified. Upon infarction, the heart modulates its chemokine expression profile that sequentially and actively recruits inflammatory monocytes, first, and healing monocytes, later. In the same way, a sudden switch from inflammatory macrophages (with microbicidal effectors) toward anti-inflammatory macrophages occurs within the myocardium very shortly after infection with Trypanosoma cruzi , the causal agent of Chagas cardiomyopathy. While in sterile injury, healing response is necessary to stop tissue damage; during an intracellular infection, the anti-inflammatory milieu in infected hearts would promote microbial persistence. The balance of mononuclear phagocytic cells seems to be also dynamic in atherosclerosis influencing plaque initiation and fate. This review summarizes the participation of mononuclear phagocyte system in cardiovascular diseases, keeping in mind that the immune system evolved to promote the reestablishment of tissue homeostasis following infection/injury, and that the effects of different mediators could modulate the magnitude and quality of the immune response. The knowledge of the effects triggered by diverse mediators would serve to identify new therapeutic targets in different cardiovascular pathologies.

Reciprocal Feedback Between miR-181a and E2/ERα in Myometrium Enhances Inflammation Leading to Labor

PubMed Central

Wang, Gang; Liu, Wei-Na; Kinser, Holly; Franco, Hector L.

2016-01-01

Context: The initiation of term and preterm labor is associated with an up-regulated inflammatory response in myometrium; however, the underlying signaling pathways remain incompletely defined. Objective: To define the regulatory mechanisms that mediate the increased myometrial inflammatory response leading to labor, we investigated the roles of microRNAs (miRNA/miR). Design and Setting: Human myometrial tissues, isolated smooth muscle cells, and animal models were used to study miR-181a regulation of uterine inflammatory pathways and contractility. Patients: Myometrial tissues from 15 term pregnant women undergoing elective cesarean section (not in labor) and 10 term pregnant women undergoing emergency cesarean section (in labor) were used. Results: Expression of the highly conserved microRNA, miR-181a, was significantly decreased in mouse and human myometrium during late gestation. By contrast, the putative miR-181a targets, TNF-α, and estrogen receptor (ER)-α, and the validated target, c-Fos, key factors in the inflammatory response leading to parturition, were coordinately up-regulated. In studies using human myometrial cells, overexpression of miR-181a mimics repressed basal as well as IL-1β-induced TNF-α, C-C motif chemokine ligand 2 and 8 expression, whereas the expression of the antiinflammatory cytokine, IL-10, was increased. Overexpression of miR-181a dramatically inhibited both spontaneous and IL-1β-induced contraction of human myometrial cells. Notably, miR-181a directly targeted ERα and decreased its expression, whereas estradiol-17β reciprocally inhibited expression of mature miR-181a in myometrial cells. Conclusions: Thus, increased estradiol-17β/ERα signaling in myometrium near term inhibits miR-181a, resulting in a further increase in ERα and proinflammatory signaling. This escalating feedback loop provides novel targets and therapeutic strategies for the prevention of preterm labor and its consequences. PMID:27459534

Adipokines and inflammation: is it a question of weight?

PubMed

Francisco, Vera; Pino, Jesus; Gonzalez-Gay, Miguel Angel; Mera, Antonio; Lago, Francisca; Gómez, Rodolfo; Mobasheri, Ali; Gualillo, Oreste

2018-05-01

Obesity has reached epidemic proportions in the Western society and is increasing in the developing world. It is considered as one of the major contributors to the global burden of disability and chronic diseases, including autoimmune, inflammatory and degenerative diseases. Research conducted on obesity and its complications over the last two decades has transformed the outdated concept of white adipose tissue (WAT) merely serving as an energy depot. WAT is now recognized as an active and inflammatory organ capable of producing a wide variety of factors known as adipokines. These molecules participate through endocrine, paracrine, autocrine or juxtacrine crosstalk mechanisms in a great variety of physiological or pathophysiological processes, regulating food intake, insulin sensitivity, immunity and inflammation. Although initially restricted to metabolic activities (regulation of glucose and lipid metabolism), adipokines currently represent a new family of proteins that can be considered key players in the complex network of soluble mediators involved in the pathophysiology of immune/inflammatory diseases. However, the complexity of the adipokine network in the pathogenesis and progression of inflammatory diseases has posed, since the beginning, the important question of whether it may be possible to target the mechanism(s) by which adipokines contribute to disease selectively without suppressing their physiological functions. Here, we explore in depth the most recent findings concerning the involvement of adipokines in inflammation and immune responses, in particular in rheumatic, inflammatory and degenerative diseases. We also highlight several possible strategies for therapeutic development and propose that adipokines and their signalling pathways may represent innovative therapeutic strategies for inflammatory disorders. © 2018 The British Pharmacological Society.

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).

Expanding Diversity in Molecular Structures and Functions of the IL-6/IL-12 Heterodimeric Cytokine Family

PubMed Central

Hasegawa, Hideaki; Mizoguchi, Izuru; Chiba, Yukino; Ohashi, Mio; Xu, Mingli; Yoshimoto, Takayuki

2016-01-01

The interleukin (IL)-6/IL-12 family cytokines have pleiotropic functions and play critical roles in multiple immune responses. This cytokine family has very unique characteristics in that they comprise two distinct subunits forming a heterodimer and each cytokine and receptor subunit shares with each other. The members of this cytokine family are increasing; currently, there are more than six cytokines, including the tentatively named cytokines IL-Y (p28/p40), IL-12 (p35/p40), IL-23 (p19/p40), IL-27 [p28/Epstein–Barr virus-induced protein 3 (EBI3)], IL-35 (p35/EBI3), and IL-39 (p19/EBI3). This family of cytokines covers a very broad range of immune responses, including pro-inflammatory responses, such as helper T (Th)1, Th2, and Th17, to anti-inflammatory responses, such as regulatory T (Treg) cells and IL-10-producing Treg cells. IL-12 is the first member of this family, and IL-12, IL-23, and IL-27 are mainly produced by activated antigen-presenting cells, such as dendritic cells and macrophages. IL-12 plays a critical role in the promotion of Th1 immune responses by inducing interferon-γ production to combat pathogens and malignant tumors. IL-23 induces IL-17 production and is necessary to maintain pathogenic Th17 cells that cause inflammatory and autoimmune diseases. IL-27 was initially reported to play a critical role in promotion of Th1 differentiation; however, subsequent studies revealed that IL-27 has broader stimulatory and inhibitory roles by inducing IL-10-producing Treg cells. IL-35 is produced by forkhead box P3+ Treg cells and activated B cells and has immunosuppressive functions to maintain immune tolerance. The most recently identified cytokine, IL-39, is produced by activated B cells and has pro-inflammatory functions. The cytokine tentatively named IL-Y seems to have anti-inflammatory functions by inhibiting Th1 and Th17 differentiation. In addition, individual cytokine subunits were also shown to have self-standing activities. Thus, promiscuity within the IL-6/IL-12 family cytokines complicates structural and functional clarification and assignment of individual cytokines. A better understanding of the recent advances and expanding diversity in molecular structures and functions of the IL-6/IL-12 family cytokines could allow the creation of novel therapeutic strategies by using them as tools and targeted molecules. PMID:27867385

Virulent Type A Francisella tularensis actively suppresses cytokine responses in human monocytes

PubMed Central

Gillette, Devyn D.; Curry, Heather M.; Cremer, Thomas; Ravneberg, David; Fatehchand, Kavin; Shah, Prexy A.; Wewers, Mark D.; Schlesinger, Larry S.; Butchar, Jonathan P.; Tridandapani, Susheela; Gavrilin, Mikhail A.

2014-01-01

Background: Human monocyte inflammatory responses differ between virulent and attenuated Francisella infection. Results: A mixed infection model showed that the virulent F. tularensis Schu S4 can attenuate inflammatory cytokine responses to the less virulent F. novicida in human monocytes. Conclusion: F. tularensis dampens inflammatory response by an active process. Significance: This suppression may contribute to enhanced pathogenicity of F. tularensis. Francisella tularensis is a Gram-negative facultative bacterium that can cause the disease tularemia, even upon exposure to low numbers of bacteria. One critical characteristic of Francisella is its ability to dampen or subvert the host immune response. Previous work has shown that monocytes infected with highly virulent F. tularensis subsp. tularensis strain Schu S4 responded with a general pattern of quantitatively reduced pro-inflammatory signaling pathway genes and cytokine production in comparison to those infected with the less virulent related F. novicida. However, it has been unclear whether the virulent Schu S4 was merely evading or actively suppressing monocyte responses. By using mixed infection assays with F. tularensis and F. novicida, we show that F. tularensis actively suppresses monocyte pro-inflammatory responses. Additional experiments show that this suppression occurs in a dose-dependent manner and is dependent upon the viability of F. tularensis. Importantly, F. tularensis was able to suppress pro-inflammatory responses to earlier infections with F. novicida. These results lend support that F. tularensis actively dampens human monocyte responses and this likely contributes to its enhanced pathogenicity. PMID:24783062

Histologic Inflammatory Response to Transvaginal Polypropylene Mesh: A Systematic Review.

PubMed

Thomas, Dominique; Demetres, Michelle; Anger, Jennifer T; Chughtai, Bilal

2018-01-01

To evaluate the inflammatory response following transvaginal implantation of polypropylene (PP) mesh. A comprehensive literature search was performed in the following databases from inception in April 2017: Ovid MEDLINE, Ovid EMBASE, and The Cochrane Library (Wiley). The studies retrieved were screened for eligibility against predefined inclusion and exclusion criteria. Twenty-three articles were included in this review. Following the implantation of PP mesh, there are immediate and local inflammatory responses. PP mesh elicits an inflammatory response that decreases over time; however, no studies documented a complete resolution. Further studies are needed to determine if there is a complete resolution of inflammation or if it persists. Copyright © 2017 Elsevier Inc. All rights reserved.

Chronic inflammatory demyelinating polyradiculoneuropathy: from pathology to phenotype

PubMed Central

Mathey, Emily K; Park, Susanna B; Hughes, Richard A C; Pollard, John D; Armati, Patricia J; Barnett, Michael H; Taylor, Bruce V; Dyck, P James B; Kiernan, Matthew C; Lin, Cindy S-Y

2015-01-01

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an inflammatory neuropathy, classically characterised by a slowly progressive onset and symmetrical, sensorimotor involvement. However, there are many phenotypic variants, suggesting that CIDP may not be a discrete disease entity but rather a spectrum of related conditions. While the abiding theory of CIDP pathogenesis is that cell-mediated and humoral mechanisms act together in an aberrant immune response to cause damage to peripheral nerves, the relative contributions of T cell and autoantibody responses remain largely undefined. In animal models of spontaneous inflammatory neuropathy, T cell responses to defined myelin antigens are responsible. In other human inflammatory neuropathies, there is evidence of antibody responses to Schwann cell, compact myelin or nodal antigens. In this review, the roles of the cellular and humoral immune systems in the pathogenesis of CIDP will be discussed. In time, it is anticipated that delineation of clinical phenotypes and the underlying disease mechanisms might help guide diagnostic and individualised treatment strategies for CIDP. PMID:25677463

Analysis of inflammatory cytokines in human blood, breath condensate, and urine using a multiplex immunoassay platform

EPA Science Inventory

A change in the expression of cytokines in human biological media indicates an inflammatory response to external stressors and reflects an early step along the adverse outcome pathway (AOP) for various health endpoints. To characterize and interpret this inflammatory response, m...

Regulation of Survival by IKKe in Inflammatory Breast Cancer Involves EpCAM

DTIC Science & Technology

2016-02-01

responses and normalizes inflammatory cytokines in murine myeloproliferative neoplasms . Blood. 2010;115(25):5232-40. 29. Duncan JS, Whittle MC, Nakamura K...responses and normalizes inflammatory cytokines in murine myeloprolifer - ative neoplasms . Blood. 2010;115(25):5232–5240. 34. Aref AR, et al. Screening

Quantitative analysis of the role of fiber length on phagocytosis and inflammatory response by alveolar macrophages

PubMed Central

Padmore, Trudy; Stark, Carahline; Turkevich, Leonid A.; Champion, Julie A.

2017-01-01

Background In the lung, macrophages attempt to engulf inhaled high aspect ratio pathogenic materials, secreting inflammatory molecules in the process. The inability of macrophages to remove these materials leads to chronic inflammation and disease. How the biophysical and biochemical mechanisms of these effects are influenced by fiber length remains undetermined. This study evaluates the role of fiber length on phagocytosis and molecular inflammatory responses to non-cytotoxic fibers, enabling development of quantitative length-based models. Methods Murine alveolar macrophages were exposed to long and short populations of JM-100 glass fibers, produced by successive sedimentation and repeated crushing, respectively. Interactions between fibers and macrophages were observed using time-lapse video microscopy, and quantified by flow cytometry. Inflammatory biomolecules (TNF-α, IL-1 α, COX-2, PGE2) were measured. Results Uptake of short fibers occurred more readily than for long, but long fibers were more potent stimulators of inflammatory molecules. Stimulation resulted in dose-dependent secretion of inflammatory biomolecules but no cytotoxicity or strong ROS production. Linear cytokine dose-response curves evaluated with length-dependent potency models, using measured fiber length distributions, resulted in identification of critical fiber lengths that cause frustrated phagocytosis and increased inflammatory biomolecule production. Conclusion Short fibers played a minor role in the inflammatory response compared to long fibers. The critical lengths at which frustrated phagocytosis occurs can be quantified by fitting dose-response curves to fiber distribution data. PMID:27784615

LOCAL ORGAN HYPERSENSITIVENESS

PubMed Central

Seegal, David; Seegal, Beatrice Carrier

1931-01-01

1. Rabbit eyes sensitized with guinea pig red blood cells or fresh egg white respond with an inflammatory reaction following the intravenous injection of the homologous antigen, but not the heterologous. 2. Two-tenths of 1.0 cc. of a multiple antigen containing ten separate ingredients, or in other words, 0.02 cc. of each foreign protein, when introduced into the rabbit's anterior chamber, is sufficient to produce an altered ocular reactivity such that when 1 cc. of one of the ten antigens is introduced intravenously the eye shows hyperemia of the iris and conjunctiva with more or less edema and lacrimation during the next 24 hours. 3. For as long as 8 months after sensitization eyes will respond with an inflammatory reaction following the intravenous injection of fractions of the total antigen. 4. Repeated daily intravenous injections of a single antigen usually produce no reaction in the sensitized eye after the first few days. Injection of different antigens intravenously on succeeding days produces a continued sterile inflammatory process in the sensitized eye. After the total number of single antigens has been injected, repetition of these injections now fails to produce a similar response. Instead, the eye reaction is at a much lower level and the inflammatory response is manifested only to a few of the antigens injected intravenously. 5. Unless massive doses of antigen are used to desensitize, permanent desensitization of the eye has not occurred in animals which have been followed for at least 8 months. Animals may develop maximal eye responses following repeated intravenous injections of the same antigen, if sufficient time has elapsed between injections. Nevertheless, the eye reactions which can be elicited 6 or 7 months after sensitization are less intense than the initial responses. 6. The ability of the eye inflammation to light up following the intravenous injection of homologous antigen is not due to an initial tissue injury as proven by the fact that the reaction is specific and anterior chambers injured with typhoid vaccine, iodine, saline, glycerine, or albolene will not respond subsequently when the various proteins used for sensitization of the other eyes are injected intravenously. 7. It has been impossible to demonstrate sensitivity in the eye by the intravenous shocking route until at least the 5th day following introduction of the antigen into the anterior chamber. 8. The eye reaction can be produced by the subcutaneous as well as the intravenous injection of antigen. 9. Rabbits vary considerably in the intensity of the eye reaction which can be elicited in them, but only rarely was an animal found which failed completely to give a reaction. PMID:19869914

Lavandula angustifolia Mill. Essential Oil Exerts Antibacterial and Anti-Inflammatory Effect in Macrophage Mediated Immune Response to Staphylococcus aureus.

PubMed

Giovannini, D; Gismondi, A; Basso, A; Canuti, L; Braglia, R; Canini, A; Mariani, F; Cappelli, G

2016-01-01

Different studies described the antibacterial properties of Lavandula angustifolia (Mill.) essential oil and its anti-inflammatory effects. Besides, no data exist on its ability to activate human macrophages during the innate response against Staphylococcus aureus. The discovery of promising regulators of macrophage-mediated inflammatory response, without side effects, could be useful for the prevention of, or as therapeutic remedy for, various inflammation-mediated diseases. This study investigated, by transcriptional analysis, how a L. angustifolia essential oil treatment influences the macrophage response to Staphylococcus aureus infection. The results showed that the treatment increases the phagocytic rate and stimulates the containment of intracellular bacterial replication by macrophages. Our data showed that this stimulation is coupled with expression of genes involved in reactive oxygen species production (i.e., CYBB and NCF4). Moreover, the essential oil treatment balanced the inflammatory signaling induced by S. aureus by repressing the principal pro-inflammatory cytokines and their receptors and inducing the heme oxygenase-1 gene transcription. These data showed that the L. angustifolia essential oil can stimulate the human innate macrophage response to a bacterium which is responsible for one of the most important nosocomial infection and might suggest the potential development of this plant extract as an anti-inflammatory and immune regulatory coadjutant drug.

Maternal Microbe-Specific Modulation of Inflammatory Response in Extremely Low-Gestational-Age Newborns

PubMed Central

Fichorova, Raina N.; Onderdonk, Andrew B.; Yamamoto, Hidemi; Delaney, Mary L.; DuBois, Andrea M.; Allred, Elizabeth; Leviton, Alan

2011-01-01

The fetal response to intrauterine inflammatory stimuli appears to contribute to the onset of preterm labor as well as fetal injury, especially affecting newborns of extremely low gestational age. To investigate the role of placental colonization by specific groups of microorganisms in the development of inflammatory responses present at birth, we analyzed 25 protein biomarkers in dry blood spots obtained from 527 newborns delivered by Caesarean section in the 23rd to 27th gestation weeks. Bacteria were detected in placentas and characterized by culture techniques. Odds ratios for having protein concentrations in the top quartile for gestation age for individual and groups of microorganisms were calculated. Mixed bacterial vaginosis (BV) organisms were associated with a proinflammatory pattern similar to those of infectious facultative anaerobes. Prevotella and Gardnerella species, anaerobic streptococci, peptostreptococci, and genital mycoplasmas each appeared to be associated with a different pattern of elevated blood levels of inflammation-related proteins. Lactobacillus was associated with low odds of an inflammatory response. This study provides evidence that microorganisms colonizing the placenta provoke distinctive newborn inflammatory responses and that Lactobacillus may suppress these responses. PMID:21264056

Isoliquiritigenin protects against sepsis-induced lung and liver injury by reducing inflammatory responses.

PubMed

Chen, Xiong; Cai, Xueding; Le, Rongrong; Zhang, Man; Gu, Xuemei; Shen, Feixia; Hong, Guangliang; Chen, Zimiao

2018-02-05

Sepsis, one of the most fatal diseases worldwide, often leads to multiple organ failure, mainly due to uncontrolled inflammatory responses. Despite accumulating knowledge obtained in recent years, effective drugs to treat sepsis in the clinic are still urgently needed. Isoliquiritigenin (ISL), a chalcone compound, has been reported to exert anti-inflammatory properties. However, little is known about the effects of ISL on sepsis and its related complications. In this study, we investigated the potential protective effects of ISL on lipopolysaccharide (LPS)-induced injuries and identified the mechanisms underlying these effects. ISL inhibited inflammatory cytokine expression in mouse primary peritoneal macrophages (MPMs) exposed to LPS. In an acute lung injury (ALI) mouse model, ISL prevented LPS-induced structural damage and inflammatory cell infiltration. Additionally, pretreatment with ISL attenuated sepsis-induced lung and liver injury, accompanied by a reduction in inflammatory responses. Moreover, these protective effects were mediated by the nuclear factor kappa B (NF-κB) pathway-mediated inhibition of inflammatory responses in vitro and in vivo. Our study suggests that ISL may be a potential therapeutic agent for sepsis-induced injuries. Copyright © 2017. Published by Elsevier Inc.

Dyadic confirmatory factor analysis of the inflammatory bowel disease family responsibility questionnaire.

PubMed

Greenley, Rachel Neff; Reed-Knight, Bonney; Blount, Ronald L; Wilson, Helen W

2013-09-01

Evaluate the factor structure of youth and maternal involvement ratings on the Inflammatory Bowel Disease Family Responsibility Questionnaire, a measure of family allocation of condition management responsibilities in pediatric inflammatory bowel disease. Participants included 251 youth aged 11-18 years with inflammatory bowel disease and their mothers. Item-level descriptive analyses, subscale internal consistency estimates, and confirmatory factor analyses of youth and maternal involvement were conducted using a dyadic data-analytic approach. Results supported the validity of 4 conceptually derived subscales including general health maintenance, social aspects, condition management tasks, and nutrition domains. Additionally, results indicated adequate support for the factor structure of a 21-item youth involvement measure and strong support for a 16-item maternal involvement measure. Additional empirical support for the validity of the Inflammatory Bowel Disease Family Responsibility Questionnaire was provided. Future research to replicate current findings and to examine the measure's clinical utility is warranted.

Orexigenic Hormone Ghrelin Attenuates Local and Remote Organ Injury after Intestinal Ischemia-Reperfusion

PubMed Central

Wu, Rongqian; Dong, Weifeng; Ji, Youxin; Zhou, Mian; Marini, Corrado P.; Ravikumar, Thanjavur S.; Wang, Ping

2008-01-01

Background Gut ischemia/reperfusion (I/R) injury is a serious condition in intensive care patients. Activation of immune cells adjacent to the huge endothelial cell surface area of the intestinal microvasculature produces initially local and then systemic inflammatory responses. Stimulation of the vagus nerve can rapidly attenuate systemic inflammatory responses through inhibiting the activation of macrophages and endothelial cells. Ghrelin, a novel orexigenic hormone, is produced predominately in the gastrointestinal system. Ghrelin receptors are expressed at a high density in the dorsal vagal complex of the brain stem. In this study, we investigated the regulation of the cholinergic anti-inflammatory pathway by the novel gastrointestinal hormone, ghrelin, after gut I/R. Methods and Findings Gut ischemia was induced by placing a microvascular clip across the superior mesenteric artery for 90 min in male adult rats. Our results showed that ghrelin levels were significantly reduced after gut I/R and that ghrelin administration inhibited pro-inflammatory cytokine release, reduced neutrophil infiltration, ameliorated intestinal barrier dysfunction, attenuated organ injury, and improved survival after gut I/R. Administration of a specific ghrelin receptor antagonist worsened gut I/R-induced organ injury and mortality. To determine whether ghrelin's beneficial effects after gut I/R require the intact vagus nerve, vagotomy was performed in sham and gut I/R animals immediately prior to the induction of gut ischemia. Our result showed that vagotomy completely eliminated ghrelin's beneficial effect after gut I/R. To further confirm that ghrelin's beneficial effects after gut I/R are mediated through the central nervous system, intracerebroventricular administration of ghrelin was performed at the beginning of reperfusion after 90-min gut ischemia. Our result showed that intracerebroventricular injection of ghrelin also protected the rats from gut I/R injury. Conclusions These findings suggest that ghrelin attenuates excessive inflammation and reduces organ injury after gut I/R through activation of the cholinergic anti-inflammatory pathway. PMID:18431503

Comparative analysis of redox and inflammatory properties of pristine nanomaterials and commonly used semiconductor manufacturing nano-abrasives.

PubMed

Flaherty, Nicole L; Chandrasekaran, Akshaya; del Pilar Sosa Peña, Maria; Roth, Gary A; Brenner, Sara A; Begley, Thomas J; Melendez, J Andrés

2015-12-15

Continued expansion of the nanotechnology industry has necessitated the self-assessment of manufacturing processes, specifically in regards to understanding the health related aspects following exposure to nanomaterials. There exists a growing concern over potential occupational exposure in the semiconductor industry where Al2O3, CeO2 and SiO2 nanoparticles are commonly featured as part of the chemical mechanical planarization (CMP) process. Chronic exposure to toxicants can result not only in acute cytotoxicity but also initiation of a chronic inflammatory state associated with diverse pathologies. In the current investigation, pristine nanoparticles and CMP slurry formulations of Al2O3, SiO2 and CeO2 were employed to assess their ability to induce cytotoxicity, inflammatory responses and reactive oxygen species in a mouse alveolar macrophage cell model. The pristine nanoparticles and slurries were not intrinsically cytotoxic and did not generate free radicals but were found to act as scavengers in the presence of an oxidant stimulant. Al2O3 and SiO2 nanoparticles increased levels of pro-inflammatory cytokines while pristine SiO2 nanoparticles induced generation of F2-Isoprostanes. In co-treatment studies, the pristine nanomaterials modulated the response to the inflammatory stimulant lipopolysaccharide. The studies have established that pristine nanoparticles and slurries do not impact the cells in a similar way indicating that they should not be used as slurry substitutes in toxicity evaluations. Further, we have defined how an alveolar cell line, which would likely be the first challenged upon nanomaterial aerosolization, responds to diverse mixtures of nanomaterials. Moreover, our findings reinforce the importance of using multiple analytic methods to define the redox state of the cell following exposure to commonly used industrial nanomaterials and toxicants. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Immunopathological Patterns from EAE and Theiler’s Virus Infection: Is Multiple Sclerosis a Homogenous 1-stage or Heterogenous 2-stage Disease?

PubMed Central

Martinez, Nicholas E.; Sato, Fumitaka; Omura, Seiichi; Minagar, Alireza; Alexander, J. Steven; Tsunoda, Ikuo

2012-01-01

Multiple sclerosis (MS) is a disease which can present in different clinical courses. The most common form of MS is the relapsing-remitting (RR) course, which in many cases evolves into secondary progressive (SP) disease. Autoimmune models such as experimental autoimmune encephalomyelitis (EAE) have been developed to represent the various clinical forms of MS. These models along with clinico-pathological evidence obtained from MS patients have allowed us to propose ‘1-stage’ and ‘2-stage’ disease theories to explain the transition in the clinical course of MS from RR to SP. Relapses in MS are associated with pro-inflammatory T helper (Th) 1/Th17 immune responses, while remissions are associated with anti-inflammatory Th2/regulatory T (Treg) immune responses. Based on the ‘1-stage disease’ theory, the transition from RR to SP disease occurs when the inflammatory immune response overwhelms the anti-inflammatory immune response. The ‘2-stage disease’ theory proposes that the transition from RR to SP-MS occurs when the Th2 response or some other responses overwhelm the inflammatory response resulting in the sustained production of anti-myelin antibodies, which cause continuing demyelination, neurodegeneration, and axonal loss. The Theiler’s virus model is also a 2-stage disease, where axonal degeneration precedes demyelination during the first stage, followed by inflammatory demyelination during the second stage. PMID:22633747

Synergistic actions of blocking angiopoietin-2 and tumor necrosis factor-α in suppressing remodeling of blood vessels and lymphatics in airway inflammation.

PubMed

Le, Catherine T K; Laidlaw, Grace; Morehouse, Christopher A; Naiman, Brian; Brohawn, Philip; Mustelin, Tomas; Connor, Jane R; McDonald, Donald M

2015-11-01

Remodeling of blood vessels and lymphatics are prominent features of sustained inflammation. Angiopoietin-2 (Ang2)/Tie2 receptor signaling and tumor necrosis factor-α (TNF)/TNF receptor signaling are known to contribute to these changes in airway inflammation after Mycoplasma pulmonis infection in mice. We determined whether Ang2 and TNF are both essential for the remodeling on blood vessels and lymphatics, and thereby influence the actions of one another. Their respective contributions to the initial stage of vascular remodeling and sprouting lymphangiogenesis were examined by comparing the effects of function-blocking antibodies to Ang2 or TNF, given individually or together during the first week after infection. As indices of efficacy, vascular enlargement, endothelial leakiness, venular marker expression, pericyte changes, and lymphatic vessel sprouting were assessed. Inhibition of Ang2 or TNF alone reduced the remodeling of blood vessels and lymphatics, but inhibition of both together completely prevented these changes. Genome-wide analysis of changes in gene expression revealed synergistic actions of the antibody combination over a broad range of genes and signaling pathways involved in inflammatory responses. These findings demonstrate that Ang2 and TNF are essential and synergistic drivers of remodeling of blood vessels and lymphatics during the initial stage of inflammation after infection. Inhibition of Ang2 and TNF together results in widespread suppression of the inflammatory response. Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Synergistic Actions of Blocking Angiopoietin-2 and Tumor Necrosis Factor-α in Suppressing Remodeling of Blood Vessels and Lymphatics in Airway Inflammation

PubMed Central

Le, Catherine T.K.; Laidlaw, Grace; Morehouse, Christopher A.; Naiman, Brian; Brohawn, Philip; Mustelin, Tomas; Connor, Jane R.; McDonald, Donald M.

2016-01-01

Remodeling of blood vessels and lymphatics are prominent features of sustained inflammation. Angiopoietin-2 (Ang2)/Tie2 receptor signaling and tumor necrosis factor-α (TNF)/TNF receptor signaling are known to contribute to these changes in airway inflammation after Mycoplasma pulmonis infection in mice. We determined whether Ang2 and TNF are both essential for the remodeling on blood vessels and lymphatics, and thereby influence the actions of one another. Their respective contributions to the initial stage of vascular remodeling and sprouting lymphangiogenesis were examined by comparing the effects of function-blocking antibodies to Ang2 or TNF, given individually or together during the first week after infection. As indices of efficacy, vascular enlargement, endothelial leakiness, venular marker expression, pericyte changes, and lymphatic vessel sprouting were assessed. Inhibition of Ang2 or TNF alone reduced the remodeling of blood vessels and lymphatics, but inhibition of both together completely prevented these changes. Genome-wide analysis of changes in gene expression revealed synergistic actions of the antibody combination over a broad range of genes and signaling pathways involved in inflammatory responses. These findings demonstrate that Ang2 and TNF are essential and synergistic drivers of remodeling of blood vessels and lymphatics during the initial stage of inflammation after infection. Inhibition of Ang2 and TNF together results in widespread suppression of the inflammatory response. PMID:26348576

Epsilon-aminocaproic acid improves postrecirculation hemodynamics by reducing intraliver activated protein C consumption in orthotopic liver transplantation.

PubMed

Kong, H Y; Wen, X H; Huang, S Q; Zhu, S M

2014-01-01

Activated protein C (APC) is related to regulating the inflammatory response and hemodynamic stability upon reperfusion in cardiac operations and orthotopic liver transplantation (OLT). Epsilon-aminocaproic acid (EACA) is frequently used to treat fibrinolysis during OLT. It also has inhibitory effects related to the inflammatory response. However, it remains to be determined whether EACA can attenuate intraliver APC consumption and improve hemodynamic stability after reperfusion during OLT. Fifty-nine recipients were randomized to receive either EACA (150 mg kg(-1) given intravenously prior to incision, followed by 15 mg kg(-1) h(-1) infusion until 2 h after the graft reperfusion) or the same volume of saline. Blood samples to assess plasma APC and protein C were obtained immediately before and after reperfusion from the inferior caval effluent or the portal veins for calculation of transliver differences (Δ). Hemodynamics and vasoactive medication use during the reperfusion period were observed in both groups. No transhepatic changes in protein C were found in either group. Immediately after reperfusion, a marked intraliver consumption of APC was noted in all recipients (P < 0.001), and intraliver consumption of APC in the control group was greater than that in the EACA-treated group (P < 0.05). Fewer requirements for vasoactive medication use after reperfusion and better initial graft function were noted in the EACA-treated group (P < 0.05). EACA can attenuate intraliver APC consumption and improve hemodynamic stability after reperfusion and initial graft function during OLT.

A multiscale modeling approach to inflammation: A case study in human endotoxemia

NASA Astrophysics Data System (ADS)

Scheff, Jeremy D.; Mavroudis, Panteleimon D.; Foteinou, Panagiota T.; An, Gary; Calvano, Steve E.; Doyle, John; Dick, Thomas E.; Lowry, Stephen F.; Vodovotz, Yoram; Androulakis, Ioannis P.

2013-07-01

Inflammation is a critical component in the body's response to injury. A dysregulated inflammatory response, in which either the injury is not repaired or the inflammatory response does not appropriately self-regulate and end, is associated with a wide range of inflammatory diseases such as sepsis. Clinical management of sepsis is a significant problem, but progress in this area has been slow. This may be due to the inherent nonlinearities and complexities in the interacting multiscale pathways that are activated in response to systemic inflammation, motivating the application of systems biology techniques to better understand the inflammatory response. Here, we review our past work on a multiscale modeling approach applied to human endotoxemia, a model of systemic inflammation, consisting of a system of compartmentalized differential equations operating at different time scales and through a discrete model linking inflammatory mediators with changing patterns in the beating of the heart, which has been correlated with outcome and severity of inflammatory disease despite unclear mechanistic underpinnings. Working towards unraveling the relationship between inflammation and heart rate variability (HRV) may enable greater understanding of clinical observations as well as novel therapeutic targets.

Glycogen synthase kinase-3β (GSK3β) inhibition suppresses the inflammatory response to Francisella infection and protects against tularemia in mice

PubMed Central

Zhang, Ping; Katz, Jenny; Michalek, Suzanne M.

2011-01-01

Francisella tularensis, the causative agent of tularemia, is currently considered a category A bioterrorism agent due to its high virulence. Infection with F. tularensis results in an inflammatory response that plays an important role in the pathogenesis of the disease; however, the cellular mechanisms regulating this response are poorly understood. Glycogen synthase kinase-3β (GSK3β) is a serine/threonine protein kinase that has recently emerged as a key regulatory switch in the modulation of the inflammatory response. In this study, we investigated the effect of GSK3β inhibition in regulating F. tularensis LVS-induced inflammatory responses. F. tularensis LVS infection of murine peritoneal macrophages induced a TLR2 dependent phosphorylation of GSK3β. Inhibition of GSK3β resulted in a significant decrease in the production of pro-inflammatory cytokine IL-6, IL-12p40 and TNF-α, as well as a significant increase in the production of the anti-inflammatory cytokine IL-10. GSK3β regulated the F. tularensis LVS-induced cytokine response by differentially affecting the activation of transcription factors NF-κB and CREB. Inhibition of GSK3β by lithium in vivo suppressed the inflammatory response in mice infected with F. tularensis LVS and conferred a survival advantage. In addition, we show that the production of IFN-γ contributed to the development of tularemia and to the fatal outcome of the infected animals, depending on the timing and the relative level of the IFN-γ produced. IFN-γ potentiated F. tularensis LVS-induced cytokine production by increasing GSK3β activity and the nuclear translocation of NF-κB. Taken together, these results demonstrate a regulatory function of GSK3β in modulating inflammatory responses that can be detrimental to the host during an F. tularensis LVS infection, and suggest that inhibition of GSK3β may represent a novel therapeutic approach in the treatment of tularemia. PMID:18929413

The Effect of C. burnetii Infection on the Cytokine Response of PBMCs from Pregnant Goats

PubMed Central

Ammerdorffer, Anne; Roest, Hendrik-I J.; Dinkla, Annemieke; Post, Jacob; Schoffelen, Teske; van Deuren, Marcel; Sprong, Tom; Rebel, Johanna M.

2014-01-01

In humans, infection with Coxiella burnetii, the causative agent of Q fever, leads to acute or chronic infection, both associated with specific clinical symptoms. In contrast, no symptoms are observed in goats during C. burnetii infection, although infection of the placenta eventually leads to premature delivery, stillbirth and abortion. It is unknown whether these differences in clinical outcome are due to the early immune responses of the goats. Therefore, peripheral blood mononuclear cells (PBMCs) were isolated from pregnant goats. In total, 17 goats were included in the study. Six goats remained naive, while eleven goats were infected with C. burnetii. Toll-like receptor (TLR) and cytokine mRNA expression were measured after in vitro stimulation with heat-killed C. burnetii at different time points (prior infection, day 7, 35 and 56 after infection). In naive goats an increased expression of interleukin (IL)-1β, tumor necrosis factor (TNF)-α, IL-10 and interferon (IFN)-γ mRNA upon C. burnetii stimulation was detected. In addition, TLR2 expression was strongly up-regulated. In goats infected with C. burnetii, PBMCs re-stimulated in vitro with C. burnetii, expressed significantly more TNF-α mRNA and IFN-γ mRNA compared to naive goats. In contrast, IL-10 mRNA production capacity was down-regulated during C. burnetii infection. Interestingly, at day 7 after inoculation a decreased IFN-γ protein level was observed in stimulated leukocytes in whole blood from infected goats, whereas at other time-points increased production of IFN-γ protein was seen. Our study shows that goats initiate a robust pro-inflammatory immune response against C. burnetii in vitro. Furthermore, PBMCs from C. burnetii infected goats show augmented pro-inflammatory cytokine responses compared to PBMCs from non-infected goats. However, despite this pro-inflammatory response, goats are not capable of clearing the C. burnetii infection. PMID:25279829

The transcriptome of a complete episode of acute otitis media.

PubMed

Hernandez, Michelle; Leichtle, Anke; Pak, Kwang; Webster, Nicholas J; Wasserman, Stephen I; Ryan, Allen F

2015-04-03

Otitis media is the most common disease of childhood, and represents an important health challenge to the 10-15% of children who experience chronic/recurrent middle ear infections. The middle ear undergoes extensive modifications during otitis media, potentially involving changes in the expression of many genes. Expression profiling offers an opportunity to discover novel genes and pathways involved in this common childhood disease. The middle ears of 320 WBxB6 F1 hybrid mice were inoculated with non-typeable Haemophilus influenzae (NTHi) or PBS (sham control). Two independent samples were generated for each time point and condition, from initiation of infection to resolution. RNA was profiled on Affymetrix mouse 430 2.0 whole-genome microarrays. Approximately 8% of the sampled transcripts defined the signature of acute NTHi-induced otitis media across time. Hierarchical clustering of signal intensities revealed several temporal gene clusters. Network and pathway enrichment analysis of these clusters identified sets of genes involved in activation of the innate immune response, negative regulation of immune response, changes in epithelial and stromal cell markers, and the recruitment/function of neutrophils and macrophages. We also identified key transcriptional regulators related to events in otitis media, which likely determine the expression of these gene clusters. A list of otitis media susceptibility genes, derived from genome-wide association and candidate gene studies, was significantly enriched during the early induction phase and the middle re-modeling phase of otitis but not in the resolution phase. Our results further indicate that positive versus negative regulation of inflammatory processes occur with highly similar kinetics during otitis media, underscoring the importance of anti-inflammatory responses in controlling pathogenesis. The results characterize the global gene response during otitis media and identify key signaling and transcription factor networks that control the defense of the middle ear against infection. These networks deserve further attention, as dysregulated immune defense and inflammatory responses may contribute to recurrent or chronic otitis in children.

Forkhead Box O1 Regulates Macrophage Polarization Following Staphylococcus aureus Infection: Experimental Murine Data and Review of the Literature.

PubMed

Wang, Yu-Chen; Ma, Hong-Di; Yin, Xue-Ying; Wang, Yin-Hu; Liu, Qing-Zhi; Yang, Jing-Bo; Shi, Qing-Hua; Sun, Baolin; Gershwin, M Eric; Lian, Zhe-Xiong

2016-12-01

The functions of macrophages that lead to effective host responses are critical for protection against Staphylococcus aureus. Deep tissue-invading S. aureus initially countered by macrophages trigger macrophage accumulation and induce inflammatory responses through surface receptors, especially toll-like receptor 2 (TLR2). Here, we found that macrophages formed sporadic aggregates in the liver during infection. Within those aggregates, macrophages co-localized with T cells and were indispensable for their infiltration. In addition, we have focused on the mechanisms underlying the polarization of macrophages in Forkhead box transcription factor O1 (FoxO1) conditional knockout Lys Cre/+ FoxO1 fl/fl mice following S. aureus infection and report herein that macrophage M1-M2 polarization via TLR2 is intrinsically regulated by FoxO1. Indeed, for effective FoxO1 activity, stimulation of TLR2 is essential. However, following S. aureus challenge, there was a decrease in macrophage FoxO1, with increased phosphorylation of FoxO1 because of TLR2-mediated activation of PI3K/Akt and c-Raf/MEK/ERK pathway. Following infection in Lys Cre/+ FoxO1 fl/fl mice, mice became more susceptible to S. aureus with reduced macrophage aggregation in the liver and attenuated Th1 and Th17 responses. FoxO1 abrogation reduced M1 pro-inflammatory responses triggered by S. aureus and enhanced M2 polarization in macrophages. In contrast, overexpression of FoxO1 in macrophages increased pro-inflammatory mediators and functional surface molecule expression. In conclusion, macrophage FoxO1 is critical to promote M1 polarization and maintain a competent T cell immune response against S. aureus infection in the liver. FoxO1 regulates macrophage M1-M2 polarization downstream of TLR2 dynamically through phosphorylation.

Patients' experiences of an open access follow up arrangement in managing inflammatory bowel disease

PubMed Central

Rogers, A; Kennedy, A; Nelson, E; Robinson, A

2004-01-01

Background: Improving access is a key policy issue in improving quality of care and extending patient choice and participation. People's experience of changing from fixed outpatient appointments to more flexible direct access arrangements for chronic disease has been underexplored. Objectives: To examine patients' views on using an open system of access compared with fixed outpatient appointments as part of a guided self-management intervention for inflammatory bowel disease (IBD). Design: Embedded qualitative study undertaken alongside a randomised controlled trial. Semi-structured interviews were undertaken to obtain an in depth understanding of patients' experience of the change in access arrangements. Participants: A purposive sample (n = 30) was drawn from the intervention group (n = 700) according to a range of responses to the trial baseline and follow up quantitative measures. Results: 28 interviews were included in the analysis. Compared with the previous system of fixed appointments, preference for the new open access system was based on enhanced personal control in contacting services and the view that it fitted better with everyday routine management and the requirement for urgent medical contact when symptoms fail to respond to medication. Preference for retaining fixed appointments was based on a sense of security from gaining access which did not require the individual to initiate the request for medical help. Conclusions: Open access may fit better with patients' self-management of their condition and everyday routines, roles and responsibilities. Ensuring that outpatient organisational arrangements and personnel are responsive to patient initiated requests for appointments is likely to impact on the acceptability of this type of access arrangement. Some people may continue to prefer the fixed appointment system which should be retained if patient choice is to be respected. PMID:15465941

Inflammatory Mechanisms and Oxidative Stress as Key Factors Responsible for Progression of Neurodegeneration: Role of Brain Innate Immune System.

PubMed

Leszek, Jerzy; Barreto, George E; Gąsiorowski, Kazimierz; Koutsouraki, Euphrosyni; Ávila-Rodrigues, Marco; Aliev, Gjumrakch

2016-01-01

Chronic inflammation is characterized by longstanding microglial activation followed by sustained release of inflammatory mediators, which aid in enhanced nitrosative and oxidative stress. The sustained release of inflammatory mediators propels the inflammatory cycle by increased microglial activation, promoting their proliferation and thus stimulating enhanced release of inflammatory factors. Elevated levels of several cytokines and chronic neuroinflammation have been associated with many neurodegenerative disorders of central nervous system like age-related macular degeneration, Alzheimer disease, multiple sclerosis, Parkinson's disease, Huntington' disease, and tauopathies. This review highlights the basic mechanisms of neuroinflammation, the characteristics of neurodegenerative diseases, and the main immunologic responses in CNS neurodegenerative disorders. A comprehensive outline for the crucial role of microglia in neuroinflammation and neurodegeneration and the role of Toll-like receptor signalling in coexistence of inflammatory mechanisms and oxidative stress as major factors responsible for progression of neurodegeneration have also been presented.

Preliminary evidence of a blunted anti-inflammatory response to exhaustive exercise in fibromyalgia

PubMed Central

Torgrimson-Ojerio, Britta; Ross, Rebecca L.; Dieckman, Nathaniel F.; Avery, Stephanie; Bennett, Robert M.; Jones, Kim D.; Guarino, Anthony J.; Wood, Lisa J.

2014-01-01

Exercise intolerance, as evidenced by a worsening of pain, fatigue, and stiffness after novel exertion, is a key feature of fibromyalgia (FM). In this pilot study, we investigate whether; insufficient muscle repair processes and impaired anti-inflammatory mechanisms result in an exaggerated pro-inflammatory cytokine response to exhaustive exercise, and consequently a worsening of muscle pain, stiffness and fatigue in the days post-exercise. We measured changes in muscle pain and tenderness, fatigue, stiffness, and serum levels of neuroendocrine and inflammatory cytokine markers in 20 women with FM and 16 healthy controls (HCs) before and after exhaustive treadmill exercise. Compared to HCs, FM participants failed to mount the expected anti-inflammatory response to exercise and experienced a worsening of symptoms post-exercise. However, changes in post-exertional symptoms were not mediated by post-exertional changes in pro-inflammatory cytokine levels. Implications of these findings are discussed. PMID:25457842

Harnessing and Modulating Inflammation in Strategies for Bone Regeneration

PubMed Central

Mountziaris, Paschalia M.; Spicer, Patrick P.; Kasper, F. Kurtis

2011-01-01

Inflammation is an immediate response that plays a critical role in healing after fracture or injury to bone. However, in certain clinical contexts, such as in inflammatory diseases or in response to the implantation of a biomedical device, the inflammatory response may become chronic and result in destructive catabolic effects on the bone tissue. Since our previous review 3 years ago, which identified inflammatory signals critical for bone regeneration and described the inhibitory effects of anti-inflammatory agents on bone healing, a multitude of studies have been published exploring various aspects of this emerging field. In this review, we distinguish between regenerative and damaging inflammatory processes in bone, update our discussion of the effects of anti-inflammatory agents on bone healing, summarize recent in vitro and in vivo studies demonstrating how inflammation can be modulated to stimulate bone regeneration, and identify key future directions in the field. PMID:21615330

Histone deacetylase inhibitors restore IL-10 expression in lipopolysaccharide-induced cell inflammation and reduce IL-1β and IL-6 production in breast silicone implant in C57BL/6J wild-type murine model.

PubMed

Di Liddo, Rosa; Valente, Sergio; Taurone, Samanta; Zwergel, Clemens; Marrocco, Biagina; Turchetta, Rosaria; Conconi, Maria Teresa; Scarpa, Carlotta; Bertalot, Thomas; Schrenk, Sandra; Mai, Antonello; Artico, Marco

2016-01-20

Among epigenetic enzymes, histone deacetylases (HDACs) are responsible for regulating the expression of an extensive array of genes by reversible deacetylation of nuclear histones as well as a large number of non-histone proteins. Initially proposed for cancer therapy, recently the interest for HDAC inhibitors (HDACi) as orally active, safe, and anti-inflammatory agents is rising due to their ability in reducing the severity of inflammatory and autoimmune diseases. In particular, selective HDAC3, HDAC6, and HDAC8 inhibitors have been described to downregulate the expression of pro-inflammatory cytokines (TNF-α, TGF-β, IL-1β, and IL-6). Herein, using KB31, C2C12, and 3T3-J2 cell lines, we demonstrated that, under lipopolysaccharide-induced in vitro inflammation, HDAC3/6/8 inhibitor MC2625 and HDAC6-selective inhibitor MC2780 were effective at a concentration of 30 ng/mL to downregulate mRNA expression of pro-inflammatory cytokines (IL-1β and IL-6) and to promote the transcription of IL-10 gene, without affecting the cell viability. Afterwards, we investigated by immunohistochemistry the activity of MC2625 and MC2780 at a concentration of 60 ng/kg animal weight to regulate silicone-triggered immune response in C57BL/6J female mice. Our findings evidenced the ability of such inhibitors to reduce host inflammation in silicone implants promoting a thickness reduction of peri-implant fibrous capsule, upregulating IL-10 expression, and reducing the production of both IL-1β and IL-6. These results underline the potential application of MC2625 and MC2780 in inflammation-related diseases.

Virulence-suppressing effects of linezolid on methicillin-resistant Staphylococcus aureus: possible contribution to early defervescence.

PubMed

Yoshizawa, Sadako; Tateda, Kazuhiro; Saga, Tomoo; Ishii, Yoshikazu; Yamaguchi, Keizo

2012-04-01

In the present study, immunomodulatory effects of linezolid (LZD) on methicillin-resistance Staphylococcus aureus (MRSA) infections were evaluated. We have retrospectively reviewed treatment effects of LZD on 52 patients with severe MRSA infections. Sixty-four percent of the febrile patients demonstrated significant defervescence within 3 days, despite the presence of positive culture results. We speculated that this finding might be due to early anti-inflammatory effects of LZD, and to investigate this further we initiated in vivo experiments using mice MRSA pneumonia models. Mice were treated with either LZD or vancomycin (VCM) immediately after intranasal administration of MRSA. Bacterial numbers and levels of inflammatory cytokines in the lungs were determined. Although the bacterial burden in the lungs was not apparently different between the two groups, LZD but not VCM treatment significantly reduced induction of inflammatory cytokines in the lungs (P < 0.05). To evaluate whether this anti-inflammatory response was due to suppression of virulence factor expression, filter-sterilized supernatants of MRSA incubated in broth overnight with sub-MICs of LZD were subcutaneously administered to mice. To clarify whether LZD possesses direct host-modulating activity, cytokine responses to the supernatants were examined in mice pretreated with LZD. Interestingly, MRSA solutions prepared in the presence of sub-MICs of LZD revealed significant suppression of interleukin 6 (IL-6) in a dose-dependent manner (P < 0.05), but pretreatment of mice with LZD revealed no changes in cytokines. These findings suggest that sub-MICs of LZD might suppress virulence factors of MRSA, which may be associated with a reduction in endogenous pyrogens. These data may explain at least in part early defervescence observed in LZD-treated individuals.

Redox regulation in metabolic programming and inflammation.

PubMed

Griffiths, Helen R; Gao, Dan; Pararasa, Chathyan

2017-08-01

Energy metabolism and redox state are intrinsically linked. In order to mount an adequate immune response, cells must have an adequate and rapidly available energy resource to migrate to the inflammatory site, to generate reactive oxygen species using NADPH as a cofactor and to engulf bacteria or damaged tissue. The first responder cells of the innate immune response, neutrophils, are largely dependent on glycolysis. Neutrophils are relatively short-lived, dying via apoptosis in the process of bacterial killing through production of hypochlorous acid and release of extracellular NETs. Later on, the most prevalent recruited innate immune cells are monocytes. Their role is to complete a damage limitation exercise initiated by neutrophils and then, as re-programmed M2 macrophages, to resolve the inflammatory event. Almost twenty five years ago, it was noted that macrophages lose their glycolytic capacity and become anti-inflammatory after treatment with corticosteroids. In support of this we now understand that, in contrast to early responders, M2 macrophages are predominantly dependent on oxidative phosphorylation for energy. During early inflammation, polarisation towards M1 macrophages is dependent on NOX2 activation which, via protein tyrosine phosphatase oxidation and AKT activation, increases trafficking of glucose transporters to the membrane and consequently increases glucose uptake for glycolysis. In parallel, mitochondrial efficiency is likely to be compromised via nitrosylation of the electron transport chain. Resolution of inflammation is triggered by encounter with apoptotic membranes exposing oxidised phosphatidylserine that interact with the scavenger receptor, CD36. Downstream of CD36, activation of AMPK and PPARγ elicits mitochondrial biogenesis, arginase expression and a switch towards oxidative phosphorylation in the M2 macrophage. Proinflammatory cytokine production by M2 cells decreases, but anti-inflammatory and wound healing growth factor production is maintained to support restoration of normal function. Copyright © 2017. Published by Elsevier B.V.

Fetal-to-maternal signaling in the timing of birth.

PubMed

Mendelson, Carole R; Montalbano, Alina P; Gao, Lu

2017-06-01

Preterm birth remains the major cause of neonatal morbidity and mortality throughout the world. This is due, in part, to our incomplete understanding of the mechanisms that underlie the maintenance of pregnancy and the initiation of parturition at term. In this article, we review our current knowledge of the complex, interrelated and concerted mechanisms whereby progesterone maintains myometrial quiescence throughout most of pregnancy, as well as those that mediate the upregulation of the inflammatory response and decline in progesterone receptor function leading to parturition. Herein, we review findings that demonstrate a role of the fetus in the timing of birth. Specifically, we focus on our own studies indicating that maturation of the fetal lung and enhanced secretion of the surfactant components, surfactant protein A (SP-A) and the potent inflammatory glycerophospholipid, platelet-activating factor (PAF), initiate a signaling cascade culminating in parturition. Our studies suggest an essential role of steroid receptor coactivators, SRC-1 and SRC-2, which activate expression of genes encoding SP-A and LPCAT1. LPCAT1 is a key enzyme in the synthesis of PAF, as well as DPPC, a highly surface-active glycerophospholipid component of surfactant. Thus, we describe a novel pathway through which the fetus contributes to the initiation of labor by signaling the mother when its lungs have achieved sufficient maturity for survival in an aerobic environment. Copyright © 2016 Elsevier Ltd. All rights reserved.

Silymarin attenuates cigarette smoke extract-induced inflammation via simultaneous inhibition of autophagy and ERK/p38 MAPK pathway in human bronchial epithelial cells.

PubMed

Li, Diandian; Hu, Jun; Wang, Tao; Zhang, Xue; Liu, Lian; Wang, Hao; Wu, Yanqiu; Xu, Dan; Wen, Fuqiang

2016-11-22

Cigarette smoke (CS) is a major risk of chronic obstructive pulmonary disease (COPD), contributing to airway inflammation. Our previous study revealed that silymarin had an anti-inflammatory effect in CS-exposed mice. In this study, we attempt to further elucidate the molecular mechanisms of silymarin in CS extract (CSE)-induced inflammation using human bronchial epithelial cells. Silymarin significantly suppressed autophagy activation and the activity of ERK/p38 mitogen-activated protein kinase (MAPK) pathway in Beas-2B cells. We also observed that inhibiting the activity of ERK with specific inhibitor U0126 led to reduced autophagic level, while knockdown of autophagic gene Beclin-1 and Atg5 decreased the levels of ERK and p38 phosphorylation. Moreover, silymarin attenuated CSE-induced upregulation of inflammatory cytokines TNF-α, IL-6 and IL-8 which could also be dampened by ERK/p38 MAPK inhibitors and siRNAs for Beclin-1 and Atg5. Finally, we validated decreased levels of both autophagy and inflammatory cytokines (TNF-α and KC) in CS-exposed mice after silymarin treatment. The present research has demonstrated that CSE-induced autophagy in bronchial epithelia, in synergism with ERK MAPK pathway, may initiate and exaggerate airway inflammation. Silymarin could attenuate inflammatory responses through intervening in the crosstalk between autophagy and ERK MAPK pathway, and might be an ideal agent treating inflammatory pulmonary diseases.

[Intrathoracic-mediastinal myofibroblastic tumor. Report and experience of one case].

PubMed

Hernández-Ascencio, Julio Abraham; Rios-Cruz, Daniel; Grube-Pagola, Peter; Gómez-Calzada, Juan Gabriel

2014-01-01

Inflammatory pseudotumor is a little known and uncommon condition. The debate continues whether it represents an inflammatory lesion or is a true neoplasm. It is considered a reactive process usually characterized by irregular growth of inflammatory cells. It has been described at various sites, the most common being the lung. The aim of this report is to emphasize the difficulty in the initial diagnosis. We present the case of a 56-year-old male who reports an 8-month history of dry cough, dyspnea, fatigue, weakness and weight loss of 20 kg. We performed two biopsies, one positive for malignancy without response to medical treatment and the second reporting chronic granulomatous inflammation. The patient underwent sternotomy, revealing a tumor of 20 × 17 × 10 cm, weighing approximately 2 kg. The tumor was dependent on the anterior mediastinum surrounding large vessels, and venous brachiocephalic, pericardium and both pleuras with firm adhesions to the right lung. Pathological report was as follows: inflammatory myofibroblastic tumor with positive immunohistochemistry for CD20 and CD3. Postoperative course was satisfactory and 1 year after surgery there was no evidence of recurrence. Inflammatory pseudotumor is a benign neoplasm of unknown origin with a chronic course. It can simulate a malignant tumor, causing constitutional manifestations, airway obstruction, cardiac alterations or other symptoms according to their location. Diagnosis is based on radiological features and direct biopsy. Treatment of choice is complete resection of the tumor with a favorable long-term outcome.

Restoration of the type I IFN-IL-1 balance through targeted blockade of PTGER4 inhibits autoimmunity in NOD mice.

PubMed

Rahman, M Jubayer; Rodrigues, Kameron B; Quiel, Juan A; Liu, Yi; Bhargava, Vipul; Zhao, Yongge; Hotta-Iwamura, Chie; Shih, Han-Yu; Lau-Kilby, Annie W; Malloy, Allison Mw; Thoner, Timothy W; Tarbell, Kristin V

2018-02-08

Type I IFN (IFN-I) dysregulation contributes to type 1 diabetes (T1D) development, and although increased IFN-I signals are pathogenic at the initiation of autoimmune diabetes, IFN-I dysregulation at later pathogenic stages more relevant for therapeutic intervention is not well understood. We discovered that 5 key antigen-presenting cell subsets from adult prediabetic NOD mice have reduced responsiveness to IFN-I that is dominated by a decrease in the tonic-sensitive subset of IFN-I response genes. Blockade of IFNAR1 in prediabetic NOD mice accelerated diabetes and increased Th1 responses. Therefore, IFN-I responses shift from pathogenic to protective as autoimmunity progresses, consistent with chronic IFN-I exposure. In contrast, IL-1-associated inflammatory pathways were elevated in prediabetic mice. These changes correlated with human T1D onset-associated gene expression. Prostaglandin E2 (PGE2) and prostaglandin receptor 4 (PTGER4), a receptor for PGE2 that mediates both inflammatory and regulatory eicosanoid signaling, were higher in NOD mice and drive innate immune dysregulation. Treating prediabetic NOD mice with a PTGER4 antagonist restored IFNAR signaling, decreased IL-1 signaling, and decreased infiltration of leukocytes into the islets. Therefore, innate cytokine alterations contribute to both T1D-associated inflammation and autoimmune pathogenesis. Modulating innate immune balance via signals such as PTGER4 may contribute to treatments for autoimmunity.

Underlying chronic inflammation alters the profile and mechanisms of acute neutrophil recruitment.

PubMed

Ma, Bin; Whiteford, James R; Nourshargh, Sussan; Woodfin, Abigail

2016-11-01

Chronically inflamed tissues show altered characteristics that include persistent populations of inflammatory leukocytes and remodelling of the vascular network. As the majority of studies on leukocyte recruitment have been carried out in normal healthy tissues, the impact of underlying chronic inflammation on ongoing leukocyte recruitment is largely unknown. Here, we investigate the profile and mechanisms of acute inflammatory responses in chronically inflamed and angiogenic tissues, and consider the implications for chronic inflammatory disorders. We have developed a novel model of chronic ischaemia of the mouse cremaster muscle that is characterized by a persistent population of monocyte-derived cells (MDCs), and capillary angiogenesis. These tissues also show elevated acute neutrophil recruitment in response to locally administered inflammatory stimuli. We determined that Gr1 low MDCs, which are widely considered to have anti-inflammatory and reparative functions, amplified acute inflammatory reactions via the generation of additional proinflammatory signals, changing both the profile and magnitude of the tissue response. Similar vascular and inflammatory responses, including activation of MDCs by transient ischaemia-reperfusion, were observed in mouse hindlimbs subjected to chronic ischaemia. This response demonstrates the relevance of the findings to peripheral arterial disease, in which patients experience transient exercise-induced ischaemia known as claudication.These findings demonstrate that chronically inflamed tissues show an altered profile and altered mechanisms of acute inflammatory responses, and identify tissue-resident MDCs as potential therapeutic targets. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Sex Differences in the Association between Stressor-Evoked Interleukin-6 Reactivity and C-Reactive Protein

PubMed Central

Lockwood, Kimberly G.; Marsland, Anna L.; Cohen, Sheldon; Gianaros, Peter J.

2016-01-01

Individuals differ consistently in the magnitude of their inflammatory responses to acute stressors, with females often showing larger responses than males. While the clinical significance of these individual differences remains unclear, it may be that greater inflammatory responses relate to increased systemic inflammation and thereby risk for chronic inflammatory disease. Here, we examined whether acute stressor-evoked interleukin (IL)-6 responses associate with resting levels of C-reactive protein (CRP), a marker of systemic inflammation, and whether this association differs by sex. Subjects were 57 healthy midlife adults (30–51 years; 33% female; 68% white). Blood was drawn before and 30-min after two mental stress tasks: a multisource interference task and a Stroop color word task. Hierarchical regressions controlling for age, sex, race, and BMI tested whether stressor-evoked IL-6 responses were associated with resting CRP and whether this association differed by sex. Results indicated that sex and stressor-evoked IL-6 responses interacted to predict CRP (ΔR2 = .08, B = −1.33, β = −.39, p = .02). In males, larger stressor-evoked IL-6 responses associated with higher CRP, whereas in females, stressor-evoked IL-6 responses showed a non-significant negative association with CRP. These findings indicate that inflammatory responses to acute stressors associate with resting levels of CRP; however, this association differs by sex. Previous literature suggests that there are sex differences in stressor-evoked IL-6 responses, but this is the first study to show sex differences in the relationship between acute inflammatory responses and systemic inflammation. The contribution of these sex differences to inflammatory disease risk warrants further investigation. PMID:27377561

Inflammation responses in patients with pulmonary tuberculosis in an intensive care unit

PubMed Central

Liu, Qiu-Yue; Han, Fen; Pan, Li-Ping; Jia, Hong-Yan; Li, Qi; Zhang, Zong-De

2018-01-01

Pulmonary tuberculosis caused by Mycobacterium tuberculosis remains a global problem. Inflammatory responses are the primary characteristics of patients with pulmonary tuberculosis in intensive care units (ICU). The aim of the present study was to investigate the clinical importance of inflammatory cells and factors for patients with pulmonary tuberculosis in ICU. A total of 124 patients with pulmonary tuberculosis in ICU were recruited for the present study. The inflammatory responses in patients with pulmonary tuberculosis in ICU were examined by changes in inflammatory cells and factors in the serum. The results indicated that serum levels of lymphocytes, plasma cells, granulocytes and monocytes were increased in patients with pulmonary tuberculosis in ICU compared with healthy controls. The serum levels of inflammatory factors interleukin (IL)-1, IL-6, IL-10, IL-12, and IL-4 were upregulated in patients with pulmonary tuberculosis in ICU. Lower plasma concentrations of IL-2, IL-15 and interferon-γ were detected in patients with pulmonary tuberculosis compared with healthy controls. It was demonstrated that high mobility group box-1 protein expression levels were higher in the serum of patients with pulmonary tuberculosis compared with healthy controls. Notably, an imbalance of T-helper cell (Th)1/Th2 cytokines was observed in patients with pulmonary tuberculosis. Pulmonary tuberculosis caused by M. tuberculosis also upregulated expression of matrix metalloproteinase (MMP)-1 and MMP-9 in hPMCs. In conclusion, these outcomes demonstrated that inflammatory responses and inflammatory factors are associated with the progression of pulmonary tuberculosis, suggesting that inhibition of inflammatory responses and inflammatory factors may be beneficial for the treatment of patients with pulmonary tuberculosis in ICU. PMID:29456674

Cellular Response to a Novel Fetal Acellular Collagen Matrix: Implications for Tissue Regeneration

PubMed Central

Rennert, Robert C.; Garg, Ravi K.; Gurtner, Geoffrey C.

2013-01-01

Introduction. PriMatrix (TEI Biosciences Inc., Boston, MA, USA) is a novel acellular collagen matrix derived from fetal bovine dermis that is designed for use in partial- and full-thickness wounds. This study analyzes the cellular response to PriMatrix in vivo, as well as the ability of this matrix to facilitate normal tissue regeneration. Methods. Five by five mm squares of rehydrated PriMatrix were implanted in a subcutaneous fashion on the dorsum of wild-type mice. Implant site tissue was harvested for histology, immunohistochemistry (IHC), and flow cytometric analyses at multiple time points until day 28. Results. PriMatrix implants were found to go through a biological progression initiated by a transient infiltrate of inflammatory cells, followed by mesenchymal cell recruitment and vascular development. IHC analysis revealed that the majority of the implanted fetal dermal collagen fibers persisted through day 28 but underwent remodeling and cellular repopulation to form tissue with a density and morphology consistent with healthy dermis. Conclusions. PriMatrix implants undergo progressive in vivo remodeling, facilitating the regeneration of histologically normal tissue through a mild inflammatory and progenitor cell response. Regeneration of normal tissue is especially important in a wound environment, and these findings warrant further investigation of PriMatrix in this setting. PMID:23970899

Cellular response to a novel fetal acellular collagen matrix: implications for tissue regeneration.

PubMed

Rennert, Robert C; Sorkin, Michael; Garg, Ravi K; Januszyk, Michael; Gurtner, Geoffrey C

2013-01-01

Introduction. PriMatrix (TEI Biosciences Inc., Boston, MA, USA) is a novel acellular collagen matrix derived from fetal bovine dermis that is designed for use in partial- and full-thickness wounds. This study analyzes the cellular response to PriMatrix in vivo, as well as the ability of this matrix to facilitate normal tissue regeneration. Methods. Five by five mm squares of rehydrated PriMatrix were implanted in a subcutaneous fashion on the dorsum of wild-type mice. Implant site tissue was harvested for histology, immunohistochemistry (IHC), and flow cytometric analyses at multiple time points until day 28. Results. PriMatrix implants were found to go through a biological progression initiated by a transient infiltrate of inflammatory cells, followed by mesenchymal cell recruitment and vascular development. IHC analysis revealed that the majority of the implanted fetal dermal collagen fibers persisted through day 28 but underwent remodeling and cellular repopulation to form tissue with a density and morphology consistent with healthy dermis. Conclusions. PriMatrix implants undergo progressive in vivo remodeling, facilitating the regeneration of histologically normal tissue through a mild inflammatory and progenitor cell response. Regeneration of normal tissue is especially important in a wound environment, and these findings warrant further investigation of PriMatrix in this setting.

The Immune System’s Role in Sepsis Progression, Resolution and Long-Term Outcome

PubMed Central

Delano, Matthew J.; Ward, Peter A.

2016-01-01

SUMMARY Sepsis occurs when an infection exceeds local tissue containment and induces a series of dysregulated physiologic responses that result in organ dysfunction. A subset of patients with sepsis progress to septic shock, defined by profound circulatory, cellular, and metabolic abnormalities, and associated with a greater mortality. Historically, sepsis-induced organ dysfunction and lethality were attributed to the complex interplay between the initial inflammatory and later anti-inflammatory responses. With advances in intensive care medicine and goal-directed interventions, early 30-day sepsis mortality has diminished, only to steadily escalate long after “recovery” from acute events. Since so many sepsis survivors succumb later to persistent, recurrent, nosocomial and secondary infections, many investigators have turned their attention to the long-term sepsis-induced alterations in cellular immune function. Sepsis clearly alters the innate and adaptive immune responses for sustained periods of time after clinical recovery, with immune suppression, chronic inflammation, and persistence of bacterial representing such alterations. Understanding that sepsis-associated immune cell defects correlate with long-term mortality, more investigations have centered on the potential for immune modulatory therapy to improve long term patient outcomes. These efforts are focused on more clearly defining and effectively reversing the persistent immune cell dysfunction associated with long-term sepsis mortality. PMID:27782333

Augmentation of antigen-stimulated allergic responses by a small amount of trichloroethylene ingestion from drinking water.

PubMed

Seo, Makoto; Yamagiwa, Takeo; Kobayashi, Ryo; Ikeda, Koji; Satoh, Masahiko; Inagaki, Naoki; Nagai, Hiroichi; Nagase, Hisamitsu

2008-11-01

In previous report, we have shown that trichloroethylene (TCE) increases histamine release and inflammatory cytokine production from antigen-stimulated mast cells. In this study, we examined the enhancing effect of a small amount of TCE ingestion from drinking water on antigen-stimulated allergic responses. After exposure of Wistar rats to TCE ingestion for 2 or 4 weeks, we performed a passive cutaneous anaphylaxis (PCA) reaction. TCE ingestion for 2 and 4 weeks enhanced PCA reaction in a dose-dependent manner. On histological examination, TCE ingestion for 2 weeks exacerbated inflammation characterized by infiltration of lymphocytes and accumulation of mast cells around the vessel in the skin. After TCE ingestion for 4 weeks, the mesenteric lymph nodes (MLNs) showed increase of the size and wet weight, and germinal centers changed distinctly. The interleukin-4 (IL-4) mRNA levels on spleen, MLNs and leukocytes were increased. Moreover, serum total IgE levels of TCE ingestion increased in a time-dependent manner. Our results suggest that TCE ingestion induces pro-inflammatory responses and causes Th1/Th2-type helper T-cell imbalance. And more, a small amount of TCE ingestion may lead to the initiation and acceleration of type I allergic reaction.

Macrophages – Key Cells in the Response to Wear Debris from Joint Replacements

PubMed Central

Nich, Christophe; Takakubo, Yuya; Pajarinen, Jukka; Ainola, Mari; Salem, Abdelhakim; Sillat, Tarvo; Rao, Allison J.; Raska, Milan; Tamaki, Yasunobu; Takagi, Michiaki; Konttinen, Yrjö T.; Goodman, Stuart B.; Gallo, Jiri

2013-01-01

The generation of wear debris is an inevitable result of normal usage of joint replacements. Wear debris particles stimulate local and systemic biological reactions resulting in chronic inflammation, periprosthetic bone destruction, and eventually, implant loosening and revision surgery. The latter may be indicated in up to 15% patients in the decade following the arthroplasty using conventional polyethylene. Macrophages play multiple roles in both inflammation and in maintaining tissue homeostasis. As sentinels of the innate immune system, they are central to the initiation of this inflammatory cascade, characterized by the release of pro-inflammatory and pro-osteoclastic factors. Similar to the response to pathogens, wear particles elicit a macrophage response, based on the unique properties of the cells belonging to this lineage, including sensing, chemotaxis, phagocytosis, and adaptive stimulation. The biological processes involved are complex, redundant, both local and systemic, and highly adaptive. Cells of the monocyte/macrophage lineage are implicated in this phenomenon, ultimately resulting in differentiation and activation of bone resorbing osteoclasts. Simultaneously, other distinct macrophage populations inhibit inflammation and protect the bone-implant interface from osteolysis. Here, the current knowledge about the physiology of monocyte/macrophage lineage cells is reviewed. In addition, the pattern and consequences of their interaction with wear debris and the recent developments in this field are presented. PMID:23568608

Neutrophil mobilization by surface-glycan altered Th17-skewing bacteria mitigates periodontal pathogen persistence and associated alveolar bone loss.

PubMed

Settem, Rajendra P; Honma, Kiyonobu; Sharma, Ashu

2014-01-01

Alveolar bone (tooth-supporting bone) erosion is a hallmark of periodontitis, an inflammatory disease that often leads to tooth loss. Periodontitis is caused by a select group of pathogens that form biofilms in subgingival crevices between the gums and teeth. It is well-recognized that the periodontal pathogen Porphyromonas gingivalis in these biofilms is responsible for modeling a microbial dysbiotic state, which then initiates an inflammatory response destructive to the periodontal tissues and bone. Eradication of this pathogen is thus critical for the treatment of periodontitis. Previous studies have shown that oral inoculation in mice with an attenuated strain of the periodontal pathogen Tannerella forsythia altered in O-glycan surface composition induces a Th17-linked mobilization of neutrophils to the gingival tissues. In this study, we sought to determine if immune priming with such a Th17-biasing strain would elicit a productive neutrophil response against P. gingivalis. Our data show that inoculation with a Th17-biasing T. forsythia strain is effective in blocking P. gingivalis-persistence and associated alveolar bone loss in mice. This work demonstrates the potential of O-glycan modified Tannerella strains or their O-glycan components for harnessing Th17-mediated immunity against periodontal and other mucosal pathogens.

Porphyromonas gingivalis: An Overview of Periodontopathic Pathogen below the Gum Line

PubMed Central

How, Kah Yan; Song, Keang Peng; Chan, Kok Gan

2016-01-01

Periodontal disease represents a group of oral inflammatory infections initiated by oral pathogens which exist as a complex biofilms on the tooth surface and cause destruction to tooth supporting tissues. The severity of this disease ranges from mild and reversible inflammation of the gingiva (gingivitis) to chronic destruction of connective tissues, the formation of periodontal pocket and ultimately result in loss of teeth. While human subgingival plaque harbors more than 500 bacterial species, considerable research has shown that Porphyromonas gingivalis, a Gram-negative anaerobic bacterium, is the major etiologic agent which contributes to chronic periodontitis. This black-pigmented bacterium produces a myriad of virulence factors that cause destruction to periodontal tissues either directly or indirectly by modulating the host inflammatory response. Here, this review provides an overview of P. gingivalis and how its virulence factors contribute to the pathogenesis with other microbiome consortium in oral cavity. PMID:26903954

Sarcoid polyneuropathy masquerading as chronic inflammatory demyelinating polyneuropathy.

PubMed

Singhal, Neel S; Irodenko, Viktoriya S; Margeta, Marta; Layzer, Robert B

2015-10-01

Sarcoid polyneuropathy is a rare and clinically heterogeneous disorder that may be the initial presentation of sarcoidosis. We report the clinical, electrophysiological, and pathological findings of a patient who carried a diagnosis of sensory-predominant chronic inflammatory demyelinating polyneuropathy (CIDP) for over a decade but was ultimately found to have sarcoid polyneuropathy. A 36-year-old man presented with a several-week history of gait difficulty and muscle cramps. He had a diagnosis of CIDP but had not received lasting benefit from steroid-sparing immunosuppressive drugs. Electrodiagnostic studies were consistent with a chronic demyelinating polyradiculoneuropathy with conduction blocks. After he developed systemic symptoms, tissue biopsies revealed granulomatous disease. Symptoms improved with steroid therapy. Sarcoid polyneuropathy presents a diagnostic challenge, but, in patients with atypical neuropathy, characteristic systemic symptoms, or a poor response to standard treatment, nerve and muscle biopsies can help diagnose this treatable disorder. © 2015 Wiley Periodicals, Inc.

Tumor necrosis factor-α: regulation of renal function and blood pressure

PubMed Central

Garvin, Jeffrey L.

2013-01-01

Tumor necrosis factor-α (TNF-α) is a pleiotropic cytokine that becomes elevated in chronic inflammatory states such as hypertension and diabetes and has been found to mediate both increases and decreases in blood pressure. High levels of TNF-α decrease blood pressure, whereas moderate increases in TNF-α have been associated with increased NaCl retention and hypertension. The explanation for these disparate effects is not clear but could simply be due to different concentrations of TNF-α within the kidney, the physiological status of the subject, or the type of stimulus initiating the inflammatory response. TNF-α alters renal hemodynamics and nephron transport, affecting both activity and expression of transporters. It also mediates organ damage by stimulating immune cell infiltration and cell death. Here we will summarize the available findings and attempt to provide plausible explanations for such discrepancies. PMID:23515717

Light and sound - emerging imaging techniques for inflammatory bowel disease

PubMed Central

Knieling, Ferdinand; Waldner, Maximilian J

2016-01-01

Patients with inflammatory bowel disease are known to have a high demand of recurrent evaluation for therapy and disease activity. Further, the risk of developing cancer during the disease progression is increasing from year to year. New, mostly non-radiant, quick to perform and quantitative methods are challenging, conventional endoscopy with biopsy as gold standard. Especially, new physical imaging approaches utilizing light and sound waves have facilitated the development of advanced functional and molecular modalities. Besides these advantages they hold the promise to predict personalized therapeutic responses and to spare frequent invasive procedures. Within this article we highlight their potential for initial diagnosis, assessment of disease activity and surveillance of cancer development in established techniques and recent advances such as wide-view full-spectrum endoscopy, chromoendoscopy, autofluorescence endoscopy, endocytoscopy, confocal laser endoscopy, multiphoton endoscopy, molecular imaging endoscopy, B-mode and Doppler ultrasound, contrast-enhanced ultrasound, ultrasound molecular imaging, and elastography. PMID:27433080

Considerations and Changes in the Evaluation, Management, and Outcomes in the Management of Diverticular Disease: The Diagnosis, Pathology, and Treatment of Diverticular Colitis.

PubMed

Kucejko, Robert J; Poggio, Juan L

2018-07-01

Diverticular colitis, also known as segmental colitis associated with diverticulosis, is a colonic inflammatory disorder on the spectrum of inflammatory bowel disease (IBD). The disease consists of macroscopic and microscopic inflammation affecting inter-diverticular mucosa, sparing peri-diverticular mucosa, with inflammation confined to the descending and sigmoid colon. The disease likely arises from the altered immune response of an individual, genetically susceptible to the IBD spectrum of diseases. Patients with segmental colitis associated with diverticulosis (SCAD) are typically older, and likely represent a subgroup of IBD-susceptible patients who lacked an environmental trigger until that point in their life. Most patients remain in remission with initial treatments of mesalamine or topical steroids, and maintenance mesalamine afterwards. Only the most severe form of the disease necessitates immunomodulatory therapy and the consideration of surgery.

Potential use of TNF-α inhibitors in systemic sclerosis.

PubMed

Murdaca, Giuseppe; Spanò, Francesca; Contatore, Miriam; Guastalla, Andrea; Puppo, Francesco

2014-01-01

Systemic sclerosis (SSc) is a rare connective tissue disease characterized by chronic inflammation and fibrosis of the skin, vascular abnormalities and variable involvement of organs. TNF-α has a central role in initial host response to infections and in the pathogenesis of various systemic immune-mediated diseases. Serum levels of TNF-α are elevated in patients with SSc and favor the development of pulmonary fibrosis and pulmonary arterial hypertension. Inflammatory arthritis can occur in patients with SSc. Infliximab and etanercept may improve the inflammatory arthritis and disability in SSc. TNF-α inhibitors reduce the systemic inflammation, improve the endothelial function decreasing the risk of pulmonary arterial hypertension progression and of acute cardiovascular and/or cerebrovascular events. Physicians need to be aware of the potential risks of tuberculosis reactivation and opportunistic infections. Randomized controlled trials with TNF-α inhibitors in patients with SSc are needed to confirm the potential role of these agents in the treatment of SSc.

Mangiferin in cancer chemoprevention and treatment: pharmacokinetics and molecular targets.

PubMed

Rajendran, Peramaiyan; Rengarajan, Thamaraiselvan; Nandakumar, Natarajan; Divya, H; Nishigaki, Ikuo

2015-02-01

A variety of bioactive food components have been shown to modulate inflammatory responses and to attenuate carcinogenesis. Polyphenols isolated several years ago from various medicinal plants now seem to have a prominent role in the prevention and therapy of a variety of ailments. Mangiferin, a unique, important, and highly investigated polyphenol, has attracted much attention of late for its potential as a chemopreventive and chemotherapeutic agent against various types of cancer. Mangiferin has been shown to target multiple proinflammatory transcription factors, cell- cycle proteins, growth factors, kinases, cytokines, chemokines, adhesion molecules, and inflammatory enzymes. These targets can potentially mediate the chemopreventive and therapeutic effects of mangiferin by inhibiting the initiation, promotion, and metastasis of cancer. This review not only summarizes the diverse molecular targets of mangiferin, but also gives the results of various preclinical studies that have been performed in the last decade with this promising polyphenol.

Hyperenhancement of the Pericardium on Cardiac Magnetic Resonance Imaging: A Marker of Acute Inflammation and Neovascularization or a Chronic Fibrotic State.

PubMed

Mullen, Liam; Chew, Pei Gee; Frost, Frederick; Ahmed, Ayesha; Khand, Aleem

2016-01-01

In cardiac magnetic resonance imaging, hyperenhancement of the pericardium post gadolinium administration in acute chest pain often signifies pericarditis with an acute inflammatory response and neovascularization. In the context of constrictive pericarditis, case series have indicated that the intensity of hyperenhancement and the thickness of the pericardium imply reversibility of the physiology of the constrictive pericarditis. We present a case of intense hyperenhancement and marked thickening of the pericardium in a patient with constrictive pericarditis with antecedent chest pain. Surgical resection of the pericardium and microscopy revealed a chronic fibrotic state with no evidence of inflammation or neovascularization, thus clarifying the failure of initial medical/anti-inflammatory treatment. Our case highlights the fact that hyperenhancement of the pericardium post gadolinium is non-specific for histology and does not necessarily imply the reversibility of pericardial constriction. © 2016 S. Karger AG, Basel.

Traumatic Brain Injury as a Risk Factor for Alzheimer's Disease: Is Inflammatory Signaling a Key Player?

PubMed

Djordjevic, Jelena; Sabbir, Mohammad Golam; Albensi, Benedict C

2016-01-01

Traumatic brain injury (TBI) has become a significant medical and social concern within the last 30 years. TBI has acute devastating effects, and in many cases, seems to initiate long-term neurodegeneration. With advances in medical technology, many people are now surviving severe brain injuries and their long term consequences. Post trauma effects include communication problems, sensory deficits, emotional and behavioral problems, physical complications and pain, increased suicide risk, dementia, and an increased risk for chronic CNS diseases, such as Alzheimer's disease (AD). In this review, we provide an introduction to TBI and hypothesize how it may lead to neurodegenerative disease in general and AD in particular. In addition, we discuss the evidence that supports the hypothesis that TBI may lead to AD. In particular, we focus on inflammatory responses as key processes in TBI-induced secondary injury, with emphasis on nuclear factor kappa B (NF-κB) signaling.

Characterization of the anti-inflammatory Lactobacillus reuteri BM36301 and its probiotic benefits on aged mice.

PubMed

Lee, Joon; Yang, Woo; Hostetler, Andrew; Schultz, Nathan; Suckow, Mark A; Stewart, Kay L; Kim, Daniel D; Kim, Hyung Soo

2016-04-19

The gut microbiota is playing more important roles in host immune regulation than was initially expected. Since many benefits of microbes are highly strain-specific and their mechanistic details remain largely elusive, further identification of new probiotic bacteria with immunoregulatory potentials is of great interest. We have screened our collection of probiotic lactic acid bacteria (LAB) for their efficacy in modulating host immune response. Some LAB are characterized by suppression of TNF-α induction when LAB culture supernatants are added to THP-1 cells, demonstrating the LAB's anti-inflammatory potential. These suppressive materials were not inactivated by heat or trypsin. On the other hand, treatment of THP-1 directly with live bacterial cells identified a group of pro-inflammatory LAB, which stimulated significant production of TNF-α. Among those, we chose the Lactobacillus reuteri BM36301 as an anti-inflammatory strain and the L. reuteri BM36304 as a pro-inflammatory strain, and further studied their in vivo effects. We supplied C57BL/6 mice with these bacteria in drinking water while feeding them a standard diet for 20 weeks. Interestingly, these L. reuteri strains evoked different consequences depending on the gender of the mice. That is, males treated with anti-inflammatory BM36301 experienced less weight gain and higher testosterone level; females treated with BM36301 maintained lower serum TNF-α as well as healthy skin with active folliculogenesis and hair growth. Furthermore, while males treated with pro-inflammatory BM36304 developed higher serum levels of TNF-α and insulin, in contrast females did not experience such effects from this bacteria strain. The L. reuteri BM36301 was selected as an anti-inflammatory strain in vitro. It helped mice maintain healthy conditions as they aged. These findings propose the L. reuteri BM36301 as a potential probiotic strain to improve various aspects of aging issues.

Evolution of the Immune Response to Chronic Airway Colonization with Aspergillus fumigatus Hyphae.

PubMed

Urb, Mirjam; Snarr, Brendan D; Wojewodka, Gabriella; Lehoux, Mélanie; Lee, Mark J; Ralph, Benjamin; Divangahi, Maziar; King, Irah L; McGovern, Toby K; Martin, James G; Fraser, Richard; Radzioch, Danuta; Sheppard, Donald C

2015-09-01

Airway colonization by the mold Aspergillus fumigatus is common in patients with underlying lung disease and is associated with chronic airway inflammation. Studies probing the inflammatory response to colonization with A. fumigatus hyphae have been hampered by the lack of a model of chronic colonization in immunocompetent mice. By infecting mice intratracheally with conidia embedded in agar beads (Af beads), we have established an in vivo model to study the natural history of airway colonization with live A. fumigatus hyphae. Histopathological examination and galactomannan assay of lung homogenates demonstrated that hyphae exited beads and persisted in the lungs of mice up to 28 days postinfection without invasive disease. Fungal lesions within the airways were surrounded by a robust neutrophilic inflammatory reaction and peribronchial infiltration of lymphocytes. Whole-lung cytokine analysis from Af bead-infected mice revealed an increase in proinflammatory cytokines and chemokines early in infection. Evidence of a Th2 type response was observed only early in the course of colonization, including increased levels of interleukin-4 (IL-4), elevated IgE levels in serum, and a mild increase in airway responsiveness. Pulmonary T cell subset analysis during infection mirrored these results with an initial transient increase in IL-4-producing CD4(+) T cells, followed by a rise in IL-17 and Foxp3(+) cells by day 14. These results provide the first report of the evolution of the immune response to A. fumigatus hyphal colonization. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Modeling TH 2 responses and airway inflammation to understand fundamental mechanisms regulating the pathogenesis of asthma.

PubMed

Foster, Paul S; Maltby, Steven; Rosenberg, Helene F; Tay, Hock L; Hogan, Simon P; Collison, Adam M; Yang, Ming; Kaiko, Gerard E; Hansbro, Philip M; Kumar, Rakesh K; Mattes, Joerg

2017-07-01

In this review, we highlight experiments conducted in our laboratories that have elucidated functional roles for CD4 + T-helper type-2 lymphocytes (T H 2 cells), their associated cytokines, and eosinophils in the regulation of hallmark features of allergic asthma. Notably, we consider the complexity of type-2 responses and studies that have explored integrated signaling among classical T H 2 cytokines (IL-4, IL-5, and IL-13), which together with CCL11 (eotaxin-1) regulate critical aspects of eosinophil recruitment, allergic inflammation, and airway hyper-responsiveness (AHR). Among our most important findings, we have provided evidence that the initiation of T H 2 responses is regulated by airway epithelial cell-derived factors, including TRAIL and MID1, which promote T H 2 cell development via STAT6-dependent pathways. Further, we highlight studies demonstrating that microRNAs are key regulators of allergic inflammation and potential targets for anti-inflammatory therapy. On the background of T H 2 inflammation, we have demonstrated that innate immune cells (notably, airway macrophages) play essential roles in the generation of steroid-resistant inflammation and AHR secondary to allergen- and pathogen-induced exacerbations. Our work clearly indicates that understanding the diversity and spatiotemporal role of the inflammatory response and its interactions with resident airway cells is critical to advancing knowledge on asthma pathogenesis and the development of new therapeutic approaches. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Acute and chronic stress and the inflammatory response in hyperprolactinemic rats.

PubMed

Ochoa-Amaya, J E; Malucelli, B E; Cruz-Casallas, P E; Nasello, A G; Felicio, L F; Carvalho-Freitas, M I R

2010-01-01

Prolactin (PRL), a hormone produced by the pituitary gland, has multiple physiological functions, including immunoregulation. PRL can also be secreted in response to stressful stimuli. During stress, PRL has been suggested to oppose the immunosuppressive effects of inflammatory mediators. Therefore, the aim of the present study was to analyze the effects of short- and long-term hyperprolactinemia on the inflammatory response in rats subjected to acute or chronic cold stress. Inflammatory edema was induced by carrageenan in male rats, and hyperprolactinemia was induced by injections of the dopamine receptor antagonist domperidone. The volume of inflammatory edema was measured by plethysmography after carrageenan injection. Additionally, the effects of hyperprolactinemia on body weight and serum corticosterone levels were evaluated. Five days of domperidone-induced hyperprolactinemia increased the volume of inflammatory edema. No differences in serum corticosterone levels were observed between groups. No significant differences were found among 30 days domperidone-induced hyperprolactinemic animals subjected to acute stress and the inflammatory response observed in chronic hyperprolactinemic animals subjected to chronic stress. The results suggest that short-term hyperprolactinemia has pro-inflammatory effects. Because such an effect was not observed in long-term hyperprolactinemic animals, PRL-induced tolerance seems likely. We suggest that short-term hyperprolactinemia may act as a protective factor in rats subjected to acute stress. These data suggest that hyperprolactinemia and stress interact differentially according to the time period. Copyright 2010 S. Karger AG, Basel.

Treatment with a New Peroxisome Proliferator-Activated Receptor Gamma Agonist, Pyridinecarboxylic Acid Derivative, Increases Angiogenesis and Reduces Inflammatory Mediators in the Heart of Trypanosoma cruzi-Infected Mice.

PubMed

Penas, Federico Nicolás; Carta, Davide; Dmytrenko, Ganna; Mirkin, Gerado A; Modenutti, Carlos Pablo; Cevey, Ágata Carolina; Rada, Maria Jimena; Ferlin, Maria Grazia; Sales, María Elena; Goren, Nora Beatriz

2017-01-01

Trypanosoma cruzi infection induces an intense inflammatory response in diverse host tissues. The immune response and the microvascular abnormalities associated with infection are crucial aspects in the generation of heart damage in Chagas disease. Upon parasite uptake, macrophages, which are involved in the clearance of infection, increase inflammatory mediators, leading to parasite killing. The exacerbation of the inflammatory response may lead to tissue damage. Peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-dependent nuclear transcription factor that exerts important anti-inflammatory effects and is involved in improving endothelial functions and proangiogenic capacities. In this study, we evaluated the intermolecular interaction between PPARγ and a new synthetic PPARγ ligand, HP 24 , using virtual docking. Also, we showed that early treatment with HP 24 , decreases the expression of NOS2, a pro-inflammatory mediator, and stimulates proangiogenic mediators (vascular endothelial growth factor A, CD31, and Arginase I) both in macrophages and in the heart of T. cruzi -infected mice. Moreover, HP 24 reduces the inflammatory response, cardiac fibrosis and the levels of inflammatory cytokines (TNF-α, interleukin 6) released by macrophages of T. cruzi -infected mice. We consider that PPARγ agonists might be useful as coadjuvants of the antiparasitic treatment of Chagas disease, to delay, reverse, or preclude the onset of heart damage.

Antigen-Specific Interferon-Gamma Responses and Innate Cytokine Balance in TB-IRIS

PubMed Central

Goovaerts, Odin; Jennes, Wim; Massinga-Loembé, Marguerite; Ceulemans, Ann; Worodria, William; Mayanja-Kizza, Harriet; Colebunders, Robert; Kestens, Luc

2014-01-01

Background Tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) remains a poorly understood complication in HIV-TB patients receiving antiretroviral therapy (ART). TB-IRIS could be associated with an exaggerated immune response to TB-antigens. We compared the recovery of IFNγ responses to recall and TB-antigens and explored in vitro innate cytokine production in TB-IRIS patients. Methods In a prospective cohort study of HIV-TB co-infected patients treated for TB before ART initiation, we compared 18 patients who developed TB-IRIS with 18 non-IRIS controls matched for age, sex and CD4 count. We analyzed IFNγ ELISpot responses to CMV, influenza, TB and LPS before ART and during TB-IRIS. CMV and LPS stimulated ELISpot supernatants were subsequently evaluated for production of IL-12p70, IL-6, TNFα and IL-10 by Luminex. Results Before ART, all responses were similar between TB-IRIS patients and non-IRIS controls. During TB-IRIS, IFNγ responses to TB and influenza antigens were comparable between TB-IRIS patients and non-IRIS controls, but responses to CMV and LPS remained significantly lower in TB-IRIS patients. Production of innate cytokines was similar between TB-IRIS patients and non-IRIS controls. However, upon LPS stimulation, IL-6/IL-10 and TNFα/IL-10 ratios were increased in TB-IRIS patients compared to non-IRIS controls. Conclusion TB-IRIS patients did not display excessive IFNγ responses to TB-antigens. In contrast, the reconstitution of CMV and LPS responses was delayed in the TB-IRIS group. For LPS, this was linked with a pro-inflammatory shift in the innate cytokine balance. These data are in support of a prominent role of the innate immune system in TB-IRIS. PMID:25415590

Helminths in the hygiene hypothesis: sooner or later?

PubMed

Maizels, R M; McSorley, H J; Smyth, D J

2014-07-01

There is increasing recognition that exposures to infectious agents evoke fundamental effects on the development and behaviour of the immune system. Moreover, where infections (especially parasitic infections) have declined, immune responses appear to be increasingly prone to hyperactivity. For example, epidemiological studies of parasite-endemic areas indicate that prenatal or early-life experience of infections can imprint an individual's immunological reactivity. However, the ability of helminths to dampen pathology in established inflammatory diseases implies that they can have therapeutic effects even if the immune system has developed in a low-infection setting. With recent investigations of how parasites are able to modulate host immune pathology at the level of individual parasite molecules and host cell populations, we are now able to dissect the nature of the host-parasite interaction at both the initiation and recall phases of the immune response. Thus the question remains - is the influence of parasites on immunity one that acts primarily in early life, and at initiation of the immune response, or in adulthood and when recall responses occur? In short, parasite immunosuppression - sooner or later? © 2014 The Authors. Clinical & Experimental Immunology published by John Wiley & Sons Ltd on behalf of British Society for Immunology.

Activation of Intrinsic Immune Responses and Microglial Phagocytosis in an Ex Vivo Spinal Cord Slice Culture Model of West Nile Virus Infection

PubMed Central

Quick, Eamon D.; Leser, J. Smith; Tyler, Kenneth L.

2014-01-01

ABSTRACT West Nile virus (WNV) is a neurotropic flavivirus that causes significant neuroinvasive disease involving the brain and/or spinal cord. Experimental mouse models of WNV infection have established the importance of innate and adaptive immune responses in controlling the extent and severity of central nervous system (CNS) disease. However, differentiating between immune responses that are intrinsic to the CNS and those that are dependent on infiltrating inflammatory cells has proven difficult. We used a murine ex vivo spinal cord slice culture (SCSC) model to determine the innate immune processes specific to the CNS during WNV infections. By 7 days after ex vivo infection of SCSCs, the majority of neurons and a substantial percentage of astrocytes were infected with WNV, resulting in apoptotic cell death and astrogliosis. Microglia, the resident immune cells of the CNS, were activated by WNV infection, as exemplified by their amoeboid morphology, the development of filopodia and lamellipodia, and phagocytosis of WNV-infected cells and debris. Microglial cell activation was concomitant with increased expression of proinflammatory cytokines and chemokines, including CXCL10, CXCL1, CCL5, CCL3, CCL2, tumor necrosis factor alpha (TNF-α), TNF-related apoptosis-inducing ligand (TRAIL), and interleukin-6 (IL-6). The application of minocycline, an inhibitor of neuroinflammation, altered the WNV-induced proinflammatory cytokine/chemokine expression profile, with inhibited production of CCL5, CCL2, and IL-6. Our findings establish that CNS-resident cells have the capacity to initiate a robust innate immune response against WNV infection in the absence of infiltrating inflammatory cells and systemic immune responses. IMPORTANCE There are no specific treatments of proven efficacy available for WNV neuroinvasive disease. A better understanding of the pathogenesis of WNV CNS infection is crucial for the rational development of novel therapies. Development of a spinal cord slice culture (SCSC) model facilitates the study of WNV pathogenesis and allows investigation of the intrinsic immune responses of the CNS. Our studies demonstrate that robust CNS innate immune responses, including microglial activation and proinflammatory cytokine/chemokine production, develop independently of contributions from the peripheral immune system and CNS-infiltrating inflammatory cells. PMID:25165111

MicroRNA Regulation of Host Immune Responses following Fungal Exposure.

PubMed

Croston, Tara L; Lemons, Angela R; Beezhold, Donald H; Green, Brett J

2018-01-01

Fungal bioaerosols are ubiquitous in the environment and human exposure can result in a variety of health effects ranging from systemic, subcutaneous, and cutaneous infections to respiratory morbidity including allergy, asthma, and hypersensitivity pneumonitis. Recent research has focused on the role of microRNAs (miRNAs) following fungal exposure and is overlooked, yet important, group of regulators capable of influencing fungal immune responses through a variety of cellular mechanisms. These small non-coding ribose nucleic acids function to regulate gene expression at the post-transcriptional level and have been shown to participate in multiple disease pathways including cancer, heart disease, apoptosis, as well as immune responses to microbial hazards and occupational allergens. Recent animal model studies have characterized miRNAs following the exposure to inflammatory stimuli. Studies focused on microbial exposure, including bacterial infections, as well as exposure to different allergens have shown miRNAs, such as miR-21, miR-146, miR-132, miR-155, and the let-7 family members, to be involved in immune and inflammatory responses. Interestingly, the few studies have assessed that the miRNA profiles following fungal exposure have identified the same critical miRNAs that have been characterized in other inflammatory-mediated and allergy-induced experimental models. Review of available in vitro , animal and human studies of exposures to Aspergillus fumigatus, Candida albicans, Cryptococcus neoformans, Paracoccidioides brasiliensis , and Stachybotrys chartarum identified several miRNAs that were shared between responses to these species including miR-125 a/b (macrophage polarization/activation), miR-132 [toll-like receptor (TLR)2-mediated signaling], miR-146a (TLR mediated signaling, alternative macrophage activation), and miR-29a/b (natural killer cell function, C-leptin signaling, inhibition of Th1 immune response). Although these datasets provide preliminary insight into the role of miRNAs in fungal exposed models, interpretation of miRNA datasets can be challenging for researchers. To assist in navigating this rapidly evolving field, the aim of this review is to describe miRNAs in the framework of host recognition mechanisms and provide initial insight into the regulatory pathways in response to fungal exposure.

The rat closely mimics oxidative stress and inflammation in humans after exercise but not after exercise combined with vitamin C administration.

PubMed

Veskoukis, Aristidis S; Goutianos, Georgios; Paschalis, Vassilis; Margaritelis, Nikos V; Tzioura, Aikaterini; Dipla, Konstantina; Zafeiridis, Andreas; Vrabas, Ioannis S; Kyparos, Antonios; Nikolaidis, Michalis G

2016-04-01

The purpose of the present study was to directly compare oxidative stress and inflammation responses between rats and humans. We contrasted rat and human oxidative stress and inflammatory responses to exercise (pro-oxidant stimulus) and/or vitamin C (anti-oxidant stimulus) administration. Vitamin C was administered orally in both species (16 mg kg(-1) of body weight). Twelve redox biomarkers and seven inflammatory biomarkers were determined in plasma and erythrocytes pre- and post-exercise or pre- and post-exercise combined with vitamin C administration. Exercise increased oxidative stress and induced an inflammatory state in rats and humans. There were only 1/19 significant species × exercise interactions (catalase), indicating similar responses to exercise between rats and humans in redox and inflammatory biomarkers. Vitamin C decreased oxidative stress and increased antioxidant capacity only in humans and did not affect the redox state of rats. In contrast, vitamin C induced an anti-inflammatory state only in rats and did not affect the inflammatory state of humans. There were 10/19 significant species × vitamin C interactions, indicating that rats poorly mimic human oxidative stress and inflammatory responses to vitamin C administration. Exercise after acute vitamin C administration altered redox state only in humans and did not affect the redox state of rats. On the contrary, inflammation biomarkers changed similarly after exercise combined with vitamin C in both rats and humans. The rat adequately mimics human responses to exercise in basic blood redox/inflammatory profile, yet this is not the case after exercise combined with vitamin C administration.

The Biological Basis for Cardiac Repair After Myocardial Infarction: From Inflammation to Fibrosis

PubMed Central

Prabhu, Sumanth D.; Frangogiannis, Nikolaos G.

2016-01-01

In adult mammals, massive sudden loss of cardiomyocytes following infarction overwhelms the limited regenerative capacity of the myocardium, resulting in formation of a collagen-based scar. Necrotic cells release danger signals, activating innate immune pathways and triggering an intense inflammatory response. Stimulation of toll-like receptor signaling and complement activation induces expression of pro-inflammatory cytokines (such as interleukin-1 and tumor necrosis factor-α) and chemokines (such as monocyte chemoattractant protein-1/CCL2). Inflammatory signals promote adhesive interactions between leukocytes and endothelial cells, leading to extravasation of neutrophils and monocytes. As infiltrating leukocytes clear the infarct from dead cells, mediators repressing inflammation are released, and anti-inflammatory mononuclear cell subsets predominate. Suppression of the inflammatory response is associated with activation of reparative cells. Fibroblasts proliferate, undergo myofibroblast transdifferentiation, and deposit large amounts of extracellular matrix proteins maintaining the structural integrity of the infarcted ventricle. The renin-angiotensin-aldosterone system and members of the transforming growth factor-β family play an important role in activation of infarct myofibroblasts. Maturation of the scar follows, as a network of cross-linked collagenous matrix is formed and granulation tissue cells become apoptotic. This review discusses the cellular effectors and molecular signals regulating the inflammatory and reparative response following myocardial infarction. Dysregulation of immune pathways, impaired suppression of post-infarction inflammation, perturbed spatial containment of the inflammatory response, and overactive fibrosis may cause adverse remodeling in patients with infarction contributing to the pathogenesis of heart failure. Therapeutic modulation of the inflammatory and reparative response may hold promise for prevention of post-infarction heart failure. PMID:27340270

Celastrol ameliorates HIV-1 Tat-induced inflammatory responses via NF-kappaB and AP-1 inhibition and heme oxygenase-1 induction in astrocytes

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

Youn, Gi Soo; Kwon, Dong-Joo; Ju, Sung Mi

HIV-1 Tat causes extensive neuroinflammation that may progress to AIDS-related encephalitis and dementia. Celastrol possesses various biological activities such as anti-oxidant, anti-tumor, and anti-inflammatory activities. In this study, we investigated the modulatory effects of celastrol on HIV-1 Tat-induced inflammatory responses and the molecular mechanisms underlying its action in astrocytes. Pre-treatment of CRT-MG human astroglioma cells with celastrol significantly inhibited HIV-1 Tat-induced expression of ICAM-1/VCAM-1 and subsequent monocyte adhesiveness in CRT-MG cells. In addition, celastrol suppressed HIV-1 Tat-induced expression of pro-inflammatory chemokines, such as CXCL10, IL-8, and MCP-1. Celastrol decreased HIV-1 Tat-induced activation of JNK MAPK, AP-1, and NF-κB. Furthermore, celastrolmore » induced mRNA and protein expression of HO-1 as well as Nrf2 activation. Blockage of HO-1 expression using siRNA reversed the inhibitory effect of celastrol on HIV-1 Tat-induced inflammatory responses. These results suggest that celastrol has regulatory effects on HIV-1 Tat-induced inflammatory responses by blocking the JNK MAPK-AP-1/NF-κB signaling pathways and inducing HO-1 expression in astrocytes. - Highlights: • Celastrol suppressed HIV-1 Tat-induced expression of pro-inflammatory genes. • Celastrol inhibited HIV-1 Tat -induced activation of JNK MAPK. • Celastrol inhibited HIV-1 Tat-induced activation of both NF-κB and AP-1. • Celastrol inhibited HIV-1 Tat-induced inflammatory responses via HO-1 induction.« less

Tat-CBR1 inhibits inflammatory responses through the suppressions of NF-κB and MAPK activation in macrophages and TPA-induced ear edema in mice

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

Kim, Young Nam; Kim, Dae Won; Jo, Hyo Sang

Human carbonyl reductase 1 (CBR1) plays a crucial role in cell survival and protects against oxidative stress response. However, its anti-inflammatory effects are not yet clearly understood. In this study, we examined whether CBR1 protects against inflammatory responses in macrophages and mice using a Tat-CBR1 protein which is able to penetrate into cells. The results revealed that purified Tat-CBR1 protein efficiently transduced into Raw 264.7 cells and inhibited lipopolysaccharide (LPS)-induced cyclooxygenase-2 (COX-2), nitric oxide (NO) and prostaglandin E{sub 2} (PGE{sub 2}) expression levels. In addition, Tat-CBR1 protein leads to decreased pro-inflammatory cytokine expression through suppression of nuclear transcription factor-kappaB (NF-κB)more » and mitogen activated protein kinase (MAPK) activation. Furthermore, Tat-CBR1 protein inhibited inflammatory responses in 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced skin inflammation when applied topically. These findings indicate that Tat-CBR1 protein has anti-inflammatory properties in vitro and in vivo through inhibition of NF-κB and MAPK activation, suggesting that Tat-CBR1 protein may have potential as a therapeutic agent against inflammatory diseases. - Highlights: • Transduced Tat-CBR1 reduces LPS-induced inflammatory mediators and cytokines. • Tat-CBR1 inhibits MAPK and NF-κB activation. • Tat-CBR1 ameliorates inflammation response in vitro and in vivo. • Tat-CBR1 may be useful as potential therapeutic agent for inflammation.« less

Brain-derived neurotrophic factor reduces inflammation and hippocampal apoptosis in experimental Streptococcus pneumoniae meningitis.

PubMed

Xu, Danfeng; Lian, Di; Wu, Jing; Liu, Ying; Zhu, Mingjie; Sun, Jiaming; He, Dake; Li, Ling

2017-08-04

Streptococcus pneumoniae meningitis is a serious inflammatory disease of the central nervous system (CNS) and is associated with high morbidity and mortality rates. The inflammatory processes initiated by recognition of bacterial components contribute to apoptosis in the hippocampal dentate gyrus. Brain-derived neurotrophic factor (BDNF) has long been recommended for the treatment of CNS diseases due to its powerful neuro-survival properties, as well as its recently reported anti-inflammatory and anti-apoptotic effects in vitro and in vivo. In this study, we investigated the effects of BDNF-related signaling on the inflammatory response and hippocampal apoptosis in experimental models of pneumococcal meningitis. Pretreatment with exogenous BDNF or the tropomyosin-receptor kinase B (TrkB) inhibitor k252a was performed to assess the activation or inhibition of the BDNF/TrkB-signaling axis prior to intracisternal infection with live S. pneumoniae. At 24 h post-infection, rats were assessed for clinical severity and sacrificed to harvest the brains. Paraffin-embedded brain sections underwent hematoxylin and eosin staining to evaluate pathological severity, and cytokine and chemokine levels in the hippocampus and cortex were evaluated by enzyme-linked immunosorbent assay. Additionally, apoptotic neurons were detected in the hippocampal dentate gyrus by terminal deoxynucleotidyl transferase dUTP-nick-end labeling, key molecules associated with the related signaling pathway were analyzed by real-time polymerase chain reaction and western blot, and the DNA-binding activity of nuclear factor kappa B (NF-κB) was measured by electrophoretic mobility shift assay. Rats administered BDNF exhibited reduced clinical impairment, pathological severity, and hippocampal apoptosis. Furthermore, BDNF pretreatment suppressed the expression of inflammatory factors, including tumor necrosis factor α, interleukin (IL)-1β, and IL-6, and increased the expression of the anti-inflammatory factor IL-10. Moreover, BDNF pretreatment increased TrkB expression, activated downstream phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling, and inhibited the myeloid differentiation primary response gene 88 (MyD88)/NF-κB-signaling pathway. These data suggested that BDNF administration exerted anti-inflammatory and anti-apoptotic effects on an experimental pneumococcal meningitis model via modulation of MyD88/NF-κB- and PI3K/AKT-signaling pathways. Our results indicated that treatment with exogenous BDNF might constitute a potential therapeutic strategy for the treatment of bacterial meningitis.

The First Endoscopy in Suspected Inflammatory Bowel Disease.

PubMed

Fausel, Rebecca A; Kornbluth, Asher; Dubinsky, Marla C

2016-10-01

In a patient presenting with suspected inflammatory bowel disease, the initial endoscopic evaluation is a valuable tool for determining the correct disease diagnosis and the extent and severity of disease. A full colonoscopy and ileoscopy should be performed when possible, with systematic biopsies from each segment. When a diagnosis of inflammatory bowel disease is established, it is possible to distinguish between Crohn disease and ulcerative colitis, and specific endoscopic features may assist in this categorization. Because patchy healing can occur with treatment, it is important to obtain a thorough and accurate assessment of disease characteristics and distribution before initiating therapy. Copyright © 2016 Elsevier Inc. All rights reserved.

HMGB1 induces an inflammatory response in endothelial cells via the RAGE-dependent endoplasmic reticulum stress pathway

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

Luo, Ying; Li, Shu-Jun; Yang, Jian

Highlights: •Mechanisms of inflammatory response induced by HMGB1 are incompletely understood. •We found that endoplasmic reticulum stress mediate the inflammatory response induced by HMGB1. •RAGE-mediated ERS pathways are involved in those processes. •We reported a new mechanism for HMGB1 induced inflammatory response. -- Abstract: The high mobility group 1B protein (HMGB1) mediates chronic inflammatory responses in endothelial cells, which play a critical role in atherosclerosis. However, the underlying mechanism is unknown. The goal of our study was to identify the effects of HMGB1 on the RAGE-induced inflammatory response in endothelial cells and test the possible involvement of the endoplasmic reticulummore » stress pathway. Our results showed that incubation of endothelial cells with HMGB1 (0.01–1 μg/ml) for 24 h induced a dose-dependent activation of endoplasmic reticulum stress transducers, as assessed by PERK and IRE1 protein expression. Moreover, HMGB1 also promoted nuclear translocation of ATF6. HMGB1-mediated ICAM-1 and P-selectin production was dramatically suppressed by PERK siRNA or IRE1 siRNA. However, non-targeting siRNA had no such effects. HMGB1-induced increases in ICAM-1 and P-selectin expression were also inhibited by a specific eIF2α inhibitor (salubrinal) and a specific JNK inhibitor (SP600125). Importantly, a blocking antibody specifically targeted against RAGE (anti-RAGE antibody) decreased ICAM-1, P-selectin and endoplasmic reticulum stress molecule (PERK, eIF2α, IRE1 and JNK) protein expression levels. Collectively, these novel findings suggest that HMGB1 promotes an inflammatory response by inducing the expression of ICAM-1 and P-selectin via RAGE-mediated stimulation of the endoplasmic reticulum stress pathway.« less

Inflammatory Breast Carcinoma Presenting with Two Different Patterns of Cutaneous Metastases: Carcinoma Telangiectaticum and Carcinoma Erysipeloides

PubMed Central

Yaghoobi, Reza; Talaizade, Abdolhasan; Lal, Karan; Ranjbari, Nastaran; Sohrabiaan, Nasibe

2015-01-01

Cutaneous metastases can have many different clinical presentations. They are seen in patients with advanced malignant disease; however, they can be the initial manifestation of undetected malignancies. Inflammatory breast carcinoma is a rare and aggressive form of breast cancer that has a nonspecific appearance mimicking many benign conditions including mastitis, breast abscesses, and/or dermatitis. The authors report the case of a 40-year-old woman with inflammatory breast carcinoma presenting with violaceous papulovesicular lesions resembling lymphangioma circumscriptum and erythematous patches resembling erysipelas. These lesions represent two different types of cutaneous metastases, both of which were the initial signs of inflammatory breast carcinoma in the patient described herein. Skin biopsy of lesions confirmed invasive breast cancer and further prompted a work up for inflammatory breast carcinoma. This case demonstrates the importance of follow-up for all breast lesions, even those considered to be of benign nature, for they can be presenting signs of metastatic breast cancer. PMID:26345728

Reliability of the identification of the systemic inflammatory response syndrome in critically ill infants and children.

PubMed

Juskewitch, Justin E; Prasad, Swati; Salas, Carlos F Santillan; Huskins, W Charles

2012-01-01

To assess interobserver reliability of the identification of episodes of the systemic inflammatory response syndrome in critically ill hospitalized infants and children. Retrospective, cross-sectional study of the application of the 2005 consensus definition of systemic inflammatory response syndrome in infants and children by two independent, trained reviewers using information in the electronic medical record. Eighteen-bed pediatric multidisciplinary medical/surgical pediatric intensive care unit. A randomly selected sample of children admitted consecutively to the pediatric intensive care unit between May 1 and September 30, 2009. None. Sixty infants and children were selected from a total of 343 admitted patients. Their median age was 3.9 yrs (interquartile range, 1.5-12.7), 57% were female, and 68% were Caucasian. Nineteen (32%) children were identified by both reviewers as having an episode of systemic inflammatory response syndrome (88% agreement, 95% confidence interval 78-94; κ = 0.75, 95% confidence interval 0.59-0.92). Among these 19 children, agreement between the reviewers for individual systemic inflammatory response syndrome criteria was: temperature (84%, 95% confidence interval 60-97); white blood cell count (89%, 95% confidence interval 67-99); respiratory rate (84%, 95% confidence interval 60-97); and heart rate (68%, 95% confidence interval 33-87). Episodes of systemic inflammatory response syndrome in critically ill infants and children can be identified reproducibly using the consensus definition.

Abdominal adiposity is the main determinant of the C-reactive response to injury in subjects undergoing inguinal hernia repair

PubMed Central

2013-01-01

Background Obesity and serum C-reactive protein (CRP) (a sensitive marker of inflammatory activity) are associated with most chronic diseases. Abdominal adiposity along with age is the strongest determinant of baseline CRP levels in healthy subjects. The mechanism of the association of serum CRP with disease is uncertain. We hypothesized that baseline serum CRP is a marker of inflammatory responsiveness to injury and that abdominal adiposity is the main determinant of this responsiveness. We studied the effect of abdominal adiposity, age and other environmental risk factors for chronic disease on the CRP response to a standardised surgical insult, unilateral hernia repair to not only test this hypothesis but to inform the factors which must be taken into account when assessing systemic inflammatory responses to surgery. Methods 102 male subjects aged 24-94 underwent unilateral hernia repair by a single operator. CRP was measured at 0, 6, 24 and 48 hrs. Response was defined as the peak CRP adjusted for baseline CRP. Results Age and waist:hip ratio (WHR) were associated both with basal CRP and CRP response with similar effect sizes after adjustment for a wide-range of covariates. The adjusted proportional difference in CRP response per 10% increase in WHR was 1.50 (1.17-1.91) p = 0.0014 and 1.15(1.00-1.31) p = 0.05 per decade increase in age. There was no evidence of important effects of other environmental cardiovascular risk factors on CRP response. Conclusion Waist:hip ratio and age need to be considered when studying the inflammatory response to surgery. The finding that age and waist:hip ratio influence baseline and post-operative CRP levels to a similar extent suggests that baseline CRP is a measure of inflammatory responsiveness to casual stimuli and that higher age and obesity modulate the generic excitability of the inflammatory system leading to both higher baseline CRP and higher CRP response to surgery. The mechanism for the association of baseline CRP and waist:hip ratio to chronic disease outcomes could be through this increase in inflammatory system excitability. PMID:23391158

Amplification and propagation of interleukin-1β signaling by murine brain endothelial and glial cells.

PubMed

Krasnow, Stephanie M; Knoll, J Gabriel; Verghese, Santhosh Chakkaramakkil; Levasseur, Peter R; Marks, Daniel L

2017-07-01

During acute infections and chronic illnesses, the pro-inflammatory cytokine interleukin-1β (IL-1β) acts within the brain to elicit metabolic derangements and sickness behaviors. It is unknown which cells in the brain are the proximal targets for IL-1β with respect to the generation of these illness responses. We performed a series of in vitro experiments to (1) investigate which brain cell populations exhibit inflammatory responses to IL-1β and (2) examine the interactions between different IL-1β-responsive cell types in various co-culture combinations. We treated primary cultures of murine brain microvessel endothelial cells (BMEC), astrocytes, and microglia with PBS or IL-1β, and then performed qPCR to measure inflammatory gene expression or immunocytochemistry to evaluate nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation. To evaluate whether astrocytes and/or BMEC propagate inflammatory signals to microglia, we exposed microglia to astrocyte-conditioned media and co-cultured endothelial cells and glia in transwells. Treatment groups were compared by Student's t tests or by ANOVA followed by Bonferroni-corrected t tests. IL-1β increased inflammatory gene expression and NF-κB activation in primary murine-mixed glia, enriched astrocyte, and BMEC cultures. Although IL-1β elicited minimal changes in inflammatory gene expression and did not induce the nuclear translocation of NF-κB in isolated microglia, these cells were more robustly activated by IL-1β when co-cultured with astrocytes and/or BMEC. We observed a polarized endothelial response to IL-1β, because the application of IL-1β to the abluminal endothelial surface produced a more complex microglial inflammatory response than that which occurred following luminal IL-1β exposure. Inflammatory signals are detected, amplified, and propagated through the CNS via a sequential and reverberating signaling cascade involving communication between brain endothelial cells and glia. We propose that the brain's innate immune response differs depending upon which side of the blood-brain barrier the inflammatory stimulus arises, thus allowing the brain to respond differently to central vs. peripheral inflammatory insults.