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Sample records for muscle resident macrophages

  1. Regular physical activity prevents chronic pain by altering resident muscle macrophage phenotype and increasing IL-10 in mice

    PubMed Central

    Leung, Audrey; Gregory, Nicholas S.; Allen, Lee-Ann H.; Sluka, Kathleen A.

    2015-01-01

    Regular physical activity in healthy individuals prevents development of chronic musculoskeletal pain; however, the mechanisms underlying this exercise-induced analgesia are not well understood. Interleukin-10(IL-10), an anti-inflammatory cytokine which can reduce nociceptor sensitization, increases during regular physical activity. Since macrophages play a major role in cytokine production and are present in muscle tissue, we propose that physical activity alters macrophage phenotype to increase IL-10 and prevent chronic pain. Physical activity was induced by allowing C57BL/6J mice free access to running wheels for 8 weeks and compared to sedentary mice with no running wheels. Using immunohistochemical staining of the gastrocnemius muscle to label regulatory (M2, secretes anti-inflammatory cytokines) and classical (M1, secretes proinflammatory cytokines) macrophages, the percentage of M2-macrophages increased significantly in physically active mice (68.5±4.6% of total) compared to sedentary mice (45.8±7.1% of total). Repeated acid injections into the muscle enhanced mechanical sensitivity of the muscle and paw in sedentary animals that does not occur in physically active mice; no sex differences occur in either sedentary or physically active mice. Blockade of IL-10 systemically or locally prevented the analgesia in physically active mice, i.e. mice developed hyperalgesia. Conversely, sedentary mice pretreated systemically or locally with IL-10 had reduced hyperalgesia after repeated acid injections. Thus, these results suggest that regular physical activity increases the percentage of regulatory macrophages in muscle and that IL-10 is an essential mediator in the analgesia produced by regular physical activity. PMID:26230740

  2. Fate of conidia of Paracoccidioides brasiliensis after ingestion by resident macrophages or cytokine-treated macrophages.

    PubMed Central

    Cano, L E; Brummer, E; Stevens, D A; Restrepo, A

    1992-01-01

    Conidia ingested by resident macrophages had an enhanced percentage of transformation to yeast cells compared with those in culture medium without macrophages. The yeast cells subsequently grew intracellularly by budding. Macrophages treated with cytokines from antigen-stimulated spleen cells from immunized mice significantly inhibited transformation of ingested conidia. PMID:1563800

  3. Fate of conidia of Paracoccidioides brasiliensis after ingestion by resident macrophages or cytokine-treated macrophages.

    PubMed

    Cano, L E; Brummer, E; Stevens, D A; Restrepo, A

    1992-05-01

    Conidia ingested by resident macrophages had an enhanced percentage of transformation to yeast cells compared with those in culture medium without macrophages. The yeast cells subsequently grew intracellularly by budding. Macrophages treated with cytokines from antigen-stimulated spleen cells from immunized mice significantly inhibited transformation of ingested conidia.

  4. Origin, Development, and Homeostasis of Tissue-resident Macrophages

    PubMed Central

    Haldar, Malay; Murphy, Kenneth M.

    2014-01-01

    Summary Macrophages are versatile cells of the hematopoietic system that display remarkable functional diversity encompassing innate immune responses, tissue development, and tissue homeostasis. Macrophages are present in almost all tissues of the body and display distinct location-specific phenotypes and gene expression profiles. Recent studies also demonstrate distinct origins of tissue-resident macrophages. This emerging picture of ontological, functional, and phenotypic heterogeneity within tissue macrophages has altered our understanding of these cells, which play important roles in many human diseases. In this review, we discuss the different origins of tissue macrophages, the transcription factors regulating their development, and the mechanisms underlying their homeostasis at steady state. PMID:25319325

  5. Tissue resident macrophages: Key players in the pathogenesis of type 2 diabetes and its complications.

    PubMed

    Meshkani, Reza; Vakili, Sanaz

    2016-11-01

    There is increasing evidence showing that chronic inflammation is an important pathogenic mediator of the development of type 2 diabetes (T2D). It is now generally accepted that tissue-resident macrophages play a major role in regulation of tissue inflammation. T2D-associated inflammation is characterized by an increased abundance of macrophages in different tissues along with production of inflammatory cytokines. The complexity of macrophage phenotypes has been reported from different human tissues. Macrophages exhibit a phenotypic range that is intermediate between two extremes, M1 (pro-inflammatory) and M2 (anti-inflammatory). Cytokines and chemokines produced by macrophages generate local and systemic inflammation and this condition leads to pancreatic β-cell dysfunction and insulin resistance in liver, adipose and skeletal muscle tissues. Data from human and animal studies also suggest that macrophages contribute to T2D complications such as nephropathy, neuropathy, retinopathy and cardiovascular diseases through cell-cell interactions and the release of pro-inflammatory cytokines, chemokines, and proteases to induce inflammatory cell recruitment, cell apoptosis, angiogenesis, and matrix protein remodeling. In this review we focus on the functions of macrophages and the importance of these cells in the pathogenesis of T2D. In addition, the contribution of macrophages to diabetes complications such as nephropathy, neuropathy, retinopathy and cardiovascular diseases is discussed.

  6. Interactions between neutrophils and macrophages promote macrophage killing of rat muscle cells in vitro

    NASA Technical Reports Server (NTRS)

    Nguyen, Hal X.; Tidball, James G.

    2003-01-01

    Current evidence indicates that the physiological functions of inflammatory cells are highly sensitive to their microenvironment, which is partially determined by the inflammatory cells and their potential targets. In the present investigation, interactions between neutrophils, macrophages and muscle cells that may influence muscle cell death are examined. Findings show that in the absence of macrophages, neutrophils kill muscle cells in vitro by superoxide-dependent mechanisms, and that low concentrations of nitric oxide (NO) protect against neutrophil-mediated killing. In the absence of neutrophils, macrophages kill muscle cells through a NO-dependent mechanism, and the presence of target muscle cells causes a three-fold increase in NO production by macrophages, with no change in the concentration of inducible nitric oxide synthase. Muscle cells that are co-cultured with both neutrophils and macrophages in proportions that are observed in injured muscle show cytotoxicity through a NO-dependent, superoxide-independent mechanism. Furthermore, the concentration of myeloid cells that is necessary for muscle killing is greatly reduced in assays that use mixed myeloid cell populations, rather than uniform populations of neutrophils or macrophages. These findings collectively show that the magnitude and mechanism of muscle cell killing by myeloid cells are modified by interactions between muscle cells and neutrophils, between muscle cells and macrophages and between macrophages and neutrophils.

  7. Macrophage depletion impairs skeletal muscle regeneration: The roles of regulatory factors for muscle regeneration.

    PubMed

    Liu, Xiaoguang; Liu, Yu; Zhao, Linlin; Zeng, Zhigang; Xiao, Weihua; Chen, Peijie

    2017-03-01

    Though macrophages are essential for skeletal muscle regeneration, which is a complex process, the roles and mechanisms of the macrophages in the process of muscle regeneration are still not fully understood. The objective of this study is to explore the roles of macrophages and the mechanisms involved in the regeneration of injured skeletal muscle. One hundred and twelve C57BL/6 mice were randomly divided into muscle contusion and macrophages depleted groups. Their gastrocnemius muscles were harvested at the time points of 12 h, 1, 3, 5, 7, 14 d post-injury. The changes in skeletal muscle morphology were assessed by hematoxylin and eosin (HE) stain. The gene expression was analyzed by real-time polymerase chain reaction. The data showed that CL-liposomes treatment did affect the expression of myogenic regulatory factors (MyoD, myogenin) after injury. In addition, CL-liposomes treatment decreased the expression of regulatory factors of muscle regeneration (HGF, uPA, COX-2, IGF-1, MGF, FGF6) and increased the expression of inflammatory cytokines (TGF-β1, TNF-α, IL-1β, RANTES) in the late stage of regeneration. Moreover, there were significant correlations between macrophages and some regulatory factors (such as HGF, uPA) for muscle regeneration. These results suggested that macrophages depletion impairs skeletal muscle regeneration and that the regulatory factors for muscle regeneration may play important roles in this process.

  8. A thrombin receptor in resident rat peritoneal macrophages

    SciTech Connect

    Kudahl, K.; Fisker, S.; Sonne, O. )

    1991-03-01

    Resident rat peritoneal macrophages possess 6 x 10(2) high-affinity binding sites per cell for bovine thrombin with a Kd of 11 pM, and 7.5 x 10(4) low-affinity sites with a Kd of 5.8 nM. These binding sites are highly specific for thrombin. Half-maximal binding of {sup 125}I-labeled bovine thrombin is achieved after 1 min at 37{degrees}C, and after 12 min at 4 degrees C. The reversibly bound fraction of the ligand dissociates according to a biexponential time course with the rate constants 0.27 and 0.06 min-1 at 4 degrees C. Part of the tracer remains cell-associated even after prolonged incubation, but all cell-associated radio-activity migrates as intact thrombin upon sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The bound thrombin is minimally endocytosed as judged by the resistance to pH 3 treatment, and the receptor does not mediate a quantitatively important degradation of the ligand. The binding is not dependent on the catalytic site of thrombin, since irreversibly inactivated thrombin also binds to the receptor. {sup 125}I-labeled thrombin covalently cross-linked to its receptor migrates in sodium dodecyl sulfate-polyacrylamide gel electrophoresis with a Mr 160,000, corresponding to an approximate receptor size of Mr 120,000.

  9. Shifts in macrophage phenotypes and macrophage competition for arginine metabolism affect the severity of muscle pathology in muscular dystrophy.

    PubMed

    Villalta, S Armando; Nguyen, Hal X; Deng, Bo; Gotoh, Tomomi; Tidball, James G

    2009-02-01

    Duchenne muscular dystrophy (DMD) is the most common, lethal, muscle-wasting disease of childhood. Previous investigations have shown that muscle macrophages may play an important role in promoting the pathology in the mdx mouse model of DMD. In the present study, we investigate the mechanism through which macrophages promote mdx dystrophy and assess whether the phenotype of the macrophages changes between the stage of peak muscle necrosis (4 weeks of age) and muscle regeneration (12 weeks). We find that 4-week-old mdx muscles contain a population of pro-inflammatory, classically activated M1 macrophages that lyse muscle in vitro by NO-mediated mechanisms. Genetic ablation of the iNOS gene in mdx mice also significantly reduces muscle membrane lysis in 4-week-old mdx mice in vivo. However, 4-week mdx muscles also contain a population of alternatively activated, M2a macrophages that express arginase. In vitro assays show that M2a macrophages reduce lysis of muscle cells by M1 macrophages through the competition of arginase in M2a cells with iNOS in M1 cells for their common, enzymatic substrate, arginine. During the transition from the acute peak of mdx pathology to the regenerative stage, expression of IL-4 and IL-10 increases, either of which can deactivate the M1 phenotype and promote activation of a CD163+, M2c phenotype that can increase tissue repair. Our findings further show that IL-10 stimulation of macrophages activates their ability to promote satellite cell proliferation. Deactivation of the M1 phenotype is also associated with a reduced expression of iNOS, IL-6, MCP-1 and IP-10. Thus, these results show that distinct subpopulations of macrophages can promote muscle injury or repair in muscular dystrophy, and that therapeutic interventions that affect the balance between M1 and M2 macrophage populations may influence the course of muscular dystrophy.

  10. Tissue-resident versus monocyte-derived macrophages in the tumor microenvironment.

    PubMed

    Lahmar, Qods; Keirsse, Jiri; Laoui, Damya; Movahedi, Kiavash; Van Overmeire, Eva; Van Ginderachter, Jo A

    2016-01-01

    The tumor-promoting role of macrophages has been firmly established in most cancer types. However, macrophage identity has been a matter of debate, since several levels of complexity result in considerable macrophage heterogeneity. Ontogenically, tissue-resident macrophages derive from yolk sac progenitors which either directly or via a fetal liver monocyte intermediate differentiate into distinct macrophage types during embryogenesis and are maintained throughout life, while a disruption of the steady state mobilizes monocytes and instructs the formation of monocyte-derived macrophages. Histologically, the macrophage phenotype is heavily influenced by the tissue microenvironment resulting in molecularly and functionally distinct macrophages in distinct organs. Finally, a change in the tissue microenvironment as a result of infectious or sterile inflammation instructs different modes of macrophage activation. These considerations are relevant in the context of tumors, which can be considered as sites of chronic sterile inflammation encompassing subregions with distinct environmental conditions (for example, hypoxic versus normoxic). Here, we discuss existing evidence on the role of macrophage subpopulations in steady state tissue and primary tumors of the breast, lung, pancreas, brain and liver.

  11. Fetal liver endothelium regulates the seeding of tissue-resident macrophages.

    PubMed

    Rantakari, Pia; Jäppinen, Norma; Lokka, Emmi; Mokkala, Elias; Gerke, Heidi; Peuhu, Emilia; Ivaska, Johanna; Elima, Kati; Auvinen, Kaisa; Salmi, Marko

    2016-10-20

    Macrophages are required for normal embryogenesis, tissue homeostasis and immunity against microorganisms and tumours. Adult tissue-resident macrophages largely originate from long-lived, self-renewing embryonic precursors and not from haematopoietic stem-cell activity in the bone marrow. Although fate-mapping studies have uncovered a great amount of detail on the origin and kinetics of fetal macrophage development in the yolk sac and liver, the molecules that govern the tissue-specific migration of these cells remain completely unknown. Here we show that an endothelium-specific molecule, plasmalemma vesicle-associated protein (PLVAP), regulates the seeding of fetal monocyte-derived macrophages to tissues in mice. We found that PLVAP-deficient mice have completely normal levels of both yolk-sac- and bone-marrow-derived macrophages, but that fetal liver monocyte-derived macrophage populations were practically missing from tissues. Adult PLVAP-deficient mice show major alterations in macrophage-dependent iron recycling and mammary branching morphogenesis. PLVAP forms diaphragms in the fenestrae of liver sinusoidal endothelium during embryogenesis, interacts with chemoattractants and adhesion molecules and regulates the egress of fetal liver monocytes to the systemic vasculature. Thus, PLVAP selectively controls the exit of macrophage precursors from the fetal liver and, to our knowledge, is the first molecule identified in any organ as regulating the migratory events during embryonic macrophage ontogeny.

  12. Paracrine cross-talk between skeletal muscle and macrophages in exercise by PGC-1α-controlled BNP

    PubMed Central

    Furrer, Regula; Eisele, Petra S.; Schmidt, Alexander; Beer, Markus; Handschin, Christoph

    2017-01-01

    Activation of resident and infiltrating immune cells is a central event in training adaptation and other contexts of skeletal muscle repair and regeneration. A precise orchestration of inflammatory events in muscle fibers and immune cells is required after recurrent contraction-relaxation cycles. However, the mechanistic aspects of this important regulation remain largely unknown. We now demonstrate that besides a dominant role in controlling cellular metabolism, the peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α) also has a profound effect on cytokine expression in muscle tissue. Muscle PGC-1α expression results in activation of tissue-resident macrophages, at least in part mediated by PGC-1α-dependent B-type natriuretic peptide (BNP) production and secretion. Positive effects of exercise in metabolic diseases and other pathologies associated with chronic inflammation could accordingly involve the PGC-1α-BNP axis and thereby provide novel targets for therapeutic approaches. PMID:28091624

  13. Neutrophil Migration into the Infected Uroepithelium Is Regulated by the Crosstalk between Resident and Helper Macrophages

    PubMed Central

    Zec, Kristina; Volke, Julia; Vijitha, Nirojah; Thiebes, Stephanie; Gunzer, Matthias; Kurts, Christian; Engel, Daniel Robert

    2016-01-01

    The antibacterial defense against infections depends on the cooperation between distinct phagocytes of the innate immune system, namely macrophages and neutrophils. However, the mechanisms driving this cooperation are incompletely understood. In this study we describe the crosstalk between Ly6C+ and Ly6C− macrophage-subtypes and neutrophils in the context of urinary tract infection (UTI) with uropathogenic E. coli (UPEC). Ly6C− macrophages acted as tissue resident sentinels and attracted circulating phagocytes by chemokines. Ly6C+ macrophages produced tumor necrosis factor (TNF) that licensed Ly6C− macrophages to release preformed CXCL2, which in turn caused matrix metalloproteinases (MMP-9) secretion by neutrophils to enable transepithelial migration. PMID:26861402

  14. Macrophage invasion does not contribute to muscle membrane injury during inflammation

    NASA Technical Reports Server (NTRS)

    Tidball, J. G.; Berchenko, E.; Frenette, J.

    1999-01-01

    Previous observations have shown that neutrophil invasion precedes macrophage invasion during muscle inflammation and that peak muscle injury is observed at the peak of ED1+ macrophage invasion. We tested the hypothesis that neutrophil invasion causes subsequent invasion by ED1+ macrophages and that ED1+ macrophages then contribute significantly to muscle membrane injury during modified muscle use. Rat hindlimbs were unloaded for 10 days followed by reloading by normal ambulation to induce inflammation. Membrane injury was measured by assaying Evans blue-bound serum protein influx through membrane lesions. Muscle neutrophil populations increased significantly during the first 2 h of reloading but ED1+ macrophages did not increase until 24 h. Neutrophil invasion was uncoupled from subsequent macrophage invasion by reloading rat hindlimbs for 2 h to cause neutrophil invasion, followed by resuspension for hours 2-24. This produced similar increases in neutrophil concentration as measured in muscles continuously reloaded for 24 h without causing an increase in macrophages. However, resuspension did not reduce the extent of muscle damage compared with that occurring in muscles that were reloaded continuously for 24 h. Thus, muscle invasion by neutrophils is not sufficient to cause invasion by ED1+ macrophages. In addition, muscle membrane injury that occurs during reloading is independent of invasion by ED1+ macrophages.

  15. Chemotherapeutic agent CPT-11 eliminates peritoneal resident macrophages by inducing apoptosis.

    PubMed

    Huang, Mei-Yun; Pan, Hao; Liang, Yi-Dan; Wei, Hong-Xia; Xu, Li-Hui; Zha, Qing-Bing; He, Xian-Hui; Ouyang, Dong-Yun

    2016-02-01

    CPT-11 (Irinotecan) is a first-line chemotherapeutic agent in clinic, but it may induce side effects including diarrhea and enteritis in patients. The underlying mechanism of CPT-11's intestinal toxicity is unclear. Peritoneal resident macrophages have been reported to be important for the maintenance of intestinal homeostasis. In this study, we evaluated the cytotoxic effects of CPT-11 on mouse peritoneal resident macrophages. CPT-11 was administered intraperitoneally to mice and their peritoneal exudate cells were isolated for evaluation. CPT-11 treatment strikingly decreased the ratio of F4/80(hi)MHCII(low) large peritoneal macrophages (LPMs), which are regarded as prenatally-originated peritoneal resident macrophages. Consistent with this, the transcription factor GATA6 specifically expressed in LPMs was barely detectable in the macrophages from CPT-11-treated mice, indicative of elimination of LPMs. Such elimination of LPMs was at least partly due to CPT-induced apoptosis in macrophages, because inhibition of apoptosis by caspase-3 inhibitor z-DEVD-fmk significantly diminished the loss of GATA6(+) LPMs. As GATA6 is a transcription factor that controls expression of multiple genes regulating peritoneal B-1 cell development and translocation, elimination of GATA6(+) LPMs led to a great reduction in B-1 cells in the peritoneal cavity after CPT-11 treatment. These results indicated that CPT-11-induced apoptosis contributed to the elimination of peritoneal resident macrophages, which might in turn impair the function of peritoneal B-1 cells in maintaining intestinal homeostasis. Our findings may at least partly explain why CPT-11 treatment in cancer patients induces diarrhea and enteritis, which may provide a novel avenue to prevent such side effects.

  16. Contribution of resident and recruited macrophages to the photodynamic intervention of colorectal tumor microenvironment.

    PubMed

    Pansa, María Florencia; Lamberti, María Julia; Cogno, Ingrid Sol; Correa, Silvia Graciela; Rumie Vittar, Natalia Belén; Rivarola, Viviana Alicia

    2016-01-01

    The study of cellular interactions in the tumor microenvironment has become one of the main areas of research in the fight against cancer. Tumor-associated macrophages (TAMs) influence tumor progression and therapy response due to its functional plasticity. Regarding cancer treatment, photodynamic therapy (PDT) is a minimally invasive and clinically approved procedure that involves the administration of a photosensitizer (PS), a nontoxic photosensitizing drug which is selectively retained in neoplastic tissue. Here, we investigated the role of resident and nonresident macrophages in the context of a PDT-treated colorectal tumor by developing a combination of 2-D and three-dimensional (3-D) experimental platform, recreating tumor-stroma interactions in vitro. Enhancement of cytotoxicity of PDT was achieved in the presence of nonresident macrophages which had a strong anti-tumor phenotype mediated by the production of nitric oxide, IL-6, and tumor necrosis factor alpha (TNF-α). On the contrary, tumor resident macrophages induced a pro-tumor phenotype promoting tumor cell migration and endothelial stimulation. Due to their plasticity, tumor-resident or tumor-recruited macrophages can differentially influence the response of tumors to PDT, so their multifactorial roles should be considered in the overall design of anti-tumor therapeutic.

  17. Tissue-resident macrophages can contain replication-competent virus in antiretroviral-naive, SIV-infected Asian macaques

    PubMed Central

    DiNapoli, Sarah R.; Ortiz, Alexandra M.; Wu, Fan; Matsuda, Kenta; Hirsch, Vanessa M.; Knox, Kenneth

    2017-01-01

    SIV DNA can be detected in lymphoid tissue–resident macrophages of chronically SIV-infected Asian macaques. These macrophages also contain evidence of recently phagocytosed SIV-infected CD4+ T cells. Here, we examine whether these macrophages contain replication-competent virus, whether viral DNA can be detected in tissue-resident macrophages from antiretroviral (ARV) therapy–treated animals and humans, and how the viral sequences amplified from macrophages and contemporaneous CD4+ T cells compare. In ARV-naive animals, we find that lymphoid tissue–resident macrophages contain replication-competent virus if they also contain viral DNA in ARV-naive Asian macaques. The genetic sequence of the virus within these macrophages is similar to those within CD4+ T cells from the same anatomic sites. In ARV-treated animals, we find that viral DNA can be amplified from lymphoid tissue–resident macrophages of SIV-infected Asian macaques that were treated with ARVs for at least 5 months, but we could not detect replication-competent virus from macrophages of animals treated with ARVs. Finally, we could not detect viral DNA in alveolar macrophages from HIV-infected individuals who received ARVs for 3 years and had undetectable viral loads. These data demonstrate that macrophages can contain replication-competent virus, but may not represent a significant reservoir for HIV in vivo. PMID:28239657

  18. Macrophage colony-stimulating factor-induced macrophage differentiation promotes regrowth in atrophied skeletal muscles and C2C12 myotubes.

    PubMed

    Dumont, Nicolas A; Frenette, Jérôme

    2013-02-01

    Skeletal muscle injury and regeneration are closely associated with an inflammatory reaction that is usually characterized by sequential recruitment of neutrophils and monocytes or macrophages. Selective macrophage depletion models have shown that macrophages are essential for complete regeneration of muscle fibers after freeze injuries, toxin injuries, ischemia-reperfusion, and hindlimb unloading and reloading. Although there is growing evidence that macrophages possess major myogenic capacities, it is not known whether the positive effects of macrophages can be optimized to stimulate muscle regrowth. We used in vivo and in vitro mouse models of atrophy to investigate the effects of stimulating macrophages with macrophage colony-stimulating factor (M-CSF) on muscle regrowth. When atrophied soleus muscles were injected intramuscularly with M-CSF, we observed a 1.6-fold increase in macrophage density and a faster recovery in muscle force (20%), combined with an increase in muscle fiber diameter (10%), after 7 days of reloading, compared with PBS-injected soleus muscles. Furthermore, coculture of atrophied myotubes with or without bone marrow-derived macrophages (BMDM) and/or M-CSF revealed that the combination of BMDMs and M-CSF was required to promote myotube growth (15%). More specifically, M-CSF promoted the anti-inflammatory macrophage phenotype, which in turn decreased protein degradation and MuRF-1 expression by 25% in growing myotubes. These results indicate that specific macrophage subsets can be stimulated to promote muscle cell regrowth after atrophy.

  19. Self-renewing resident arterial macrophages arise from embryonic CX3CR1(+) precursors and circulating monocytes immediately after birth.

    PubMed

    Ensan, Sherine; Li, Angela; Besla, Rickvinder; Degousee, Norbert; Cosme, Jake; Roufaiel, Mark; Shikatani, Eric A; El-Maklizi, Mahmoud; Williams, Jesse W; Robins, Lauren; Li, Cedric; Lewis, Bonnie; Yun, Tae Jin; Lee, Jun Seong; Wieghofer, Peter; Khattar, Ramzi; Farrokhi, Kaveh; Byrne, John; Ouzounian, Maral; Zavitz, Caleb C J; Levy, Gary A; Bauer, Carla M T; Libby, Peter; Husain, Mansoor; Swirski, Filip K; Cheong, Cheolho; Prinz, Marco; Hilgendorf, Ingo; Randolph, Gwendalyn J; Epelman, Slava; Gramolini, Anthony O; Cybulsky, Myron I; Rubin, Barry B; Robbins, Clinton S

    2016-02-01

    Resident macrophages densely populate the normal arterial wall, yet their origins and the mechanisms that sustain them are poorly understood. Here we use gene-expression profiling to show that arterial macrophages constitute a distinct population among macrophages. Using multiple fate-mapping approaches, we show that arterial macrophages arise embryonically from CX3CR1(+) precursors and postnatally from bone marrow-derived monocytes that colonize the tissue immediately after birth. In adulthood, proliferation (rather than monocyte recruitment) sustains arterial macrophages in the steady state and after severe depletion following sepsis. After infection, arterial macrophages return rapidly to functional homeostasis. Finally, survival of resident arterial macrophages depends on a CX3CR1-CX3CL1 axis within the vascular niche.

  20. Transplantable Subcutaneous Hepatoma 22a Affects Functional Activity of Resident Tissue Macrophages in Periphery

    PubMed Central

    Kisseleva, Ekaterina P.; Krylov, Andrei V.; Stepanova, Olga I.; Lioudyno, Victoria I.

    2011-01-01

    Tumors spontaneously develop central necroses due to inadequate blood supply. Recent data indicate that dead cells and their products are immunogenic to the host. We hypothesized that macrophage tumor-dependent reactions can be mediated differentially by factors released from live or dead tumor cells. In this study, functional activity of resident peritoneal macrophages was investigated in parallel with tumor morphology during the growth of syngeneic nonimmunogenic hepatoma 22a. Morphometrical analysis of tumor necroses, mitoses and leukocyte infiltration was performed in histological sections. We found that inflammatory potential of peritoneal macrophages in tumor-bearing mice significantly varied depending on the stage of tumor growth and exhibited two peaks of activation as assessed by nitroxide and superoxide anion production, 5′-nucleotidase activity and pinocytosis. Increased inflammatory reactions were not followed by the enhancement of angiogenic potential as assessed by Vascular Endothelial Growth Factor mRNA expression. Phases of macrophage activity corresponded to the stages of tumor growth characterized by high proliferative potential. The appearance and further development of necrotic tissue inside the tumor did not coincide with changes in macrophage behavior and therefore indirectly indicated that activation of macrophages was a reaction mostly to the signals produced by live tumor cells. PMID:21760797

  1. Unloading stress disturbs muscle regeneration through perturbed recruitment and function of macrophages.

    PubMed

    Kohno, Shohei; Yamashita, Yui; Abe, Tomoki; Hirasaka, Katsuya; Oarada, Motoko; Ohno, Ayako; Teshima-Kondo, Shigetada; Higashibata, Akira; Choi, Inho; Mills, Edward M; Okumura, Yuushi; Terao, Junji; Nikawa, Takeshi

    2012-05-01

    Skeletal muscle is one of the most sensitive tissues to mechanical loading, and unloading inhibits the regeneration potential of skeletal muscle after injury. This study was designed to elucidate the specific effects of unloading stress on the function of immunocytes during muscle regeneration after injury. We examined immunocyte infiltration and muscle regeneration in cardiotoxin (CTX)-injected soleus muscles of tail-suspended (TS) mice. In CTX-injected TS mice, the cross-sectional area of regenerating myofibers was smaller than that of weight-bearing (WB) mice, indicating that unloading delays muscle regeneration following CTX-induced skeletal muscle damage. Delayed infiltration of macrophages into the injured skeletal muscle was observed in CTX-injected TS mice. Neutrophils and macrophages in CTX-injected TS muscle were presented over a longer period at the injury sites compared with those in CTX-injected WB muscle. Disturbance of activation and differentiation of satellite cells was also observed in CTX-injected TS mice. Further analysis showed that the macrophages in soleus muscles were mainly Ly-6C-positive proinflammatory macrophages, with high expression of tumor necrosis factor-α and interleukin-1β, indicating that unloading causes preferential accumulation and persistence of proinflammatory macrophages in the injured muscle. The phagocytic and myotube formation properties of macrophages from CTX-injected TS skeletal muscle were suppressed compared with those from CTX-injected WB skeletal muscle. We concluded that the disturbed muscle regeneration under unloading is due to impaired macrophage function, inhibition of satellite cell activation, and their cooperation.

  2. Comparison of activities of rifapentine and rifampin against Mycobacterium tuberculosis residing in human macrophages.

    PubMed Central

    Mor, N; Simon, B; Mezo, N; Heifets, L

    1995-01-01

    The activities of rifapentine and rifampin against Mycobacterium tuberculosis residing in human monocyte-derived macrophages were determined. The MICs and MBCs of rifapentine for intracellular bacteria were two- to fourfold lower than those of rifampin. For extracellular bacteria, this difference was less noticeable. Nevertheless, the more favorable pharmacokinetics of rifapentine over rifampin was addressed in other experimental models. These models showed substantial differences after short pulsed exposures of the infected macrophages to the drugs and when the infected macrophages were exposed to changing drug concentrations that imitated the pharmacokinetic curves observed in blood. Once-a-week exposures to rifapentine concentrations equivalent to those attained in blood after one 600-mg dose resulted during the first week in a dramatic decline in the number of bacteria, and this decline was maintained at a minimal level for a period of four weeks. The results of this study have shown the suitability of rifapentine for intermittent-treatment regimens. The prolonged effect of rifapentine found in this study may be associated with high ratios of intracellular accumulation, which were four- to fivefold higher than those found for rifampin. Further studies on the intracellular distribution of rifamycins and on the sites of actual interaction between the drugs and bacteria residing in macrophages are necessary. PMID:8540718

  3. Suppression of macrophage functions impairs skeletal muscle regeneration with severe fibrosis

    SciTech Connect

    Segawa, Masashi; Fukada, So-ichiro Yamamoto, Yukiko; Yahagi, Hiroshi; Kanematsu, Masanori; Sato, Masaki; Ito, Takahito; Uezumi, Akiyoshi; Hayashi, Shin'ichi; Miyagoe-Suzuki, Yuko; Takeda, Shin'ichi; Tsujikawa, Kazutake; Yamamoto, Hiroshi

    2008-10-15

    When damaged, skeletal muscle regenerates. In the early phases of regeneration, inflammatory cells such as neutrophils/granulocytes and macrophages infiltrate damaged muscle tissue. To reveal the roles of macrophages during skeletal muscle regeneration, we injected an antibody, AFS98 that blocks the binding of M-CSF to its receptor into normal mice that received muscle damages. Anti-M-CSF receptor administration suppressed macrophage but not neutrophil infiltration. Histological study indicated that suppression of macrophages function leads to the incomplete muscle regeneration. In addition FACS and immunohistochemical study showed that the acute lack of macrophages delayed proliferation and differentiation of muscle satellite cells in vivo. Furthermore, mice injected with the anti-M-CSF receptor antibody exhibited not only adipogenesis, but also significant collagen deposition, i.e., fibrosis and continuous high expression of connective tissue growth factor. Finally we indicate that these fibrosis markers were strongly enriched in CD90(+) cells that do not include myogenic cells. These results indicate that macrophages directly affect satellite cell proliferation and that a macrophage deficiency severely impairs skeletal muscle regeneration and causes fibrosis.

  4. Myelopotentiating effect of curcumin in tumor-bearing host: Role of bone marrow resident macrophages

    SciTech Connect

    Vishvakarma, Naveen Kumar; Kumar, Anjani; Kumar, Ajay; Kant, Shiva; Bharti, Alok Chandra; Singh, Sukh Mahendra

    2012-08-15

    The present investigation was undertaken to study if curcumin, which is recognized for its potential as an antineoplastic and immunopotentiating agent, can also influence the process of myelopoiesis in a tumor-bearing host. Administration of curcumin to tumor-bearing host augmented count of bone marrow cell (BMC) accompanied by an up-regulated BMC survival and a declined induction of apoptosis. Curcumin administration modulated expression of cell survival regulatory molecules: Bcl2, p53, caspase-activated DNase (CAD) and p53-upregulated modulator of apoptosis (PUMA) along with enhanced expression of genes of receptors for M-CSF and GM-CSF in BMC. The BMC harvested from curcumin-administered hosts showed an up-regulated colony forming ability with predominant differentiation into bone marrow-derived macrophages (BMDM), responsive for activation to tumoricidal state. The number of F4/80 positive bone marrow resident macrophages (BMM), showing an augmented expression of M-CSF, was also augmented in the bone marrow of curcumin-administered host. In vitro reconstitution experiments indicated that only BMM of curcumin-administered hosts, but not in vitro curcumin-exposed BMM, augmented BMC survival. It suggests that curcumin-dependent modulation of BMM is of indirect nature. Such prosurvival action of curcumin is associated with altered T{sub H1}/T{sub H2} cytokine balance in serum. Augmented level of serum-borne IFN-γ was found to mediate modulation of BMM to produce enhanced amount of monokines (IL-1, IL-6, TNF-α), which are suggested to augment the BMC survival. Taken together the present investigation indicates that curcumin can potentiate myelopoiesis in a tumor-bearing host, which may have implications in its therapeutic utility. Highlights: ► Curcumin augments myelopoiesis in tumor-bearing host. ► Bone marrow resident macrophages mediate curcumin-dependent augmented myelopoiesis. ► Serum borne cytokine are implicated in modulation of bone marrow resident

  5. Local Inhibition of Macrophage and Smooth Muscle Cell Proliferation to Suppress Plaque Progression

    PubMed Central

    Sukhovershin, Roman A.; Toledano Furman, Naama E.; Tasciotti, Ennio; Trachtenberg, Barry H.

    2016-01-01

    Atherosclerosis is a complex process responsible for a major burden of cardiovascular morbidity and mortality. Macrophages and smooth muscle cells (SMCs) are abundant within atherosclerotic plaques. This review discusses the role of macrophages and SMCs in plaque progression and provides an overview of nanoparticle-based approaches and other current methods for local targeting of atherosclerotic plaques. PMID:27826367

  6. Bone marrow chimeric rats reveal the unique distribution of resident and recruited macrophages in the contused rat spinal cord.

    PubMed

    Popovich, P G; Hickey, W F

    2001-07-01

    Brain and spinal cord inflammation that develops after traumatic injury is believed to differentially influence the structural and/or physiological integrity of surviving neurons and glia. It is possible that the functional dichotomy of CNS inflammation results from the activity of a heterogeneous macrophage population elicited by trauma. Indeed, unique functions have been attributed to macrophages derived from resident microglia versus those originating from infiltrating monocytes. Thus, whether progressive tissue injury or repair is favored could be explained by the disproportionate contributions of one macrophage subset relative to the other. Descriptive neuroanatomical studies are a reasonable first approach to revealing a relationship between microglia, recruited blood monocytes/macrophages, and regions of tissue degeneration and/or repair. Unfortunately, it is not possible to differentiate between CNS macrophage subsets using conventional immunohistochemical approaches. In the present study, we have used radiation bone marrow chimeric rats to definitively characterize the macrophage reaction elicited by experimental spinal contusion injury. In chimeric animals, antibodies raised against unique cell surface molecules expressed on bone marrow-derived cells (BMCs) were used to distinguish infiltrating BMCs from resident microglial-derived macrophages. Our findings indicate that the onset and plateau of macrophage activation (previously shown to be 3 and 7 days postinjury, respectively) is dominated initially by microglial-derived macrophages and then is supplanted by hematogenous cells. While resident macrophages are ubiquitously distributed throughout the injury site, leukocyte-derived monocytes exclusively infiltrate the gray matter and to a lesser extent subpial white matter. Generally, monocyte foci in white matter remain associated with the lumen or abluminal surface of blood vessels, i.e. few cells actually infiltrate the parenchyma. If functional

  7. Crosstalk of mesenchymal stem cells and macrophages promotes cardiac muscle repair.

    PubMed

    Wang, Mei; Zhang, Guoru; Wang, Yaling; Liu, Tao; Zhang, Yang; An, Yu; Li, Yongjun

    2015-01-01

    Transplantation of bone-marrow derived mesenchymal stem cells (MSCs) has potential therapeutic effects on cardiac muscle repair. However, the underlying mechanism remains not completely clarified. Here we show that transplantation of MSCs significantly increased local recruitment of macrophages to facilitate cardiac muscle repair. MSCs-induced recovery of cardiac function and attenuation of fibrosis after injury were all abolished by either impaired macrophage infiltration, or by MSCs depletion after macrophage recruitment. However, angiogenesis seemed to be only affected by depletion of macrophages, but not by depletion of MSCs, suggesting that macrophages are responsible for the augmented angiogenesis after MSCs transplantation, while MSCs do not directly contribute to angiogenesis in the functional cardiac repair. Moreover, high level of transforming growth factor β 1 (TGFβ1) was detected in macrophages and high level of BMP7 was detected in MSCs, suggesting that MSCs not only may recruit macrophages to enhance angiogenesis to promote regeneration, but also may secrete BMP7 to contradict the fibrogenic effect of TGFβ1 by macrophages. Our study thus sheds new insight on the interaction of MSCs and macrophages in a functional cardiac repair triggered by MSCs transplantation.

  8. Macrophage density in pharyngeal and laryngeal muscles greatly exceeds that in other striated muscles: an immunohistochemical study using elderly human cadavers

    PubMed Central

    Rhee, Sunki; Kitamura, Kei; Masaaki, Kasahara; Katori, Yukio; Murakami, Gen; Abe, Shin-ichi

    2016-01-01

    Macrophages play an important role in aging-related muscle atrophy (i.e., sarcopenia). We examined macrophage density in six striated muscles (cricopharyngeus muscle, posterior cricoarytenoideus muscle, genioglossus muscle, masseter muscle, infraspinatus muscle, and external anal sphincter). We examined 14 donated male cadavers and utilized CD68 immunohistochemistry to clarify macrophage density in muscles. The numbers of macrophages per striated muscle fiber in the larynx and pharynx (0.34 and 0.31) were 5–6 times greater than those in the tongue, shoulder, and anus (0.05–0.07) with high statistical significance. Thick muscle fibers over 80 µm in diameter were seen in the pharynx, larynx, and anal sphincter of two limited specimens. Conversely, in the other sites or specimens, muscle fibers were thinner than 50 µm. We did not find any multinuclear muscle cells suggestive of regeneration. At the beginning of the study, we suspected that mucosal macrophages might have invaded into the muscle layer of the larynx and pharynx, but we found no evidence of inflammation in the mucosa. Likewise, the internal anal sphincter (a smooth muscle layer near the mucosa) usually contained fewer macrophages than the external sphincter. The present result suggest that, in elderly men, thinning and death of striated muscle fibers occur more frequently in the larynx and pharynx than in other parts of the body. PMID:27722010

  9. Role of hepatic resident and infiltrating macrophages in liver repair after acute injury.

    PubMed

    You, Qiang; Holt, Michael; Yin, Hao; Li, Guiying; Hu, Cheng-Jun; Ju, Cynthia

    2013-09-15

    Treatment of liver disease, caused by hepatotoxins, viral infections, alcohol ingestion, or autoimmune conditions, remains challenging and costly. The liver has a powerful capacity to repair and regenerate, thus a thorough understanding of this tightly orchestrated process will undoubtedly improve clinical means of restoring liver function after injury. Using a murine model of acute liver injury caused by overdose of acetaminophen (APAP), our studies demonstrated that the combined absence of liver resident macrophages (Kupffer cells, KCs), and infiltrating macrophages (IMs) resulted in a marked delay in liver repair, even though the initiation and extent of peak liver injury was not impacted. This delay was not due to impaired hepatocyte proliferation but rather prolonged vascular leakage, which is caused by APAP-induced liver sinusoidal endothelial cell (LSEC) injury. We also found that KCs and IMs express an array of angiogenic factors and induce LSEC proliferation and migration. Our mechanistic studies suggest that hypoxia-inducible factor (HIF) may be involved in regulating the angiogenic effect of hepatic macrophages (Macs), as we found that APAP challenge resulted in hypoxia and stabilization of HIF in the liver and hepatic Macs. Together, these data indicate an important role for hepatic Macs in liver blood vessel repair, thereby contributing to tissue recovery from acute injury.

  10. The roles of blood-derived macrophages and resident microglia in the neuroinflammatory response to implanted intracortical microelectrodes.

    PubMed

    Ravikumar, Madhumitha; Sunil, Smrithi; Black, James; Barkauskas, Deborah S; Haung, Alex Y; Miller, Robert H; Selkirk, Stephen M; Capadona, Jeffrey R

    2014-09-01

    Resident microglia and blood-borne macrophages have both been implicated to play a dominant role in mediating the neuroinflammatory response affecting implanted intracortical microelectrodes. However, the distinction between each cell type has not been demonstrated due to a lack of discriminating cellular markers. Understanding the subtle differences of each cell population in mediating neuroinflammation can aid in determining the appropriate therapeutic approaches to improve microelectrode performance. Therefore, the goal of this study is to characterize the role of infiltrating blood-derived cells, specifically macrophages, in mediating neuroinflammation following intracortical microelectrode implantation. Interestingly, we found no correlation between microglia and neuron populations at the microelectrode-tissue interface. On the other hand, blood-borne macrophages consistently dominated the infiltrating cell population following microelectrode implantation. Most importantly, we found a correlation between increased populations of blood-derived cells (including the total macrophage population) and neuron loss at the microelectrode-tissue interface. Specifically, the total macrophage population was greatest at two and sixteen weeks post implantation, at the same time points when we observed the lowest densities of neuronal survival in closest proximity to the implant. Together, our results suggest a dominant role of infiltrating macrophages, and not resident microglia, in mediating neurodegeneration following microelectrode implantation.

  11. Macrophages protect against muscle atrophy and promote muscle recovery in vivo and in vitro: a mechanism partly dependent on the insulin-like growth factor-1 signaling molecule.

    PubMed

    Dumont, Nicolas; Frenette, Jérôme

    2010-05-01

    Hindlimb unloading and reloading are characterized by a major loss of muscle force and are associated with classic leukocyte infiltration during recovery from muscle atrophy. Macrophages act as a cellular cornerstone by playing both pro- and anti-inflammatory roles during muscle recovery from atrophy. In the present study, we investigated the role of macrophages in muscle atrophy and regrowth using in vivo and in vitro models. Mice depleted in monocytes/macrophages and submitted to a hindlimb unloading and reloading protocol experienced a significant delay in muscle force recovery compared with matched placebo mice at 7 and 14 days after reloading. Furthermore, an in vitro myotube/macrophage coculture showed that anti-inflammatory macrophages, which contain apoptotic neutrophils and express low levels of cyclooxygenase-2, completely prevented the loss of protein content and the myotube atrophy observed after 2 days in low serum medium. The presence of macrophages also protected against the decrease in myosin heavy chain content in myotubes exposed to low serum medium for 1 day. Interestingly, the addition of an anti-IGF-1 antibody to the coculture significantly decreased the ability of macrophages to protect against myotube atrophy and myosin heavy chain loss after 2 days in low serum medium. These results clearly indicate that macrophages and, more precisely, the release of IGF-1 by macrophages, play an important role in recovery from muscle atrophy.

  12. MicroRNA-155 facilitates skeletal muscle regeneration by balancing pro- and anti-inflammatory macrophages

    PubMed Central

    Nie, M; Liu, J; Yang, Q; Seok, H Y; Hu, X; Deng, Z-L; Wang, D-Z

    2016-01-01

    Skeletal muscle has remarkable regeneration capacity and regenerates in response to injury. Muscle regeneration largely relies on muscle stem cells called satellite cells. Satellite cells normally remain quiescent, but in response to injury or exercise they become activated and proliferate, migrate, differentiate, and fuse to form multinucleate myofibers. Interestingly, the inflammatory process following injury and the activation of the myogenic program are highly coordinated, with myeloid cells having a central role in modulating satellite cell activation and regeneration. Here, we show that genetic deletion of microRNA-155 (miR-155) in mice substantially delays muscle regeneration. Surprisingly, miR-155 does not appear to directly regulate the proliferation or differentiation of satellite cells. Instead, miR-155 is highly expressed in myeloid cells, is essential for appropriate activation of myeloid cells, and regulates the balance between pro-inflammatory M1 macrophages and anti-inflammatory M2 macrophages during skeletal muscle regeneration. Mechanistically, we found that miR-155 suppresses SOCS1, a negative regulator of the JAK-STAT signaling pathway, during the initial inflammatory response upon muscle injury. Our findings thus reveal a novel role of miR-155 in regulating initial immune responses during muscle regeneration and provide a novel miRNA target for improving muscle regeneration in degenerative muscle diseases. PMID:27277683

  13. Macrophage secretory products selectively stimulate dermatan sulfate proteoglycan production in cultured arterial smooth muscle cells.

    PubMed Central

    Edwards, I. J.; Wagner, W. D.; Owens, R. T.

    1990-01-01

    Arterial dermatan sulfate proteoglycan has been shown to increase with atherosclerosis progression, but factors responsible for this increase are unknown. To test the hypothesis that smooth muscle cell proteoglycan synthesis may be modified by macrophage products, pigeon arterial smooth muscle cells were exposed to the media of either cholesteryl ester-loaded pigeon peritoneal macrophages or a macrophage cell line P388D1. Proteoglycans radiolabeled with [35S]sulfate and [3H]serine were isolated from culture media and smooth muscle cells and purified following precipitation with 1-hexadecylpyridinium chloride and chromatography. Increasing concentrations of macrophage-conditioned media were associated with a dose-response increase in [35S]sulfate incorporation into secreted proteoglycans, but there was no change in cell-associated proteoglycans. Incorporation of [3H]serine into total proteoglycan core proteins was not significantly different (5.2 X 10(5) dpm and 5.5 X 10(5) disintegrations per minute (dpm) in control and conditioned media-treated cultures, respectively), but selective effects were observed on individual proteoglycan types. Twofold increases in dermatan sulfate proteoglycan and limited degradation of chondroitin sulfate proteoglycan were apparent based on core proteins separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). Immunoinhibition studies indicated that interleukin-1 was involved in the modulation of proteoglycan synthesis by macrophage-conditioned media. These data provide support for the role of macrophages in alteration of the matrix proteoglycans synthesized by smooth muscle cells and provide a mechanism to account for the reported increased dermatan sulfate/chondroitin sulfate ratios in the developing atherosclerotic lesion. Images Figure 6 PMID:2316626

  14. Macrophages and smooth muscle cells express lipoprotein lipase in human and rabbit atherosclerotic lesions.

    PubMed Central

    Ylä-Herttuala, S; Lipton, B A; Rosenfeld, M E; Goldberg, I J; Steinberg, D; Witztum, J L

    1991-01-01

    Lipoprotein lipase (LPL; EC 3.1.1.34) may promote atherogenesis by producing remnant lipoproteins on the endothelial surface and by acting on lipoproteins in the artery wall. In vitro, smooth muscle cells and macrophages synthesize LPL, but in human carotid lesions only a few smooth muscle cells were reported to contain LPL protein. Endothelial cells do not synthesize LPL in vitro, but in normal arteries intense immunostaining for LPL is present on the endothelium. We used Northern blot analysis, in situ hybridization, and immunocytochemistry of human and rabbit arteries to determine cellular distribution and the site of the synthesis of LPL in atherosclerotic lesions. Northern blot analysis showed that LPL mRNA was detectable in macrophage-derived foam cells isolated from arterial lesions of "ballooned" cholesterol-fed rabbits. In situ hybridization studies of atherosclerotic lesions with an antisense riboprobe showed a strong hybridization signal for LPL mRNA in some, but not all, lesion macrophages, which were mostly located in the subendothelial and edge areas of the lesions. Also, some smooth muscle cells in lesion areas also expressed LPL mRNA. Immunocytochemistry of frozen sections of rabbit lesions with a monoclonal antibody to human milk LPL showed intense staining for LPL protein in macrophage-rich intimal lesions. The results suggest that lesion macrophages and macrophage-derived foam cells express LPL mRNA and protein. Some smooth muscle cells in the lesion areas also synthesize LPL. These data are consistent with an important role for LPL in atherogenesis. Images PMID:1719546

  15. Macrophage secretory products selectively stimulate dermatan sulfate proteoglycan production in cultured arterial smooth muscle cells

    SciTech Connect

    Edwards, I.J.; Wagner, W.D.; Owens, R.T. )

    1990-03-01

    Arterial dermatan sulfate proteoglycan has been shown to increase with atherosclerosis progression, but factors responsible for this increase are unknown. To test the hypothesis that smooth muscle cell proteoglycan synthesis may be modified by macrophage products, pigeon arterial smooth muscle cells were exposed to the media of either cholesteryl ester-loaded pigeon peritoneal macrophages or a macrophage cell line P388D1. Proteoglycans radiolabeled with (35S)sulfate and (3H)serine were isolated from culture media and smooth muscle cells and purified following precipitation with 1-hexadecylpyridinium chloride and chromatography. Increasing concentrations of macrophage-conditioned media were associated with a dose-response increase in (35S)sulfate incorporation into secreted proteoglycans, but there was no change in cell-associated proteoglycans. Incorporation of (3H)serine into total proteoglycan core proteins was not significantly different (5.2 X 10(5) dpm and 5.5 X 10(5) disintegrations per minute (dpm) in control and conditioned media-treated cultures, respectively), but selective effects were observed on individual proteoglycan types. Twofold increases in dermatan sulfate proteoglycan and limited degradation of chondroitin sulfate proteoglycan were apparent based on core proteins separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). Immunoinhibition studies indicated that interleukin-1 was involved in the modulation of proteoglycan synthesis by macrophage-conditioned media. These data provide support for the role of macrophages in alteration of the matrix proteoglycans synthesized by smooth muscle cells and provide a mechanism to account for the reported increased dermatan sulfate/chondroitin sulfate ratios in the developing atherosclerotic lesion.

  16. Resident peritoneal leukocytes are important sources of MMP-9 during zymosan peritonitis: superior contribution of macrophages over mast cells.

    PubMed

    Kolaczkowska, Elzbieta; Lelito, Monika; Kozakiewicz, Elzbieta; van Rooijen, Nico; Plytycz, Barbara; Arnold, Bernd

    2007-11-15

    Metalloproteinase 9 (MMP-9) is crucial for normal neutrophil infiltration into zymosan-inflamed peritoneum. During the course of zymosan peritonitis MMP-9 is produced in a biphasic-manner as its presence is detectable as early as 30 min post zymosan and then between 2 and 8 h of inflammation. As inflammatory leukocytes were shown to produce MMP-9 we asked if also resident leukocytes, mast cells and macrophages, contribute to its production. And furthermore, if their contribution is limited only to the early phase of inflammation or extends to the later stages. For this purpose some mice were depleted of either resident macrophages or functional mast cells and expression of MMP-9 in peritoneal leukocytes and its release to the exudate were monitored. It turned out that depletion of peritoneal macrophages decreased both MMP-9 content in the leukocytes and its release to the inflammatory exudate at 30 min and 6h of peritonitis. The functional depletion of mast cells also caused a significant decrease in the production/release of MMP-9 that was especially apparent at the early time point (30 min). Moreover, the study shows concomitant kinetics of MMP-9 expression in leukocytes and its release to the exudatory fluid. The findings indicate that resident tissue leukocytes, and among them especially macrophages, constitute an important source of MMP-9 during acute peritoneal inflammation. Overall, the study shows that resident tissue leukocytes, mostly macrophages, constitute an important cellular source(s) of inflammation-related factors and should be regarded as possible targets of anti-inflammatory treatment.

  17. OPN‐a induces muscle inflammation by increasing recruitment and activation of pro‐inflammatory macrophages

    PubMed Central

    Many, Gina M.; Yokosaki, Yasuyuki; Uaesoontrachoon, Kitipong; Nghiem, Peter P.; Bello, Luca; Dadgar, Sherry; Yin, Ying; Damsker, Jesse M.; Cohen, Heather B.; Kornegay, Joe N.; Bamman, Marcas M.; Mosser, David M.; Nagaraju, Kanneboyina

    2016-01-01

    New Findings What is the central question of this study? What is the functional relevance of OPN isoform expression in muscle pathology? What is the main finding and its importance? The full‐length human OPN‐a isoform is the most pro‐inflammatory isoform in the muscle microenvironment, acting on macrophages and myoblasts in an RGD‐integrin‐dependent manner. OPN‐a upregulates expression of tenascin‐C (TNC), a known Toll‐like receptor 4 (TLR4) agonist. Blocking TLR4 signalling inhibits the pro‐inflammatory effects of OPN‐a, suggesting that a potential mechanism of OPN action is by promoting TNC–TLR4 signalling. Although osteopontin (OPN) is an important mediator of muscle remodelling in health and disease, functional differences in human spliced OPN variants in the muscle microenvironment have not been characterized. We thus sought to define the pro‐inflammatory activities of human OPN isoforms (OPN‐a, OPN‐b and OPN‐c) on cells present in regenerating muscle. OPN transcripts were quantified in normal and dystrophic human and dog muscle. Human macrophages and myoblasts were stimulated with recombinant human OPN protein isoforms, and cytokine mRNA and protein induction was assayed. OPN isoforms were greatly increased in dystrophic human (OPN‐a > OPN‐b > OPN‐c) and dog muscle (OPN‐a = OPN‐c). In healthy human muscle, mechanical loading also upregulated OPN‐a expression (eightfold; P < 0.01), but did not significantly upregulate OPN‐c expression (twofold; P > 0.05). In vitro, OPN‐a displayed the most pronounced pro‐inflammatory activity among isoforms, acting on both macrophages and myoblasts. In vitro and in vivo data revealed that OPN‐a upregulated tenascin‐C (TNC), a known Toll‐like receptor 4 (TLR4) agonist. Inhibition of TLR4 signalling attenuated OPN‐mediated macrophage cytokine production. In summary, OPN‐a is the most abundant and functionally active human spliced isoform in the skeletal muscle

  18. Lung-resident tissue macrophages generate Foxp3+ regulatory T cells and promote airway tolerance

    PubMed Central

    Soroosh, Pejman; Doherty, Taylor A.; Duan, Wei; Mehta, Amit Kumar; Choi, Heonsik; Adams, Yan Fei; Mikulski, Zbigniew; Khorram, Naseem; Rosenthal, Peter; Broide, David H.

    2013-01-01

    Airway tolerance is the usual outcome of inhalation of harmless antigens. Although T cell deletion and anergy are likely components of tolerogenic mechanisms in the lung, increasing evidence indicates that antigen-specific regulatory T cells (inducible Treg cells [iTreg cells]) that express Foxp3 are also critical. Several lung antigen-presenting cells have been suggested to contribute to tolerance, including alveolar macrophages (MØs), classical dendritic cells (DCs), and plasmacytoid DCs, but whether these possess the attributes required to directly promote the development of Foxp3+ iTreg cells is unclear. Here, we show that lung-resident tissue MØs coexpress TGF-β and retinal dehydrogenases (RALDH1 and RALDH 2) under steady-state conditions and that their sampling of harmless airborne antigen and presentation to antigen-specific CD4 T cells resulted in the generation of Foxp3+ Treg cells. Treg cell induction in this model depended on both TGF-β and retinoic acid. Transfer of the antigen-pulsed tissue MØs into the airways correspondingly prevented the development of asthmatic lung inflammation upon subsequent challenge with antigen. Moreover, exposure of lung tissue MØs to allergens suppressed their ability to generate iTreg cells coincident with blocking airway tolerance. Suppression of Treg cell generation required proteases and TLR-mediated signals. Therefore, lung-resident tissue MØs have regulatory functions, and strategies to target these cells might hold promise for prevention or treatment of allergic asthma. PMID:23547101

  19. Increases of M2a macrophages and fibrosis in aging muscle are influenced by bone marrow aging and negatively regulated by muscle-derived nitric oxide.

    PubMed

    Wang, Ying; Wehling-Henricks, Michelle; Samengo, Giuseppina; Tidball, James G

    2015-08-01

    Muscle aging is associated with changes in myeloid cell phenotype that may influence age-related changes in muscle structure. We tested whether preventing age-related reductions in muscle neuronal nitric oxide synthase (nNOS) would obviate age-related changes in myeloid cells in muscle. Our findings show that muscle aging is associated with elevations of anti-inflammatory M2a macrophages that can increase muscle fibrosis. Expression of a muscle-specific nNOS transgene in mice prevented age-related increases in M2a macrophages. Transgene expression also reduced expression of collagens and decreased muscle fibrosis. The nNOS transgene prevented age-related increases in arginase-1 but did not influence TGFβ expression, indicating that the transgene may prevent age-related muscle fibrosis by inhibiting the arginase-dependent profibrotic pathway. Although aged satellite cells or fibro-adipogenic precursor (FAPs) cells also promote fibrosis, transgene expression had no effect on the expression of key signaling molecules that regulate fibrogenic activity of those cells. Finally, we tested whether increases in M2a macrophages and the associated increase in fibrosis were attributable to aging of myeloid lineage cells. Young bone marrow cells (BMCs) were transplanted into young or old mice, and muscles were collected 8 months later. Muscles of young mice receiving young BMCs showed no effect on M2a macrophage number or collagen accumulation compared to age-matched, nontransplanted controls. However, muscles of old mice receiving young BMCs showed fewer M2a macrophages and less accumulation of collagen. Thus, the age-related increase in M2a macrophages in aging muscle and the associated muscle fibrosis are determined in part by the age of bone marrow cells.

  20. Design and utilization of macrophage and vascular smooth muscle cell co-culture systems in atherosclerotic cardiovascular disease investigation.

    PubMed

    Zuniga, Mary C; White, Sharla L Powell; Zhou, Wei

    2014-10-01

    Atherosclerotic cardiovascular disease has been acknowledged as a chronic inflammatory condition. Monocytes and macrophages lead the inflammatory pathology of atherosclerosis whereas changes in atheromatous plaque thickness and matrix composition are attributed to vascular smooth muscle cells. Because these cell types are key players in atherosclerosis progression, it is crucial to utilize a reliable system to investigate their interaction. In vitro co-culture systems are useful platforms to study specific molecular mechanisms between cells. This review aims to summarize the various co-culture models that have been developed to investigate vascular smooth muscle cell and monocyte/macrophage interactions, focusing on the monocyte/macrophage effects on vascular smooth muscle cell function.

  1. Relationship between membrane potential changes and superoxide-releasing capacity in resident and activated mouse peritoneal macrophages

    SciTech Connect

    Kitagawa, S.; Johnston, R.B. Jr.

    1985-11-01

    To understand better the molecular basis for the enhanced respiratory burst of activated macrophages (M phi), the relationship between the stimulus-induced changes in membrane potential and release of superoxide anion (O/sub 2//sup -/) in mouse peritoneal M phi was investigated. Resident M phi and M phi elicited by injection of lipopolysaccharide (LPS-M phi) or obtained from animals infected with bacille Calmette-Guerin (BCG-M phi) were used. LPS-M phi and BCG-M phi showed more pronounced changes in membrane potential (depolarization) and greater release of O/sub 2//sup -/ on contact with phorbol myristate acetate (PMA) than did resident macrophages. The lag time between addition of stimulus and onset of release of O/sub 2//sup -/ was reduced in activated compared with resident cells. Membrane potential changes began 60 to 90 sec before release of O/sub 2//sup -/ could be detected in each cell type. The dose-response curves for triggering of membrane potential changes and O/sub 2//sup -/ release by PMA were identical. The magnitude of membrane potential changes and of O/sub 2//sup -/ release in LPS-M phi and BCG-M phi declined progressively during in vitro culture, and values on day 3 approached those in resident macrophages (deactivation). Extracellular glucose was required for effective stimulated change in membrane potential and O/sub 2//sup -/ release. These findings indicate that membrane potential changes are closely associated with O/sub 2//sup -/-releasing capacity in macrophages, and that the systems that mediate membrane potential changes and production of O/sub 2//sup -/ develop or decline concomitantly during activation or deactivation of the cells.

  2. CX3CR1 deficiency promotes muscle repair and regeneration by enhancing macrophage ApoE production.

    PubMed

    Arnold, Ludovic; Perrin, Hélène; de Chanville, Camille Baudesson; Saclier, Marielle; Hermand, Patricia; Poupel, Lucie; Guyon, Elodie; Licata, Fabrice; Carpentier, Wassila; Vilar, José; Mounier, Rémi; Chazaud, Bénédicte; Benhabiles, Nora; Boissonnas, Alexandre; Combadiere, Béhazine; Combadiere, Christophe

    2015-12-03

    Muscle injury triggers inflammation in which infiltrating mononuclear phagocytes are crucial for tissue regeneration. The interaction of the CCL2/CCR2 and CX3CL1/CX3CR1 chemokine axis that guides phagocyte infiltration is incompletely understood. Here, we show that CX3CR1 deficiency promotes muscle repair and rescues Ccl2(-/-) mice from impaired muscle regeneration as a result of altered macrophage function, not infiltration. Transcriptomic analysis of muscle mononuclear phagocytes reveals that Apolipoprotein E (ApoE) is upregulated in mice with efficient regeneration. ApoE treatment enhances phagocytosis by mononuclear phagocytes in vitro, and restores phagocytic activity and muscle regeneration in Ccl2(-/-) mice. Because CX3CR1 deficiency may compensate for defective CCL2-dependant monocyte recruitment by modulating ApoE-dependent macrophage phagocytic activity, targeting CX3CR1 expressed by macrophages might be a powerful therapeutic approach to improve muscle regeneration.

  3. CX3CR1 deficiency promotes muscle repair and regeneration by enhancing macrophage ApoE production

    PubMed Central

    Arnold, Ludovic; Perrin, Hélène; de Chanville, Camille Baudesson; Saclier, Marielle; Hermand, Patricia; Poupel, Lucie; Guyon, Elodie; Licata, Fabrice; Carpentier, Wassila; Vilar, José; Mounier, Rémi; Chazaud, Bénédicte; Benhabiles, Nora; Boissonnas, Alexandre; Combadiere, Béhazine; Combadiere, Christophe

    2015-01-01

    Muscle injury triggers inflammation in which infiltrating mononuclear phagocytes are crucial for tissue regeneration. The interaction of the CCL2/CCR2 and CX3CL1/CX3CR1 chemokine axis that guides phagocyte infiltration is incompletely understood. Here, we show that CX3CR1 deficiency promotes muscle repair and rescues Ccl2−/− mice from impaired muscle regeneration as a result of altered macrophage function, not infiltration. Transcriptomic analysis of muscle mononuclear phagocytes reveals that Apolipoprotein E (ApoE) is upregulated in mice with efficient regeneration. ApoE treatment enhances phagocytosis by mononuclear phagocytes in vitro, and restores phagocytic activity and muscle regeneration in Ccl2−/− mice. Because CX3CR1 deficiency may compensate for defective CCL2-dependant monocyte recruitment by modulating ApoE-dependent macrophage phagocytic activity, targeting CX3CR1 expressed by macrophages might be a powerful therapeutic approach to improve muscle regeneration. PMID:26632270

  4. Phosphatidylserine receptor Tim-4 is essential for the maintenance of the homeostatic state of resident peritoneal macrophages.

    PubMed

    Wong, Kit; Valdez, Patricia A; Tan, Christine; Yeh, Sherry; Hongo, Jo-Anne; Ouyang, Wenjun

    2010-05-11

    Tim-4 is a phosphatidylserine (PS) receptor that is expressed on various macrophage subsets. It mediates phagocytosis of apoptotic cells by peritoneal macrophages. The in vivo functions of Tim-4 in phagocytosis and immune responses, however, are still unclear. In this study, we show that Tim-4 quickly forms punctate caps on contact with apoptotic cells, in contrast to its normal diffused expression on the surface of phagocytes. Despite its expression in marginal zone and tingible body macrophages, Tim-4 deficiency only minimally affects outcomes of several acute immune challenges, including the trapping of apoptotic cells in the marginal zone, the clearance apoptotic cells by tingible body macrophages, and the formation of germinal centers and elicitation of antibody responses against sheep red blood cells (SRBCs). In addition, Tim-4(-/-) resident peritoneal macrophages (rPMs) phagocytose necrotic cells and other opsonized targets normally. However, their ability to bind and engulf apoptotic cells is significantly compromised both in vitro and in vivo. Most importantly, Tim-4 deficiency results in increased cellularity in the peritoneum. Resting rPMs produce higher TNF-alpha in culture. Their response to LPS, on the contrary, is dampened. Our data support an indispensible role of Tim-4 in maintaining the homeostasis of rPMs.

  5. Subcellular localization of the PGE2 synthesis activity in mouse resident peritoneal macrophages

    PubMed Central

    1984-01-01

    The aim of this work was to establish, on a quantitative basis, the subcellular distribution of the enzyme system that converts arachidonic acid into prostaglandin (PG) E2 in mouse resident peritoneal (MRP) macrophages. Kinetic studies were conducted on cell-free extracts derived from cells cultivated for 1 d, using [1-14C]arachidonic acid as substrate and measuring the label in PGE2 after extraction and thin layer chromatography. The activity was synergistically enhanced by L- adrenaline and reduced glutathione, inhibited by indomethacin, and linearly related to the concentration of the cell-free extract. It was labile at 0 degrees C in the medium used for homogenization and fractionation of the cells (half-life less than 2 h). Addition of catalase (0.15 mg/ml) to the suspension medium increased the initial activity (by congruent to 70%) and the stability (half-life congruent to 6 h) of the enzyme in cytoplasmic extracts. It enabled us to establish the density distribution after isopycnic centrifugation in a linear gradient of sucrose. The sample centrifuged consisted of untreated cytoplasmic extracts, or cytoplasmic extracts treated with digitonin and Na pyrophosphate. Comparison of the centrifugation behavior of PGE2 synthesis activity with that of various enzymes used as reference for the major subcellular entities has revealed that PGE2 synthesis fairly fits the density profile of sulfatase C in each case. The conclusion is that at least the rate-limiting reaction in the conversion of arachidonic acid into PGE2 is catalyzed by an enzyme associated with the endoplasmic reticulum. PMID:6420497

  6. A muscle resident cell population promotes fibrosis in hindlimb skeletal muscles of mdx mice through the Wnt canonical pathway.

    PubMed

    Trensz, Frédéric; Haroun, Sonia; Cloutier, Alexandre; Richter, Martin V; Grenier, Guillaume

    2010-11-01

    Previous work has pointed to a role for the Wnt canonical pathway in fibrosis formation in aged skeletal muscles. In the present study, we studied the dystrophic mdx mouse, which displays skeletal muscle fibrosis. Our results indicated that the muscle resident stromal cell (mrSC) population in the muscles of dystrophic mice is higher than in the muscles of age-matched wild-type mice. Wnt3a promoted the proliferation of and collagen expression by cultured mrSCs but arrested the growth of and collagen expression by cultured myoblasts. Injections of Wnt3A in the tibialis anterior muscles of adult wild-type mice significantly enhanced the mrSC population and collagen deposition compared with the contralateral muscles. Conversely, an injection of the Wnt antagonist Dickkof protein (DKK1) into the skeletal muscles of mdx mice significantly reduced collagen deposition. These results suggested that the Wnt canonical pathway expands the population of mrSCs and stimulates their production of collagen as observed during aging and in various myopathies.

  7. Central Role of CD169+ Lymph Node Resident Macrophages in the Adjuvanticity of the QS-21 Component of AS01

    PubMed Central

    Detienne, Sophie; Welsby, Iain; Collignon, Catherine; Wouters, Sandrine; Coccia, Margherita; Delhaye, Sophie; Van Maele, Laurye; Thomas, Séverine; Swertvaegher, Maëlle; Detavernier, Aurélie; Elouahabi, Abdelatif; Goriely, Stanislas; Didierlaurent, Arnaud M.

    2016-01-01

    Saponins represent a promising class of vaccine adjuvant. Together with the TLR4-ligand MPL, QS-21 is part of the Adjuvant System AS01, a key component of the malaria and zoster candidate vaccines that display demonstrated clinical efficacy. However, the mechanism of action of QS-21 in this liposomal formulation is poorly understood. Upon intra-muscular immunisation, we observed that QS-21 rapidly accumulated in CD169+ resident macrophages of the draining lymph node where it elicited a local innate immune response. Depletion of these cells abrogated QS-21-mediated innate cell recruitment to the lymph node, dendritic cell (DC) phenotypic maturation as well as the adjuvant effect on T-cell and antibody responses to co-administered antigens. DCs rather than lymph node-resident macrophages were directly involved in T-cell priming by QS-21, as revealed by the decrease in antigen-specific T-cell response in Batf3−/− mice. Further analysis showed that the adjuvant effect of QS-21 depended on the integration of Caspase-1 and MyD88 pathways, at least in part through the local release of HMGB1. Taken together, this work unravels the key role of lymph node sentinel macrophage in controlling the adjuvant effect of a molecule proven to improve vaccine response in humans. PMID:27996000

  8. Heart-resident CCR2(+) macrophages promote neutrophil extravasation through TLR9/MyD88/CXCL5 signaling.

    PubMed

    Li, Wenjun; Hsiao, Hsi-Min; Higashikubo, Ryuji; Saunders, Brian T; Bharat, Ankit; Goldstein, Daniel R; Krupnick, Alexander S; Gelman, Andrew E; Lavine, Kory J; Kreisel, Daniel

    2016-08-04

    It is well established that maladaptive innate immune responses to sterile tissue injury represent a fundamental mechanism of disease pathogenesis. In the context of cardiac ischemia reperfusion injury, neutrophils enter inflamed heart tissue, where they play an important role in potentiating tissue damage and contributing to contractile dysfunction. The precise mechanisms that govern how neutrophils are recruited to and enter the injured heart are incompletely understood. Using a model of cardiac transplant-mediated ischemia reperfusion injury and intravital 2-photon imaging of beating mouse hearts, we determined that tissue-resident CCR2(+) monocyte-derived macrophages are essential mediators of neutrophil recruitment into ischemic myocardial tissue. Our studies revealed that neutrophil extravasation is mediated by a TLR9/MyD88/CXCL5 pathway. Intravital 2-photon imaging demonstrated that CXCL2 and CXCL5 play critical and nonredundant roles in guiding neutrophil adhesion and crawling, respectively. Together, these findings uncover a specific role for a tissue-resident monocyte-derived macrophage subset in sterile tissue inflammation and support the evolving concept that macrophage ontogeny is an important determinant of function. Furthermore, our results provide the framework for targeting of cell-specific signaling pathways in myocardial ischemia reperfusion injury.

  9. Heart-resident CCR2+ macrophages promote neutrophil extravasation through TLR9/MyD88/CXCL5 signaling

    PubMed Central

    Li, Wenjun; Higashikubo, Ryuji; Saunders, Brian T.; Bharat, Ankit; Goldstein, Daniel R.; Krupnick, Alexander S.; Gelman, Andrew E.; Lavine, Kory J.

    2016-01-01

    It is well established that maladaptive innate immune responses to sterile tissue injury represent a fundamental mechanism of disease pathogenesis. In the context of cardiac ischemia reperfusion injury, neutrophils enter inflamed heart tissue, where they play an important role in potentiating tissue damage and contributing to contractile dysfunction. The precise mechanisms that govern how neutrophils are recruited to and enter the injured heart are incompletely understood. Using a model of cardiac transplant–mediated ischemia reperfusion injury and intravital 2-photon imaging of beating mouse hearts, we determined that tissue-resident CCR2+ monocyte–derived macrophages are essential mediators of neutrophil recruitment into ischemic myocardial tissue. Our studies revealed that neutrophil extravasation is mediated by a TLR9/MyD88/CXCL5 pathway. Intravital 2-photon imaging demonstrated that CXCL2 and CXCL5 play critical and nonredundant roles in guiding neutrophil adhesion and crawling, respectively. Together, these findings uncover a specific role for a tissue-resident monocyte-derived macrophage subset in sterile tissue inflammation and support the evolving concept that macrophage ontogeny is an important determinant of function. Furthermore, our results provide the framework for targeting of cell-specific signaling pathways in myocardial ischemia reperfusion injury. PMID:27536731

  10. Bone marrow-derived macrophages distinct from tissue-resident macrophages play a pivotal role in Concanavalin A-induced murine liver injury via CCR9 axis

    PubMed Central

    Amiya, Takeru; Nakamoto, Nobuhiro; Chu, Po-sung; Teratani, Toshiaki; Nakajima, Hideaki; Fukuchi, Yumi; Taniki, Nobuhito; Yamaguchi, Akihiro; Shiba, Shunsuke; Miyake, Rei; Katayama, Tadashi; Ebinuma, Hirotoshi; Kanai, Takanori

    2016-01-01

    The fundamental mechanism how heterogeneous hepatic macrophage (Mφ) subsets fulfill diverse functions in health and disease has not been elucidated. We recently reported that CCR9+ inflammatory Mφs play a critical role in the course of acute liver injury. To clarify the origin and differentiation of CCR9+Mφs, we used a unique partial bone marrow (BM) chimera model with liver shielding for maintaining hepatic resident Mφs. First, irradiated mice developed less liver injury with less Mφs accumulation by Concanavalin A (Con A) regardless of liver shielding. In mice receiving further BM transplantation, CD11blowF4/80high hepatic-resident Mφs were not replaced by transplanted donors under steady state, while under inflammatory state by Con A, CCR9+Mφs were firmly replaced by donors, indicating that CCR9+Mφs originate from BM, but not from hepatic-resident cells. Regarding the mechanism of differentiation and proliferation, EdU+CCR9+Mφs with a proliferative potential were detected specifically in the inflamed liver, and in vitro study revealed that BM-derived CD11b+ cells co-cultured with hepatic stellate cells (HSCs) or stimulated with retinoic acids could acquire CCR9 with antigen-presenting ability. Collectively, our study demonstrates that inflammatory Mφs originate from BM and became locally differentiated and proliferated by interaction with HSCs via CCR9 axis during acute liver injury. PMID:27725760

  11. 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

  12. The Development of Macrophage-Mediated Cell Therapy to Improve Skeletal Muscle Function after Injury

    PubMed Central

    Rybalko, Viktoriya; Hsieh, Pei-Ling; Merscham-Banda, Melissa; Suggs, Laura J.; Farrar, Roger P.

    2015-01-01

    Skeletal muscle regeneration following acute injury is a multi-step process involving complex changes in tissue microenvironment. Macrophages (MPs) are one of the key cell types involved in orchestration and modulation of the repair process. Multiple studies highlight the essential role of MPs in the control of the myogenic program and inflammatory response during skeletal muscle regeneration. A variety of MP phenotypes have been identified and characterized in vitro as well as in vivo. As such, MPs hold great promise for cell-based therapies in the field of regenerative medicine. In this study we used bone-marrow derived in vitro LPS/IFN-y-induced M1 MPs to enhance functional muscle recovery after tourniquet-induced ischemia/reperfusion injury (TK-I/R). We detected a 15% improvement in specific tension and force normalized to mass after M1 (LPS/IFN-γ) MP transplantation 24 hours post-reperfusion. Interestingly, we found that M0 bone marrow-derived unpolarized MPs significantly impaired muscle function highlighting the complexity of temporally coordinated skeletal muscle regenerative program. Furthermore, we show that delivery of M1 (LPS/IFN-γ) MPs early in regeneration accelerates myofiber repair, decreases fibrotic tissue deposition and increases whole muscle IGF-I expression. PMID:26717325

  13. Human lung-resident macrophages express CB1 and CB2 receptors whose activation inhibits the release of angiogenic and lymphangiogenic factors

    PubMed Central

    Staiano, Rosaria I.; Loffredo, Stefania; Borriello, Francesco; Iannotti, Fabio Arturo; Piscitelli, Fabiana; Orlando, Pierangelo; Secondo, Agnese; Granata, Francescopaolo; Lepore, Maria Teresa; Fiorelli, Alfonso; Varricchi, Gilda; Santini, Mario; Triggiani, Massimo; Di Marzo, Vincenzo; Marone, Gianni

    2016-01-01

    Macrophages are pivotal effector cells in immune responses and tissue remodeling by producing a wide spectrum of mediators, including angiogenic and lymphangiogenic factors. Activation of cannabinoid receptor types 1 and 2 has been suggested as a new strategy to modulate angiogenesis in vitro and in vivo. We investigated whether human lung-resident macrophages express a complete endocannabinoid system by assessing their production of endocannabinoids and expression of cannabinoid receptors. Unstimulated human lung macrophage produce 2-arachidonoylglycerol, N-arachidonoyl-ethanolamine, N-palmitoyl-ethanolamine, and N-oleoyl-ethanolamine. On LPS stimulation, human lung macrophages selectively synthesize 2-arachidonoylglycerol in a calcium-dependent manner. Human lung macrophages express cannabinoid receptor types 1 and 2, and their activation induces ERK1/2 phosphorylation and reactive oxygen species generation. Cannabinoid receptor activation by the specific synthetic agonists ACEA and JWH-133 (but not the endogenous agonist 2-arachidonoylglycerol) markedly inhibits LPS-induced production of vascular endothelial growth factor-A, vascular endothelial growth factor-C, and angiopoietins and modestly affects IL-6 secretion. No significant modulation of TNF-α or IL-8/CXCL8 release was observed. The production of vascular endothelial growth factor-A by human monocyte-derived macrophages is not modulated by activation of cannabinoid receptor types 1 and 2. Given the prominent role of macrophage-assisted vascular remodeling in many tumors, we identified the expression of cannabinoid receptors in lung cancer-associated macrophages. Our results demonstrate that cannabinoid receptor activation selectively inhibits the release of angiogenic and lymphangiogenic factors from human lung macrophage but not from monocyte-derived macrophages. Activation of cannabinoid receptors on tissue-resident macrophages might be a novel strategy to modulate macrophage-assisted vascular

  14. Human lung-resident macrophages express CB1 and CB2 receptors whose activation inhibits the release of angiogenic and lymphangiogenic factors.

    PubMed

    Staiano, Rosaria I; Loffredo, Stefania; Borriello, Francesco; Iannotti, Fabio Arturo; Piscitelli, Fabiana; Orlando, Pierangelo; Secondo, Agnese; Granata, Francescopaolo; Lepore, Maria Teresa; Fiorelli, Alfonso; Varricchi, Gilda; Santini, Mario; Triggiani, Massimo; Di Marzo, Vincenzo; Marone, Gianni

    2016-04-01

    Macrophages are pivotal effector cells in immune responses and tissue remodeling by producing a wide spectrum of mediators, including angiogenic and lymphangiogenic factors. Activation of cannabinoid receptor types 1 and 2 has been suggested as a new strategy to modulate angiogenesis in vitro and in vivo. We investigated whether human lung-resident macrophages express a complete endocannabinoid system by assessing their production of endocannabinoids and expression of cannabinoid receptors. Unstimulated human lung macrophage produce 2-arachidonoylglycerol,N-arachidonoyl-ethanolamine,N-palmitoyl-ethanolamine, and N-oleoyl-ethanolamine. On LPS stimulation, human lung macrophages selectively synthesize 2-arachidonoylglycerol in a calcium-dependent manner. Human lung macrophages express cannabinoid receptor types 1 and 2, and their activation induces ERK1/2 phosphorylation and reactive oxygen species generation. Cannabinoid receptor activation by the specific synthetic agonists ACEA and JWH-133 (but not the endogenous agonist 2-arachidonoylglycerol) markedly inhibits LPS-induced production of vascular endothelial growth factor-A, vascular endothelial growth factor-C, and angiopoietins and modestly affects IL-6 secretion. No significant modulation of TNF-α or IL-8/CXCL8 release was observed. The production of vascular endothelial growth factor-A by human monocyte-derived macrophages is not modulated by activation of cannabinoid receptor types 1 and 2. Given the prominent role of macrophage-assisted vascular remodeling in many tumors, we identified the expression of cannabinoid receptors in lung cancer-associated macrophages. Our results demonstrate that cannabinoid receptor activation selectively inhibits the release of angiogenic and lymphangiogenic factors from human lung macrophage but not from monocyte-derived macrophages. Activation of cannabinoid receptors on tissue-resident macrophages might be a novel strategy to modulate macrophage-assisted vascular remodeling

  15. Influence of Rhodococcus equi on the respiratory burst of resident alveolar macrophages from horses

    SciTech Connect

    Brumbaugh, G.W.

    1986-01-01

    Rhodococcus equi is the etiologic agent of a devastating pneumonia of sporadic incidence in foals. The purpose of this study was to evaluate the influence of R. equi on the superoxide anion production, measured spectrophotometrically as the reduction of cytochrome C, and hexose monophosphate shunt activity, measured by /sup 14/CO/sub 2/ liberation from /sup 14/C-1-D-glucose, of alveolar macrophages from horses. Alveolar macrophages were harvested from 6 anesthetized, healthy, light-breed, adult horses by bronchoalveolar lavage. Following a randomized complete block design, the suspension of cells was divided into aliquots of 10/sup 6/ viable alveolar macrophages which were exposed to 1, 10 or 100 g. of opsonized R. equi or opsonized zymosan A at 37 C for 2 hours. In this study the respiratory burst of equine alveolar macrophages was only evidenced by the hexose monophosphate shunt activity and superoxide anion was not coincidentally produced. Rhodococcus equi did not adversely affect that response. The insignificant superoxide anion production by the alveolar macrophages suggests that this may not be a significant oxygen metabolite in those cells.

  16. Immunostaining of macrophages, endothelial cells and smooth muscle cells in the atherosclerotic mouse aorta

    PubMed Central

    Menon, Prashanthi; Fisher, Edward A.

    2016-01-01

    The atherosclerotic mouse aorta consists of a heterogeneous population of cells, including macrophages, endothelial cells (EC) and smooth muscle cells (SMC), that play critical roles in cardiovascular disease. Identification of these vascular cells in the vessel wall is important to understanding their function in pathological conditions. Immunohistochemistry is an invaluable technique used to detect the presence of cells in different tissues. Here, we describe immunohistochemical techniques commonly used for the detection of the vascular cells in the atherosclerotic mouse aorta using cell specific markers. PMID:26445786

  17. Alternate radiolabeled markers for detecting metabolic activity of Mycobacterium leprae residing in murine macrophages

    SciTech Connect

    Prasad, H.K.; Hastings, R.C.

    1985-05-01

    This study demonstrated the utility of using 4% NaOH as a murine macrophage cell-solubilizing agent to discriminate between host macrophage metabolism and that of intracellular Mycobacterium leprae. A 4% concentration of NaOH had no deleterious effect on labeled mycobacteria. Thereby, alternate radiolabeled indicators of the metabolic activity of intracellular M. leprae could be experimented with. Significant incorporation of /sup 14/C-amino acid mixture, (/sup 14/C)leucine, (/sup 14/C)uridine, and carrier-free /sup 32/P was observed in cultures containing freshly extracted (''live'') strains of M. leprae as compared with control cultures containing autoclaved bacilli.

  18. Shrimp Protein Hydrolysate Modulates the Timing of Proinflammatory Macrophages in Bupivacaine-Injured Skeletal Muscles in Rats

    PubMed Central

    Leblanc, Nadine; Bryl, Piotr; Fortin, Marie-Gil; Carbonneau, Marie-Elise; Lavigne, Charles

    2016-01-01

    This study was designed to determine whether marine-derived proteins other than cod could have beneficial effects on inflammation following muscle injury. Macrophage and neutrophil densities were measured from bupivacaine-injured tibialis anterior muscle of rats fed isoenergetic diets containing either shrimp hydrolysate (Shr), casein hydrolysate (CaH), or whole casein (Ca). In this study, Shr reduced ED1+-macrophages at day 2 (p = 0.013), day 5 (p = 0.006), and day 14 after injury (p = 0.038) compared with Ca, indicating faster resolution of inflammation in Shr. Except for day 2 after injury where Shr led to lower ED1+-macrophages compared with CaH (p = 0.006), both Shr and CaH responded similarly at days 5, 14, and 28 after injury. This findings suggest that beneficial effects of Shr on ED1+-cells might be related to generation of anti-inflammatory peptides through the hydrolysis process, in addition to its high content of anti-inflammatory amino acids. However, while increasing myofiber cross-sectional area in noninjured muscles compared with both Ca and CaH, Shr failed to have a positive effect in corresponding injured muscles. These data indicate that shrimp hydrolysate can facilitate resolution of inflammation after muscle injury mainly through modulating proinflammatory macrophage accumulation but have less effect on optimal recovery in terms of muscle mass and fiber size. PMID:27868064

  19. Macrophages are comprised of resident brain microglia not infiltrating peripheral monocytes acutely after neonatal stroke

    PubMed Central

    Denker, Sheryl P.; Ji, Shaoquan; Dingman, Andra; Lee, Sarah Y.; Derugin, Nikita; Wendland, Michael F.; Vexler, Zinaida S.

    2008-01-01

    Macrophages can be both beneficial and detrimental after CNS injury. We previously showed rapid accumulation of macrophages in injured immature brain acutely after ischemia-reperfusion. To determine whether these macrophages are microglia or invading monocytes, we subjected post-natal day 7 (P7) rats to transient 3 h middle cerebral artery (MCA) occlusion and used flow cytometry at 24 and 48 h post-reperfusion to distinguish invading monocytes (CD45high/CD11b+) from microglia (CD45low/medium/CD11b+). Inflammatory cytokines and chemokines were determined in plasma, injured and contralateral tissue 1–24 h post-reperfusion using ELISA-based cytokine multiplex assays. At 24 h, the number of CD45+/CD11b+ cells increased 3-fold in injured compared to uninjured brain tissue and CD45 expression shifted from low to medium with less than 10% of the population expressing CD45high. MCA occlusion induced rapid and transient asynchronous increases in the pro-inflammatory cytokine IL-β and chemokines cytokine-induced neutrophil chemoattractant protein 1 (CINC-1) and monocyte-chemoattractant protein 1 (MCP-1), first in systemic circulation and then in injured brain. Double immunofluorescence with cell-type specific markers showed that multiple cell types in the injured brain produce MCP-1. Our findings show that despite profound increases in MCP-1 in injured regions, monocyte infiltration is low and the majority of macrophages in acutely injured regions are microglia. PMID:17212701

  20. Embryonic Hematopoietic Progenitor Cells Reside in Muscle before Bone Marrow Hematopoiesis.

    PubMed

    Tanaka, Yuka; Inoue-Yokoo, Tomoko; Kulkeaw, Kasem; Yanagi-Mizuochi, Chiyo; Shirasawa, Senji; Nakanishi, Yoichi; Sugiyama, Daisuke

    2015-01-01

    In mice, hematopoietic cells home to bone marrow from fetal liver prenatally. To elucidate mechanisms underlying homing, we performed immunohistochemistry with the hematopoietic cell marker c-Kit, and observed c-Kit(+) cells localized inside muscle surrounding bone after 14.5 days post coitum. Flow cytometric analysis showed that CD45(+) c-Kit(+) hematopoietic cells were more abundant in muscle than in bone marrow between 14.5 and 17.5 days post coitum, peaking at 16.5 days post coitum. CD45(+) c-Kit(+) cells in muscle at 16.5 days post coitum exhibited higher expression of Gata2, among several hematopoietic genes, than did fetal liver or bone marrow cells. Colony formation assays revealed that muscle hematopoietic cells possess hematopoietic progenitor activity. Furthermore, exo utero transplantation revealed that fetal liver hematopoietic progenitor cells home to muscle and then to BM. Our findings demonstrate that hematopoietic progenitor cell homing occurs earlier than previously reported and that hematopoietic progenitor cells reside in muscle tissue before bone marrow hematopoiesis occurs during mouse embryogenesis.

  1. IL-4 directly signals tissue-resident macrophages to proliferate beyond homeostatic levels controlled by CSF-1

    PubMed Central

    Ruckerl, Dominik; Thomas, Graham D.; Hewitson, James P.; Duncan, Sheelagh; Brombacher, Frank; Maizels, Rick M.; Hume, David A.; Allen, Judith E.

    2013-01-01

    Macrophages (MΦs) colonize tissues during inflammation in two distinct ways: recruitment of monocyte precursors and proliferation of resident cells. We recently revealed a major role for IL-4 in the proliferative expansion of resident MΦs during a Th2-biased tissue nematode infection. We now show that proliferation of MΦs during intestinal as well as tissue nematode infection is restricted to sites of IL-4 production and requires MΦ-intrinsic IL-4R signaling. However, both IL-4Rα–dependent and –independent mechanisms contributed to MΦ proliferation during nematode infections. IL-4R–independent proliferation was controlled by a rise in local CSF-1 levels, but IL-4Rα expression conferred a competitive advantage with higher and more sustained proliferation and increased accumulation of IL-4Rα+ compared with IL-4Rα− cells. Mechanistically, this occurred by conversion of IL-4Rα+ MΦs from a CSF-1–dependent to –independent program of proliferation. Thus, IL-4 increases the relative density of tissue MΦs by overcoming the constraints mediated by the availability of CSF-1. Finally, although both elevated CSF1R and IL-4Rα signaling triggered proliferation above homeostatic levels, only CSF-1 led to the recruitment of monocytes and neutrophils. Thus, the IL-4 pathway of proliferation may have developed as an alternative to CSF-1 to increase resident MΦ numbers without coincident monocyte recruitment. PMID:24101381

  2. Modulation of functional characteristics of resident and thioglycollate-elicited peritoneal murine macrophages by a recombinant banana lectin.

    PubMed

    Marinkovic, Emilija; Djokic, Radmila; Lukic, Ivana; Filipovic, Ana; Inic-Kanada, Aleksandra; Kosanovic, Dejana; Gavrovic-Jankulovic, Marija; Stojanovic, Marijana

    2017-01-01

    We demonstrated that a recombinant banana lectin (rBanLec), which structural characteristics and physiological impacts highly resemble those reported for its natural counterparts, binds murine peritoneal macrophages and specifically modulates their functional characteristics. By using rBanLec in concentrations ranging from 1 μg to 10 μg to stimulate resident (RMs) and thioglycollate-elicited (TGMs) peritoneal macrophages from BALB/c and C57BL/6 mice, we have shown that effects of rBanLec stimulation depend on its concentration but also on the functional status of macrophages and their genetic background. rBanLec, in a positive dose-dependent manner, promotes the proliferation of TGMs from both BALB/c and C57BL/6 mice, while its mitogenic influence on RMs is significantly lower (BALB/c mice) or not detectable (C57BL/6 mice). In all peritoneal macrophages, irrespective of their type and genetic background, rBanLec, in a positive dose dependent manner, enhances the secretion of IL-10. rBanLec stimulation of RMs from both BALB/c and C57BL/6 resulted in a positive dose-dependent promotion of proinflammatory phenotype (enhancement of NO production and IL-12 and TNFα secretion, reduction of arginase activity). Positive dose-dependent skewing toward proinflammatory phenotype was also observed in TGMs from C57BL/6 mice. However, the enhancement of rBanLec stimulation promotes skewing of TGMs from BALB/c mice towards anti-inflammatory profile (reduction of NO production and IL-12 secretion, enhancement of arginase activity and TGFβ and IL-4 secretion). Moreover, we established that rBanLec binds oligosaccharide structures of TLR2 and CD14 and that blocking of signaling via these receptors significantly impairs the production of TNFα and NO in BALB/c macrophages. Since the outcome of rBanLec stimulation depends on rBanLec concentration as well as on the functional characteristics of its target cells and their genetic background, further studies are needed to investigate

  3. Modulation of functional characteristics of resident and thioglycollate-elicited peritoneal murine macrophages by a recombinant banana lectin

    PubMed Central

    Marinkovic, Emilija; Djokic, Radmila; Lukic, Ivana; Filipovic, Ana; Inic-Kanada, Aleksandra; Kosanovic, Dejana; Gavrovic-Jankulovic, Marija; Stojanovic, Marijana

    2017-01-01

    We demonstrated that a recombinant banana lectin (rBanLec), which structural characteristics and physiological impacts highly resemble those reported for its natural counterparts, binds murine peritoneal macrophages and specifically modulates their functional characteristics. By using rBanLec in concentrations ranging from 1 μg to 10 μg to stimulate resident (RMs) and thioglycollate-elicited (TGMs) peritoneal macrophages from BALB/c and C57BL/6 mice, we have shown that effects of rBanLec stimulation depend on its concentration but also on the functional status of macrophages and their genetic background. rBanLec, in a positive dose-dependent manner, promotes the proliferation of TGMs from both BALB/c and C57BL/6 mice, while its mitogenic influence on RMs is significantly lower (BALB/c mice) or not detectable (C57BL/6 mice). In all peritoneal macrophages, irrespective of their type and genetic background, rBanLec, in a positive dose dependent manner, enhances the secretion of IL-10. rBanLec stimulation of RMs from both BALB/c and C57BL/6 resulted in a positive dose-dependent promotion of proinflammatory phenotype (enhancement of NO production and IL-12 and TNFα secretion, reduction of arginase activity). Positive dose-dependent skewing toward proinflammatory phenotype was also observed in TGMs from C57BL/6 mice. However, the enhancement of rBanLec stimulation promotes skewing of TGMs from BALB/c mice towards anti-inflammatory profile (reduction of NO production and IL-12 secretion, enhancement of arginase activity and TGFβ and IL-4 secretion). Moreover, we established that rBanLec binds oligosaccharide structures of TLR2 and CD14 and that blocking of signaling via these receptors significantly impairs the production of TNFα and NO in BALB/c macrophages. Since the outcome of rBanLec stimulation depends on rBanLec concentration as well as on the functional characteristics of its target cells and their genetic background, further studies are needed to investigate

  4. FACS Fractionation and Differentiation of Skeletal-Muscle Resident Multipotent Tie2+ Progenitors.

    PubMed

    Biswas, Arpita A; Goldhamer, David J

    2016-01-01

    The skeletal muscle niche is complex and heterogeneous. Over the past few decades, various groups have reported the existence of multiple adult stem cell populations within this environment. Techniques commonly used to identify and assess the differentiation capacities of these cellular fractions, oftentimes rare populations, include the use of lineage tracers, immunofluorescence and histochemistry, flow cytometry, gene expression assays, and phenotypic analysis in culture or in vivo. In 2012, our lab identified and characterized a skeletal-muscle resident Tie2+ progenitor that exhibits adipogenic, chondrogenic, and osteogenic differentiation potentials (Wosczyna et al., J Bone Miner Res 27:1004-1017, 2012). This Tie2+ progenitor also expresses the markers PDGFRα and Sca-1 which in turn label a population of muscle-resident fibro/adipogenic progenitors (FAPs) (Joe et al., Nat Cell Biol 12:153-163, 2010; Uezumi et al., Nat Cell Biol 12:143-152, 2010), suggesting similar identities or overlap in the two mesenchymal progenitor populations. Our study demonstrated that these Tie2-expressing mesenchymal progenitors contribute robustly to BMP-induced heterotopic ossification (HO) in mice, and therefore could represent a key cellular target for therapeutic intervention in HO treatment (Wosczyna et al., J Bone Miner Res 27:1004-1017, 2012). In this chapter, we provide a detailed description of our updated fluorescence-activated cell sorting (FACS) strategy and describe cell culture methods for differentiation of Tie2+ progenitors to adipogenic and osteogenic fates. This strategy is easily adaptable for the prospective isolation of other rare subpopulations resident in skeletal muscle.

  5. Identification of inducible brown adipocyte progenitors residing in skeletal muscle and white fat

    PubMed Central

    Schulz, Tim J.; Huang, Tian Lian; Tran, Thien T.; Zhang, Hongbin; Townsend, Kristy L.; Shadrach, Jennifer L.; Cerletti, Massimiliano; McDougall, Lindsay E.; Giorgadze, Nino; Tchkonia, Tamara; Schrier, Denis; Falb, Dean; Kirkland, James L.; Wagers, Amy J.; Tseng, Yu-Hua

    2011-01-01

    Brown fat is specialized for energy expenditure and has therefore been proposed to function as a defense against obesity. Despite recent advances in delineating the transcriptional regulation of brown adipocyte differentiation, cellular lineage specification and developmental cues specifying brown-fat cell fate remain poorly understood. In this study, we identify and isolate a subpopulation of adipogenic progenitors (Sca-1+/CD45−/Mac1−; referred to as Sca-1+ progenitor cells, ScaPCs) residing in murine brown fat, white fat, and skeletal muscle. ScaPCs derived from different tissues possess unique molecular expression signatures and adipogenic capacities. Importantly, although the ScaPCs from interscapular brown adipose tissue (BAT) are constitutively committed brown-fat progenitors, Sca-1+ cells from skeletal muscle and subcutaneous white fat are highly inducible to differentiate into brown-like adipocytes upon stimulation with bone morphogenetic protein 7 (BMP7). Consistent with these findings, human preadipocytes isolated from subcutaneous white fat also exhibit the greatest inducible capacity to become brown adipocytes compared with cells isolated from mesenteric or omental white fat. When muscle-resident ScaPCs are re-engrafted into skeletal muscle of syngeneic mice, BMP7-treated ScaPCs efficiently develop into adipose tissue with brown fat-specific characteristics. Importantly, ScaPCs from obesity-resistant mice exhibit markedly higher thermogenic capacity compared with cells isolated from obesity-prone mice. These data establish the molecular characteristics of tissue-resident adipose progenitors and demonstrate a dynamic interplay between these progenitors and inductive signals that act in concert to specify brown adipocyte development. PMID:21173238

  6. Interkeukin-34, a cytokine crucial for the differentiation and maintenance of tissue resident macrophages and Langerhans cells.

    PubMed

    Wang, Yaming; Colonna, Marco

    2014-06-01

    IL-34 is a recently discovered cytokine that acts on tissue resident macrophages and Langerhans cells upon binding the receptor for CSF-1, CSF-1R. The existence of two ligands for CSF-1R, IL-34, and CSF-1, raises several intriguing questions. Are IL-34 and CSF-1 redundant or does each perform temporally and spatially distinct functions? Is IL-34 involved in human pathology? Would therapeutic strategies based on selective inhibition or administration of either IL-34 or CSF-1 be advantageous for preventing human pathology? Recent in vivo studies indicate that IL-34 promotes the development, survival, and function of microglia and Langerhans cells; therefore, this cytokine may predominately function in brain and skin biology. Here, we review the evidence for IL-34 as a key cytokine in the development and function of these two diverse cell types and discuss its potential role in pathological conditions.

  7. Interkeukin-34, a cytokine crucial for the differentiation and maintenance of tissue resident macrophages and Langerhans cells

    PubMed Central

    Wang, Yaming; Colonna, Marco

    2014-01-01

    IL-34 is a recently discovered cytokine that acts on tissue resident macrophages and Langerhans cells upon binding the receptor for CSF-1, CSF-1R. The existence of two ligands for CSF-1R, IL-34, and CSF-1, raises several intriguing questions. Are IL-34 and CSF-1 redundant or does each perform temporally and spatially distinct functions? Is IL-34 involved in human pathology? Would therapeutic strategies based on selective inhibition or administration of either IL-34 or CSF-1 be advantageous for preventing human pathology? Recent in vivo studies indicate that IL-34 promotes the development, survival, and function of microglia and Langerhans cells; therefore, this cytokine may predominately function in brain and skin biology. Here, we review the evidence for IL-34 as a key cytokine in the development and function of these two diverse cell types and discuss its potential role in pathological conditions. PMID:24737461

  8. Palmitoleic acid prevents palmitic acid-induced macrophage activation and consequent p38 MAPK-mediated skeletal muscle insulin resistance.

    PubMed

    Talbot, Nicola A; Wheeler-Jones, Caroline P; Cleasby, Mark E

    2014-08-05

    Obesity and saturated fatty acid (SFA) treatment are both associated with skeletal muscle insulin resistance (IR) and increased macrophage infiltration. However, the relative effects of SFA and unsaturated fatty acid (UFA)-activated macrophages on muscle are unknown. Here, macrophages were treated with palmitic acid, palmitoleic acid or both and the effects of the conditioned medium (CM) on C2C12 myotubes investigated. CM from palmitic acid-treated J774s (palm-mac-CM) impaired insulin signalling and insulin-stimulated glycogen synthesis, reduced Inhibitor κBα and increased phosphorylation of p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase in myotubes. p38 MAPK inhibition or siRNA partially ameliorated these defects, as did addition of tumour necrosis factor-α blocking antibody to the CM. Macrophages incubated with both FAs generated CM that did not induce IR, while palmitoleic acid-mac-CM alone was insulin sensitising. Thus UFAs may improve muscle insulin sensitivity and counteract SFA-mediated IR through an effect on macrophage activation.

  9. Exercise mitigates the adverse effects of hyperhomocysteinemia on macrophages, MMP-9, skeletal muscle, and white adipocytes.

    PubMed

    Winchester, Lee; Veeranki, Sudhakar; Givvimani, Srikanth; Tyagi, Suresh C

    2014-07-01

    Regular exercise is a great medicine with its benefits encompassing everything from prevention of cardiovascular risk to alleviation of different muscular myopathies. Interestingly, elevated levels of homocysteine (Hcy), also known as hyperhomocysteinemia (HHcy), antagonizes beta-2 adrenergic receptors (β2AR), gamma amino butyric acid (GABA), and peroxisome proliferator-activated receptor-gamma (PPARγ) receptors. HHcy also stimulates an elevation of the M1/M2 macrophage ratio, resulting in a more inflammatory profile. In this review we discuss several potential targets altered by HHcy that result in myopathy and excessive fat accumulation. Several of these HHcy mediated changes can be countered by exercise and culminate into mitigation of HHcy induced myopathy and metabolic syndrome. We suggest that exercise directly impacts levels of Hcy, matrix metalloproteinase 9 (MMP-9), macrophages, and G-protein coupled receptors (GPCRs, especially Gs). While HHcy promotes the M1 macrophage phenotype, it appears that exercise may diminish the M1/M2 ratio, resulting in a less inflammatory phenotype. HHcy through its influence on GPCRs, specifically β₂AR, PPARγ and GABA receptors, promotes accumulation of white fat, whereas exercise enhances the browning of white fat and counters HHcy-mediated effects on GPCRs. Alleviation of HHcy-associated pathologies with exercise also includes reversal of excessive MMP-9 activation. Moreover, exercise, by reducing plasma Hcy levels, may prevent skeletal muscle myopathy, improve exercise capacity and rescue the obese phenotype. The purpose of this review is to summarize the pathological conditions surrounding HHcy and to clarify the importance of regular exercise as a method of disease prevention.

  10. Administration of the non-steroidal anti-inflammatory drug ibuprofen increases macrophage concentrations but reduces necrosis during modified muscle use

    NASA Technical Reports Server (NTRS)

    Cheung, E. V.; Tidball, J. G.

    2003-01-01

    OBJECTIVE: To test the hypothesis that ibuprofen administration during modified muscle use reduces muscle necrosis and invasion by select myeloid cell populations. METHODS: Rats were subjected to hindlimb unloading for 10 days, after which they experienced muscle reloading by normal weight-bearing to induce muscle inflammation and necrosis. Some animals received ibuprofen by intraperitoneal injection 8 h prior to the onset of muscle reloading, and then again at 8 and 16 h following the onset of reloading. Other animals received buffer injection at 8 h prior to reloading and then ibuprofen at 8 and 16 h following the onset of reloading. Control animals received buffer only at each time point. Quantitative immunohistochemical analysis was used to assess the presence of necrotic muscle fibers, total inflammatory infiltrate, neutrophils, ED1+ macrophages and ED2+ macrophages at 24 h following the onset of reloading. RESULT: Administration of ibuprofen beginning 8 h prior to reloading caused significant reduction in the concentration of necrotic fibers, but increased the concentration of inflammatory cells in muscle. The increase in inflammatory cells was attributable to a 2.6-fold increase in the concentration of ED2+ macrophages. Animals treated with ibuprofen 8 h following the onset of reloading showed no decrease in muscle necrosis or increase in ED2+ macrophage concentrations. CONCLUSION: Administration of ibuprofen prior to increased muscle loading reduces muscle damage, but increases the concentration of macrophages that express the ED2 antigen. The increase in ED2+ macrophage concentration and decrease in necrosis may be mechanistically related because ED2+ macrophages have been associated with muscle regeneration and repair.

  11. Monocyte/macrophage cytokine activity regulates vascular smooth muscle cell function within a degradable polyurethane scaffold.

    PubMed

    Battiston, K G; Ouyang, B; Labow, R S; Simmons, C A; Santerre, J P

    2014-03-01

    Tissue engineering strategies rely on the ability to promote cell proliferation and migration into porous biomaterial constructs, as well as to support specific phenotypic states of the cells in vitro. The present study investigated the use of released factors from monocytes and their derived macrophages (MDM) and the mechanism by which they regulate vascular smooth muscle cell (VSMC) response in a VSMC-monocyte co-culture system within a porous degradable polyurethane (D-PHI) scaffold. VSMCs cultured in monocyte/MDM-conditioned medium (MCM), generated from the culture of monocytes/MDM on D-PHI scaffolds for up to 28 days, similarly affected VSMC contractile marker expression, growth and three-dimensional migration when compared to direct VSMC-monocyte co-culture. Monocyte chemotactic protein-1 (MCP-1) and interleukin-6 (IL-6) were identified as two cytokines present in MCM, at concentrations that have previously been shown to influence VSMC phenotype. VSMCs cultured alone on D-PHI scaffolds and exposed to MCP-1 (5 ng ml(-1)) or IL-6 (1 ng ml(-1)) for 7 days experienced a suppression in contractile marker expression (with MCP-1 or IL-6) and increased growth (with MCP-1) compared to no cytokine medium supplementation. These effects were also observed in VSMC-monocyte co-culture on D-PHI. Neutralization of IL-6, but not MCP-1, was subsequently shown to decrease VSMC growth and enhance calponin expression for VSMC-monocyte co-cultures on D-PHI scaffolds for 7 days, implying that IL-6 mediates VSMC response in monocyte-VSMC co-cultures. This study highlights the use of monocytes and their derived macrophages in conjunction with immunomodulatory biomaterials, such as D-PHI, as agents for regulating VSMC response, and demonstrates the importance of monocyte/MDM-released factors, such as IL-6 in particular, in this process.

  12. IL-10 Cytokine Released from M2 Macrophages Is Crucial for Analgesic and Anti-inflammatory Effects of Acupuncture in a Model of Inflammatory Muscle Pain

    PubMed Central

    da Silva, Morgana D.; Bobinski, Franciane; Sato, Karina L.; Kolker, Sandra J.; Sluka, Kathleen A.; Santos, Adair R. S.

    2014-01-01

    Muscle pain is a common medical problem that is difficult to treat. One nonpharmacological treatment used is acupuncture, a procedure in which fine needles are inserted into body points with the intent of relieving pain and other symptoms. Here we investigated the effects of manual acu-puncture (MA) on modulating macrophage phenotype and interleukin-10 (IL-10) concentrations in animals with muscle inflammation. Carrageenan, injected in the gastrocnemius muscle of mice, induces an inflammatory response characterized by mechanical hyperalgesia and edema. The inflammation is initially a neutrophilic infiltration that converts to a macrophage-dominated inflammation by 48 h. MA of the Sanyinjiao or Spleen 6 (SP6) acupoint reduces nociceptive behaviors, heat, and mechanical hyperalgesia and enhanced escape/avoidance and the accompanying edema. SP6 MA increased muscle IL-10 levels and was ineffective in reducing pain behaviors and edema in IL-10 knockout (IL-10−/−) mice. Repeated daily treatments with SP6 MA induced a phenotypic switch of muscle macrophages with reduced M1 macrophages (pro-inflammatory cells) and an increase of M2 macrophages (anti-inflammatory cells and important IL-10 source). These findings provide new evidence that MA produces a phenotypic switch in macrophages and increases IL-10 concentrations in muscle to reduce pain and inflammation. PMID:24961568

  13. IL-17A induces hypo-contraction of intestinal smooth muscle via induction of iNOS in muscularis macrophages.

    PubMed

    Mori, Daisuke; Watanabe, Nobumasa; Kaminuma, Osamu; Murata, Takahisa; Hiroi, Takachika; Ozaki, Hiroshi; Hori, Masatoshi

    2014-01-01

    Intestinal inflammation causes disorder in bowel motility. Th17 cytokines are involved in intestinal inflammation. To understand the role of interleukin (IL)-17 in intestinal motility, we examined effects of IL-17A on contractile activities of organ-cultured ileum. Rat ileal smooth muscle strips were organ cultured with IL-17A. Muscle contraction was measured, and cells expressing inducible nitric oxide synthase (iNOS) were identified with immunohistochemistry. Creating Th17-transferred colitis model mice, in vivo effects of IL-17 on contractile activities, and iNOS mRNA expression in colonic smooth muscle were investigated. Treatment with IL-17A for 12 h and 3 days attenuated carbachol- and membrane depolarization-induced contractions in organ-cultured rat ileum. N(G)-Nitro-l-arginine methyl ester (100 μM), a nitric oxide synthase inhibitor, completely reversed the IL-17A-induced inhibition of contractile force. Ileal tissue cultured in the presence of IL-17A showed increased expression of iNOS mRNA and protein. Immunohistochemical analysis using an iNOS antibody revealed that iNOS protein was expressed on ED2-positive muscularis macrophages. The level of iNOS mRNA was also increased in inflamed colonic smooth muscle of Th17-transferred colitis model mice. In intestinal inflammation, IL-17A induces an intestinal motility disorder through iNOS expression in muscularis macrophages.

  14. Inhibition of human arterial smooth muscle cell growth by human monocyte/macrophages: a co-culture study.

    PubMed

    Proudfoot, D; Fitzsimmons, C; Torzewski, J; Bowyer, D E

    1999-07-01

    Monocyte/macrophages produce a variety of substances which may influence the function of smooth muscle cells (SMC). During atherogenesis, macrophages are thought to modulate SMC migration, proliferation and synthesis of extracellular matrix. Such modulation is the balance between stimulatory and inhibitory influences. Thus, for example, our earlier studies have shown that macrophages not only secrete mitogens, but also produce small molecular weight inhibitors of SMC proliferation. In the present study, we have used a co-culture system in which human monocyte/macrophages were separated from human arterial SMC (hSMC) by a filter with the optional addition of a 12 kDa cut-off dialysis membrane, in order to assess their effect on hSMC growth. We have found that human peripheral blood-derived monocytes produced a substance of < 12 kDa that inhibited hSMC growth in the co-culture system. The monocyte-derived factor causing this effect was completely blocked by indomethacin, indicating that growth-inhibitory factors produced by the monocytes were cyclooxygenase products. We have shown that PGE1 and PGE2 inhibit hSMC growth, making them likely candidates for the effector molecules released from monocytes in our co-culture system.

  15. Th2 cytokine-induced alterations in intestinal smooth muscle function depend on alternatively activated macrophages

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Enteric nematode infection induces a strong Th2 cytokine response and is characterized by increased infiltration of various immune cells including macrophages. The role of these immune cells in host defense against enteric nematode infection, however, remains poorly defined. The present study invest...

  16. Monocytes/Macrophages Upregulate the Hyaluronidase HYAL1 and Adapt Its Subcellular Trafficking to Promote Extracellular Residency upon Differentiation into Osteoclasts

    PubMed Central

    Puissant, Emeline; Boonen, Marielle

    2016-01-01

    Osteoclasts are giant bone-resorbing cells originating from monocytes/macrophages. During their differentiation, they overexpress two lysosomal enzymes, cathepsin K and TRAP, which are secreted into the resorption lacuna, an acidified sealed area in contact with bone matrix where bone degradation takes place. Here we report that the acid hydrolase HYAL1, a hyaluronidase able to degrade the glycosaminoglycans hyaluronic acid (HA) and chondroitin sulfate, is also upregulated upon osteoclastogenesis. The mRNA expression and protein level of HYAL1 are markedly increased in osteoclasts differentiated from RAW264.7 mouse macrophages or primary mouse bone marrow monocytes compared to these precursor cells. As a result, the HYAL1-mediated HA hydrolysis ability of osteoclasts is strongly enhanced. Using subcellular fractionation, we demonstrate that HYAL1 proteins are sorted to the osteoclast lysosomes even though, in contrast to cathepsin K and TRAP, HYAL1 is poorly mannose 6-phosphorylated. We reported previously that macrophages secrete HYAL1 proforms by constitutive secretion, and that these are recaptured by the cell surface mannose receptor, processed in endosomes and sorted to lysosomes. Present work highlights that osteoclasts secrete HYAL1 in two ways, through lysosomal exocytosis and constitutive secretion, and that these cells promote the extracellular residency of HYAL1 through downregulation of the mannose receptor. Interestingly, the expression of the other main hyaluronidase, HYAL2, and of lysosomal exoglycosidases involved in HA degradation, does not increase similarly to HYAL1 upon osteoclastogenesis. Taken together, these findings point out the predominant involvement of HYAL1 in bone HA metabolism and perhaps bone remodeling via the resorption lacuna. PMID:27755597

  17. Tissues Use Resident Dendritic Cells and Macrophages to Maintain Homeostasis and to Regain Homeostasis upon Tissue Injury: The Immunoregulatory Role of Changing Tissue Environments

    PubMed Central

    Lech, Maciej; Gröbmayr, Regina; Weidenbusch, Marc; Anders, Hans-Joachim

    2012-01-01

    Most tissues harbor resident mononuclear phagocytes, that is, dendritic cells and macrophages. A classification that sufficiently covers their phenotypic heterogeneity and plasticity during homeostasis and disease does not yet exist because cell culture-based phenotypes often do not match those found in vivo. The plasticity of mononuclear phagocytes becomes obvious during dynamic or complex disease processes. Different data interpretation also originates from different conceptual perspectives. An immune-centric view assumes that a particular priming of phagocytes then causes a particular type of pathology in target tissues, conceptually similar to antigen-specific T-cell priming. A tissue-centric view assumes that changing tissue microenvironments shape the phenotypes of their resident and infiltrating mononuclear phagocytes to fulfill the tissue's need to maintain or regain homeostasis. Here we discuss the latter concept, for example, why different organs host different types of mononuclear phagocytes during homeostasis. We further discuss how injuries alter tissue environments and how this primes mononuclear phagocytes to enforce this particular environment, for example, to support host defense and pathogen clearance, to support the resolution of inflammation, to support epithelial and mesenchymal healing, and to support the resolution of fibrosis to the smallest possible scar. Thus, organ- and disease phase-specific microenvironments determine macrophage and dendritic cell heterogeneity in a temporal and spatial manner, which assures their support to maintain and regain homeostasis in whatever condition. Mononuclear phagocytes contributions to tissue pathologies relate to their central roles in orchestrating all stages of host defense and wound healing, which often become maladaptive processes, especially in sterile and/or diffuse tissue injuries. PMID:23251037

  18. Characterization of adipocytes derived from fibro/adipogenic progenitors resident in human skeletal muscle

    PubMed Central

    Arrighi, N; Moratal, C; Clément, N; Giorgetti-Peraldi, S; Peraldi, P; Loubat, A; Kurzenne, J-Y; Dani, C; Chopard, A; Dechesne, C A

    2015-01-01

    A population of fibro/adipogenic but non-myogenic progenitors located between skeletal muscle fibers was recently discovered. The aim of this study was to determine the extent to which these progenitors differentiate into fully functional adipocytes. The characterization of muscle progenitor-derived adipocytes is a central issue in understanding muscle homeostasis. They are considered as being the cellular origin of intermuscular adipose tissue that develops in several pathophysiological situations. Here fibro/adipogenic progenitors were isolated from a panel of 15 human muscle biopsies on the basis of the specific cell-surface immunophenotype CD15+/PDGFRα+CD56−. This allowed investigations of their differentiation into adipocytes and the cellular functions of terminally differentiated adipocytes. Adipogenic differentiation was found to be regulated by the same effectors as those regulating differentiation of progenitors derived from white subcutaneous adipose tissue. Similarly, basic adipocyte functions, such as triglyceride synthesis and lipolysis occurred at levels similar to those observed with subcutaneous adipose tissue progenitor-derived adipocytes. However, muscle progenitor-derived adipocytes were found to be insensitive to insulin-induced glucose uptake, in association with the impairment of phosphorylation of key insulin-signaling effectors. Our findings indicate that muscle adipogenic progenitors give rise to bona fide white adipocytes that have the unexpected feature of being insulin-resistant. PMID:25906156

  19. Satellite cells attract monocytes and use macrophages as a support to escape apoptosis and enhance muscle growth

    PubMed Central

    Chazaud, Bénédicte; Sonnet, Corinne; Lafuste, Peggy; Bassez, Guillaume; Rimaniol, Anne-Cécile; Poron, Françoise; Authier, François-Jérôme; Dreyfus, Patrick A.; Gherardi, Romain K.

    2003-01-01

    Once escaped from the quiescence niche, precursor cells interact with stromal components that support their survival, proliferation, and differentiation. We examined interplays between human myogenic precursor cells (mpc) and monocyte/macrophages (MP), the main stromal cell type observed at site of muscle regeneration. mpc selectively and specifically attracted monocytes in vitro after their release from quiescence, chemotaxis declining with differentiation. A DNA macroarray–based strategy identified five chemotactic factors accounting for 77% of chemotaxis: MP-derived chemokine, monocyte chemoattractant protein-1, fractalkine, VEGF, and the urokinase system. MP showed lower constitutive chemotactic activity than mpc, but attracted monocytes much strongly than mpc upon cross-stimulation, suggesting mpc-induced and predominantly MP-supported amplification of monocyte recruitment. Determination of [3H]thymidine incorporation, oligosomal DNA levels and annexin-V binding showed that MP stimulate mpc proliferation by soluble factors, and rescue mpc from apoptosis by direct contacts. We conclude that once activated, mpc, which are located close by capillaries, initiate monocyte recruitment and interplay with MP to amplify chemotaxis and enhance muscle growth. PMID:14662751

  20. Satellite cells attract monocytes and use macrophages as a support to escape apoptosis and enhance muscle growth.

    PubMed

    Chazaud, Bénédicte; Sonnet, Corinne; Lafuste, Peggy; Bassez, Guillaume; Rimaniol, Anne-Cécile; Poron, Françoise; Authier, François-Jerome; Dreyfus, Patrick A; Gherardi, Romain K

    2003-12-08

    Once escaped from the quiescence niche, precursor cells interact with stromal components that support their survival, proliferation, and differentiation. We examined interplays between human myogenic precursor cells (mpc) and monocyte/macrophages (MP), the main stromal cell type observed at site of muscle regeneration. mpc selectively and specifically attracted monocytes in vitro after their release from quiescence, chemotaxis declining with differentiation. A DNA macroarray-based strategy identified five chemotactic factors accounting for 77% of chemotaxis: MP-derived chemokine, monocyte chemoattractant protein-1, fractalkine, VEGF, and the urokinase system. MP showed lower constitutive chemotactic activity than mpc, but attracted monocytes much strongly than mpc upon cross-stimulation, suggesting mpc-induced and predominantly MP-supported amplification of monocyte recruitment. Determination of [3H]thymidine incorporation, oligosomal DNA levels and annexin-V binding showed that MP stimulate mpc proliferation by soluble factors, and rescue mpc from apoptosis by direct contacts. We conclude that once activated, mpc, which are located close by capillaries, initiate monocyte recruitment and interplay with MP to amplify chemotaxis and enhance muscle growth.

  1. CD8 T cells are involved in skeletal muscle regeneration through facilitating MCP-1 secretion and Gr1(high) macrophage infiltration.

    PubMed

    Zhang, Jing; Xiao, Zhicheng; Qu, Chao; Cui, Wei; Wang, Xiaonan; Du, Jie

    2014-11-15

    Inflammatory microenvironments play a key role in skeletal muscle regeneration. The infiltration of CD8 T cells into injured muscle has been reported. However, the role of CD8 T cells during skeletal muscle regeneration remains unclear. In this study, we used cardiotoxin-induced mouse skeletal muscle injury/regeneration model to investigate the role of CD8 T cells. Muscle regeneration was impaired and matrix deposit was increased in CD8α-deficient mice compared with wild-type (WT) mice whose CD8 T cells were infiltrated into damaged muscle after cardiotoxin injection. Adoptive transfer of CD8 T cells to CD8α-deficient mice improved muscle regeneration and inhibited matrix remodeling. Compared with WT mice, CD8α deficiency limited the recruitment of Gr1(high) macrophages (MPs) into muscle, resulting in the reduction of satellite cell number. The expression of MCP-1 (MCP-1/CCL2), which regulates the migration of Gr1(high) MPs, was reduced in CD8α-deficient mice compared with WT mice. Coculture CD8 T cells with MPs promoted MCP-1 secretion. The i.m. injection of MCP-1 markedly promoted the recruitment of Gr1(high) MPs and improved muscle regeneration in CD8α-deficient mice. We conclude that CD8 T cells are involved in skeletal muscle regeneration by regulating the secretion of MCP-1 to recruit Gr1(high) MPs, which facilitate myoblast proliferation.

  2. A MicroRNA93-IRF9-IRG1-Itaconic Acid Pathway Modulates M2-like-Macrophage Polarization to Revascularize Ischemic Muscle.

    PubMed

    Ganta, Vijay Chaitanya; Choi, Min Hyub; Kutateladze, Anna; Fox, Todd E; Farber, Charles R; Annex, Brian H

    2017-03-29

    Background -Currently no therapies exist for treating, and improving outcomes in patients with severe peripheral arterial disease (PAD). MicroRNA93 (miR93) has been shown to favorably modulate angiogenesis and reduce tissue loss in genetic PAD models. However, the cell specific function, downstream mechanisms or signaling involved in miR93 mediated ischemic muscle neovascularization is not clear. Macrophages were best known to modulate arteriogenic response in PAD and the extent of arteriogenic response induced by macrophages is dependent on greater M2 to M1-activation/polarization state. In the current study, we identified a novel mechanism by which miR93 regulates macrophage-polarization to promote angiogenesis and arteriogenesis to revascularize ischemic muscle in experimental-PAD. Methods -In vitro (macrophages, endothelial cells, skeletal muscle cells under normal and hypoxia serum starvation (HSS) conditions) and in vivo experiments in preclinical-PAD models (unilateral femoral artery ligation and resection) were conducted to examine the role of miR93-interferon regulatory factor-9 (IRF9)-immune responsive gene-1 (IRG1)-itaconic acid pathway in macrophage-polarization, angiogenesis, arteriogenesis and perfusion recovery. Results -In vivo, compared to wild type (WT) controls, miR106b-93-25 cluster deficient mice (miR106b-93-25(-/-)) showed decreased angiogenesis and arteriogenesis correlating with increased M1-like-macrophages following experimental-PAD. Intra-muscular delivery of miR93 in miR106b-93-25(-/-) PAD mice increased angiogenesis, arteriogenesis, the extent of perfusion which correlated with more M2-like-macrophages in the proximal and distal hind-limb muscles. In vitro, miR93 promotes and sustains M2-like-polarization even under M1-like-polarizing conditions (HSS). Delivery of bone marrow derived macrophages from miR106b-93-25(-/-) to WT ischemic-muscle decreased angiogenesis, arteriogenesis and perfusion, while transfer of wild-type macrophages to

  3. Cholesterol loading re-programs the miR-143/145-myocardin axis to convert aortic smooth muscle cells to a dysfunctional macrophage-like phenotype

    PubMed Central

    Vengrenyuk, Yuliya; Nishi, Hitoo; Long, Xiaochun; Ouimet, Mireille; Savji, Nazir; Martinez, Fernando O.; Cassella, Courtney P.; Moore, Kathryn J.; Ramsey, Stephen A.; Miano, Joseph M.; Fisher, Edward A.

    2015-01-01

    Objective We previously showed that cholesterol loading in vitro converts mouse aortic vascular smooth muscle cells (VSMC) from a contractile state to one resembling macrophages. In human and mouse atherosclerotic plaques it has become appreciated that ~40% of cells classified as macrophages by histological markers may be of VSMC origin. We therefore sought to gain insight into the molecular regulation of this clinically relevant process. Approach and Results VSMC of mouse (or human) origin were incubated with cyclodextrin-cholesterol complexes for 72 hours, at which time the expression at the protein and mRNA levels of contractile-related proteins were reduced and of macrophage markers increased. Concurrent was down regulation of miR-143/145, which positively regulate the master VSMC-differentiation transcription factor myocardin (MYOCD). Mechanisms were further probed in mouse VSMC. Maintaining the expression of MYOCD or miR-143/145 prevented and reversed phenotypic changes caused by cholesterol loading. Reversal was also seen when cholesterol efflux was stimulated after loading. Notably, despite expression of macrophage markers, bioinformatic analyses showed that cholesterol-loaded cells remained closer to the VSMC state, consistent with impairment in classical macrophage functions of phagocytosis and efferocytosis. In apoE-deficient atherosclerotic plaques, cells positive for VSMC and macrophage markers were found lining the cholesterol-rich necrotic core. Conclusions Cholesterol loading of VSMC converts them to a macrophage–appearing state by downregulating the miR-143/145-myocardin axis. Though these cells would be classified by immunohistochemistry as macrophages in human and mouse plaques, their transcriptome and functional properties imply that their contributions to atherogenesis would not be those of classical macrophages. PMID:25573853

  4. 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

  5. EPA protects against muscle damage in the mdx mouse model of Duchenne muscular dystrophy by promoting a shift from the M1 to M2 macrophage phenotype.

    PubMed

    Carvalho, Samara Camaçari de; Apolinário, Leticia Montanholi; Matheus, Selma Maria Michelin; Santo Neto, Humberto; Marques, Maria Julia

    2013-11-15

    In dystrophic mdx mice and in Duchenne muscular dystrophy, inflammation contributes to myonecrosis. Previously, we demonstrated that eicosapentaenoic acid (EPA) decreased inflammation and necrosis in dystrophic muscle. In the present study, we examined the effects of EPA and the corticoid deflazacort (DFZ) as modulators of M1 (iNOS-expressing cells) and M2 (CD206-expressing cells) macrophages. Mdx mice (14 days old) received EPA or DFZ for 16 days. The diaphragm, biceps brachii and quadriceps muscles were studied. Immunofluorescence, immunoblotting and ELISA assays showed that EPA increased interleucin-10, reduced interferon-γ and was more effective than DFZ in promoting a shift from M1 to M2.

  6. Prostaglandin E2 affects differently the release of inflammatory mediators from resident macrophages by LPS and muramyl tripeptides.

    PubMed Central

    Dieter, P; Hempel, U; Kamionka, S; Kolada, A; Malessa, B; Fitzke, E; Tran-Thi, T A

    1999-01-01

    LPS and MTP-PE (liposome-encapsulated N-acetyl-muramyl-L-alanyl-D-isoglutaminyl-L-alanine-2-:[1',2'dipalmitoyl -sni-glycero-3-(hydroxy-phosphoryl-oxyl)] etylamide) induce in liver macrophages a synthesis and release of TNF-alpha, nitric oxide and prostanoids. Both agents induce an expression of mRNA's encoding TNF-alpha, inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2, and of corresponding proteins. LPS and MTP-PE induce a rapid activation of the extracellular regulated kinase (ERK) isoenzymes-1 and -2. Inhibition of map kinase isoenzymes leads to a decreased release of TNF-alpha, nitric oxide and prostaglandin (PG) E2 after both agents. The transcription factors NF-kappaB and AP-1 are strongly activated by LPS within 30 minutes. MTP-PE induces a weak activation of both transcription factors only after 5 hours. Inhibition of NF-kappaB inhibits the LPS- but not the MTP-PE-induced release of TNF-alpha, nitric oxide and PGE2. PGE2 release after LPS is higher than after MTP-PE. Exogenously added PGE2 inhibits the activation of map kinase and TNF-alpha release by LPS, but not by MTP-PE. Release of nitric oxide after LPS and MTP-PE is enhanced after prior addition of PGE2. PGD2 is without any effect. MTP-PE, but not LPS, induces a cytotoxicity of Kupffer cells against P815 tumor target cells. The MTP-PE-induced cytotoxicity is reduced by TNF-alpha neutralizing antibodies, indicating the involvement of TNF-alpha. Thus our results suggest that the different potencies of LPS and MTP-PE as immunomodulators probably result from different actions on Kupffer cells, resulting in differences in the amounts and kinetics of released TNF-alpha and PGE2, and that PGE2 plays an important regulatory role in the action of LPS, but not in the actions of MTP-PE. PMID:10815618

  7. Adult vascular smooth muscle cells in culture express neural stem cell markers typical of resident multipotent vascular stem cells.

    PubMed

    Kennedy, Eimear; Mooney, Ciaran J; Hakimjavadi, Roya; Fitzpatrick, Emma; Guha, Shaunta; Collins, Laura E; Loscher, Christine E; Morrow, David; Redmond, Eileen M; Cahill, Paul A

    2014-10-01

    Differentiation of resident multipotent vascular stem cells (MVSCs) or de-differentiation of vascular smooth muscle cells (vSMCs) might be responsible for the SMC phenotype that plays a major role in vascular diseases such as arteriosclerosis and restenosis. We examined vSMCs from three different species (rat, murine and bovine) to establish whether they exhibit neural stem cell characteristics typical of MVSCs. We determined their SMC differentiation, neural stem cell marker expression and multipotency following induction in vitro by using immunocytochemistry, confocal microscopy, fluorescence-activated cell sorting analysis and quantitative real-time polymerase chain reaction. MVSCs isolated from rat aortic explants, enzymatically dispersed rat SMCs and rat bone-marrow-derived mesenchymal stem cells served as controls. Murine carotid artery lysates and primary rat aortic vSMCs were both myosin-heavy-chain-positive but weakly expressed the neural crest stem cell marker, Sox10. Each vSMC line examined expressed SMC differentiation markers (smooth muscle α-actin, myosin heavy chain and calponin), neural crest stem cell markers (Sox10(+), Sox17(+)) and a glia marker (S100β(+)). Serum deprivation significantly increased calponin and myosin heavy chain expression and decreased stem cell marker expression, when compared with serum-rich conditions. vSMCs did not differentiate to adipocytes or osteoblasts following adipogenic or osteogenic inductive stimulation, respectively, or respond to transforming growth factor-β1 or Notch following γ-secretase inhibition. Thus, vascular SMCs in culture express neural stem cell markers typical of MVSCs, concomitant with SMC differentiation markers, but do not retain their multipotency. The ultimate origin of these cells might have important implications for their use in investigations of vascular proliferative disease in vitro.

  8. Culture media-based selection of endothelial cells, pericytes, and perivascular-resident macrophage-like melanocytes from the young mouse vestibular system.

    PubMed

    Zhang, Jinhui; Chen, Songlin; Cai, Jing; Hou, Zhiqiang; Wang, Xiaohan; Kachelmeier, Allan; Shi, Xiaorui

    2017-03-01

    The vestibular blood-labyrinth barrier (BLB) is comprised of perivascular-resident macrophage-like melanocytes (PVM/Ms) and pericytes (PCs), in addition to endothelial cells (ECs) and basement membrane (BM), and bears strong resemblance to the cochlear BLB in the stria vascularis. Over the past few decades, in vitro cell-based models have been widely used in blood-brain barrier (BBB) and blood-retina barrier (BRB) research, and have proved to be powerful tools for studying cell-cell interactions in their respective organs. Study of both the vestibular and strial BLB has been limited by the unavailability of primary culture cells from these barriers. To better understand how barrier component cells interact in the vestibular system to control BLB function, we developed a novel culture medium-based method for obtaining EC, PC, and PVM/M primary cells from tiny explants of the semicircular canal, sacculus, utriculus, and ampullae tissue of young mouse ears at post-natal age 8-12 d. Each phenotype is grown in a specific culture medium which selectively supports the phenotype in a mixed population of vestibular cell types. The unwanted phenotypes do not survive passaging. The protocol does not require additional equipment or special enzyme treatment. The harvesting process takes less than 2 h. Primary cell types are generated within 7-10 d. The primary culture ECs, PCs, and PVM/M shave consistent phenotypes more than 90% pure after two passages (∼ 3 weeks). The highly purified primary cell lines can be used for studying cell-cell interactions, barrier permeability, and angiogenesis.

  9. Induction of bone-type alkaline phosphatase in human vascular smooth muscle cells: roles of tumor necrosis factor-alpha and oncostatin M derived from macrophages.

    PubMed

    Shioi, Atsushi; Katagi, Miwako; Okuno, Yasuhisa; Mori, Katsuhito; Jono, Shuichi; Koyama, Hidenori; Nishizawa, Yoshiki

    2002-07-12

    Inflammatory cells such as macrophages and T lymphocytes play an important role in vascular calcification associated with atherosclerosis and cardiac valvular disease. In particular, macrophages activated with cytokines derived from T lymphocytes such as interferon-gamma (IFN-gamma) may contribute to the development of vascular calcification. Moreover, we have shown the stimulatory effect of 1alpha,25-dihydroxyvitamin D3 (1,25(OH)2D3) on in vitro calcification through increasing the expression of alkaline phosphatase (ALP), an ectoenzyme indispensable for bone mineralization, in vascular smooth muscle cells. Therefore, we hypothesized that macrophages may induce calcifying phenotype, especially the expression of ALP in human vascular smooth muscle cells (HVSMCs) in the presence of IFN-gamma and 1,25(OH)2D3. To test this hypothesis, we used cocultures of HVSMCs with human monocytic cell line (THP-1) or peripheral blood monocytes (PBMCs) in the presence of IFN-gamma and 1,25(OH)2D3. THP-1 cells or PBMCs induced ALP activity and its gene expression in HVSMCs and the cells with high expression of ALP calcified their extracellular matrix by the addition of beta-glycerophosphate. Thermostability and immunoassay showed that ALP induced in HVSMCs was bone-specific enzyme. We further identified tumor necrosis factor-alpha (TNF-alpha) and oncostatin M (OSM) as major factors inducing ALP in HVSMCs in the culture supernatants of THP-1 cells. TNF-alpha and OSM, only when applied together, increased ALP activities and in vitro calcification in HVSMCs in the presence of IFN-gamma and 1,25(OH)2D3. These results suggest that macrophages may contribute to the development of vascular calcification through producing various inflammatory mediators, especially TNF-alpha and OSM.

  10. Effects of hyperbaric oxygen at 1.25 atmospheres absolute with normal air on macrophage number and infiltration during rat skeletal muscle regeneration.

    PubMed

    Fujita, Naoto; Ono, Miharu; Tomioka, Tomoka; Deie, Masataka

    2014-01-01

    Use of mild hyperbaric oxygen less than 2 atmospheres absolute (2026.54 hPa) with normal air is emerging as a common complementary treatment for severe muscle injury. Although hyperbaric oxygen at over 2 atmospheres absolute with 100% O2 promotes healing of skeletal muscle injury, it is not clear whether mild hyperbaric oxygen is equally effective. The purpose of the present study was to investigate the impact of hyperbaric oxygen at 1.25 atmospheres absolute (1266.59 hPa) with normal air on muscle regeneration. The tibialis anterior muscle of male Wistar rats was injured by injection of bupivacaine hydrochloride, and rats were randomly assigned to a hyperbaric oxygen experimental group or to a non-hyperbaric oxygen control group. Immediately after the injection, rats were exposed to hyperbaric oxygen, and the treatment was continued for 28 days. The cross-sectional area of centrally nucleated muscle fibers was significantly larger in rats exposed to hyperbaric oxygen than in controls 5 and 7 days after injury. The number of CD68- or CD68- and CD206-positive cells was significantly higher in rats exposed to hyperbaric oxygen than in controls 24 h after injury. Additionally, tumor necrosis factor-α and interleukin-10 mRNA expression levels were significantly higher in rats exposed to hyperbaric oxygen than in controls 24 h after injury. The number of Pax7- and MyoD- or MyoD- and myogenin-positive nuclei per mm2 and the expression levels of these proteins were significantly higher in rats exposed to hyperbaric oxygen than in controls 5 days after injury. These results suggest that mild hyperbaric oxygen promotes skeletal muscle regeneration in the early phase after injury, possibly due to reduced hypoxic conditions leading to accelerated macrophage infiltration and phenotype transition. In conclusion, mild hyperbaric oxygen less than 2 atmospheres absolute with normal air is an appropriate support therapy for severe muscle injuries.

  11. The roles of supernatant of macrophage treated by excretory-secretory products from muscle larvae of Trichinella spiralis on the differentiation of C2C12 myoblasts.

    PubMed

    Bai, X; Wang, X L; Tang, B; Shi, H N; Boireau, P; Rosenthal, B; Wu, X P; Liu, M Y; Liu, X L

    2016-11-15

    The excretory-secretory products (ESPs) released by the muscle-larvae (ML) stage of Trichinella spiralis have been suggested to be involved in nurse cell formation. However, the molecular mechanisms by which ML-ESPs modulate nurse cell formation remain unclear. Macrophages exert either beneficial or deleterious effects on tissue repair, depending on their activation/polarization state. They are crucial for skeletal muscle repair, notably, via their actions on myogenic precursor cells. However, these interactions during T. spiralis infection have not been characterized. In the present study, the ability of conditioned medium (CM) from J774A.1 macrophages treated with ML-ESPs to influence the differentiation of murine myoblasts, and the mechanisms of this influence, were investigated in vitro. The results showed that the expression of Myogenic Regulatory Factors (MRFs) MyoD and myogenin, myosin heavy chain (MyHC), and the p21 cyclin-dependent kinase inhibitor were reduced in CM treated cells compared to their expression in the control group. These findings indicated that CM inhibited myoblast differentiation. Conversely, CM promoted myoblast proliferation and increased cyclin D1 levels. Taken together, results of our study suggested that CM can indirectly influence myoblast differentiation and proliferation, which provides a new method for the elucidation of the complex mechanisms involved in cell-parasite and cell-cell interactions during T. spiralis infection.

  12. Role of bone marrow macrophages in controlling homeostasis and repair in bone and bone marrow niches.

    PubMed

    Kaur, Simranpreet; Raggatt, Liza Jane; Batoon, Lena; Hume, David Arthur; Levesque, Jean-Pierre; Pettit, Allison Robyn

    2017-01-01

    Macrophages, named for their phagocytic ability, participate in homeostasis, tissue regeneration and inflammatory responses. Bone and adjacent marrow contain multiple functionally unique resident tissue macrophage subsets which maintain and regulate anatomically distinct niche environments within these interconnected tissues. Three subsets of bone-bone marrow resident tissue macrophages have been characterised; erythroblastic island macrophages, haematopoietic stem cell niche macrophages and osteal macrophages. The role of these macrophages in controlling homeostasis and repair in bone and bone marrow niches is reviewed in detail.

  13. Macrophages in Synovial Inflammation

    PubMed Central

    Kennedy, Aisling; Fearon, Ursula; Veale, Douglas J.; Godson, Catherine

    2011-01-01

    Synovial macrophages are one of the resident cell types in synovial tissue and while they remain relatively quiescent in the healthy joint, they become activated in the inflamed joint and, along with infiltrating monocytes/macrophages, regulate secretion of pro-inflammatory cytokines and enzymes involved in driving the inflammatory response and joint destruction. Synovial macrophages are positioned throughout the sub-lining layer and lining layer at the cartilage–pannus junction and mediate articular destruction. Sub-lining macrophages are now also considered as the most reliable biomarker for disease severity and response to therapy in rheumatoid arthritis (RA). There is a growing understanding of the molecular drivers of inflammation and an appreciation that the resolution of inflammation is an active process rather than a passive return to homeostasis, and this has implications for our understanding of the role of macrophages in inflammation. Macrophage phenotype determines the cytokine secretion profile and tissue destruction capabilities of these cells. Whereas inflammatory synovial macrophages have not yet been classified into one phenotype or another it is widely known that TNFα and IL-l, characteristically released by M1 macrophages, are abundant in RA while IL-10 activity, characteristic of M2 macrophages, is somewhat diminished. Here we will briefly review our current understanding of macrophages and macrophage polarization in RA as well as the elements implicated in controlling polarization, such as cytokines and transcription factors like NFκB, IRFs and NR4A, and pro-resolving factors, such as LXA4 and other lipid mediators which may promote a non-inflammatory, pro-resolving phenotype, and may represent a novel therapeutic paradigm. PMID:22566842

  14. Transcriptional Regulation and Macrophage Differentiation.

    PubMed

    Hume, David A; Summers, Kim M; Rehli, Michael

    2016-06-01

    Monocytes and macrophages are professional phagocytes that occupy specific niches in every tissue of the body. Their survival, proliferation, and differentiation are controlled by signals from the macrophage colony-stimulating factor receptor (CSF-1R) and its two ligands, CSF-1 and interleukin-34. In this review, we address the developmental and transcriptional relationships between hematopoietic progenitor cells, blood monocytes, and tissue macrophages as well as the distinctions from dendritic cells. A huge repertoire of receptors allows monocytes, tissue-resident macrophages, or pathology-associated macrophages to adapt to specific microenvironments. These processes create a broad spectrum of macrophages with different functions and individual effector capacities. The production of large transcriptomic data sets in mouse, human, and other species provides new insights into the mechanisms that underlie macrophage functional plasticity.

  15. The application of adjuvant autologous antravesical macrophage cell therapy vs. BCG in non-muscle invasive bladder cancer: a multicenter, randomized trial

    PubMed Central

    2010-01-01

    Introduction While adjuvant immunotherapy with Bacille Calmette Guérin (BCG) is effective in non-muscle-invasive bladder cancer (BC), adverse events (AEs) are considerable. Monocyte-derived activated killer cells (MAK) are discussed as essential in antitumoural immunoresponse, but their application may imply risks. The present trial compared autologous intravesical macrophage cell therapy (BEXIDEM®) to BCG in patients after transurethral resection (TURB) of BC. Materials and methods This open-label trial included 137 eligible patients with TaG1-3, T1G1-2 plurifocal or unifocal tumours and ≥ 2 occurrences within 24 months and was conducted from June 2004 to March 2007. Median follow-up for patients without recurrence was 12 months. Patients were randomized to BCG or mononuclear cells collected by apheresis after ex vivo cell processing and activation (BEXIDEM). Either arm treatment consisted of 6 weekly instillations and 2 cycles of 3 weekly instillations at months 3 and 6. Toxicity profile (primary endpoint) and prophylactic effects (secondary endpoint) were assessed. Results Patient characteristics were evenly distributed. Of 73 treated with BCG and 64 with BEXIDEM, 85% vs. 45% experienced AEs and 26% vs. 14% serious AEs (SAE), respectively (p < 0.001). Recurrence occurred significantly less frequent with BCG than with BEXIDEM (12% vs. 38%; p < 0.001). Discussion This initial report of autologous intravesical macrophage cell therapy in BC demonstrates BEXIDEM treatment to be safe. Recurrence rates were significantly lower with BCG however. As the efficacy of BEXIDEM remains uncertain, further data, e.g. marker lesions studies, are warranted. Trial registration The trial has been registered in the ISRCTN registry http://isrctn.org under the registration number ISRCTN35881130. PMID:20529333

  16. Functionally deficient mesenchymal stem cells reside in the bone marrow niche with M2-macrophages and amyloid-β protein adjacent to loose total joint implants.

    PubMed

    Margulies, Bryan S; DeBoyace, Sean D; Parsons, Adrienne M; Policastro, Connor G; Ee, Jessica S S; Damron, Timothy S

    2015-05-01

    We sought to demonstrate whether there is a difference in the local mesenchymal stem cells (MSC) niche obtained from patients undergoing their first total joint replacement surgery versus those patients undergoing a revision surgery for an failing total joint implant. Bone marrow aspirates collected from patients undergoing revision total joint arthroplasty were observed to be less clonal and the expression of PDGFRα, CD51, ALCAM, endoglin, CXCL12, nestin, and nucleostemin were decreased. Revision MSC were also less able to commit to an osteoblast-lineage or an adipocyte-lineage. Further, in revision MSC, OPG, and IL6 expression were increased. Monocytes, derived from revision whole marrow aspirates, were less capable of differentiating into osteoclasts, the cells implicated in the pathologic degradation of bone. Osteoclasts were also not observed in tissue samples collected adjacent to the implants of revision patients; however, the alternatatively activated M2-macrophage phenotype was observed in parallel with pathologic accumulations of amyloid-β, τ-protien and 3-nitrotyrosine. Despite the limited numbers of patients examined, our data suggest that nucleostemin may be a useful functional marker for MSC while the observation of M2-macrophage infiltration around the implant lays the foundation for future investigation into a novel mechanism that we propose is associated with loose total joint implants.

  17. Macrophage elastase kills bacteria within murine macrophages.

    PubMed

    Houghton, A McGarry; Hartzell, William O; Robbins, Clinton S; Gomis-Rüth, F Xavier; Shapiro, Steven D

    2009-07-30

    Macrophages are aptly positioned to function as the primary line of defence against invading pathogens in many organs, including the lung and peritoneum. Their ability to phagocytose and clear microorganisms has been well documented. Macrophages possess several substances with which they can kill bacteria, including reactive oxygen species, nitric oxide, and antimicrobial proteins. We proposed that macrophage-derived proteinases may contribute to the antimicrobial properties of macrophages. Macrophage elastase (also known as matrix metalloproteinase 12 or MMP12) is an enzyme predominantly expressed in mature tissue macrophages and is implicated in several disease processes, including emphysema. Physiological functions for MMP12 have not been described. Here we show that Mmp12(-/-) mice exhibit impaired bacterial clearance and increased mortality when challenged with both gram-negative and gram-positive bacteria at macrophage-rich portals of entry, such as the peritoneum and lung. Intracellular stores of MMP12 are mobilized to macrophage phagolysosomes after the ingestion of bacterial pathogens. Once inside phagolysosomes, MMP12 adheres to bacterial cell walls where it disrupts cellular membranes resulting in bacterial death. The antimicrobial properties of MMP12 do not reside within its catalytic domain, but rather within the carboxy-terminal domain. This domain contains a unique four amino acid sequence on an exposed beta loop of the protein that is required for the observed antimicrobial activity. The present study represents, to our knowledge, the first report of direct antimicrobial activity by a matrix metallopeptidase, and describes a new antimicrobial peptide that is sequentially and structurally unique in nature.

  18. Rosiglitazone Inhibits Acyl-CoA Synthetase Activity and Fatty Acid Partitioning to Diacylglycerol and Triacylglycerol via a Peroxisome Proliferator–Activated Receptor-γ–Independent Mechanism in Human Arterial Smooth Muscle Cells and Macrophages

    PubMed Central

    Askari, Bardia; Kanter, Jenny E.; Sherrid, Ashley M.; Golej, Deidre L.; Bender, Andrew T.; Liu, Joey; Hsueh, Willa A.; Beavo, Joseph A.; Coleman, Rosalind A.; Bornfeldt, Karin E.

    2010-01-01

    Rosiglitazone is an insulin-sensitizing agent that has recently been shown to exert beneficial effects on atherosclerosis. In addition to peroxisome proliferator–activated receptor (PPAR)-γ, rosiglitazone can affect other targets, such as directly inhibiting recombinant long-chain acyl-CoA synthetase (ACSL)-4 activity. Because it is unknown if ACSL4 is expressed in vascular cells involved in atherosclerosis, we investigated the ability of rosiglitazone to inhibit ACSL activity and fatty acid partitioning in human and murine arterial smooth muscle cells (SMCs) and macrophages. Human and murine SMCs and human macrophages expressed Acsl4, and rosiglitazone inhibited Acsl activity in these cells. Furthermore, rosiglitazone acutely inhibited partitioning of fatty acids into phospholipids in human SMCs and inhibited fatty acid partitioning into diacylglycerol and triacylglycerol in human SMCs and macrophages through a PPAR-γ–independent mechanism. Conversely, murine macrophages did not express ACSL4, and rosiglitazone did not inhibit ACSL activity in these cells, nor did it affect acute fatty acid partitioning into cellular lipids. Thus, rosiglitazone inhibits ACSL activity and fatty acid partitioning in human and murine SMCs and in human macrophages through a PPAR-γ–independent mechanism likely to be mediated by ACSL4 inhibition. Therefore, rosiglitazone might alter the biological effects of fatty acids in these cells and in atherosclerosis. PMID:17259370

  19. The Elusive Antifibrotic Macrophage

    PubMed Central

    Adhyatmika, Adhyatmika; Putri, Kurnia S. S.; Beljaars, Leonie; Melgert, Barbro N.

    2015-01-01

    Fibrotic diseases, especially of the liver, the cardiovascular system, the kidneys, and the lungs, account for approximately 45% of deaths in Western societies. Fibrosis is a serious complication associated with aging and/or chronic inflammation or injury and cannot be treated effectively yet. It is characterized by excessive deposition of extracellular matrix (ECM) proteins by myofibroblasts and impaired degradation by macrophages. This ultimately destroys the normal structure of an organ, which leads to loss of function. Most efforts to develop drugs have focused on inhibiting ECM production by myofibroblasts and have not yielded many effective drugs yet. Another option is to stimulate the cells that are responsible for degradation and uptake of excess ECM, i.e., antifibrotic macrophages. However, macrophages are plastic cells that have many faces in fibrosis, including profibrotic behavior-stimulating ECM production. This can be dependent on their origin, as the different organs have tissue-resident macrophages with different origins and a various influx of incoming monocytes in steady-state conditions and during fibrosis. To be able to pharmacologically stimulate the right kind of behavior in fibrosis, a thorough characterization of antifibrotic macrophages is necessary, as well as an understanding of the signals they need to degrade ECM. In this review, we will summarize the current state of the art regarding the antifibrotic macrophage phenotype and the signals that stimulate its behavior. PMID:26618160

  20. Tumor associated macrophages polarization dictates the efficacy of BCG instillation in non-muscle invasive urothelial bladder cancer

    PubMed Central

    2013-01-01

    Background To evaluate the prognostic role of TAMs in patients affected by non-muscle invasive bladder cancer (NMIBC), undergone Trans Urethral Resection of Bladder (TURB) and Bacillus Calmette-Guerin (BCG) therapy. Methods Data from 40 patients (36 men, 4 women), mean age 69 years (40-83 years), treated for NMIBC with TURB and BCG instillation were collected. Two different groups were considered: group with and group without bladder cancer recurrence. Correlations between immunofluorescence measured Mtot, M1 and M2 infiltration and clinicopathological parameters were evaluated using Spearman and Mann–Whitney methods. The recurrence-free survival rate was calculated using the Kaplan-Meier method. Results CD68 positive cells (Mtot) were observed in all specimens tested. High Mtot, M1 and M2 infiltration was observed in patients with disease recurrence, even before endovescical BCG instillation. Significant value for M2 infiltration (p = 0,042) was found calculating significativity between two group medians before BCG therapy. p = 0,072 and p = 0,180 were observed correlating median of Mtot and M1 between two groups of patients respectively. Values of p = 0,44, p = 0,23 and p = 0,64 from correlation between DFS and Mtot, M1 and M2 median in patients before endovescical BCG instillation, were calculated respectively. Comparing DFS and Mtot, M1 and M2 median in patients group after endovescical BCG instillation significant values were obtained (p = 0,020; p = 0,02; and p = 0,029 respectively). Conclusions M2 tumor infiltration could be a prognostic value of recurrence in patients with NMIBC. PMID:24423367

  1. Intracellular multiplication of Paracoccidioides brasiliensis in macrophages: killing and restriction of multiplication by activated macrophages.

    PubMed Central

    Brummer, E; Hanson, L H; Restrepo, A; Stevens, D A

    1989-01-01

    The effect of coculturing yeast-form Paracoccidioides brasiliensis with murine cells was studied. Coculture of resident peritoneal or pulmonary macrophages with P. brasiliensis for 72 h dramatically enhanced fungal multiplication 19.3 +/- 2.4- and 4.7 +/- 0.8-fold, respectively, compared with cocultures with lymph node cells or complete tissue culture medium alone. Support of P. brasiliensis multiplication by resident peritoneal macrophages was macrophage dose dependent. Lysates of macrophages, supernatants from macrophage cultures, or McVeigh-Morton broth, like complete tissue culture medium, did not support multiplication of P. brasiliensis in 72-h cultures. Time course microscopic studies of cocultures in slide wells showed that macrophages ingested P. brasiliensis cells and that the ingested cells multiplied intracellularly. In sharp contrast to resident macrophages, lymphokine-activated peritoneal and pulmonary macrophages not only prevented multiplication but reduced inoculum CFU by 96 and 100%, respectively, in 72 h. Microscopic studies confirmed killing and digestion of P. brasiliensis ingested by activated macrophages in 48 h. These findings indicate that resident macrophages are permissive for intracellular multiplication of P. brasiliensis and that this could be a factor in pathogenicity. By contrast, activated macrophages are fungicidal for P. brasiliensis. Images PMID:2744848

  2. Regenerative function of immune system: Modulation of muscle stem cells.

    PubMed

    Saini, Jasdeep; McPhee, Jamie S; Al-Dabbagh, Sarah; Stewart, Claire E; Al-Shanti, Nasser

    2016-05-01

    Ageing is characterised by progressive deterioration of physiological systems and the loss of skeletal muscle mass is one of the most recognisable, leading to muscle weakness and mobility impairments. This review highlights interactions between the immune system and skeletal muscle stem cells (widely termed satellite cells or myoblasts) to influence satellite cell behaviour during muscle regeneration after injury, and outlines deficits associated with ageing. Resident neutrophils and macrophages in skeletal muscle become activated when muscle fibres are damaged via stimuli (e.g. contusions, strains, avulsions, hyperextensions, ruptures) and release high concentrations of cytokines, chemokines and growth factors into the microenvironment. These localised responses serve to attract additional immune cells which can reach in excess of 1×10(5) immune cell/mm(3) of skeletal muscle in order to orchestrate the repair process. T-cells have a delayed response, reaching peak activation roughly 4 days after the initial damage. The cytokines and growth factors released by activated T-cells play a key role in muscle satellite cell proliferation and migration, although the precise mechanisms of these interactions remain unclear. T-cells in older people display limited ability to activate satellite cell proliferation and migration which is likely to contribute to insufficient muscle repair and, consequently, muscle wasting and weakness. If the factors released by T-cells to activate satellite cells can be identified, it may be possible to develop therapeutic agents to enhance muscle regeneration and reduce the impact of muscle wasting during ageing and disease.

  3. Macrophage Polarization.

    PubMed

    Murray, Peter J

    2017-02-10

    Macrophage polarization refers to how macrophages have been activated at a given point in space and time. Polarization is not fixed, as macrophages are sufficiently plastic to integrate multiple signals, such as those from microbes, damaged tissues, and the normal tissue environment. Three broad pathways control polarization: epigenetic and cell survival pathways that prolong or shorten macrophage development and viability, the tissue microenvironment, and extrinsic factors, such as microbial products and cytokines released in inflammation. A plethora of advances have provided a framework for rationally purifying, describing, and manipulating macrophage polarization. Here, I assess the current state of knowledge about macrophage polarization and enumerate the major questions about how activated macrophages regulate the physiology of normal and damaged tissues.

  4. Biology of Bony Fish Macrophages

    PubMed Central

    Hodgkinson, Jordan W.; Grayfer, Leon; Belosevic, Miodrag

    2015-01-01

    Macrophages are found across all vertebrate species, reside in virtually all animal tissues, and play critical roles in host protection and homeostasis. Various mechanisms determine and regulate the highly plastic functional phenotypes of macrophages, including antimicrobial host defenses (pro-inflammatory, M1-type), and resolution and repair functions (anti-inflammatory/regulatory, M2-type). The study of inflammatory macrophages in immune defense of teleosts has garnered much attention, and antimicrobial mechanisms of these cells have been extensively studied in various fish models. Intriguingly, both similarities and differences have been documented for the regulation of lower vertebrate macrophage antimicrobial defenses, as compared to what has been described in mammals. Advances in our understanding of the teleost macrophage M2 phenotypes likewise suggest functional conservation through similar and distinct regulatory strategies, compared to their mammalian counterparts. In this review, we discuss the current understanding of the molecular mechanisms governing teleost macrophage functional heterogeneity, including monopoetic development, classical macrophage inflammatory and antimicrobial responses as well as alternative macrophage polarization towards tissues repair and resolution of inflammation. PMID:26633534

  5. Macrophages in tissue repair, regeneration, and fibrosis

    PubMed Central

    Wynn, Thomas A.; Vannella, Kevin M.

    2016-01-01

    Inflammatory monocytes and resident tissue macrophages are key regulators of tissue repair, regeneration, and fibrosis. Following tissue injury, monocytes and macrophages undergo marked phenotypic and functional changes to play critical roles during the initiation, maintenance, and resolution phases of tissue repair. Disturbances in macrophage function can lead to aberrant repair, with uncontrolled inflammatory mediator and growth factor production, deficient generation of anti-inflammatory macrophages, or failed communication between macrophages and epithelial cells, endothelial cells, fibroblasts, and stem or tissue progenitor cells all contributing to a state of persistent injury, which may lead to the development of pathological fibrosis. In this review, we discuss the mechanisms that instruct macrophages to adopt pro-inflammatory, pro-wound healing, pro-fibrotic, anti-inflammatory, anti-fibrotic, pro-resolving, and tissue regenerating phenotypes following injury, and highlight how some of these mechanisms and macrophage activation states could be exploited therapeutically. PMID:26982353

  6. Regulation of macrophage functions by L-arginine

    PubMed Central

    1989-01-01

    Sites of inflammation with prominent macrophage infiltration, such as wounds and certain tumors, are uniquely deficient in free arginine. The effects of arginine availability on macrophage physiology were investigated. When cultured in media containing less than 0.1 mM L- arginine, rat resident peritoneal macrophages exhibited enhanced spreading, tumor cytotoxicity, superoxide production, phagocytosis, and protein synthesis. Thus, arginine concentrations similar to those found in sites of inflammation can augment macrophage functions, while those found in plasma (approximately 0.1 mM) and in commonly used culture media (0.4 to 1.2 mM) are inhibitory. Culture in homoarginine, but not D-arginine, ornithine, citrulline, urea, histidine, or lysine also inhibited macrophage tumor cytotoxicity, indicating the specificity of the effect. In contrast to resident macrophages, the tumor cytotoxicity of peritoneal macrophages obtained after C. parvum injection was suppressed by culture in arginine-deficient media. However, L-arginine- deficient media enhanced all other activation-associated functions in C. parvum-elicited macrophages as in resident cells. Arginine-free wound fluid promoted resident macrophage tumoricidal activity when compared with rat serum, and again, the addition of L-arginine was inhibitory. The marked effects of L-arginine availability on macrophage functions, together with the knowledge that these cells modify the extracellular arginine concentration in sites of inflammation through arginase, provide evidence for an autoregulatory mechanism of macrophage activation. PMID:2538541

  7. Muscle repair and regeneration: stem cells, scaffolds, and the contributions of skeletal muscle to amphibian limb regeneration.

    PubMed

    Milner, Derek J; Cameron, Jo Ann

    2013-01-01

    Skeletal muscle possesses a robust innate capability for repair of tissue damage. Natural repair of muscle damage is a stepwise process that requires the coordinated activity of a number of cell types, including infiltrating macrophages, resident myogenic and non-myogenic stem cells, and connective tissue fibroblasts. Despite the proficiency of this intrinsic repair capability, severe injuries that result in significant loss of muscle tissue overwhelm the innate repair process and require intervention if muscle function is to be restored. Recent advances in stem cell biology, regenerative medicine, and materials science have led to attempts at developing tissue engineering-based methods for repairing severe muscle defects. Muscle tissue also plays a role in the ability of tailed amphibians to regenerate amputated limbs through epimorphic regeneration. Muscle contributes adult stem cells to the amphibian regeneration blastema, but it can also contribute blastemal cells through the dedifferentiation of multinucleate myofibers into mononuclear precursors. This fascinating plasticity and its contributions to limb regeneration have prompted researchers to investigate the potential for mammalian muscle to undergo dedifferentiation. Several works have shown that mammalian myotubes can be fragmented into mononuclear cells and induced to re-enter the cell cycle, but mature myofibers are resistant to fragmentation. However, recent works suggest that there may be a path to inducing fragmentation of mature myofibers into proliferative multipotent cells with the potential for use in muscle tissue engineering and regenerative therapies.

  8. Macrophages: Their Emerging Roles in Bone

    PubMed Central

    Sinder, Benjamin P; Pettit, Allison R; McCauley, Laurie K

    2016-01-01

    Macrophages are present in nearly all tissues and are critical for development, homeostasis, and regeneration. Resident tissue macrophages of bone, termed osteal macrophages, are recently classified myeloid cells that are distinct from osteoclasts. Osteal macrophages are located immediately adjacent to osteoblasts, regulate bone formation, and play diverse roles in skeletal homeostasis. Genetic or pharmacological modulation of macrophages in vivo results in significant bone phenotypes, and these phenotypes depend on which macrophage subsets are altered. Macrophages are also key mediators of osseous wound healing and fracture repair, with distinct roles at various stages of the repair process. A central function of macrophages is their phagocytic ability. Each day, billions of cells die in the body and efferocytosis (phagocytosis of apoptotic cells) is a critical process in both clearing dead cells and recruitment of replacement progenitor cells to maintain homeostasis. Recent data suggest a role for efferocytosis in bone biology and these new mechanisms are outlined. Finally, although macrophages have an established role in primary tumors, emerging evidence suggests that macrophages in bone support cancers which preferentially metastasize to the skeleton. Collectively, this developing area of osteoimmunology raises new questions and promises to provide novel insights into pathophysiologic conditions as well as therapeutic and regenerative approaches vital for skeletal health. PMID:26531055

  9. Genome-wide approaches to defining macrophage identity and function

    PubMed Central

    Fonseca, Gregory J; Seidman, Jason S; Glass, Christopher K

    2016-01-01

    Macrophages play essential roles in the response to injury and infection and contribute to the development and/or homeostasis of the various tissues they reside in. Conversely, macrophages also influence the pathogenesis of metabolic, neurodegenerative, and neoplastic diseases. Mechanisms that contribute to the phenotypic diversity of macrophages in health and disease remain poorly understood. Here we review the recent application of genome-wide approaches to characterize the transcriptomes and epigenetic landscapes of tissue-resident macrophages. These studies are beginning to provide insights into how distinct tissue environments are interpreted by transcriptional regulatory elements to drive specialized programs of gene expression. PMID:28087927

  10. Pathophysiological relevance of macrophage subsets in atherogenesis.

    PubMed

    Liberale, Luca; Dallegri, Franco; Montecucco, Fabrizio; Carbone, Federico

    2017-01-05

    Macrophages are highly heterogeneous and plastic cells. They were shown to play a critical role in all stages of atherogenesis, from the initiation to the necrotic core formation and plaque rupture. Lesional macrophages primarily derive from blood monocyte, but local macrophage proliferation as well as differentiation from smooth muscle cells have also been described. Within atherosclerotic plaques, macrophages rapidly respond to changes in the microenvironment, shifting between pro- (M1) or anti-inflammatory (M2) functional phenotypes. Furthermore, different stimuli have been associated with differentiation of newly discovered M2 subtypes: IL-4/IL-13 (M2a), immune-complex (M2b), IL-10/glucocorticoids (M2c), and adenosine receptor agonist (M2d). More recently, additional intraplaque macrophage phenotypes were also recognized in response to CXCL4 (M4), oxidized phospholipids (Mox), haemoglobin/haptoglobin complexes (HA-mac/M(Hb)), and heme (Mhem). Such macrophage polarization was described as a progression among multiple phenotypes, which reflect the activity of different transcriptional factors and the cross-talk between intracellular signalling. Finally, the distribution of macrophage subsets within different plaque areas was markedly associated with cardiovascular (CV) vulnerability. The aim of this review is to update the current knowledge on the role of macrophage subsets in atherogenesis. In addition, the molecular mechanisms underlying macrophage phenotypic shift will be summarised and discussed. Finally, the role of intraplaque macrophages as predictors of CV events and the therapeutic potential of these cells will be discussed.

  11. Macrophage-mediated inflammation and glial response in the skeletal muscle of a rat model of familial amyotrophic lateral sclerosis (ALS).

    PubMed

    Van Dyke, Jonathan M; Smit-Oistad, Ivy M; Macrander, Corey; Krakora, Dan; Meyer, Michael G; Suzuki, Masatoshi

    2016-03-01

    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor dysfunction and loss of large motor neurons in the spinal cord and brain stem. While much research has focused on mechanisms of motor neuron cell death in the spinal cord, degenerative processes in skeletal muscle and neuromuscular junctions (NMJs) are also observed early in disease development. Although recent studies support the potential therapeutic benefits of targeting the skeletal muscle in ALS, relatively little is known about inflammation and glial responses in skeletal muscle and near NMJs, or how these responses contribute to motor neuron survival, neuromuscular innervation, or motor dysfunction in ALS. We recently showed that human mesenchymal stem cells modified to release glial cell line-derived neurotrophic factor (hMSC-GDNF) extend survival and protect NMJs and motor neurons in SOD1(G93A) rats when delivered to limb muscles. In this study, we evaluate inflammatory and glial responses near NMJs in the limb muscle collected from a rat model of familial ALS (SOD1(G93A) transgenic rats) during disease progression and following hMSC-GDNF transplantation. Muscle samples were collected from pre-symptomatic, symptomatic, and end-stage animals. A significant increase in the expression of microglial inflammatory markers (CD11b and CD68) occurred in the skeletal muscle of symptomatic and end-stage SOD1(G93A) rats. Inflammation was confirmed by ELISA for inflammatory cytokines interleukin-1 β (IL-1β) and tumor necrosis factor-α (TNF-α) in muscle homogenates of SOD1(G93A) rats. Next, we observed active glial responses in the muscle of SOD1(G93A) rats, specifically near intramuscular axons and NMJs. Interestingly, strong expression of activated glial markers, glial fibrillary acidic protein (GFAP) and nestin, was observed in the areas adjacent to NMJs. Finally, we determined whether ex vivo trophic factor delivery influences inflammation and terminal

  12. Macrophage-mediated inflammation and glial response in the skeletal muscle of a rat model of familial amyotrophic lateral sclerosis (ALS)

    PubMed Central

    Van Dyke, Jonathan M.; Smit-Oistad, Ivy M.; Macrander, Corey; Krakora, Dan; Meyer, Michael G.; Suzuki, Masatoshi

    2016-01-01

    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor dysfunction and loss of large motor neurons in the spinal cord and brain stem. While much research has focused on mechanisms of motor neuron cell death in the spinal cord, degenerative processes in skeletal muscle and neuromuscular junctions (NMJs) are also observed early in disease development. Although recent studies support the potential therapeutic benefits of targeting the skeletal muscle in ALS, relatively little is known about inflammation and glial responses in skeletal muscle and near NMJs, or how these responses contribute to motor neuron survival, neuromuscular innervation, or motor dysfunction in ALS. We recently showed that human mesenchymal stem cells modified to release glial cell line-derived neurotrophic factor (hMSC-GDNF) extend survival and protect NMJs and motor neurons in SOD1G93A rats when delivered to limb muscles. In this study, we evaluate inflammatory and glial responses near NMJs in the limb muscle collected from a rat model of familial ALS (SOD1G93A transgenic rats) during disease progression and following hMSC-GDNF transplantation. Muscle samples were collected from pre-symptomatic, symptomatic, and end-stage animals. A significant increase in the expression of microglial inflammatory markers (CD11b and CD68) occurred in the skeletal muscle of symptomatic and end-stage SOD1G93A rats. Inflammation was confirmed by ELISA for inflammatory cytokines interleukin-1 β (IL-1β) and tumor necrosis factor-α (TNF-α) in muscle homogenates of SOD1G93A rats. Next, we observed active glial responses in the muscle of SOD1G93A rats, specifically near intramuscular axons and NMJs. Interestingly, strong expression of activated glial markers, glial fibrillary acidic protein (GFAP) and nestin, was observed in the areas adjacent to NMJs. Finally, we determined whether ex vivo trophic factor delivery influences inflammation and terminal Schwann cell

  13. Interleukin-10 reduces the pathology of mdx muscular dystrophy by deactivating M1 macrophages and modulating macrophage phenotype.

    PubMed

    Villalta, S Armando; Rinaldi, Chiara; Deng, Bo; Liu, Grace; Fedor, Brian; Tidball, James G

    2011-02-15

    M1 macrophages play a major role in worsening muscle injury in the mdx mouse model of Duchenne muscular dystrophy. However, mdx muscle also contains M2c macrophages that can promote tissue repair, indicating that factors regulating the balance between M1 and M2c phenotypes could influence the severity of the disease. Because interleukin-10 (IL-10) modulates macrophage activation in vitro and its expression is elevated in mdx muscles, we tested whether IL-10 influenced the macrophage phenotype in mdx muscle and whether changes in IL-10 expression affected the pathology of muscular dystrophy. Ablation of IL-10 expression in mdx mice increased muscle damage in vivo and reduced mouse strength. Treating mdx muscle macrophages with IL-10 reduced activation of the M1 phenotype, assessed by iNOS expression, and macrophages from IL-10 null mutant mice were more cytolytic than macrophages isolated from wild-type mice. Our data also showed that muscle cells in mdx muscle expressed the IL-10 receptor, suggesting that IL-10 could have direct effects on muscle cells. We assayed whether ablation of IL-10 in mdx mice affected satellite cell numbers, using Pax7 expression as an index, but found no effect. However, IL-10 mutation significantly increased myogenin expression in vivo during the acute and the regenerative phase of mdx pathology. Together, the results show that IL-10 plays a significant regulatory role in muscular dystrophy that may be caused by reducing M1 macrophage activation and cytotoxicity, increasing M2c macrophage activation and modulating muscle differentiation.

  14. Regulatory interactions between muscle and the immune system during muscle regeneration.

    PubMed

    Tidball, James G; Villalta, S Armando

    2010-05-01

    Recent discoveries reveal complex interactions between skeletal muscle and the immune system that regulate muscle regeneration. In this review, we evaluate evidence that indicates that the response of myeloid cells to muscle injury promotes muscle regeneration and growth. Acute perturbations of muscle activate a sequence of interactions between muscle and inflammatory cells. The initial inflammatory response is a characteristic Th1 inflammatory response, first dominated by neutrophils and subsequently by CD68(+) M1 macrophages. M1 macrophages can propagate the Th1 response by releasing proinflammatory cytokines and cause further tissue damage through the release of nitric oxide. Myeloid cells in the early Th1 response stimulate the proliferative phase of myogenesis through mechanisms mediated by TNF-alpha and IL-6; experimental prolongation of their presence is associated with delayed transition to the early differentiation stage of myogenesis. Subsequent invasion by CD163(+)/CD206(+) M2 macrophages attenuates M1 populations through the release of anti-inflammatory cytokines, including IL-10. M2 macrophages play a major role in promoting growth and regeneration; their absence greatly slows muscle growth following injury or modified use and inhibits muscle differentiation and regeneration. Chronic muscle injury leads to profiles of macrophage invasion and function that differ from acute injuries. For example, mdx muscular dystrophy yields invasion of muscle by M1 macrophages, but their early invasion is accompanied by a subpopulation of M2a macrophages. M2a macrophages are IL-4 receptor(+)/CD206(+) cells that reduce cytotoxicity of M1 macrophages. Subsequent invasion of dystrophic muscle by M2c macrophages is associated with progression of the regenerative phase in pathophysiology. Together, these findings show that transitions in macrophage phenotype are an essential component of muscle regeneration in vivo following acute or chronic muscle damage.

  15. Regulatory interactions between muscle and the immune system during muscle regeneration

    PubMed Central

    Villalta, S. Armando

    2010-01-01

    Recent discoveries reveal complex interactions between skeletal muscle and the immune system that regulate muscle regeneration. In this review, we evaluate evidence that indicates that the response of myeloid cells to muscle injury promotes muscle regeneration and growth. Acute perturbations of muscle activate a sequence of interactions between muscle and inflammatory cells. The initial inflammatory response is a characteristic Th1 inflammatory response, first dominated by neutrophils and subsequently by CD68+ M1 macrophages. M1 macrophages can propagate the Th1 response by releasing proinflammatory cytokines and cause further tissue damage through the release of nitric oxide. Myeloid cells in the early Th1 response stimulate the proliferative phase of myogenesis through mechanisms mediated by TNF-α and IL-6; experimental prolongation of their presence is associated with delayed transition to the early differentiation stage of myogenesis. Subsequent invasion by CD163+/CD206+ M2 macrophages attenuates M1 populations through the release of anti-inflammatory cytokines, including IL-10. M2 macrophages play a major role in promoting growth and regeneration; their absence greatly slows muscle growth following injury or modified use and inhibits muscle differentiation and regeneration. Chronic muscle injury leads to profiles of macrophage invasion and function that differ from acute injuries. For example, mdx muscular dystrophy yields invasion of muscle by M1 macrophages, but their early invasion is accompanied by a subpopulation of M2a macrophages. M2a macrophages are IL-4 receptor+/CD206+ cells that reduce cytotoxicity of M1 macrophages. Subsequent invasion of dystrophic muscle by M2c macrophages is associated with progression of the regenerative phase in pathophysiology. Together, these findings show that transitions in macrophage phenotype are an essential component of muscle regeneration in vivo following acute or chronic muscle damage. PMID:20219869

  16. Macrophage skewing by Phd2 haplodeficiency prevents ischaemia by inducing arteriogenesis.

    PubMed

    Takeda, Yukiji; Costa, Sandra; Delamarre, Estelle; Roncal, Carmen; Leite de Oliveira, Rodrigo; Squadrito, Mario Leonardo; Finisguerra, Veronica; Deschoemaeker, Sofie; Bruyère, Françoise; Wenes, Mathias; Hamm, Alexander; Serneels, Jens; Magat, Julie; Bhattacharyya, Tapan; Anisimov, Andrey; Jordan, Benedicte F; Alitalo, Kari; Maxwell, Patrick; Gallez, Bernard; Zhuang, Zhen W; Saito, Yoshihiko; Simons, Michael; De Palma, Michele; Mazzone, Massimiliano

    2011-10-09

    PHD2 serves as an oxygen sensor that rescues blood supply by regulating vessel formation and shape in case of oxygen shortage. However, it is unknown whether PHD2 can influence arteriogenesis. Here we studied the role of PHD2 in collateral artery growth by using hindlimb ischaemia as a model, a process that compensates for the lack of blood flow in case of major arterial occlusion. We show that Phd2 (also known as Egln1) haplodeficient (Phd2(+/-)) mice displayed preformed collateral arteries that preserved limb perfusion and prevented tissue necrosis in ischaemia. Improved arteriogenesis in Phd2(+/-) mice was due to an expansion of tissue-resident, M2-like macrophages and their increased release of arteriogenic factors, leading to enhanced smooth muscle cell (SMC) recruitment and growth. Both chronic and acute deletion of one Phd2 allele in macrophages was sufficient to skew their polarization towards a pro-arteriogenic phenotype. Mechanistically, collateral vessel preconditioning relied on the activation of canonical NF-κB pathway in Phd2(+/-) macrophages. These results unravel how PHD2 regulates arteriogenesis and artery homeostasis by controlling a specific differentiation state in macrophages and suggest new treatment options for ischaemic disorders.

  17. Monocyte and Macrophage Dynamics during Atherogenesis

    PubMed Central

    Ley, Klaus; Miller, Yury I.; Hedrick, Catherine C.

    2011-01-01

    Vascular inflammation is associated with and in large part driven by changes in the leukocyte compartment of the vessel wall. Here, we focus on monocyte influx during atherosclerosis, the most common form of vascular inflammation. Although the arterial wall contains a large number of resident macrophages and some resident dendritic cells, atherosclerosis drives a rapid influx of inflammatory monocytes (Ly-6C+ in mice) and other monocytes (Ly-6C− in mice, also known as patrolling monocytes). Once in the vessel wall, Ly-6C+ monocytes differentiate to a phenotype consistent with inflammatory macrophages and inflammatory dendritic cells. The phenotype of these cells is modulated by lipid uptake, Toll-like receptor ligands, hematopoietic growth factors, cytokines and chemokines. In addition to newly recruited macrophages, it is likely that resident macrophages also change their phenotype. Monocyte-derived inflammatory macrophages have a short half-life. After undergoing apoptosis, they may be taken up by surrounding macrophages or, if the phagocytic capacity is overwhelmed, can undergo secondary necrosis, a key event in forming the necrotic core of atherosclerotic lesions. In this review, we discuss these and other processes associated with monocytic cell dynamics in the vascular wall and their role in the initiation and progression of atherosclerosis. PMID:21677293

  18. The Effects of Increased Cardiac Output, Surgical Isolation and Countercurrent Exchange at the Femoral Artery on the Residence Time of Xenon in Muscle

    DTIC Science & Technology

    1993-11-01

    Correct positioning was confirmed by a continuous pressure recording (Gould). We removed the skin and subcutaneous tissues of the left gastrocnemius muscle...hypoxemia persisted and was resistant to efforts to correct it ( recessing the endotracheal tube, increasing airway pressures) for the duration of the

  19. Macrophages and Uveitis in Experimental Animal Models

    PubMed Central

    Mérida, Salvador; Palacios, Elena; Bosch-Morell, Francisco

    2015-01-01

    Resident and infiltrated macrophages play relevant roles in uveitis as effectors of innate immunity and inductors of acquired immunity. They are major effectors of tissue damage in uveitis and are also considered to be potent antigen-presenting cells. In the last few years, experimental animal models of uveitis have enabled us to enhance our understanding of the leading role of macrophages in eye inflammation processes, including macrophage polarization in experimental autoimmune uveoretinitis and the major role of Toll-like receptor 4 in endotoxin-induced uveitis. This improved knowledge should guide advantageous iterative research to establish mechanisms and possible therapeutic targets for human uveitis resolution. PMID:26078494

  20. Monocyte/macrophage differentiation in dermatomyositis and polymyositis.

    PubMed

    Rostasy, Kevin M; Piepkorn, Martin; Goebel, Hans-Hilmar; Menck, Sylvia; Hanefeld, Folker; Schulz-Schaeffer, Walter J

    2004-08-01

    Recent advances have revealed significant differences in the pathogenesis of inflammatory myopathies. To determine whether different patterns of macrophage differentiation are a useful tool to delineate the major groups of inflammatory myopathies, the muscle biopsies of 11 patients with dermatomyositis and 12 patients with polymyositis were studied using different macrophage markers. In polymyositis, the early-activation markers MRP14 and 27E10 stained the majority of macrophages, which were recognized by the pan-macrophage marker Ki-M1P and which were located primarily in the endomysium. In dermatomyositis, macrophages predominantly expressed the late-activation marker 25F9 and were found mainly in the perimysium. Thus, the location and presence of different subsets of macrophages distinguish dermatomyositis and polymyositis. The predominance of early-activated macrophages in polymyositis indicates a more acute disease process. The findings in dermatomyositis, by contrast, suggest a role of persistent monocytes/macrophages in the disease process.

  1. Developmental origin of lung macrophage diversity

    PubMed Central

    Tan, Serena Y. S.; Krasnow, Mark A.

    2016-01-01

    Macrophages are specialized phagocytic cells, present in all tissues, which engulf and digest pathogens, infected and dying cells, and debris, and can recruit and regulate other immune cells and the inflammatory response and aid in tissue repair. Macrophage subpopulations play distinct roles in these processes and in disease, and are typically recognized by differences in marker expression, immune function, or tissue of residency. Although macrophage subpopulations in the brain have been found to have distinct developmental origins, the extent to which development contributes to macrophage diversity between tissues and within tissues is not well understood. Here, we investigate the development and maintenance of mouse lung macrophages by marker expression patterns, genetic lineage tracing and parabiosis. We show that macrophages populate the lung in three developmental waves, each giving rise to a distinct lineage. These lineages express different markers, reside in different locations, renew in different ways, and show little or no interconversion. Thus, development contributes significantly to lung macrophage diversity and targets each lineage to a different anatomical domain. PMID:26952982

  2. Macrophages: Regulators of the Inflammatory Microenvironment during Mammary Gland Development and Breast Cancer

    PubMed Central

    Brady, Nicholas J.; Chuntova, Pavlina; Schwertfeger, Kathryn L.

    2016-01-01

    Macrophages are critical mediators of inflammation and important regulators of developmental processes. As a key phagocytic cell type, macrophages evolved as part of the innate immune system to engulf and process cell debris and pathogens. Macrophages produce factors that act directly on their microenvironment and also bridge innate immune responses to the adaptive immune system. Resident macrophages are important for acting as sensors for tissue damage and maintaining tissue homeostasis. It is now well-established that macrophages are an integral component of the breast tumor microenvironment, where they contribute to tumor growth and progression, likely through many of the mechanisms that are utilized during normal wound healing responses. Because macrophages contribute to normal mammary gland development and breast cancer growth and progression, this review will discuss both resident mammary gland macrophages and tumor-associated macrophages with an emphasis on describing how macrophages interact with their surrounding environment during normal development and in the context of cancer. PMID:26884646

  3. Macrophages: Regulators of the Inflammatory Microenvironment during Mammary Gland Development and Breast Cancer.

    PubMed

    Brady, Nicholas J; Chuntova, Pavlina; Schwertfeger, Kathryn L

    2016-01-01

    Macrophages are critical mediators of inflammation and important regulators of developmental processes. As a key phagocytic cell type, macrophages evolved as part of the innate immune system to engulf and process cell debris and pathogens. Macrophages produce factors that act directly on their microenvironment and also bridge innate immune responses to the adaptive immune system. Resident macrophages are important for acting as sensors for tissue damage and maintaining tissue homeostasis. It is now well-established that macrophages are an integral component of the breast tumor microenvironment, where they contribute to tumor growth and progression, likely through many of the mechanisms that are utilized during normal wound healing responses. Because macrophages contribute to normal mammary gland development and breast cancer growth and progression, this review will discuss both resident mammary gland macrophages and tumor-associated macrophages with an emphasis on describing how macrophages interact with their surrounding environment during normal development and in the context of cancer.

  4. Effect of lipopolysaccharide on protein accumulation by murine peritoneal macrophages: the correlation to activation for macrophage tumoricidal function

    SciTech Connect

    Tannenbaum, C.S.

    1987-01-01

    The protein synthetic patterns of tumoricidal murine peritoneal macrophage populations have been compared to those of non-tumoricidal populations utilizing two dimensional polyacrylamide gel electrophoresis (2D PAGE) of (/sup 35/S)-methionine-labeled proteins. While the protein synthetic patterns exhibited by resident, inflammatory and activated macrophages had numerous common features which distinguished them from the other normal non-macrophage cell types examined, unique proteins also distinguished each macrophage population from the others. Peritoneal macrophages elicited by treatment with heat killed Propionibacterium acnes, the live, attenuated Mycobacterium bovis strain BCG, Listeria monocytogenes and the protozoan flagellate Trypanosoma rhodesiense, all exhibited tumoricidal activity in 16h or 72h functional assays, and shared a common protein synthetic profile which differentiated them from the synthetic patterns characteristic of the non-tumoricidal resident and inflammatory macrophages.

  5. Resident vascular progenitor cells.

    PubMed

    Torsney, Evelyn; Xu, Qingbo

    2011-02-01

    Homeostasis of the vessel wall is essential for maintaining its function, including blood pressure and patency of the lumen. In physiological conditions, the turnover rate of vascular cells, i.e. endothelial and smooth muscle cells, is low, but markedly increased in diseased situations, e.g. vascular injury after angioplasty. It is believed that mature vascular cells have an ability to proliferate to replace lost cells normally. On the other hand, recent evidence indicates stem/progenitor cells may participate in vascular repair and the formation of neointimal lesions in severely damaged vessels. It was found that all three layers of the vessels, the intima, media and adventitia, contain resident progenitor cells, including endothelial progenitor cells, mesenchymal stromal cells, Sca-1+ and CD34+ cells. Data also demonstrated that these resident progenitor cells could differentiate into a variety of cell types in response to different culture conditions. However, collective data were obtained mostly from in vitro culture assays and phenotypic marker studies. There are many unanswered questions concerning the mechanism of cell differentiation and the functional role of these cells in vascular repair and the pathogenesis of vascular disease. In the present review, we aim to summarize the data showing the presence of the resident progenitor cells, to highlight possible signal pathways orchestrating cell differentiation toward endothelial and smooth muscle cells, and to discuss the data limitations, challenges and controversial issues related to the role of progenitors. This article is part of a special issue entitled, "Cardiovascular Stem Cells Revisited".

  6. A muscle stem cell for every muscle: variability of satellite cell biology among different muscle groups.

    PubMed

    Randolph, Matthew E; Pavlath, Grace K

    2015-01-01

    The human body contains approximately 640 individual skeletal muscles. Despite the fact that all of these muscles are composed of striated muscle tissue, the biology of these muscles and their associated muscle stem cell populations are quite diverse. Skeletal muscles are affected differentially by various muscular dystrophies (MDs), such that certain genetic mutations specifically alter muscle function in only a subset of muscles. Additionally, defective muscle stem cells have been implicated in the pathology of some MDs. The biology of muscle stem cells varies depending on the muscles with which they are associated. Here we review the biology of skeletal muscle stem cell populations of eight different muscle groups. Understanding the biological variation of skeletal muscles and their resident stem cells could provide valuable insight into mechanisms underlying the susceptibility of certain muscles to myopathic disease.

  7. A muscle stem cell for every muscle: variability of satellite cell biology among different muscle groups

    PubMed Central

    Randolph, Matthew E.; Pavlath, Grace K.

    2015-01-01

    The human body contains approximately 640 individual skeletal muscles. Despite the fact that all of these muscles are composed of striated muscle tissue, the biology of these muscles and their associated muscle stem cell populations are quite diverse. Skeletal muscles are affected differentially by various muscular dystrophies (MDs), such that certain genetic mutations specifically alter muscle function in only a subset of muscles. Additionally, defective muscle stem cells have been implicated in the pathology of some MDs. The biology of muscle stem cells varies depending on the muscles with which they are associated. Here we review the biology of skeletal muscle stem cell populations of eight different muscle groups. Understanding the biological variation of skeletal muscles and their resident stem cells could provide valuable insight into mechanisms underlying the susceptibility of certain muscles to myopathic disease. PMID:26500547

  8. Permanent resident.

    PubMed

    Fisher, John F

    2016-01-01

    The training of physicians in the past century was based primarily on responsibility and the chain-of-command. Those with the bulk of that responsibility in the fields of pediatrics and internal medicine were residents. Residents trained the medical students and supervised them carefully in caring for patients. Most attending physicians supervised their teams at arm's length, primarily serving as teachers of the finer points of diagnosis and treatment during set periods of the day or week with a perfunctory signature on write-ups or progress notes. Residents endeavored to protect the attending physician from being heavily involved unless they were unsure about a clinical problem. Before contacting the attending physician, a more senior resident would be called. Responsibility was the ultimate teacher. The introduction of diagnosis-related groups by the federal government dramatically changed the health care delivery system, placing greater emphasis on attending physician visibility in the medical record, ultimately resulting in more attending physician involvement in day-to-day care of patients in academic institutions. Without specified content in attending notes, hospital revenues would decline. Although always in charge technically, attending physicians increasingly have assumed the role once dominated by the resident. Using biographical experiences of more than 40 years, the author acknowledges and praises the educational role of responsibility in his own training and laments its declining role in today's students and house staff.

  9. CRIg-expressing peritoneal macrophages are associated with disease severity in patients with cirrhosis and ascites

    PubMed Central

    Irvine, Katharine M.; Banh, Xuan; Gadd, Victoria L.; Wojcik, Kyle K.; Ariffin, Juliana K.; Jose, Sara; Lukowski, Samuel; Baillie, Gregory J.; Sweet, Matthew J.; Powell, Elizabeth E.

    2016-01-01

    Infections are an important cause of morbidity and mortality in patients with decompensated cirrhosis and ascites. Hypothesizing that innate immune dysfunction contributes to susceptibility to infection, we assessed ascitic fluid macrophage phenotype and function. The expression of complement receptor of the immunoglobulin superfamily (CRIg) and CCR2 defined two phenotypically and functionally distinct peritoneal macrophage subpopulations. The proportion of CRIghi macrophages differed between patients and in the same patient over time, and a high proportion of CRIghi macrophages was associated with reduced disease severity (model for end-stage liver disease) score. As compared with CRIglo macrophages, CRIghi macrophages were highly phagocytic and displayed enhanced antimicrobial effector activity. Transcriptional profiling by RNA sequencing and comparison with human macrophage and murine peritoneal macrophage expression signatures highlighted similarities among CRIghi cells, human macrophages, and mouse F4/80hi resident peritoneal macrophages and among CRIglo macrophages, human monocytes, and mouse F4/80lo monocyte-derived peritoneal macrophages. These data suggest that CRIghi and CRIglo macrophages may represent a tissue-resident population and a monocyte-derived population, respectively. In conclusion, ascites fluid macrophage subset distribution and phagocytic capacity is highly variable among patients with chronic liver disease. Regulating the numbers and/or functions of these macrophage populations could provide therapeutic opportunities in cirrhotic patients. PMID:27699269

  10. Mechanisms of Organ Injury and Repair by Macrophages.

    PubMed

    Vannella, Kevin M; Wynn, Thomas A

    2017-02-10

    Macrophages regulate tissue regeneration following injury. They can worsen tissue injury by producing reactive oxygen species and other toxic mediators that disrupt cell metabolism, induce apoptosis, and exacerbate ischemic injury. However, they also produce a variety of growth factors, such as IGF-1, VEGF-α, TGF-β, and Wnt proteins that regulate epithelial and endothelial cell proliferation, myofibroblast activation, stem and tissue progenitor cell differentiation, and angiogenesis. Proresolving macrophages in turn restore tissue homeostasis by functioning as anti-inflammatory cells, and macrophage-derived matrix metalloproteinases regulate fibrin and collagen turnover. However, dysregulated macrophage function impairs wound healing and contributes to the development of fibrosis. Consequently, the mechanisms that regulate these different macrophage activation states have become active areas of research. In this review, we discuss the common and unique mechanisms by which macrophages instruct tissue repair in the liver, nervous system, heart, lung, skeletal muscle, and intestine and illustrate how macrophages might be exploited therapeutically.

  11. Antimicrobial proteins of murine macrophages.

    PubMed Central

    Hiemstra, P S; Eisenhauer, P B; Harwig, S S; van den Barselaar, M T; van Furth, R; Lehrer, R I

    1993-01-01

    Three murine microbicidal proteins (MUMPs) were purified from cells of the murine macrophage cell line RAW264.7 that had been activated by gamma interferon. Similar proteins were also present in nonactivated RAW264.7 cells, in cells of the murine macrophage cell line J774A.1, and in resident and activated murine peritoneal macrophages. MUMP-1, MUMP-2, and MUMP-3 killed Salmonella typhimurium, Escherichia coli, Staphylococcus aureus, Listeria monocytogenes, Mycobacterium fortuitum, and Cryptococcus neoformans in vitro. MUMP-1 resembled an H1 histone but was unusual because its N-terminal residue (serine) was not N acetylated. Although MUMP-2 was N terminally blocked, its high lysine/arginine ratio and its reactivity with an antibody to H1 histones suggested that it also belonged to the H1 histone family. MUMP-3 was identical to histone H2B in 30 of 30 amino-terminal residues. Although the antimicrobial properties of histones have been recognized for decades, this is the first evidence that such proteins may endow the lysosomal apparatus of macrophages with nonoxidative antimicrobial potential. Other MUMPs, including some with a more restricted antimicrobial spectrum and one that appeared to be induced in RAW264.7 cells after gamma interferon stimulation, were noted but remain to be characterized. Images PMID:8514411

  12. Macrophage origin limits functional plasticity in helminth-bacterial co-infection

    PubMed Central

    Campbell, Sharon M.; Duncan, Sheelagh; Hewitson, James P.; Barr, Tom A.; Jackson-Jones, Lucy H.; Maizels, Rick M.

    2017-01-01

    Rapid reprogramming of the macrophage activation phenotype is considered important in the defense against consecutive infection with diverse infectious agents. However, in the setting of persistent, chronic infection the functional importance of macrophage-intrinsic adaptation to changing environments vs. recruitment of new macrophages remains unclear. Here we show that resident peritoneal macrophages expanded by infection with the nematode Heligmosomoides polygyrus bakeri altered their activation phenotype in response to infection with Salmonella enterica ser. Typhimurium in vitro and in vivo. The nematode-expanded resident F4/80high macrophages efficiently upregulated bacterial induced effector molecules (e.g. MHC-II, NOS2) similarly to newly recruited monocyte-derived macrophages. Nonetheless, recruitment of blood monocyte-derived macrophages to Salmonella infection occurred with equal magnitude in co-infected animals and caused displacement of the nematode-expanded, tissue resident-derived macrophages from the peritoneal cavity. Global gene expression analysis revealed that although nematode-expanded resident F4/80high macrophages made an anti-bacterial response, this was muted as compared to newly recruited F4/80low macrophages. However, the F4/80high macrophages adopted unique functional characteristics that included enhanced neutrophil-stimulating chemokine production. Thus, our data provide important evidence that plastic adaptation of MΦ activation does occur in vivo, but that cellular plasticity is outweighed by functional capabilities specific to the tissue origin of the cell. PMID:28334040

  13. Gap junctional communication between vascular cells. Induction of connexin43 messenger RNA in macrophage foam cells of atherosclerotic lesions.

    PubMed Central

    Polacek, D.; Lal, R.; Volin, M. V.; Davies, P. F.

    1993-01-01

    The structure and function of blood vessels depend on the ability of vascular cells to receive and transduce signals and to communicate with each other. One means by which vascular cells have been shown to communicate is via gap junctions, specifically connexin43. In atherosclerosis, the normal physical patterns of communication are disrupted by the subendothelial infiltration and accumulation of blood monocytes, which in turn can differentiate into resident foam cells. In this paper we report that neither freshly isolated human peripheral blood monocytes nor differentiated monocytes/macrophages exhibit functional gap junctional dye transfer in homo-cellular culture or in co-culture with endothelial cells or smooth muscle cells. By Northern analysis, neither freshly isolated blood monocytes nor pure cultures of differentiated monocyte/macrophages expressed gap junction messenger RNA. However, immunohistochemical staining followed by in situ hybridization on sections of human atherosclerotic carotid arteries revealed strong expression of gap junction connexin43 messenger RNA by macrophage foam cells. These results suggest that tissue-specific conditions present in atherosclerotic arteries induce expression of connexin43 messenger RNA in monocyte/macrophages. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 PMID:8382009

  14. Functional modifications of macrophage activity after sublethal irradiation. [Toxoplasma gondii

    SciTech Connect

    Swartz, R.P.

    1982-01-01

    The modifications of macrophage activity following sublethal irradiation, both in vivo and in vitro, were studied using spreading and C3b-receptor-mediated ingestion assays. Nonelicited peritoneal washout cells were examined for changes in activity and selected population characteristics. The cells from irradiated mice were from a resident peritoneal population and not immigrating cells. The macrophage population showed enhanced activity early with a refractory period (24-48) when the macrophages were unresponsive to stimulation by irradiated lymphocytes. The enhanced activity was inversely dose dependent on macrophage. The lymphocytes showed a regulatory function(s) on the time post irradiation at which they were examined. Early lymphocytes exhibited the ability to enhance the activity of normal macrophages while lymphocytes removed 24 hours post irradiation could suppress the activity of already activated macrophages. The effect(s) of the various lymphocyte populations were reproduced with cell-free supernatants which was indicative of the production of lymphokines. Separation on nylon wool columns indicated that the activity resided primarily in the T-cell population of lymphocytes. In vitro irradiation indicated that stimulation of the lymphocytes is macrophage dependent. Additional work indicated that sublethally irradiated macrophages did not inhibit replication of the coccidian protozoon Toxoplasma gondii although they did show increased phagocytosis. Examination of the serum from whole body irradiated mice showed the presence of a postirradiation substance which enhanced the phagocytosis of normal macrophages. It was not present in the serum of normal mice and was not endotoxin.

  15. Macrophages in diabetic gastroparesis– the missing link?

    PubMed Central

    Neshatian, Leila; Gibbons, Simon J.; Farrugia, Gianrico

    2015-01-01

    Background Diabetic gastroparesis results in significant morbidity for patients and major economic burden for society. Treatment options for diabetic gastroparesis are currently directed at symptom control rather than the underlying disease and are limited. The pathophysiology of diabetic gastroparesis includes damage to intrinsic and extrinsic neurons, smooth muscle and interstitial cells of Cajal (ICC). Oxidative damage in diabetes appears to be one of the primary insults involved in the pathogenesis of several complications of diabetes, including gastroparesis. Recent studies have highlighted the potential role of macrophages as key cellular elements in the pathogenesis of diabetic gastroparesis. Macrophages are important for both homeostasis and defense against a variety of pathogens. Heme oxygenase 1 (HO1), an enzyme expressed in a subset of macrophages has emerged as a major protective mechanism against oxidative stress. Activation of macrophages with high levels of HO1 expression protects against development of delayed gastric emptying in animal models of diabetes, while activation of macrophages that do not express HO1 are linked to neuromuscular cell injury. Targeting macrophages and HO1 may therefore be a therapeutic option in diabetic gastroparesis. Purpose This report briefly reviews the pathophysiology of diabetic gastroparesis with a focus on oxidative damage and how activation and polarization of different subtypes of macrophages in the muscularis propria determines development of delay in gastric emptying or protects against its development. PMID:25168158

  16. Macrophage physiology in the eye.

    PubMed

    Chinnery, Holly R; McMenamin, Paul G; Dando, Samantha J

    2017-04-01

    The eye is a complex sensory organ composed of a range of tissue types including epithelia, connective tissue, smooth muscle, vascular and neural tissue. While some components of the eye require a high level of transparency to allow light to pass through unobstructed, other tissues are characterized by their dense pigmentation, which functions to absorb light and thus control its passage through the ocular structures. Macrophages are present in all ocular tissues, from the cornea at the anterior surface through to the choroid/sclera at the posterior pole. This review will describe the current understanding of the distribution, phenotype, and physiological role of ocular macrophages, and provide a summary of evidence pertaining to their proposed role during pathological conditions.

  17. Origins and Hallmarks of Macrophages: Development, Homeostasis, and Disease

    PubMed Central

    Wynn, Thomas A.; Chawla, Ajay; Pollard, Jeffrey W.

    2013-01-01

    Preface Macrophages the most plastic cells of the hematopoietic system are found in all tissues and exhibit great functional diversity. They have roles in development, homeostasis, tissue repair, and immunity. While anatomically distinct, resident tissue macrophages exhibit different transcriptional profiles, and functional capabilities, they are all required for the maintenance of homeostasis. However, these reparative and homeostatic functions can be subverted by chronic insults, resulting in a causal association of macrophages with disease states. In this review, we discuss how macrophages regulate normal physiology and development and provide several examples of their pathophysiologic roles in disease. We define the “hallmarks” of macrophages performing particular functions, taking into account novel insights into the diversity of their lineages, identity, and regulation. This diversity is essential to understand because macrophages have emerged as important therapeutic targets in many important human diseases. PMID:23619691

  18. Pivotal role for skin transendothelial radio-resistant anti-inflammatory macrophages in tissue repair

    PubMed Central

    Barreiro, Olga; Cibrian, Danay; Clemente, Cristina; Alvarez, David; Moreno, Vanessa; Valiente, Íñigo; Bernad, Antonio; Vestweber, Dietmar; Arroyo, Alicia G; Martín, Pilar; von Andrian, Ulrich H; Sánchez Madrid, Francisco

    2016-01-01

    Heterogeneity and functional specialization among skin-resident macrophages are incompletely understood. In this study, we describe a novel subset of murine dermal perivascular macrophages that extend protrusions across the endothelial junctions in steady-state and capture blood-borne macromolecules. Unlike other skin-resident macrophages that are reconstituted by bone marrow-derived progenitors after a genotoxic insult, these cells are replenished by an extramedullary radio-resistant and UV-sensitive Bmi1+ progenitor. Furthermore, they possess a distinctive anti-inflammatory transcriptional profile, which cannot be polarized under inflammatory conditions, and are involved in repair and remodeling functions for which other skin-resident macrophages appear dispensable. Based on all their properties, we define these macrophages as Skin Transendothelial Radio-resistant Anti-inflammatory Macrophages (STREAM) and postulate that their preservation is important for skin homeostasis. DOI: http://dx.doi.org/10.7554/eLife.15251.001 PMID:27304075

  19. Macrophage phenotypes in atherosclerosis.

    PubMed

    Colin, Sophie; Chinetti-Gbaguidi, Giulia; Staels, Bart

    2014-11-01

    Initiation and progression of atherosclerosis depend on local inflammation and accumulation of lipids in the vascular wall. Although many cells are involved in the development and progression of atherosclerosis, macrophages are fundamental contributors. For nearly a decade, the phenotypic heterogeneity and plasticity of macrophages has been studied. In atherosclerotic lesions, macrophages are submitted to a large variety of micro-environmental signals, such as oxidized lipids and cytokines, which influence the phenotypic polarization and activation of macrophages resulting in a dynamic plasticity. The macrophage phenotype spectrum is characterized, at the extremes, by the classical M1 macrophages induced by T-helper 1 (Th-1) cytokines and by the alternative M2 macrophages induced by Th-2 cytokines. M2 macrophages can be further classified into M2a, M2b, M2c, and M2d subtypes. More recently, additional plaque-specific macrophage phenotypes have been identified, termed as Mox, Mhem, and M4. Understanding the mechanisms and functional consequences of the phenotypic heterogeneity of macrophages will contribute to determine their potential role in lesion development and plaque stability. Furthermore, research on macrophage plasticity could lead to novel therapeutic approaches to counteract cardiovascular diseases such as atherosclerosis. The present review summarizes our current knowledge on macrophage subsets in atherosclerotic plaques and mechanism behind the modulation of the macrophage phenotype.

  20. Single-cell analysis reveals new subset markers of murine peritoneal macrophages and highlights macrophage dynamics upon Staphylococcus aureus peritonitis.

    PubMed

    Accarias, Solène; Genthon, Clémence; Rengel, David; Boullier, Séverine; Foucras, Gilles; Tabouret, Guillaume

    2016-07-01

    Resident macrophages play a central role in maintaining tissue homeostasis and immune surveillance. Here, we used single cell-based qPCR coupled with flow cytometry analysis to further define the phenotypes of large and small resident peritoneal macrophages (LPMs and SPMs, respectively) in mice. We demonstrated that the expression of Cxcl13, IfngR1, Fizz-1 and Mrc-1 clearly distinguished between LPMs and SPMs subsets. Using these markers, the dynamics of peritoneal macrophages in a Staphylococcus aureus-induced peritonitis model were analyzed. We found that S. aureus infection triggers a massive macrophage disappearance reaction in both subsets. Thereafter, inflammatory monocytes rapidly infiltrated the cavity and differentiated to replenish the SPMs. Although phenotypically indistinguishable from resident SPMs by flow cytometry, newly recruited SPMs had a different pattern of gene expression dominated by M2 markers combined with M1 associated features (inos expression). Interestingly, S. aureus elicited SPMs showed a robust expression of Cxcl13, suggesting that these cells may endorse the role of depleted LPMs and contribute to restoring peritoneal homeostasis. These data provide information on both resident and recruited macrophages dynamics upon S. aureus infection and demonstrate that single-cell phenotyping is a promising and highly valuable approach to unraveling macrophage diversity and plasticity.

  1. Metabolism Supports Macrophage Activation

    PubMed Central

    Langston, P. Kent; Shibata, Munehiko; Horng, Tiffany

    2017-01-01

    Macrophages are found in most tissues of the body, where they have tissue- and context-dependent roles in maintaining homeostasis as well as coordinating adaptive responses to various stresses. Their capacity for specialized functions is controlled by polarizing signals, which activate macrophages by upregulating transcriptional programs that encode distinct effector functions. An important conceptual advance in the field of macrophage biology, emerging from recent studies, is that macrophage activation is critically supported by metabolic shifts. Metabolic shifts fuel multiple aspects of macrophage activation, and preventing these shifts impairs appropriate activation. These findings raise the exciting possibility that macrophage functions in various contexts could be regulated by manipulating their metabolism. Here, we review the rapidly evolving field of macrophage metabolism, discussing how polarizing signals trigger metabolic shifts and how these shifts enable appropriate activation and sustain effector activities. We also discuss recent studies indicating that the mitochondria are central hubs in inflammatory macrophage activation. PMID:28197151

  2. Pulmonary and thoracic macrophage subpopulations and clearance of particles from the lung.

    PubMed Central

    Lehnert, B E

    1992-01-01

    Pulmonary macrophages consist of several subpopulations that can be defined by their anatomical locations as well as by other criteria. In addition to the well-known alveolar macrophages that reside on the alveolar surface, pulmonary macrophages also occur in the conducting airways, in various pulmonary interstitial regions, and, in some mammalian species, in the lung's intravascular compartment. Other thoracic macrophages of relevance to pulmonary defense and some lung disease processes are the pleural macrophages resident in the pleural space and macrophages present in regional lymph nodes that receive lymphatic drainage from the lung. Of the above subpopulations of pulmonary and thoracic macrophages, the alveolar macrophages have received the most experimental attention in the context of the pulmonary clearance and retention of deposited particles. Accordingly, less information is currently available regarding the roles other pulmonary and thoracic populations of macrophages may play in the removal of particles from the lower respiratory tract and associated tissue compartments. This report provides an overview of the various subpopulations of pulmonary and thoracic macrophages, as defined by their anatomical locations. The known and postulated roles of macrophages in the pulmonary clearance and retention of particles are reviewed, with particular emphasis on macrophage-associated processes involved in the pulmonary clearance of relatively insoluble particles. Images FIGURE 1. FIGURE 2. FIGURE 3. FIGURE 5. FIGURE 8. FIGURE 12. FIGURE 14. FIGURE 15. FIGURE 16. FIGURE 17. FIGURE 18. FIGURE 19. A FIGURE 19. B FIGURE 21. FIGURE 22. PMID:1396454

  3. Macrophages Subvert Adaptive Immunity to Urinary Tract Infection

    PubMed Central

    Mora-Bau, Gabriela; Platt, Andrew M.; van Rooijen, Nico; Randolph, Gwendalyn J.; Albert, Matthew L.; Ingersoll, Molly A.

    2015-01-01

    Urinary tract infection (UTI) is one of the most common bacterial infections with frequent recurrence being a major medical challenge. Development of effective therapies has been impeded by the lack of knowledge of events leading to adaptive immunity. Here, we establish conclusive evidence that an adaptive immune response is generated during UTI, yet this response does not establish sterilizing immunity. To investigate the underlying deficiency, we delineated the naïve bladder immune cell compartment, identifying resident macrophages as the most populous immune cell. To evaluate their impact on the establishment of adaptive immune responses following infection, we measured bacterial clearance in mice depleted of either circulating monocytes, which give rise to macrophages, or bladder resident macrophages. Surprisingly, mice depleted of resident macrophages, prior to primary infection, exhibited a nearly 2-log reduction in bacterial burden following secondary challenge compared to untreated animals. This increased bacterial clearance, in the context of a challenge infection, was dependent on lymphocytes. Macrophages were the predominant antigen presenting cell to acquire bacteria post-infection and in their absence, bacterial uptake by dendritic cells was increased almost 2-fold. These data suggest that bacterial uptake by tissue macrophages impedes development of adaptive immune responses during UTI, revealing a novel target for enhancing host responses to bacterial infection of the bladder. PMID:26182347

  4. Macrophages Subvert Adaptive Immunity to Urinary Tract Infection.

    PubMed

    Mora-Bau, Gabriela; Platt, Andrew M; van Rooijen, Nico; Randolph, Gwendalyn J; Albert, Matthew L; Ingersoll, Molly A

    2015-07-01

    Urinary tract infection (UTI) is one of the most common bacterial infections with frequent recurrence being a major medical challenge. Development of effective therapies has been impeded by the lack of knowledge of events leading to adaptive immunity. Here, we establish conclusive evidence that an adaptive immune response is generated during UTI, yet this response does not establish sterilizing immunity. To investigate the underlying deficiency, we delineated the naïve bladder immune cell compartment, identifying resident macrophages as the most populous immune cell. To evaluate their impact on the establishment of adaptive immune responses following infection, we measured bacterial clearance in mice depleted of either circulating monocytes, which give rise to macrophages, or bladder resident macrophages. Surprisingly, mice depleted of resident macrophages, prior to primary infection, exhibited a nearly 2-log reduction in bacterial burden following secondary challenge compared to untreated animals. This increased bacterial clearance, in the context of a challenge infection, was dependent on lymphocytes. Macrophages were the predominant antigen presenting cell to acquire bacteria post-infection and in their absence, bacterial uptake by dendritic cells was increased almost 2-fold. These data suggest that bacterial uptake by tissue macrophages impedes development of adaptive immune responses during UTI, revealing a novel target for enhancing host responses to bacterial infection of the bladder.

  5. Your Muscles

    MedlinePlus

    ... Room? What Happens in the Operating Room? Your Muscles KidsHealth > For Kids > Your Muscles A A A ... and skeletal (say: SKEL-uh-tul) muscle. Smooth Muscles Smooth muscles — sometimes also called involuntary muscles — are ...

  6. Macrophages: Master Regulators of Inflammation and Fibrosis

    PubMed Central

    Wynn, Thomas A.; Barron, Luke

    2010-01-01

    Macrophages are found in close proximity with collagen-producing myofibroblasts and indisputably play a key role in fibrosis. They produce profibrotic mediators that directly activate fibroblasts, including transforming growth factor-β1 and platelet-derived growth factor, and control extracellular matrix turnover by regulating the balance of various matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases. Macrophages also regulate fibrogenesis by secreting chemokines that recruit fibroblasts and other inflammatory cells. With their potential to act in both a pro- and antifibrotic capacity, as well as their ability to regulate the activation of resident and recruited myofibroblasts, macrophages and the factors they express are integrated into all stages of the fibrotic process. These various, and sometimes opposing, functions may be performed by distinct macrophage subpopulations, the identification of which is a growing focus of fibrosis research. Although collagen-secreting myofibroblasts once were thought of as the master “producers” of fibrosis, this review will illustrate how macrophages function as the master “regulators” of fibrosis. PMID:20665377

  7. Crosstalk between Muscularis Macrophages and Enteric Neurons Regulates Gastrointestinal Motility

    PubMed Central

    Muller, Paul Andrew; Koscsó, Balázs; Rajani, Gaurav Manohar; Stevanovic, Korey; Berres, Marie-Luise; Hashimoto, Daigo; Mortha, Arthur; Leboeuf, Marylene; Li, Xiu-Min; Mucida, Daniel; Stanley, E. Richard; Dahan, Stephanie; Margolis, Kara Gross; Gershon, Michael David; Merad, Miriam; Bogunovic, Milena

    2014-01-01

    SUMMARY Intestinal peristalsis is a dynamic physiologic process influenced by dietary and microbial changes. It is tightly regulated by complex cellular interactions; however, our understanding of these controls is incomplete. A distinct population of macrophages is distributed in the intestinal muscularis externa. We demonstrate that in the steady state muscularis macrophages regulate peristaltic activity of the colon. They change the pattern of smooth muscle contractions by secreting bone morphogenetic protein 2 (BMP2), which activates BMP receptor (BMPR) expressed by enteric neurons. Enteric neurons, in turn, secrete colony stimulatory factor 1 (CSF1), a growth factor required for macrophage development. Finally, stimuli from microbial commensals regulate BMP2 expression by macrophages and CSF1 expression by enteric neurons. Our findings identify a plastic, microbiota-driven, crosstalk between muscularis macrophages and enteric neurons, which controls gastrointestinal motility. PMID:25036630

  8. Time Course of Chemokine Expression and Leukocyte Infiltration after Acute Skeletal Muscle Injury in Mice

    DTIC Science & Technology

    2015-01-01

    and their receptors peaked at 48 h post-injury. 15. SUBJECT TERMS Inflammation, macrophage, microarray, muscle recovery , neutrophil 16. SECURITY...macrophage, microarray, muscle recovery , neutrophil Date received: 18 July 2013; revised: 23 December 2013; accepted: 26 January 2014 Introduction Pro...recruitment of neutrophils and M1 macrophages during the first 48 h is critical to muscle recovery . 1School of Nursing, University of Nevada, Las Vegas

  9. Involvement of Macrophages in the Pathogenesis of Familial Amyloid Polyneuropathy and Efficacy of Human iPS Cell-Derived Macrophages in Its Treatment

    PubMed Central

    Komohara, Yoshihiro; Takamatsu, Koutaro; Kakuma, Tatsuyuki; Tasaki, Masayoshi; Misumi, Yohei; Ueda, Mitsuharu; Ito, Takaaki; Senju, Satoru; Ando, Yukio

    2016-01-01

    We hypothesized that tissue-resident macrophages in familial amyloid polyneuropathy (FAP) patients will exhibit qualitative or quantitative abnormalities, that may accelerate transthyretin (TTR)-derived amyloid deposition. To evaluate this, we examined the number and subset of tissue-resident macrophages in heart tissue from amyloid-deposited FAP and control patients. In both FAP and control patients, tissue-resident macrophages in heart tissue were all Iba+/CD163+/CD206+ macrophages. However, the number of macrophages was significantly decreased in FAP patients compared with control patients. Furthermore, the proportion of intracellular TTR in CD14+ monocytes was reduced in peripheral blood compared with healthy donors. Based on these results, we next examined degradation and endocytosis of TTR in human induced pluripotent stem (iPS) cell-derived myeloid lineage cells (MLs), which function like macrophages. iPS-MLs express CD163 and CD206, and belong to the inhibitory macrophage category. In addition, iPS-MLs degrade both native and aggregated TTR in a cell-dependent manner in vitro. Further, iPS-MLs endocytose aggregated, and especially polymerized, TTR. These results suggest that decreased tissue-localized macrophages disrupt clearance of TTR-derived amyloid deposits, leading to progression of a pathological condition in FAP patients. To improve this situation, clinical application of pluripotent stem cell-derived MLs may be useful as an approach for FAP therapy. PMID:27695122

  10. Macrophage proliferation, provenance, and plasticity in macroparasite infection.

    PubMed

    Rückerl, Dominik; Allen, Judith E

    2014-11-01

    Macrophages have long been center stage in the host response to microbial infection, but only in the past 10-15 years has there been a growing appreciation for their role in helminth infection and the associated type 2 response. Through the actions of the IL-4 receptor α (IL-4Rα), type 2 cytokines result in the accumulation of macrophages with a distinctive activation phenotype. Although our knowledge of IL-4Rα-induced genes is growing rapidly, the specific functions of these macrophages have yet to be established in most disease settings. Understanding the interplay between IL-4Rα-activated macrophages and the other cellular players is confounded by the enormous transcriptional heterogeneity within the macrophage population and by their highly plastic nature. Another level of complexity is added by the new knowledge that tissue macrophages can be derived either from a resident prenatal population or from blood monocyte recruitment and that IL-4 can increase macrophage numbers through proliferative expansion. Here, we review current knowledge on the contribution of macrophages to helminth killing and wound repair, with specific attention paid to distinct cellular origins and plasticity potential.

  11. Molecular and epigenetic basis of macrophage polarized activation.

    PubMed

    Porta, Chiara; Riboldi, Elena; Ippolito, Alessandro; Sica, Antonio

    2015-08-01

    Macrophages are unique cells for origin, heterogeneity and plasticity. At steady state most of macrophages are derived from fetal sources and maintained in adulthood through self-renewing. Despite sharing common progenitors, a remarkable heterogeneity characterized tissue-resident macrophages indicating that local signals educate them to express organ-specific functions. Macrophages are extremely plastic: chromatin landscape and transcriptional programs can be dynamically re-shaped in response to microenvironmental changes. Owing to their ductility, macrophages are crucial orchestrators of both initiation and resolution of immune responses and key supporters of tissue development and functions in homeostatic and pathological conditions. Herein, we describe current understanding of heterogeneity and plasticity of macrophages using the M1-M2 dichotomy as operationally useful simplification of polarized activation. We focused on the complex network of signaling cascades, metabolic pathways, transcription factors, and epigenetic changes that control macrophage activation. In particular, this network was addressed in sepsis, as a paradigm of a pathological condition determining dynamic macrophage reprogramming.

  12. Macrophages are critical effectors of antibody therapies for cancer.

    PubMed

    Weiskopf, Kipp; Weissman, Irving L

    2015-01-01

    Macrophages are innate immune cells that derive from circulating monocytes, reside in all tissues, and participate in many states of pathology. Macrophages play a dichotomous role in cancer, where they promote tumor growth but also serve as critical immune effectors of therapeutic antibodies. Macrophages express all classes of Fcγ receptors, and they have immense potential to destroy tumors via the process of antibody-dependent phagocytosis. A number of studies have demonstrated that macrophage phagocytosis is a major mechanism of action of many antibodies approved to treat cancer. Consequently, a number of approaches to augment macrophage responses to therapeutic antibodies are under investigation, including the exploration of new targets and development of antibodies with enhanced functions. For example, the interaction of CD47 with signal-regulatory protein α (SIRPα) serves as a myeloid-specific immune checkpoint that limits the response of macrophages to antibody therapies, and CD47-blocking agents overcome this barrier to augment phagocytosis. The response of macrophages to antibody therapies can also be enhanced with engineered Fc variants, bispecific antibodies, or antibody-drug conjugates. Macrophages have demonstrated success as effectors of cancer immunotherapy, and further investigation will unlock their full potential for the benefit of patients.

  13. Stromal down-regulation of macrophage CD4/CCR5 expression and NF-κB activation mediates HIV-1 non-permissiveness in intestinal macrophages.

    PubMed

    Shen, Ruizhong; Meng, Gang; Ochsenbauer, Christina; Clapham, Paul R; Grams, Jayleen; Novak, Lea; Kappes, John C; Smythies, Lesley E; Smith, Phillip D

    2011-05-01

    Tissue macrophages are derived exclusively from blood monocytes, which as monocyte-derived macrophages support HIV-1 replication. However, among human tissue macrophages only intestinal macrophages are non-permissive to HIV-1, suggesting that the unique microenvironment in human intestinal mucosa renders lamina propria macrophages non-permissive to HIV-1. We investigated this hypothesis using blood monocytes and intestinal extracellular matrix (stroma)-conditioned media (S-CM) to model the exposure of newly recruited monocytes and resident macrophages to lamina propria stroma, where the cells take up residence in the intestinal mucosa. Exposure of monocytes to S-CM blocked up-regulation of CD4 and CCR5 expression during monocyte differentiation into macrophages and inhibited productive HIV-1 infection in differentiated macrophages. Importantly, exposure of monocyte-derived macrophages simultaneously to S-CM and HIV-1 also inhibited viral replication, and sorted CD4+ intestinal macrophages, a proportion of which expressed CCR5+, did not support HIV-1 replication, indicating that the non-permissiveness to HIV-1 was not due to reduced receptor expression alone. Consistent with this conclusion, S-CM also potently inhibited replication of HIV-1 pseudotyped with vesicular stomatitis virus glycoprotein, which provides CD4/CCR5-independent entry. Neutralization of TGF-β in S-CM and recombinant TGF-β studies showed that stromal TGF-β inhibited macrophage nuclear translocation of NF-κB and HIV-1 replication. Thus, the profound inability of intestinal macrophages to support productive HIV-1 infection is likely the consequence of microenvironmental down-regulation of macrophage HIV-1 receptor/coreceptor expression and NF-κB activation.

  14. Killing of Paracoccidioides brasiliensis conidia by pulmonary macrophages and the effect of cytokines.

    PubMed

    Cano, L E; Arango, R; Salazar, M E; Brummer, E; Stevens, D A; Restrepo, A

    1992-01-01

    The ability of conidia, the infectious form of the dimorphic fungus Paracoccidioides brasiliensis, to be killed in vitro by murine pulmonary macrophages was studied. Mice were immunized by intravenous injection of killed conidia, which resulted in cellular immunity demonstrated by delayed type hypersensitivity in vivo and macrophage migration inhibition factor production in vitro. Resident pulmonary macrophages from non-immune mice were able to significantly kill the conidia (28%). Such macrophages treated with supernatants (cytokines) from antigen-stimulated immune mononuclears had a markedly enhanced ability to kill conidia (73%). These results show that activated pulmonary macrophages are potent killers of conidia of P. brasiliensis and that immune mononuclears play a role in activation of macrophages. Activated macrophages may be important for pulmonary defense against the initial stages of infection with this fungus.

  15. Gallium arsenide differentially affects processing of phagolysosomal targeted antigen by macrophages.

    PubMed

    Lewis, T A; Hartmann, C B; McCoy, K L

    1998-03-01

    Gallium arsenide, a semiconductor utilized in the electronics industry, causes immunosuppression in animals. The chemical's effect on macrophages to process antigen for activating pigeon cytochrome-specific helper T cell hybridoma was investigated. Mice were administered 200 mg/kg gallium arsenide or vehicle intraperitoneally. Five-day exposure suppressed processing by splenic macrophages but augmented processing by thioglycollate-elicited and resident peritoneal macrophages. Cytochrome coupled to latex beads was targeted to phagolysosomes to examine processing in lysosomes. Cytochrome beads required phagocytosis for processing and were located in phagolysosomes. Gallium arsenide did not alter the phagocytic ability of macrophages. Peritoneal macrophages normally processed the targeted antigen, indicating that gallium arsenide influenced compartment(s) preceding lysosomes. However, the processing efficiency of exposed splenic macrophages depended on the size of particulate cytochrome, suggesting that processing varied in phagolysosomes of different sizes. Gallium arsenide impacted different intracellular compartments in these macrophages, perhaps contributing to systemic immunotoxicity and local inflammation caused by exposure.

  16. Satellite cells: the architects of skeletal muscle.

    PubMed

    Chang, Natasha C; Rudnicki, Michael A

    2014-01-01

    The outstanding regenerative capacity of skeletal muscle is attributed to the resident muscle stem cell termed satellite cell. Satellite cells are essential for skeletal muscle regeneration as they ultimately provide the myogenic precursors that rebuild damaged muscle tissue. Satellite cells characteristically are a heterogeneous population of stem cells and committed progenitor cells. Delineation of cellular hierarchy and understanding how lineage fate choices are determined within the satellite cell population will be invaluable for the advancement of muscle regenerative therapies.

  17. Repositioning forelimb superficialis muscles: tendon attachment and muscle activity enable active relocation of functional myofibers.

    PubMed

    Huang, Alice H; Riordan, Timothy J; Wang, Lingyan; Eyal, Shai; Zelzer, Elazar; Brigande, John V; Schweitzer, Ronen

    2013-09-16

    The muscles that govern hand motion are composed of extrinsic muscles that reside within the forearm and intrinsic muscles that reside within the hand. We find that the extrinsic muscles of the flexor digitorum superficialis (FDS) first differentiate as intrinsic muscles within the hand and then relocate as myofibers to their final position in the arm. This remarkable translocation of differentiated myofibers across a joint is dependent on muscle contraction and muscle-tendon attachment. Interestingly, the intrinsic flexor digitorum brevis (FDB) muscles of the foot are identical to the FDS in tendon pattern and delayed developmental timing but undergo limited muscle translocation, providing strong support for evolutionary homology between the FDS and FDB muscles. We propose that the intrinsic FDB pattern represents the original tetrapod limb and that translocation of the muscles to form the FDS is a mammalian evolutionary addition.

  18. Intracellular survival of Clostridium chauvoei in bovine macrophages.

    PubMed

    Pires, Prhiscylla Sadanã; Santos, Renato Lima; da Paixão, Tatiane Alves; de Oliveira Bernardes, Laura Cristina; de Macêdo, Auricélio Alves; Gonçalves, Luciana Aramuni; de Oliveira Júnior, Carlos Augusto; Silva, Rodrigo Otávio Silveira; Lobato, Francisco Carlos Faria

    2017-02-01

    Clostridium chauvoei is the etiological agent of blackleg, a severe disease of domestic ruminants, causing myonecrosis and serious toxemia with high mortality. Despite the known importance of this agent, studies evaluating its pathogenesis of blackleg are scarce, and many are based on an unproven hypothesis that states that macrophages are responsible for carrying C. chauvoei spores from the intestines to muscles in the early stages of blackleg. Therefore, the present study aimed to investigate the survival of C. chauvoei vegetative cells or spores after phagocytosis by a murine macrophage cell line (RAW 264.7) and bovine monocyte-derived macrophages and to profile inflammatory and anti-inflammatory cytokine transcripts of bovine macrophages infected with C. chauvoei vegetative cells or spores. Both vegetative cells and spores of C. chauvoei remain viable after internalization by murine and bovine macrophages. Bovine macrophages infected with vegetative cells showed a pro-inflammatory profile, while those infected with spores displayed an anti-inflammatory profile. Together, these results corroborate the classical hypothesis that macrophages may play a role in the early pathogenesis of blackleg. Moreover, this is the first study to evaluate the infection kinetics and cytokine profile of bovine monocyte-derived macrophages infected with a Clostridium species.

  19. Specific binding sites for muramyl peptides on murine macrophages

    SciTech Connect

    Silverman, D.H.S.; Krueger, J.M.; Karnovsky, M.L.

    1986-03-15

    Two radiolabeled (/sup 125/I) muramyl peptide derivatives of high specific activity were prepared: a tripeptide with an iodinated C-terminal tyrosine methyl ester (Ligand I), and a muramyl tripeptide with a C-terminal lysine derivatized with Bolton-Hunter reagent (Ligand II). These were used to characterize binding of muramyl peptides to monolayers of murine macrophages. Saturable high-affinity binding to resident, caseinate-elicited, and Listeria-activated peritoneal cells was observed with both radioligands. Binding affinities varied with the state of activation of the macrophages, and K/sub D/ values ranged from 48 +/- 33 pM (for resident macrophages, Ligand I) to 1020 +/- 90 pM (for activated macrophages, Ligand II). Specific binding sites were also found on a macrophage-derived cell line. The ability of several unlabeled muramyl peptides to compete with Ligands I and II for their binding sites was tested. Competition was stereospecific and correlated with known biological activities of these compounds (i.e., immunoadjuvanticity, pyrogenicity, and somnogenicity). The sites identified here for Ligands I and II may mediate some of the effects that muramyl peptides have previously been demonstrated to have on macrophages.

  20. Interaction with Epithelial Cells Modifies Airway Macrophage Response to Ozone

    EPA Science Inventory

    The initial innate immune response to ozone (03) in the lung is orchestrated by structural cells, such as epithelial cells, and resident immune cells, such as airway macrophages (Macs). We developed an epithelial cell-Mac coculture model to investigate how epithelial cell-derived...

  1. Characterization of Distinct Macrophage Subpopulations during Nitrogen Mustard–Induced Lung Injury and Fibrosis

    PubMed Central

    Venosa, Alessandro; Malaviya, Rama; Choi, Hyejeong; Gow, Andrew J.; Laskin, Jeffrey D.

    2016-01-01

    Nitrogen mustard (NM) is an alkylating agent known to cause extensive pulmonary injury progressing to fibrosis. This is accompanied by a persistent macrophage inflammatory response. In these studies, we characterized the phenotype of macrophages accumulating in the lung over time following NM exposure. Treatment of rats with NM (0.125 mg/kg, intratracheally) resulted in an increase in CD11b+ macrophages in histologic sections. These cells consisted of inducible nitric oxide synthase+ (iNOS) proinflammatory M1 macrophages, and CD68+, CD163+, CD206+, YM-1+, and arginase-II+antiinflammatory M2 macrophages. Although M1 macrophages were prominent 1–3 days after NM, M2 macrophages were most notable at 28 days. At this time, they were enlarged and vacuolated, consistent with a profibrotic phenotype. Flow cytometric analysis of isolated lung macrophages identified three phenotypically distinct subpopulations: mature CD11b−, CD43−, and CD68+ resident macrophages, which decreased in numbers after NM; and two infiltrating (CD11b+) macrophage subsets: immature CD43+ M1 macrophages and mature CD43− M2 macrophages, which increased sequentially. Time-related increases in M1 (iNOS, IL-12α, COX-2, TNF-α, matrix metalloproteinase-9, matrix metalloproteinase-10) and M2 (IL-10, pentraxin-2, connective tissue growth factor, ApoE) genes, as well as chemokines/chemokine receptors associated with trafficking of M1 (CCR2, CCR5, CCL2, CCL5) and M2 (CX3CR1, fractalkine) macrophages to sites of injury, were also noted in macrophages isolated from the lung after NM. The appearance of M1 and M2 macrophages in the lung correlated with NM-induced acute injury and the development of fibrosis, suggesting a potential role of these macrophage subpopulations in the pathogenic response to NM. PMID:26273949

  2. Characterization of Distinct Macrophage Subpopulations during Nitrogen Mustard-Induced Lung Injury and Fibrosis.

    PubMed

    Venosa, Alessandro; Malaviya, Rama; Choi, Hyejeong; Gow, Andrew J; Laskin, Jeffrey D; Laskin, Debra L

    2016-03-01

    Nitrogen mustard (NM) is an alkylating agent known to cause extensive pulmonary injury progressing to fibrosis. This is accompanied by a persistent macrophage inflammatory response. In these studies, we characterized the phenotype of macrophages accumulating in the lung over time following NM exposure. Treatment of rats with NM (0.125 mg/kg, intratracheally) resulted in an increase in CD11b(+) macrophages in histologic sections. These cells consisted of inducible nitric oxide synthase(+) (iNOS) proinflammatory M1 macrophages, and CD68(+), CD163(+), CD206(+), YM-1(+), and arginase-II(+)antiinflammatory M2 macrophages. Although M1 macrophages were prominent 1-3 days after NM, M2 macrophages were most notable at 28 days. At this time, they were enlarged and vacuolated, consistent with a profibrotic phenotype. Flow cytometric analysis of isolated lung macrophages identified three phenotypically distinct subpopulations: mature CD11b(-), CD43(-), and CD68(+) resident macrophages, which decreased in numbers after NM; and two infiltrating (CD11b(+)) macrophage subsets: immature CD43(+) M1 macrophages and mature CD43(-) M2 macrophages, which increased sequentially. Time-related increases in M1 (iNOS, IL-12α, COX-2, TNF-α, matrix metalloproteinase-9, matrix metalloproteinase-10) and M2 (IL-10, pentraxin-2, connective tissue growth factor, ApoE) genes, as well as chemokines/chemokine receptors associated with trafficking of M1 (CCR2, CCR5, CCL2, CCL5) and M2 (CX3CR1, fractalkine) macrophages to sites of injury, were also noted in macrophages isolated from the lung after NM. The appearance of M1 and M2 macrophages in the lung correlated with NM-induced acute injury and the development of fibrosis, suggesting a potential role of these macrophage subpopulations in the pathogenic response to NM.

  3. Glutamine Modulates Macrophage Lipotoxicity

    PubMed Central

    He, Li; Weber, Kassandra J.; Schilling, Joel D.

    2016-01-01

    Obesity and diabetes are associated with excessive inflammation and impaired wound healing. Increasing evidence suggests that macrophage dysfunction is responsible for these inflammatory defects. In the setting of excess nutrients, particularly dietary saturated fatty acids (SFAs), activated macrophages develop lysosome dysfunction, which triggers activation of the NLRP3 inflammasome and cell death. The molecular pathways that connect lipid stress to lysosome pathology are not well understood, but may represent a viable target for therapy. Glutamine uptake is increased in activated macrophages leading us to hypothesize that in the context of excess lipids glutamine metabolism could overwhelm the mitochondria and promote the accumulation of toxic metabolites. To investigate this question we assessed macrophage lipotoxicity in the absence of glutamine using LPS-activated peritoneal macrophages exposed to the SFA palmitate. We found that glutamine deficiency reduced lipid induced lysosome dysfunction, inflammasome activation, and cell death. Under glutamine deficient conditions mTOR activation was decreased and autophagy was enhanced; however, autophagy was dispensable for the rescue phenotype. Rather, glutamine deficiency prevented the suppressive effect of the SFA palmitate on mitochondrial respiration and this phenotype was associated with protection from macrophage cell death. Together, these findings reveal that crosstalk between activation-induced metabolic reprogramming and the nutrient microenvironment can dramatically alter macrophage responses to inflammatory stimuli. PMID:27077881

  4. Macrophage activation and polarization.

    PubMed

    Martinez, Fernando Oneissi; Sica, Antonio; Mantovani, Alberto; Locati, Massimo

    2008-01-01

    Macrophages are widely distributed immune system cells that play an indispensable role in homeostasis and defense. They can be phenotypically polarized by the microenvironment to mount specific functional programs. Polarized macrophages can be broadly classified in two main groups: classically activated macrophages (or M1), whose prototypical activating stimuli are IFNgamma and LPS, and alternatively activated macrophages (or M2), further subdivided in M2a (after exposure to IL-4 or IL-13), M2b (immune complexes in combination with IL-1beta or LPS) and M2c (IL-10, TGFbeta or glucocorticoids). M1 exhibit potent microbicidal properties and promote strong IL-12-mediated Th1 responses, whilst M2 support Th2-associated effector functions. Beyond infection M2 polarized macrophages play a role in resolution of inflammation through high endocytic clearance capacities and trophic factor synthesis, accompanied by reduced pro-inflammatory cytokine secretion. Similar functions are also exerted by tumor-associated macrophages (TAM), which also display an alternative-like activation phenotype and play a detrimental pro-tumoral role. Here we review the main functions of polarized macrophages and discuss the perspectives of this field.

  5. Genetic and genomic approaches to understanding macrophage identity and function.

    PubMed

    Glass, Christopher K

    2015-04-01

    A major goal of our laboratory is to understand the molecular mechanisms that underlie the development and functions of diverse macrophage phenotypes in health and disease. Recent studies using genetic and genomic approaches suggest a relatively simple model of collaborative and hierarchical interactions between lineage-determining and signal-dependent transcription factors that enable selection and activation of transcriptional enhancers that specify macrophage identity and function. In addition, we have found that it is possible to use natural genetic variation as a powerful tool for advancing our understanding of how the macrophage deciphers the information encoded by the genome to attain specific phenotypes in a context-dependent manner. Here, I will describe our recent efforts to extend genetic and genomic approaches to investigate the roles of distinct tissue environments in determining the phenotypes of different resident populations of macrophages.

  6. Macrophages and tissue injury: agents of defense or destruction?

    PubMed

    Laskin, Debra L; Sunil, Vasanthi R; Gardner, Carol R; Laskin, Jeffrey D

    2011-01-01

    The past several years have seen the accumulation of evidence demonstrating that tissue injury induced by diverse toxicants is due not only to their direct effects on target tissues but also indirectly to the actions of resident and infiltrating macrophages. These cells release an array of mediators with cytotoxic, pro- and anti-inflammatory, angiogenic, fibrogenic, and mitogenic activity, which function to fight infections, limit tissue injury, and promote wound healing. However, following exposure to toxicants, macrophages can become hyperresponsive, resulting in uncontrolled or dysregulated release of mediators that exacerbate acute tissue injury and/or promote the development of chronic diseases such as fibrosis and cancer. Evidence suggests that the diverse activity of macrophages is mediated by distinct subpopulations that develop in response to signals within their microenvironment. Understanding the precise roles of these different macrophage populations in the pathogenic response to toxicants is key to designing effective treatments for minimizing tissue damage and chronic disease and for facilitating wound repair.

  7. Macrophage Stimulating Protein (MSP) evokes superoxide anion production by human macrophages of different origin

    PubMed Central

    Brunelleschi, Sandra; Penengo, Lorenza; Lavagno, Luisa; Santoro, Claudio; Colangelo, Donato; Viano, Ilario; Gaudino, Giovanni

    2001-01-01

    Macrophage Stimulating Protein (MSP), a serum factor related to Hepatocyte Growth Factor, was originally discovered to stimulate chemotaxis of murine resident peritoneal macrophages. MSP is the ligand for Ron, a member of the Met subfamily of tyrosine kinase receptors. The effects of MSP on human macrophages and the role played in human pathophysiology have long been elusive.We show here that human recombinant MSP (hrMSP) evokes a dose-dependent superoxide anion production in human alveolar and peritoneal macrophages as well as in monocyte-derived macrophages, but not in circulating human monocytes. Consistently, the mature Ron protein is expressed by the MSP responsive cells but not by the unresponsive monocytes. The respiratory burst evoked by hrMSP is quantitatively higher than the one induced by N-formylmethionyl-leucyl-phenylalanine and similar to phorbol myristate acetate-evoked one.To investigate the mechanisms involved in NADPH oxidase activation, leading to superoxide anion production, different signal transduction inhibitors were used. By using the non selective tyrosine kinase inhibitor genistein, the selective c-Src inhibitor PP1, the tyrosine phosphatase inhibitor sodium orthovanadate, the phosphatidylinositol 3-kinase inhibitor wortmannin, the p38 inhibitor SB203580, the MEK inhibitor PD098059, we demonstrate that hrMSP-evoked superoxide production is mediated by tyrosine kinase activity, requires the activation of Src but not of PI 3-kinase. We also show that MAP kinase and p38 signalling pathways are involved.These results clearly indicate that hrMSP induces the respiratory burst in human macrophages but not in monocytes, suggesting for the MSP/Ron complex a role of activator as well as of possible marker for human mature macrophages. PMID:11704649

  8. Pulmonary Chlamydia muridarum challenge activates lung interstitial macrophages which correlate with IFN-γ production and infection control in mice.

    PubMed

    Gracey, Eric; Baglaenko, Yuriy; Prayitno, Nadia; Van Rooijen, Nico; Akram, Ali; Lin, Aifeng; Chiu, Basil; Inman, Robert D

    2015-12-01

    Protective immunity to the pathogen Chlamydia is dependent on a robust IFN-γ response generated by innate and adaptive lymphocytes. Here we assess the role of the macrophage in orchestrating a protective response in vivo to the murine pathogen, Chlamydia muridarum. During acute pulmonary and peritoneal infection, resident macrophages in both sites are infected with C. muridarum and adopt an inflammatory phenotype. In the lung, this activation is restricted to interstitial macrophages, which harbor higher levels of C. muridarum 16sRNA than alveolar macrophages. We examined innate and adaptive lymphocyte activation in the peritoneal cavity with macrophage depletion and with adoptive transfer of infected macrophages. These experiments demonstrate macrophage activation correlates with a protective IFN-γ response and effective control of C. muridarum. These studies suggest that a quantitative or qualitative alteration in macrophages may play a key role in the development of Chlamydia-associated diseases.

  9. Trypanosoma cruzi: modification of macrophage function during infection

    PubMed Central

    1977-01-01

    Infection of mice with Trypanosoma cruzi and subsequent intraperitoneal challenge with heat-killed trypanosomes elicits peritoneal macrophages which display in vitro microbicidal activity against trypomastigotes of T. cruzi. These cells also display other activated properties including rapid spreading, intense membrane activity, secretion of high levels of plasminogen activator, and ingestion mediated by the C3 receptor. An intravenous infection with BCG, followed by an intraperitoneal challenge with mycobacterial antigens brings about macrophages with similar properties. These criteria of macrophage activation were compared in normal and BCG- or T. cruzi-immune mice, with or without an intraperitoneal challenge with specific or unrelated antigens. Trypanocidal activity is displayed by both BCG- and T. cruzi-immune macrophages after intraperitoneal challenge with either antigen. Resident-immune macrophages from both T. cruzi- and BCG-infected mice show a trypanostatic, rather than trypanocidal activity. Macrophages from noninfected mice, challenged with the same antigens, show neither trypanostatic nor trypanocidal activity. Increased secretion of plasminogen activator shows a definite immunological specificity. Challenge with the specific antigen induces the appearance of macrophages secreting high levels of plasminogen activator, while unrelated antigens induce much smaller levels. Noninfected mice challenged with the same antigens do not display any enchancement in secretion. In contrast, increased spreading and phagocytosis mediated by the complement receptor are also displayed by cells from noninfected mice challenged with any of the agents tested. PMID:327012

  10. Effect of low-level laser therapy on the modulation of the mitochondrial activity of macrophages

    PubMed Central

    Souza, Nadhia H. C.; Ferrari, Raquel A. M.; Silva, Daniela F. T.; Nunes, Fabio D.; Bussadori, Sandra K.; Fernandes, Kristianne P. S.

    2014-01-01

    BACKGROUND: Macrophages play a major role among the inflammatory cells that invade muscle tissue following an injury. Low-level laser therapy (LLLT) has long been used in clinical practice to accelerate the muscle repair process. However, little is known regarding its effect on macrophages. OBJECTIVE: This study evaluated the effect of LLLT on the mitochondrial activity (MA) of macrophages. METHOD: J774 macrophages were treated with lipopolysaccharide (LPS) and interferon - gamma (IFN-γ) (activation) for 24 h to simulate an inflammatory process, then irradiated with LLLT using two sets of parameters (780 nm; 70 mW; 3 J/cm2 and 660 nm; 15 mW; 7.5 J/cm2). Non-activated/non-irradiated cells composed the control group. MA was evaluated by the cell mitochondrial activity (MTT) assay (after 1, 3 and 5 days) in three independent experiments. The data were analyzed statistically. RESULTS: After 1 day of culture, activated and 780 nm irradiated macrophages showed lower MA than activated macrophages, but activated and 660 nm irradiated macrophages showed MA similar to activated cells. After 3 days, activated and irradiated (660 nm and 780 nm) macrophages showed greater MA than activated macrophages, and after 5 days, the activated and irradiated (660 nm and 780 nm) macrophages showed similar MA to the activated macrophages. CONCLUSIONS: These results show that 660 nm and 780 nm LLLT can modulate the cellular activation status of macrophages in inflammation, highlighting the importance of this resource and of the correct determination of its parameters in the repair process of skeletal muscle. PMID:25076002

  11. Antigen presentation by peritoneal macrophages from young adult and old mice

    SciTech Connect

    Perkins, E.H.; Massucci, J.M.; Glover, P.L.

    1982-01-01

    Macrophages perform vital inductive and regulatory functions in immune processes and host defense mechanisms. However, macrophage function during senescence has not been extensively studied. Although antibody response is dramatically reduced in old animals, antigen presentation has never been directly assessed. Therefore, the antigen-presenting capabilities of purified peritoneal macrophages from young adult and old mice were studied by quantitatively measuring their ability to induce antigen specific proliferation of lymph node T lymphocytes. Increasing numbers (10/sup 2/ to 10/sup 5/) of macrophages from nonimmunized young adult (3 to 6 months) or aged (27 to 36 months) animals were cultured in the presence of antigen with a constant number (2 x 10/sup 5/) of column-separated popliteal lymph node cells from young adult mice. The latter had been immunized with the dinitrophenyl conjugate of bovine ..gamma..-globulin in complete Freund's adjuvant by footpad injection. Macrophages from old animals were equal to macrophages from young adult in stimulating T-lymphocyte proliferation, and the kinetics of incorporation was identical with increasing numbers of macrophages from either young adult or old animals. However, greater numbers of resident or induced peritoneal macrophages were always harvested from old animals. Differences in macrophage activity as assessed by different functional parameters may be reconciled by implicating subpopulations of macrophages that perform separate functions, e.g. Ia-positive antigen presenter and Ia-negative scavenger macrophages.

  12. Life After Residency.

    PubMed

    Sorrel, Amy Lynn

    2016-04-01

    Many residents don't receive any formal business training. The University of Texas at Austin Dell Medical School created a crash course to teach residents some of the business and job-hunting basics they'll need.

  13. Functional and phenotypic characteristics of testicular macrophages in experimental autoimmune orchitis.

    PubMed

    Rival, C; Theas, M S; Suescun, M O; Jacobo, P; Guazzone, V; van Rooijen, N; Lustig, L

    2008-06-01

    Testicular inflammation with compromised fertility can occur despite the fact that the testis is considered an immunoprivileged organ. Testicular macrophages have been described as cells with an immunosuppressor profile, thus contributing to the immunoprivilege of the testis. Experimental autoimmune orchitis (EAO) is a model of organ-specific autoimmunity and testicular inflammation. EAO is characterized by an interstitial inflammatory mononuclear cell infiltration, damage of the seminiferous tubules and germ cell apoptosis. Here we studied the phenotype and functions of testicular macrophages during the development of EAO. By stereological analysis, we detected an increased number of resident (ED2+) and non-resident (ED1+) macrophages in the testicular interstitium of rats with orchitis. We showed that this increase was mainly due to monocyte recruitment. The in vivo administration of liposomes containing clodronate in rats undergoing EAO led to a reduction in the number of testicular macrophages, which correlated with a decreased incidence and severity of the testicular damage and suggests a pathogenic role of macrophages in EAO. By immunohistochemistry and flow cytometry we detected an increased number of testicular macrophages expressing MHC class II, CD80 and CD86 costimulatory molecules in rats with orchitis. Also, testicular macrophages from rats with EAO showed a higher production of IFNgamma (ELISA). We conclude that testicular macrophages participate in EAO development, and the ED1+ macrophage subset is the main pathogenic subpopulation. They stimulate the immune response through the production of pro-inflammatory cytokines and antigen presentation and thus activation of T cells in the target organ.

  14. Measuring autophagy in macrophages.

    PubMed

    Harris, James; Hanrahan, Orla; De Haro, Sergio A

    2009-11-01

    Macroautophagy is a conserved intracellular homeostatic mechanism for the degradation of cytosolic constituents. Autophagy can promote cell survival by providing essential amino acids from the breakdown of macromolecules during periods of nutrient deprivation, and can remove damaged or excess organelles, such as mitochondria and peroxisomes. More recently, autophagy has been shown to play an important role in innate and adaptive immune responses to pathogenic bacteria in macrophages and dendritic cells. This unit presents protocols for the measurement of autophagy in macrophages.

  15. Macrophage polarization in pathology.

    PubMed

    Sica, Antonio; Erreni, Marco; Allavena, Paola; Porta, Chiara

    2015-11-01

    Macrophages are cells of the innate immunity constituting the mononuclear phagocyte system and endowed with remarkable different roles essential for defense mechanisms, development of tissues, and homeostasis. They derive from hematopoietic precursors and since the early steps of fetal life populate peripheral tissues, a process continuing throughout adult life. Although present essentially in every organ/tissue, macrophages are more abundant in the gastro-intestinal tract, liver, spleen, upper airways, and brain. They have phagocytic and bactericidal activity and produce inflammatory cytokines that are important to drive adaptive immune responses. Macrophage functions are settled in response to microenvironmental signals, which drive the acquisition of polarized programs, whose extremes are simplified in the M1 and M2 dichotomy. Functional skewing of monocyte/macrophage polarization occurs in physiological conditions (e.g., ontogenesis and pregnancy), as well as in pathology (allergic and chronic inflammation, tissue repair, infection, and cancer) and is now considered a key determinant of disease development and/or regression. Here, we will review evidence supporting a dynamic skewing of macrophage functions in disease, which may provide a basis for macrophage-centered therapeutic strategies.

  16. Muscle Cramps

    MedlinePlus

    Muscle cramps are sudden, involuntary contractions or spasms in one or more of your muscles. They often occur after exercise or at night, ... to several minutes. It is a very common muscle problem. Muscle cramps can be caused by nerves ...

  17. Muscle Disorders

    MedlinePlus

    Your muscles help you move and help your body work. Different types of muscles have different jobs. There are many problems that can affect muscles. Muscle disorders can cause weakness, pain or even ...

  18. Your Muscles

    MedlinePlus

    ... of the heart because it controls the heartbeat. Skeletal Muscle Now, let's talk about the kind of muscle ... soccer ball into the goal. These are your skeletal muscles — sometimes called striated (say: STRY-ay-tud) muscle ...

  19. Minireview: Emerging Concepts in Islet Macrophage Biology in Type 2 Diabetes

    PubMed Central

    2015-01-01

    Chronic systemic inflammation is a hallmark feature of obesity and type 2 diabetes. Both resident and recruited islet macrophages contribute to the proinflammatory milieu of the diabetic islet. However, macrophages also appear to be critical for β-cell formation during development and support β-cell replication in experimental models of pancreas regeneration. In light of these findings, perhaps macrophages in the islet need to be viewed more as a fulcrum where deleterious inflammatory activation is balanced with beneficial tissue repair processes. Undoubtedly, defining the factors that contribute to the ontogeny, heterogeneity, and functionality of macrophages in normal, diseased, and regenerating islets will be necessary to determine whether that fulcrum can be moved to preserve functional β-cell mass in persons with diabetes. The intent of this review is to introduce the reader to emerging concepts of islet macrophage biology that may challenge the perception that macrophage accumulation in islets is merely a pathological feature of type 2 diabetes. PMID:26001058

  20. Long-term insulin-like growth factor-I expression in skeletal muscles attenuates the enhanced in vitro proliferation ability of the resident satellite cells in transgenic mice

    NASA Technical Reports Server (NTRS)

    Chakravarthy, M. V.; Fiorotto, M. L.; Schwartz, R. J.; Booth, F. W.

    2001-01-01

    Insulin-like growth factor-I (IGF-I) overexpression for 1-month in mouse skeletal muscle increases satellite cell proliferation potential. However, it is unknown whether this beneficial enhancement by IGF-I expression would persist over a longer-term duration in aged mice. This is an important issue to address if a prolonged course of IGF-I is to be used clinically in muscle-wasting conditions where satellite cells may become limiting. Using the IGF-I transgenic (IGF-I Tg) mouse that selectively expresses the IGF-I transgene in striated muscles, we found that 18-months of continuous IGF-I overexpression led to a loss in the enhanced in vitro proliferative capacity of satellite cells from Tg skeletal muscles. Also 18-month-old IGF-I Tg satellite cells lost the enhanced BrdU incorporation, greater pRb and Akt phosphorylations, and decreased p27(Kip1) levels initially observed in cells from 1-month-old IGF-I Tg mice. The levels of those biochemical markers reverted to similar values seen in the 18-months WT littermates. These findings, therefore, suggest that there is no further beneficial effect on enhancing satellite cell proliferation ability with persistent long-term expression of IGF-I in skeletal muscles of these transgenic mice.

  1. Lipoprotein lipase is synthesized by macrophage-derived foam cells in human coronary atherosclerotic plaques.

    PubMed Central

    O'Brien, K D; Gordon, D; Deeb, S; Ferguson, M; Chait, A

    1992-01-01

    Lipoprotein lipase (LPL), hydrolyzes the core triglycerides of lipoproteins, thereby playing a role in their maturation. LPL may be important in the metabolic pathways that lead to atherosclerosis, since it is secreted in vitro by both of the predominant cell types of the atherosclerotic plaque, i.e., macrophages and smooth muscle cells. Because of uncertainty concerning the primary cellular source of LPL in atherosclerotic lesions, in situ hybridization assays for LPL mRNA were performed on 12 coronary arteries obtained from six cardiac allograft recipients. Macrophages and smooth muscle cells were identified on adjacent sections with cell-specific antibodies and foam cells were identified morphologically. LPL protein was localized using a polyclonal antibody. LPL mRNA was produced by a proportion of plaque macrophages, particularly macrophage-derived foam cells, but was not detected in association with any intimal or medial smooth muscle cells. These findings were confirmed by combined immunocytochemistry and in situ hybridization on the same tissue sections. LPL protein was detected in association with macrophage-derived foam cells, endothelial cells, adventitial adipocytes, and medial smooth muscle cells, and, to a lesser extent, in intimal smooth muscle cells and media underlying well-developed plaque. These results indicate that macrophage-derived foam cells are the primary source of LPL in atherosclerotic plaques and are consistent with a role for LPL in the pathogenesis of atherosclerosis. Images PMID:1569193

  2. Distinct Hepatic Macrophage Populations in Lean and Obese Mice

    PubMed Central

    Mayoral Monibas, Rafael; Johnson, Andrew M. F.; Osborn, Olivia; Traves, Paqui G.; Mahata, Sushil K.

    2016-01-01

    Obesity is a complex metabolic disorder associated with the development of non-communicable diseases such as cirrhosis, non-alcoholic fatty liver disease, and type 2 diabetes. In humans and rodents, obesity promotes hepatic steatosis and inflammation, which leads to increased production of pro-inflammatory cytokines and acute-phase proteins. Liver macrophages (resident as well as recruited) play a significant role in hepatic inflammation and insulin resistance (IR). Interestingly, depletion of hepatic macrophages protects against the development of high-fat-induced steatosis, inflammation, and IR. Kupffer cells (KCs), liver-resident macrophages, are the first-line defense against invading pathogens, clear toxic or immunogenic molecules, and help to maintain the liver in a tolerogenic immune environment. During high fat diet feeding and steatosis, there is an increased number of recruited hepatic macrophages (RHMs) in the liver and activation of KCs to a more inflammatory or M1 state. In this review, we will focus on the role of liver macrophages (KCs and RHMs) during obesity. PMID:27999564

  3. Macrophage polarization in inflammatory diseases.

    PubMed

    Liu, Yan-Cun; Zou, Xian-Biao; Chai, Yan-Fen; Yao, Yong-Ming

    2014-01-01

    Diversity and plasticity are two hallmarks of macrophages. M1 macrophages (classically activated macrophages) are pro-inflammatory and have a central role in host defense against infection, while M2 macrophages (alternatively activated macrophages) are associated with responses to anti-inflammatory reactions and tissue remodeling, and they represent two terminals of the full spectrum of macrophage activation. Transformation of different phenotypes of macrophages regulates the initiation, development, and cessation of inflammatory diseases. Here we reviewed the characters and functions of macrophage polarization in infection, atherosclerosis, obesity, tumor, asthma, and sepsis, and proposed that targeting macrophage polarization and skewing their phenotype to adapt to the microenvironment might hold great promise for the treatment of inflammatory diseases.

  4. Integrating Immunometabolism and Macrophage Diversity

    PubMed Central

    Artyomov, Maxim; Sergushichev, Alexey; Schilling, Joel D.

    2017-01-01

    Macrophages are heterogeneous cells that play a key role in inflammatory and tissue reparative responses. Over the past decade it has become clear that shifts in cellular metabolism are important determinants of macrophage function and phenotype. At the same time, our appreciation of macrophage diversity in vivo has also been increasing. Factors such as cell origin and tissue localization are now recognized as important variables that influence macrophage biology. Whether different macrophage populations also have unique metabolic phenotypes has not been extensively explored. In this article, we will discuss the importance of understanding how macrophage origin can modulate metabolic programming and influence inflammatory responses. PMID:27771140

  5. Conditioned medium from alternatively activated macrophages induce mesangial cell apoptosis via the effect of Fas

    SciTech Connect

    Huang, Yuan; Luo, Fangjun; Li, Hui; Jiang, Tao; Zhang, Nong

    2013-11-15

    During inflammation in the glomerulus, the proliferation of myofiroblast-like mesangial cells is commonly associated with the pathological process. Macrophages play an important role in regulating the growth of resident mesangial cells in the glomeruli. Alternatively activated macrophage (M2 macrophage) is a subset of macrophages induced by IL-13/IL-4, which is shown to play a repair role in glomerulonephritis. Prompted by studies of development, we performed bone marrow derived macrophage and rat mesangial cell co-culture study. Conditioned medium from IL-4 primed M2 macrophages induced rat mesangial cell apoptosis. The pro-apoptotic effect of M2 macrophages was demonstrated by condensed nuclei stained with Hoechst 33258, increased apoptosis rates by flow cytometry analysis and enhanced caspase-3 activation by western blot. Fas protein was up-regulated in rat mesangial cells, and its neutralizing antibody ZB4 partly inhibited M2 macrophage-induced apoptosis. The up-regulated arginase-1 expression in M2 macrophage also contributed to this apoptotic effect. These results indicated that the process of apoptosis triggered by conditioned medium from M2 macrophages, at least is partly conducted through Fas in rat mesangial cells. Our findings provide compelling evidence that M2 macrophages control the growth of mesangial cells in renal inflammatory conditions. - Highlights: • Conditioned-medium from M2 macrophages induces rat mesangial cell (MsC) apoptosis. • M2 macrophage conditioned medium exerts its pro-apoptotic effects via Fas ligand. • Arginase-1 activity in M2 macrophages plays a role in inducing apoptosis in rat MsC.

  6. Neuro-immune interactions drive tissue programming in intestinal macrophages

    PubMed Central

    Gabanyi, Ilana; Muller, Paul A; Feighery, Linda; Oliveira, Thiago Y; Costa-Pinto, Frederico A; Mucida, Daniel

    2015-01-01

    Summary Proper adaptation to environmental perturbations is essential for tissue homeostasis. In the intestine, diverse environmental cues can be sensed by immune cells, which must balance resistance to microorganisms with tolerance, avoiding excess tissue damage. By applying imaging and transcriptional profiling tools, we interrogated how distinct microenvironments in the gut regulate resident macrophages. We discovered that macrophages exhibit a high degree of gene-expression specialization dependent on their proximity to the gut lumen. Lamina propria macrophages (LpMs) preferentially expressed a pro-inflammatory phenotype when compared to muscularis macrophages (MMs), which displayed a tissue-protective phenotype. Upon luminal bacterial infection, MMs further enhanced tissue-protective programs, and this was attributed to swift activation of extrinsic sympathetic neurons innervating the gut muscularis and norepinephrine signaling to β2 adrenergic receptors on MMs. Our results reveal unique intra-tissue macrophage specialization and identify neuro-immune communication between enteric neurons and macrophages that induces rapid tissue-protective responses to distal perturbations. PMID:26777404

  7. [Macrophages in asthma].

    PubMed

    Medina Avalos, M A; Orea Solano, M

    1997-01-01

    Every time they exist more demonstrations of the paper than performs the line monocytes-macrophage in the patogenesis of the bronchial asthma. The mononuclear phagocytes cells, as the alveolar macrophages, also they can be activated during allergic methods. The monocytes macrophages are possible efficient inductors of the inflammation; this due to the fact that they can secrete inflammatory mediators, between those which are counted the pre-forming granules of peptides, metabolites of oxidation activation, activator of platelets activator and metabolites of the arachidonic acid. The identification of IL-1 in the liquidate of the bronchial ablution of sick asthmatic, as well as the identification of IL-1 in the I bronchioalveolar washing of places of allergens cutaneous prick, supports the activation concept mononuclear of phagocytic cells in allergic sufferings.

  8. Regenerative Capacity of Macrophages for Remyelination

    PubMed Central

    Rawji, Khalil S.; Mishra, Manoj K.; Yong, V. Wee

    2016-01-01

    White matter injury, consisting of loss of axons, myelin, and oligodendrocytes, is common in many neurological disorders and is believed to underlie several motor and sensory deficits. Remyelination is the process in which the insulative myelin sheath is restored to axons, thereby facilitating recovery from functional loss. Remyelination proceeds with oligodendrocyte precursor cells (OPCs) that differentiate into oligodendrocytes to synthesize the new myelin sheath after demyelination. This process is influenced by several factors, including trophic factors, inhibitory molecules in the lesion microenvironment, age of the subject, as well as the inflammatory response. Currently studied strategies that enhance remyelination consist of pharmacological approaches that directly induce OPC differentiation or using agents to neutralize the inhibitory microenvironment. Another strategy is to harness a reparative inflammatory response. This response, coordinated by central nervous system resident microglia and peripherally-derived infiltrating macrophages, has been shown to be important in the remyelination process. These innate immune cells perform important functions in remyelination, including the proteolysis and phagocytosis of inhibitory molecules present in the lesion microenvironment, the provision of trophic and metabolic factors to OPCs, in addition to iron handling capacity. Additionally, an initial pro-inflammatory phase followed by a regulatory/anti-inflammatory phase has been shown to be important for OPC proliferation and differentiation, respectively. This review will discuss the beneficial roles of macrophages/microglia in remyelination and discuss therapeutic strategies to obtain the optimal regenerative macrophage phenotype for enhanced remyelination. PMID:27243011

  9. Targeting macrophage Histone deacetylase 3 stabilizes atherosclerotic lesions

    PubMed Central

    Hoeksema, Marten A; Gijbels, Marion JJ; Van den Bossche, Jan; van der Velden, Saskia; Sijm, Ayestha; Neele, Annette E; Seijkens, Tom; Stöger, J Lauran; Meiler, Svenja; Boshuizen, Marieke CS; Dallinga-Thie, Geesje M; Levels, Johannes HM; Boon, Louis; Mullican, Shannon E; Spann, Nathanael J; Cleutjens, Jack P; Glass, Chris K; Lazar, Mitchell A; de Vries, Carlie JM; Biessen, Erik AL; Daemen, Mat JAP; Lutgens, Esther; de Winther, Menno PJ

    2014-01-01

    Macrophages are key immune cells found in atherosclerotic plaques and critically shape atherosclerotic disease development. Targeting the functional repertoire of macrophages may hold novel approaches for future atherosclerosis management. Here, we describe a previously unrecognized role of the epigenomic enzyme Histone deacetylase 3 (Hdac3) in regulating the atherosclerotic phenotype of macrophages. Using conditional knockout mice, we found that myeloid Hdac3 deficiency promotes collagen deposition in atherosclerotic lesions and thus induces a stable plaque phenotype. Also, macrophages presented a switch to anti-inflammatory wound healing characteristics and showed improved lipid handling. The pro-fibrotic phenotype was directly linked to epigenetic regulation of the Tgfb1 locus upon Hdac3 deletion, driving smooth muscle cells to increased collagen production. Moreover, in humans, HDAC3 was the sole Hdac upregulated in ruptured atherosclerotic lesions, Hdac3 associated with inflammatory macrophages, and HDAC3 expression inversely correlated with pro-fibrotic TGFB1 expression. Collectively, we show that targeting the macrophage epigenome can improve atherosclerosis outcome and we identify Hdac3 as a potential novel therapeutic target in cardiovascular disease. PMID:25007801

  10. PHD2 regulates arteriogenic macrophages through TIE2 signalling

    PubMed Central

    Hamm, Alexander; Veschini, Lorenzo; Takeda, Yukiji; Costa, Sandra; Delamarre, Estelle; Squadrito, Mario Leonardo; Henze, Anne-Theres; Wenes, Mathias; Serneels, Jens; Pucci, Ferdinando; Roncal, Carmen; Anisimov, Andrey; Alitalo, Kari; De Palma, Michele; Mazzone, Massimiliano

    2013-01-01

    Occlusion of the main arterial route redirects blood flow to the collateral circulation. We previously reported that macrophages genetically modified to express low levels of prolyl hydroxylase domain protein 2 (PHD2) display an arteriogenic phenotype, which promotes the formation of collateral vessels and protects the skeletal muscle from ischaemic necrosis. However, the molecular mechanisms underlying this process are unknown. Here, we demonstrate that femoral artery occlusion induces a switch in macrophage phenotype through angiopoietin-1 (ANG1)-mediated Phd2 repression. ANG blockade by a soluble trap prevented the downregulation of Phd2 expression in macrophages and their phenotypic switch, thus inhibiting collateral growth. ANG1-dependent Phd2 repression initiated a feed-forward loop mediated by the induction of the ANG receptor TIE2 in macrophages. Gene silencing and cell depletion strategies demonstrate that TIE2 induction in macrophages is required to promote their proarteriogenic functions, enabling collateral vessel formation following arterial obstruction. These results indicate an indispensable role for TIE2 in sustaining in situ programming of macrophages to a proarteriogenic, M2-like phenotype, suggesting possible new venues for the treatment of ischaemic disorders. PMID:23616286

  11. Skeletal muscle

    Technology Transfer Automated Retrieval System (TEKTRAN)

    There are approximately 650-850 muscles in the human body these include skeletal (striated), smooth and cardiac muscle. The approximation is based on what some anatomists consider separate muscle or muscle systems. Muscles are classified based on their anatomy (striated vs. smooth) and if they are v...

  12. Monocytes and macrophages in abdominal aortic aneurysm.

    PubMed

    Raffort, Juliette; Lareyre, Fabien; Clément, Marc; Hassen-Khodja, Réda; Chinetti, Giulia; Mallat, Ziad

    2017-04-13

    Abdominal aortic aneurysm (AAA) is a life-threatening disease associated with high morbidity, and high mortality in the event of aortic rupture. Major advances in open surgical and endovascular repair of AAA have been achieved during the past 2 decades. However, drug-based therapies are still lacking, highlighting a real need for better understanding of the molecular and cellular mechanisms involved in AAA formation and progression. The main pathological features of AAA include extracellular matrix remodelling associated with degeneration and loss of vascular smooth muscle cells and accumulation and activation of inflammatory cells. The inflammatory process has a crucial role in AAA and substantially influences many determinants of aortic wall remodelling. In this Review, we focus specifically on the involvement of monocytes and macrophages, summarizing current knowledge on the roles, origin, and functions of these cells in AAA development and its complications. Furthermore, we show and propose that distinct monocyte and macrophage subsets have critical and differential roles in initiation, progression, and healing of the aneurysmal process. On the basis of experimental and clinical studies, we review potential translational applications to detect, assess, and image macrophage subsets in AAA, and discuss the relevance of these applications for clinical practice.

  13. Optimizing the customized residency plan.

    PubMed

    Phillips, Holly; Wilkinson, Samaneh T; Buck, Brian

    2013-06-01

    Residents and residency program directors (RPDs) understand that the goal of the residency year is to earn a residency certificate through achievement of established goals and objectives. The customized residency plan provides a map for the resident and RPD to follow throughout the course of the residency year, helping to keep everyone on track to accomplish the established goals and objectives of the program. It also provides information that allows preceptors to take the individual resident's plan into consideration when customizing a learning experience. This article will focus on the process for developing a customized residency plan and implementing it over the course of the residency year.

  14. Muscle Deoxygenation Causes Muscle Fatigue

    NASA Technical Reports Server (NTRS)

    Murthy, G.; Hargens, A. R.; Lehman, S.; Rempel, D.

    1999-01-01

    Muscle fatigue is a common musculoskeletal disorder in the work place, and may be a harbinger for more disabling cumulative trauma disorders. Although the cause of fatigue is multifactorial, reduced blood flow and muscle oxygenation may be the primary factor in causing muscle fatigue during low intensity muscle exertion. Muscle fatigue is defined as a reduction in muscle force production, and also occurs among astronauts who are subjected to postural constraints while performing lengthy, repetitive tasks. The objectives of this research are to: 1) develop an objective tool to study the role of decreased muscle oxygenation on muscle force production, and 2) to evaluate muscle fatigue during prolonged glovebox work.

  15. Osteopontin ablation ameliorates muscular dystrophy by shifting macrophages to a pro-regenerative phenotype

    PubMed Central

    Capote, Joana; Martinez, Leonel; Vetrone, Sylvia; Barton, Elisabeth R.; Sweeney, H. Lee; Miceli, M. Carrie

    2016-01-01

    In the degenerative disease Duchenne muscular dystrophy, inflammatory cells enter muscles in response to repetitive muscle damage. Immune factors are required for muscle regeneration, but chronic inflammation creates a profibrotic milieu that exacerbates disease progression. Osteopontin (OPN) is an immunomodulator highly expressed in dystrophic muscles. Ablation of OPN correlates with reduced fibrosis and improved muscle strength as well as reduced natural killer T (NKT) cell counts. Here, we demonstrate that the improved dystrophic phenotype observed with OPN ablation does not result from reductions in NKT cells. OPN ablation skews macrophage polarization toward a pro-regenerative phenotype by reducing M1 and M2a and increasing M2c subsets. These changes are associated with increased expression of pro-regenerative factors insulin-like growth factor 1, leukemia inhibitory factor, and urokinase-type plasminogen activator. Furthermore, altered macrophage polarization correlated with increases in muscle weight and muscle fiber diameter, resulting in long-term improvements in muscle strength and function in mdx mice. These findings suggest that OPN ablation promotes muscle repair via macrophage secretion of pro-myogenic growth factors. PMID:27091452

  16. Osteopontin ablation ameliorates muscular dystrophy by shifting macrophages to a pro-regenerative phenotype.

    PubMed

    Capote, Joana; Kramerova, Irina; Martinez, Leonel; Vetrone, Sylvia; Barton, Elisabeth R; Sweeney, H Lee; Miceli, M Carrie; Spencer, Melissa J

    2016-04-25

    In the degenerative disease Duchenne muscular dystrophy, inflammatory cells enter muscles in response to repetitive muscle damage. Immune factors are required for muscle regeneration, but chronic inflammation creates a profibrotic milieu that exacerbates disease progression. Osteopontin (OPN) is an immunomodulator highly expressed in dystrophic muscles. Ablation of OPN correlates with reduced fibrosis and improved muscle strength as well as reduced natural killer T (NKT) cell counts. Here, we demonstrate that the improved dystrophic phenotype observed with OPN ablation does not result from reductions in NKT cells. OPN ablation skews macrophage polarization toward a pro-regenerative phenotype by reducing M1 and M2a and increasing M2c subsets. These changes are associated with increased expression of pro-regenerative factors insulin-like growth factor 1, leukemia inhibitory factor, and urokinase-type plasminogen activator. Furthermore, altered macrophage polarization correlated with increases in muscle weight and muscle fiber diameter, resulting in long-term improvements in muscle strength and function in mdx mice. These findings suggest that OPN ablation promotes muscle repair via macrophage secretion of pro-myogenic growth factors.

  17. Iron homeostasis: a new job for macrophages in adipose tissue?

    PubMed Central

    Hubler, Merla J.; Peterson, Kristin R.; Hasty, Alyssa H.

    2015-01-01

    Elevated serum ferritin and increased cellular iron concentrations are risk factors for diabetes; however, the etiology of this association is unclear. Metabolic tissues such as pancreas, liver, and adipose tissue (AT), as well as the immune cells resident in these tissues, may be involved. Recent studies demonstrate that the polarization status of macrophages has important relevance to their iron handling capabilities. Furthermore, a subset of macrophages in AT have elevated iron concentrations and a gene expression profile indicative of iron handling, a capacity diminished in obesity. Because iron overload in adipocytes increases systemic insulin resistance, iron handling by AT macrophages may have relevance not only to adipocyte iron stores but also to local and systemic insulin sensitivity. PMID:25600948

  18. Rain Forest Dance Residency.

    ERIC Educational Resources Information Center

    Watson, Dawn

    1997-01-01

    Outlines the author's experience as a dancer and choreographer artist-in-residence with third graders at a public elementary school, providing a cultural arts experience to tie in with a theme study of the rain forest. Details the residency and the insights she gained working with students, teachers, and theme. (SR)

  19. Rewarding the Resident Teacher

    ERIC Educational Resources Information Center

    McBride, Jennifer M.; Drake, Richard L.

    2011-01-01

    Residents routinely make significant contributions to the education of medical students. However, little attention has been paid to rewarding these individuals for their involvement in these academic activities. This report describes a program that rewards resident teachers with an academic appointment as a Clinical Instructor. The residents…

  20. Muscle disorder

    MedlinePlus

    Myopathic changes; Myopathy; Muscle problem ... Blood tests sometimes show abnormally high muscle enzymes. If a muscle disorder might also affect other family members, genetic testing may be done. When someone has symptoms and signs ...

  1. Muscle aches

    MedlinePlus

    ... common cause of muscle aches and pain is fibromyalgia , a condition that causes tenderness in your muscles ... imbalance, such as too little potassium or calcium Fibromyalgia Infections, including the flu, Lyme disease , malaria , muscle ...

  2. Macrophage in chronic kidney disease

    PubMed Central

    Flaquer, Maria; Cruzado, Josep M.

    2016-01-01

    Chronic kidney disease (CKD) has become a major health problem worldwide. This review describes the role of macrophages in CKD and highlights the importance of anti-inflammatory M2 macrophage activation in both renal fibrosis and wound healing processes. Furthermore, the mechanisms by which M2 macrophages induce renal repair and regeneration are still under debate and currently demand more attention. The M1/M2 macrophage balance is related to the renal microenvironment and could influence CKD progression. In fact, an inflammatory renal environment and M2 plasticity can be the major hurdles to establishing macrophage cell-based therapies in CKD. M2 macrophage cell-based therapy is promising if the M2 phenotype remains stable and is ‘fixed’ by in vitro manipulation. However, a greater understanding of phenotype polarization is still required. Moreover, better strategies and targets to induce reparative macrophages in vivo should guide future investigations in order to abate kidney diseases. PMID:27994852

  3. Macrophage polarization in kidney diseases.

    PubMed

    Tian, Shaojiang; Chen, Shi-You

    Macrophage accumulation associates closely with the degree of renal structural injury and renal dysfunction in human kidney diseases. Depletion of macrophages reduces while adoptive transfer of macrophages worsens inflammation in animal models of the renal injury. However, emerging evidence support that macrophage polarization plays a critical role in the progression of a number of kidney diseases including obstructive nephropathy, ischemia-reperfusion injury, glomerulonephritis, diabetic nephropathy, and other kidney diseases. In this mini-review, we briefly summarize the macrophage infiltration and polarization in these inflammatory and fibrotic kidney diseases, discussing the results mostly from studies in animal models. In view of the critical role of macrophage in the progression of these diseases, manipulating macrophage phenotype may be a potential effective strategy to treat various kidney diseases.

  4. Studies on a novel macrophage-specific calmodulin binding glycoprotein

    SciTech Connect

    Orlow, S.J.

    1986-01-01

    The murine macrophage-like cell line J774 and peritoneal exudate cells elicited with thioglycollate or starch contain a major calmodulin-binding protein which is absent in trifluoperazine-resistant variants of J774, resident peritoneal macrophages and these elicited with concanavalin A, lipopolysaccharide, proteose peptone or Bacillus Clamette Guerin. Resident murine peritoneal cells maintained in tissue culture for 3 days begin to accumulate this protein as do human peripheral blood monocytes after 7 days of culture. A specific competitive displacement radioimmunoassay was developed using a rabbit antiserum raised to the partially purified calmodulin binding protein and (/sup 125/I) calmodulin covalently crosslinked to the principal calmodulin binding protein in the preparation. The radioimmunoassay confirmed the unique cellular distribution of this protein suggesting that it may be a marker for certain stages of macrophage differentiation. Monoclonal antibodies were prepared and one of these was used to further purify the protein by immunoaffinity chromatography. A protein of molecular weight 50,000 to 60,000 was isolated. It could be selectively adsorbed to wheat germ agglutinin agarose and subsequently eluted with N-acetyl glucosamine. This property plus its sensitivity to endoglycosidase F led to the conclusion that it is a glycoprotein. The cellular distribution, subcellular localization and evidence of glycosylation suggest that this protein may be a macrophage-specific receptor with a high affinity for calcium-calmodulin.

  5. Beyond macrophages: the diversity of mononuclear cells in tuberculosis.

    PubMed

    Srivastava, Smita; Ernst, Joel D; Desvignes, Ludovic

    2014-11-01

    Mycobacterium tuberculosis, the bacterium that causes tuberculosis (TB), is an intracellular pathogen of mononuclear phagocytes. Although M. tuberculosis has traditionally been thought to survive and replicate in macrophages, recent work in our laboratory and others has revealed that M. tuberculosis infects multiple subsets of mononuclear phagocytes in vivo and in vitro. In experimental animals, M. tuberculosis infects no fewer than five distinct cell subsets in the lungs, including resident alveolar macrophages and 4 types of cells that recruited to the lungs in response to inflammatory signals: neutrophils, monocytes, interstitial macrophages, and dendritic cells. A characteristic of the adaptive immune response in TB is that it is delayed for several weeks following infection, and we have determined that this delay is due to prolonged residence of the bacteria in lung phagocytes prior to acquisition of the bacteria by dendritic cells. Among the mechanisms used by M. tuberculosis to delay acquisition by dendritic cells is to inhibit apoptosis of alveolar macrophages and neutrophils, which sequester the bacteria and prevent their acquisition by dendritic cells in the early stages of infection. We hypothesize that each infected cell subset makes a distinct contribution to the overall biology of M. tuberculosis and allows the bacteria to evade elimination by T-cell responses and to avoid rapid killing by antimycobacterial drugs.

  6. Control of macrophage metabolism and activation by mTOR and Akt signaling

    PubMed Central

    Covarrubias, Anthony J.; Aksoylar, H. Ibrahim; Horng, Tiffany

    2015-01-01

    Macrophages are pleiotropic cells that assume a variety of functions depending on their tissue of residence and tissue state. They maintain homeostasis as well as coordinate responses to stresses such as infection and metabolic challenge. The ability of macrophages to acquire diverse, context-dependent activities requires their activation (or polarization) to distinct functional states. While macrophage activation is well understood at the level of signal transduction and transcriptional regulation, the metabolic underpinnings are poorly understood. Importantly, emerging studies indicate that metabolic shifts play a pivotal role in control of macrophage activation and acquisition of context-dependent effector activities. The signals that drive macrophage activation impinge on metabolic pathways, allowing for coordinate control of macrophage activation and metabolism. Here we discuss how mTOR and Akt, major metabolic regulators and targets of such activation signals, control macrophage metabolism and activation. Dysregulated macrophage activities contribute to many diseases, including infectious, inflammatory, and metabolic diseases and cancer, thus a better understanding of metabolic control of macrophage activation could pave the way to the development of new therapeutic strategies. PMID:26360589

  7. Control of macrophage metabolism and activation by mTOR and Akt signaling.

    PubMed

    Covarrubias, Anthony J; Aksoylar, H Ibrahim; Horng, Tiffany

    2015-08-01

    Macrophages are pleiotropic cells that assume a variety of functions depending on their tissue of residence and tissue state. They maintain homeostasis as well as coordinate responses to stresses such as infection and metabolic challenge. The ability of macrophages to acquire diverse, context-dependent activities requires their activation (or polarization) to distinct functional states. While macrophage activation is well understood at the level of signal transduction and transcriptional regulation, the metabolic underpinnings are poorly understood. Importantly, emerging studies indicate that metabolic shifts play a pivotal role in control of macrophage activation and acquisition of context-dependent effector activities. The signals that drive macrophage activation impinge on metabolic pathways, allowing for coordinate control of macrophage activation and metabolism. Here we discuss how mTOR and Akt, major metabolic regulators and targets of such activation signals, control macrophage metabolism and activation. Dysregulated macrophage activities contribute to many diseases, including infectious, inflammatory, and metabolic diseases and cancer, thus a better understanding of metabolic control of macrophage activation could pave the way to the development of new therapeutic strategies.

  8. Macrophages in Progressive Human Immunodeficiency Virus/Simian Immunodeficiency Virus Infections

    PubMed Central

    DiNapoli, Sarah R.; Hirsch, Vanessa M.

    2016-01-01

    The cells that are targeted by primate lentiviruses (HIV and simian immunodeficiency virus [SIV]) are of intense interest given the renewed effort to identify potential cures for HIV. These viruses have been reported to infect multiple cell lineages of hematopoietic origin, including all phenotypic and functional CD4 T cell subsets. The two most commonly reported cell types that become infected in vivo are memory CD4 T cells and tissue-resident macrophages. Though viral infection of CD4 T cells is routinely detected in both HIV-infected humans and SIV-infected Asian macaques, significant viral infection of macrophages is only routinely observed in animal models wherein CD4 T cells are almost entirely depleted. Here we review the roles of macrophages in lentiviral disease progression, the evidence that macrophages support viral replication in vivo, the animal models where macrophage-mediated replication of SIV is thought to occur, how the virus can interact with macrophages in vivo, pathologies thought to be attributed to viral replication within macrophages, how viral replication in macrophages might contribute to the asymptomatic phase of HIV/SIV infection, and whether macrophages represent a long-lived reservoir for the virus. PMID:27307568

  9. The transcriptional signature of human ovarian carcinoma macrophages is associated with extracellular matrix reorganization

    PubMed Central

    Adhikary, Till; Wortmann, Annika; Hoffmann, Nathalie; Bieringer, Tim; Nist, Andrea; Stiewe, Thorsten; Jansen, Julia M.; Wagner, Uwe; Müller-Brüsselbach, Sabine; Müller, Rolf

    2016-01-01

    Macrophages occur as resident cells of fetal origin or as infiltrating blood monocyte-derived cells. Despite the critical role of tumor-associated macrophages (TAMs) in tumor progression, the contribution of these developmentally and functionally distinct macrophage subsets and their alteration by the tumor microenvironment are poorly understood. We have addressed this question by comparing TAMs from human ovarian carcinoma ascites, resident peritoneal macrophages (pMPHs) and monocyte-derived macrophages (MDMs). Our study revealed striking a similarity between TAMs and pMPHs, which was considerably greater that the resemblance of TAMs and MDMs, including their transcriptomes, their inflammation-related activation state, the presence of receptors mediating immune functions and the expression of tumor-promoting mediators. Consistent with these results, TAMs phagocytized bacteria, presented peptide antigens and activated cytotoxic T cells within their pathophysiological environment. These observations support the notion that tumor-promoting properties of TAMs may reflect, at least to some extent, normal features of resident macrophages rather than functions induced by the tumor microenvironment. In spite of these surprising similarities between TAMs and pMPHs, bioinformatic analyses identified a TAM-selective signature of 30 genes that are upregulated relative to both pMPHs and MDMs. The majority of these genes is linked to extracellular matrix (ECM) remodeling, supporting a role for TAMs in cancer cell invasion and ovarian cancer progression. PMID:27659538

  10. Antihistoplasma effect of activated mouse splenic macrophages involves production of reactive nitrogen intermediates.

    PubMed Central

    Lane, T E; Wu-Hsieh, B A; Howard, D H

    1994-01-01

    The mechanism by which recombinant murine gamma interferon (rMuIFN-gamma) and bacterial lipopolysaccharide (LPS) activate mouse resident splenic macrophages to inhibit the intracellular growth of the fungus Histoplasma capsulatum was examined. Growth inhibition depended on L-arginine metabolism. The growth inhibitory state normally induced by rMuIFN-gamma and LPS in resident splenic macrophages did not occur when the macrophages were cultured in the presence of NG-monomethyl-L-arginine, a competitive inhibitor of L-arginine metabolism. Resident splenic macrophages treated with rMuIFN-gamma and LPS produced nitrite (NO2-), an end product of L-arginine metabolism. When macrophages were cultured in the presence of NG-monomethyl-L-arginine together with rMuIFN-gamma and LPS, only baseline levels of NO2- were detected. Spleen cells from H. capsulatum-infected mice produced high levels of NO2- in culture. The production of NO2- correlated with in vitro inhibition of the intracellular growth of H. capsulatum. Anti-tumor necrosis factor alpha antibody did not block NO2- production by the immigrant splenic macrophages and did not abolish the antihistoplasma activity. PMID:8168960

  11. Macrophage infection models for Mycobacterium tuberculosis.

    PubMed

    Johnson, Benjamin K; Abramovitch, Robert B

    2015-01-01

    Mycobacterium tuberculosis colonizes, survives, and grows inside macrophages. In vitro macrophage infection models, using both primary macrophages and cell lines, enable the characterization of the pathogen response to macrophage immune pressure and intracellular environmental cues. We describe methods to propagate and infect primary murine bone marrow-derived macrophages and J774 and THP-1 macrophage-like cell lines. We also present methods on the characterization of M. tuberculosis intracellular survival and the preparation of infected macrophages for imaging.

  12. Macrophages Contribute to the Cyclic Activation of Adult Hair Follicle Stem Cells

    PubMed Central

    Castellana, Donatello; Paus, Ralf; Perez-Moreno, Mirna

    2014-01-01

    Skin epithelial stem cells operate within a complex signaling milieu that orchestrates their lifetime regenerative properties. The question of whether and how immune cells impact on these stem cells within their niche is not well understood. Here we show that skin-resident macrophages decrease in number because of apoptosis before the onset of epithelial hair follicle stem cell activation during the murine hair cycle. This process is linked to distinct gene expression, including Wnt transcription. Interestingly, by mimicking this event through the selective induction of macrophage apoptosis in early telogen, we identify a novel involvement of macrophages in stem cell activation in vivo. Importantly, the macrophage-specific pharmacological inhibition of Wnt production delays hair follicle growth. Thus, perifollicular macrophages contribute to the activation of skin epithelial stem cells as a novel, additional cue that regulates their regenerative activity. This finding may have translational implications for skin repair, inflammatory skin diseases and cancer. PMID:25536657

  13. Imaging macrophages with nanoparticles

    NASA Astrophysics Data System (ADS)

    Weissleder, Ralph; Nahrendorf, Matthias; Pittet, Mikael J.

    2014-02-01

    Nanomaterials have much to offer, not only in deciphering innate immune cell biology and tracking cells, but also in advancing personalized clinical care by providing diagnostic and prognostic information, quantifying treatment efficacy and designing better therapeutics. This Review presents different types of nanomaterial, their biological properties and their applications for imaging macrophages in human diseases, including cancer, atherosclerosis, myocardial infarction, aortic aneurysm, diabetes and other conditions. We anticipate that future needs will include the development of nanomaterials that are specific for immune cell subsets and can be used as imaging surrogates for nanotherapeutics. New in vivo imaging clinical tools for noninvasive macrophage quantification are thus ultimately expected to become relevant to predicting patients' clinical outcome, defining treatment options and monitoring responses to therapy.

  14. Survival and replication of Escherichia coli O157:H7 inside the mice peritoneal macrophages

    PubMed Central

    Al-Mariri, Ayman

    2008-01-01

    The replication of Escherichia coli O157:H7 on the resident peritoneal macrophages of four mice strains (BALB/c, CD1, C57BL, and Swiss) has been investigated. Macrophagial bactericidal killing activity was estimated via studying their ability to internalize (gentamicin-protected) E. coli during 2, 4, 24, and 48 h assays. Host genetic background has been found to show no significant effect on the ability of resident peritoneal macrophages to kill E. coli O157:H7. PMID:24031167

  15. Macrophage polarization following chitosan implantation.

    PubMed

    Vasconcelos, Daniela P; Fonseca, Ana C; Costa, Madalena; Amaral, Isabel F; Barbosa, Mário A; Águas, Artur P; Barbosa, Judite N

    2013-12-01

    Macrophages are a key cell in the host response to implants and can be polarized into different phenotypes capable of inducing both detrimental and beneficial outcomes in tissue repair and remodeling, being important in tissue engineering and regenerative medicine. The objective of this study was to evaluate the macrophage response to 3D porous chitosan (Ch) scaffolds with different degrees of acetylation (DA, 5% and 15%). The M1/M2 phenotypic polarization profile of macrophages was investigated in vivo using a rodent air-pouch model. Our results show that the DA affects the macrophage response. Ch scaffolds with DA 5% induced the adhesion of lower numbers of inflammatory cells, being the M2 the predominant phenotypic profile among the adherent macrophages. In the inflammatory exudates F4/80(+)/CD206(+) cells (M2 macrophages) appeared in higher numbers then F4/80(+)/CCR7(+) cells (M1 macrophages), in addition, lower levels of pro-inflammatory cytokines together with higher levels of anti-inflammatory cytokines were found. Ch scaffolds with DA 15% showed opposite results, since M1 were the predominant macrophages both adherent to the scaffold and in the exudates, together with high levels of pro-inflammatory cytokines. In conclusion, Ch scaffolds with DA 5% induced a benign M2 anti-inflammatory macrophage response, whereas Ch scaffolds with DA 15% caused a macrophage M1 pro-inflammatory response.

  16. Mycobacteria manipulate macrophage recruitment through coordinated use of membrane lipids.

    PubMed

    Cambier, C J; Takaki, Kevin K; Larson, Ryan P; Hernandez, Rafael E; Tobin, David M; Urdahl, Kevin B; Cosma, Christine L; Ramakrishnan, Lalita

    2014-01-09

    The evolutionary survival of Mycobacterium tuberculosis, the cause of human tuberculosis, depends on its ability to invade the host, replicate, and transmit infection. At its initial peripheral infection site in the distal lung airways, M. tuberculosis infects macrophages, which transport it to deeper tissues. How mycobacteria survive in these broadly microbicidal cells is an important question. Here we show in mice and zebrafish that M. tuberculosis, and its close pathogenic relative Mycobacterium marinum, preferentially recruit and infect permissive macrophages while evading microbicidal ones. This immune evasion is accomplished by using cell-surface-associated phthiocerol dimycoceroserate (PDIM) lipids to mask underlying pathogen-associated molecular patterns (PAMPs). In the absence of PDIM, these PAMPs signal a Toll-like receptor (TLR)-dependent recruitment of macrophages that produce microbicidal reactive nitrogen species. Concordantly, the related phenolic glycolipids (PGLs) promote the recruitment of permissive macrophages through a host chemokine receptor 2 (CCR2)-mediated pathway. Thus, we have identified coordinated roles for PDIM, known to be essential for mycobacterial virulence, and PGL, which (along with CCR2) is known to be associated with human tuberculosis. Our findings also suggest an explanation for the longstanding observation that M. tuberculosis initiates infection in the relatively sterile environment of the lower respiratory tract, rather than in the upper respiratory tract, where resident microflora and inhaled environmental microbes may continually recruit microbicidal macrophages through TLR-dependent signalling.

  17. Arachidonic acid metabolism in glutathione-deficient macrophages.

    PubMed Central

    Rouzer, C A; Scott, W A; Griffith, O W; Hamill, A L; Cohn, Z A

    1982-01-01

    Mouse resident peritoneal macrophages were treated with the glutathione (GSH) synthesis inhibitor buthionine sulfoximine to deplete intracellular GSH. The arachidonic acid metabolites released by the GSH-depleted macrophages in response to a zymosan challenge were analyzed by HPLC. Buthionine sulfoximine treatment resulted in inhibition of both prostaglandin E2 and leukotriene C synthesis that was directly related to the degree of GSH depletion. Macrophages in which GSH levels were reduced to 3% of normal exhibited reductions to 4% and 1%, respectively, in PGE2 and LTC formation. The total quantity of cyclooxygenase metabolites secreted by GSH-deficient macrophages was identical to that of control cells as a result of increased synthesis of prostacyclin and, to a lesser extent, 12-L-hydroxy-5,8,10-heptadecatrienoic acid. Total lipoxygenase products were decreased, however; increased formation of hydroxyicosatetraenoic acids only partially compensated for the deficit in leukotriene C production. These findings extent our earlier observations on the inhibition of leukotriene C synthesis in GSH-depleted macrophages and confirm with intact cells the previously suggested role of GSH in prostaglandin E2 formation. PMID:6803245

  18. Association of Legionella pneumophila with the macrophage endoplasmic reticulum.

    PubMed Central

    Swanson, M S; Isberg, R R

    1995-01-01

    Legionella pneumophila replicates within a membrane-bounded compartment that is studded with ribosomes. In this study we investigated whether these ribosomes originate from the cytoplasmic pool or are associated with host endoplasmic reticulum (ER). Immunofluorescence and electron microscopic localization studies of ER proteins in macrophages infected with L. pneumophila indicated that the bacteria reside in a compartment surrounded by ER. An L. pneumophila mutant that grows slowly in macrophages was slow to associate with host ER, providing genetic evidence in support of the hypothesis that this specialized vacuole is required for intracellular bacterial growth. Ultrastructural studies, in which the ER luminal protein BiP was labeled by immunoperoxidase cytochemistry, revealed that L. pneumophila replication vacuoles resemble nascent autophagosomes. Furthermore, short-term amino acid starvation of macrophages, which stimulated host autophagosomes. Furthermore, short-term amino acid starvation of macrophages, which stimulated host autophagy, increased association of the bacteria with the ER and enhanced bacterial growth. These results are compatible with the hypothesis that L. pneumophila exploits the autophagy machinery of macrophages to establish an intracellular niche favorable for replication. PMID:7642298

  19. Molecular imaging of microglia/macrophages in the brain

    PubMed Central

    Venneti, Sriram; Lopresti, Brian J.; Wiley, Clayton A.

    2013-01-01

    Neuroinflammation perpetuates neuronal damage in many neurological disorders. Activation of resident microglia and infiltration of monocytes/macrophages contributes to neuronal injury and synaptic damage. Non-invasive imaging of these cells in vivo provides a means to monitor progression of disease as well as assess efficacies of potential therapeutics. This review provides an overview of positron emission tomography (PET) and magnetic resonance (MR) imaging of microglia/macrophages in the brain. We describe the rationale behind PET imaging of microglia/macrophages with ligands that bind to translocator protein-18 kDa (TSPO). We discuss the prototype TSPO radioligand [11C]PK11195, its limitations, and the development of newer TSPO ligands as PET imaging agents. PET imaging agents for targets other than TSPO are emerging, and we outline the potential of these agents for imaging brain microglia/macrophage activity in vivo. Finally, we briefly summarize advances in MR imaging of microglia/macrophages using iron oxide nanoparticles and ultra-small super paramagnetic particles that are phagocytosed. Despite many technical advances, more sensitive agents are required to be useful indicators of neuroinflammation in brain. PMID:22615180

  20. Epigenomics of macrophages.

    PubMed

    Gosselin, David; Glass, Christopher K

    2014-11-01

    Macrophages play essential roles in tissue homeostasis, pathogen elimination, and tissue repair. A defining characteristic of these cells is their ability to efficiently adapt to a variety of abruptly changing and complex environments. This ability is intrinsically linked to a capacity to quickly alter their transcriptome, and this is tightly associated with the epigenomic organization of these cells and, in particular, their enhancer repertoire. Indeed, enhancers are genomic sites that serve as platforms for the integration of signaling pathways with the mechanisms that regulate mRNA transcription. Notably, transcription is pervasive at active enhancers and enhancer RNAs (eRNAs) are tightly coupled to regulated transcription of protein-coding genes. Furthermore, given that each cell type possesses a defining enhancer repertoire, studies on enhancers provide a powerful method to study how specialization of functions among the diverse macrophage subtypes may arise. Here, we review recent studies providing insights into the distinct mechanisms that contribute to the establishment of enhancers and their role in the regulation of transcription in macrophages.

  1. Facilty Focus: Residence Halls.

    ERIC Educational Resources Information Center

    Hunnewell, James F., Jr.

    2002-01-01

    Describes the Western Ridge Residence at Colorado College and Beard Hall at Wheaton College. The buildings feature multiple levels that take advantage of views and also help create a "homey" feeling. (EV)

  2. Atypical presentation of macrophagic myofasciitis 10 years post vaccination.

    PubMed

    Ryan, Aisling M; Bermingham, Niamh; Harrington, Hugh J; Keohane, Catherine

    2006-12-01

    Macrophagic myofasciitis (MMF) is an uncommon inflammatory disorder of muscle believed to be due to persistence of vaccine-derived aluminium hydroxide at the site of injection. The condition is characterised by diffuse myalgias, arthralgia and fatigue. We describe a patient with histologically confirmed MMF whose presentation was atypical with left chest and upper limb pain beginning more than 10 years post vaccination. Treatment with steroids led to symptomatic improvement. Although rare, clinicians should consider MMF in cases of atypical myalgia.

  3. Residents' Perspectives on Professionalism

    PubMed Central

    Krain, Lewis P.; Lavelle, Ellen

    2009-01-01

    Background Research defining professionalism exists, yet little is known about how residents view this important attribute for medical practice. Knowing more about residents' interpretations of professionalism and about how they value professionalism would enhance definitions and facilitate support for the development of professionalism skills and behaviors at the graduate level. Purpose The purpose of this phenomenological study was to investigate how residents think about professionalism, how they value it, and how it plays out in their educational lives. Methods This study uses qualitative methods, employing 5 focus groups representative of a range of disciplines. Methods include providing unstructured prompts, member checking and informant feedback to support credibility, and content analysis to discern significant patterns. Results Content analysis supported that residents highly value professionalism and see it as a complex construct, dependent on the situation, discipline, and on personal experience. Challenges to professionalism are common in graduate medical education and a great concern for residents. Conclusions Physician educators often discuss professionalism as an overarching concept in medicine, especially in classes during the preclinical years. Although some general principles are applicable, residents relate more deeply to aspects of professionalism that concern their own clinical practice, situation, and specialty. Implications for measurement of professional skills and for further research are included in this report. PMID:21975982

  4. Distinct inflammatory properties of late-activated macrophages in inflammatory myopathies

    PubMed Central

    Rostasy, KM; Schmidt, J; Bahn, E; Pfander, T; Piepkorn, M; Wilichowski, E; Schulz-Schaeffer, J

    2008-01-01

    Summary Distinct mechanisms such as humeral immunity in dermatomyositis (DM) and T-cell-mediated cytotoxicity in polymyositis (PM) contribute to the pathology of inflammatory myopathies. In addition, different subsets of macrophages are present in both diseases. Herein, the characteristics of 25F9-positive macrophages in skeletal muscle inflammation are outlined. Muscle biopsies of subjects with DM and PM were studied by immunohistochemical multi-labelling using the late-activation marker 25F9, together with markers characterizing macrophage function including IFN-γ, iNOS, and TGF-β. In PM, a robust expression of IFN-γ, iNOS, and TGF-β was observed in inflammatory cells. Double- and serial-labelling revealed that a subset of 25F9-positive macrophages in the vicinity of injured muscle fibres expressed iNOS and TGF-β, but not IFN-γ. In DM, IFN-γ, iNOS and TGF-β were also expressed in inflammatory cells in the endomysium. Double- and serial-labelling studies in DM indicated that 25F9-positive macrophages expressed TGF-β and to a lesser degree iNOS, but not IFN-γ. In conclusion, our data suggest that late-activated macrophages contribute to the pathology of inflammatory myopathies. PMID:19364061

  5. Distinct inflammatory properties of late-activated macrophages in inflammatory myopathies.

    PubMed

    Rostasy, K M; Schmidt, J; Bahn, E; Pfander, T; Piepkorn, M; Wilichowski, E; Schulz-Schaeffer, J

    2008-10-01

    Distinct mechanisms such as humeral immunity in dermatomyositis (DM) and T-cell-mediated cytotoxicity in polymyositis (PM) contribute to the pathology of inflammatory myopathies. In addition, different subsets of macrophages are present in both diseases. Herein, the characteristics of 25F9-positive macrophages in skeletal muscle inflammation are outlined. Muscle biopsies of subjects with DM and PM were studied by immunohistochemical multi-labelling using the late-activation marker 25F9, together with markers characterizing macrophage function including IFN-gamma, iNOS, and TGF-beta. In PM, a robust expression of IFN-gamma, iNOS, and TGF-beta was observed in inflammatory cells. Double- and serial-labelling revealed that a subset of 25F9-positive macrophages in the vicinity of injured muscle fibres expressed iNOS and TGF-beta, but not IFN-gamma. In DM, IFN-gamma, iNOS and TGF-beta were also expressed in inflammatory cells in the endomysium. Double- and serial-labelling studies in DM indicated that 25F9-positive macrophages expressed TGF-beta and to a lesser degree iNOS, but not IFN-gamma. In conclusion, our data suggest that late-activated macrophages contribute to the pathology of inflammatory myopathies.

  6. Redox Control of Skeletal Muscle Regeneration.

    PubMed

    Le Moal, Emmeran; Pialoux, Vincent; Juban, Gaëtan; Groussard, Carole; Zouhal, Hassane; Chazaud, Bénédicte; Mounier, Rémi

    2017-02-06

    Skeletal muscle shows high plasticity in response to external demand. Moreover, adult skeletal muscle is capable of complete regeneration after injury, due to the properties of muscle stem cells (MuSCs), the satellite cells, which follow a tightly regulated myogenic program to generate both new myofibers and new MuSCs for further needs. Although reactive oxygen species (ROS) and reactive nitrogen species (RNS) have long been associated with skeletal muscle physiology, their implication in the cell and molecular processes at work during muscle regeneration is more recent. This review focuses on redox regulation during skeletal muscle regeneration. An overview of the basics of ROS/RNS and antioxidant chemistry and biology occurring in skeletal muscle is first provided. Then, the comprehensive knowledge on redox regulation of MuSCs and their surrounding cell partners (macrophages, endothelial cells) during skeletal muscle regeneration is presented in normal muscle and in specific physiological (exercise-induced muscle damage, aging) and pathological (muscular dystrophies) contexts. Recent advances in the comprehension of these processes has led to the development of therapeutic assays using antioxidant supplementation, which result in inconsistent efficiency, underlying the need for new tools that are aimed at precisely deciphering and targeting ROS networks. This review should provide an overall insight of the redox regulation of skeletal muscle regeneration while highlighting the limits of the use of nonspecific antioxidants to improve muscle function. Antioxid. Redox Signal. 00, 000-000.

  7. The macrophages in rheumatic diseases

    PubMed Central

    Laria, Antonella; Lurati, Alfredomaria; Marrazza, Mariagrazia; Mazzocchi, Daniela; Re, Katia Angela; Scarpellini, Magda

    2016-01-01

    Macrophages belong to the innate immune system giving us protection against pathogens. However it is known that they are also involved in rheumatic diseases. Activated macrophages have two different phenotypes related to different stimuli: M1 (classically activated) and M2 (alternatively activated). M1 macrophages release high levels of pro-inflammatory cytokines, reactive nitrogen and oxygen intermediates killing microorganisms and tumor cells; while M2 macrophages are involved in resolution of inflammation through phagocytosis of apoptotic neutrophils, reduced production of pro-inflammatory cytokines, and increased synthesis of mediators important in tissue remodeling, angiogenesis, and wound repair. The role of macrophages in the different rheumatic diseases is different according to their M1/M2 macrophages phenotype. PMID:26929657

  8. Comparative analysis of the internalization of the macrophage receptor sialoadhesin in human and mouse primary macrophages and cell lines.

    PubMed

    De Schryver, Marjorie; Leemans, Annelies; Pintelon, Isabel; Cappoen, Davie; Maes, Louis; Caljon, Guy; Cos, Paul; Delputte, Peter L

    2016-11-21

    Sialoadhesin (Sn) is a surface receptor expressed on resident macrophages with the ability to bind with sialic acids. During inflammation, an upregulation of Sn is observed. Upon binding of monoclonal antibodies to Sn, the receptor becomes internalized and this has been observed in multiple species. The latter characteristic, combined with the strong upregulation of Sn on inflammatory macrophages and the fact that Sn-positive macrophages contribute to certain inflammatory diseases, makes Sn an interesting entry portal for phenotype-modulating or cytotoxic drugs. Such drugs or toxins can be linked to Sn-specific antibodies which should enable their targeted uptake by macrophages. However, the activity of such drugs depends not only on their internalization but also on the intracellular trafficking and final fate in the endolysosomal system. Although information is available for porcine Sn, the detailed mechanisms of human and mouse Sn internalization and subsequent intracellular trafficking are currently unknown. To allow development of Sn-targeted therapies, differences across species and cellular background need to be characterized in more detail. In the current report, we show that internalization of human and mouse Sn is dynamin-dependent and clathrin-mediated, both in primary macrophages and CHO cell lines expressing a recombinant Sn. In primary macrophages, internalized Sn-specific F(ab')2 fragments are located mostly in the early endosomes. With Fc containing Sn-specific antibodies, there is a slight shift towards lysosomal localization in mouse macrophages, possibly because of an interaction with Fc receptors. Surprisingly, in CHO cell lines expressing Sn, there is a predominant lysosomal localization. Our results show that the mechanism of Sn internalization and intracellular trafficking is concurrent in the tested species. The cellular background in which Sn is expressed and the type of antibody used can affect the intracellular fate, which in turn can

  9. Complement activation promotes muscle inflammation during modified muscle use

    NASA Technical Reports Server (NTRS)

    Frenette, J.; Cai, B.; Tidball, J. G.

    2000-01-01

    Modified muscle use can result in muscle inflammation that is triggered by unidentified events. In the present investigation, we tested whether the activation of the complement system is a component of muscle inflammation that results from changes in muscle loading. Modified rat hindlimb muscle loading was achieved by removing weight-bearing from the hindlimbs for 10 days followed by reloading through normal ambulation. Experimental animals were injected with the recombinant, soluble complement receptor sCR1 to inhibit complement activation. Assays for complement C4 or factor B in sera showed that sCR1 produced large reductions in the capacity for activation of the complement system through both the classical and alternative pathways. Analysis of complement C4 concentration in serum in untreated animals showed that the classical pathway was activated during the first 2 hours of reloading. Analysis of factor B concentration in untreated animals showed activation of the alternative pathway at 6 hours of reloading. Administration of sCR1 significantly attenuated the invasion of neutrophils (-49%) and ED1(+) macrophages (-52%) that occurred in nontreated animals after 6 hours of reloading. The presence of sCR1 also reduced significantly the degree of edema by 22% as compared to untreated animals. Together, these data show that increased muscle loading activated the complement system which then briefly contributes to the early recruitment of inflammatory cells during modified muscle loading.

  10. Satisfaction among residents in ASHP-accredited pharmacy residency programs.

    PubMed

    VanDenBerg, C; Murphy, J E

    1997-07-01

    The level of work satisfaction among pharmacists in ASHP-accredited residencies was studied. In March 1996 a questionnaire designed to measure residency satisfaction was mailed to 697 individuals in ASHP-accredited pharmacy practice and specialty practice residencies. Subjects responded to 16 statements relating to intrinsic and extrinsic determinants of work satisfaction on a scale of 1 to 5, where 1 = strongly disagree and 5 = strongly agree. Questionnaires were returned by 413 (59%) of the residents. The respondents were predominantly women (76%), and most (86%) had at least a Pharm. D. degree. Hospitals were the primary work setting (88%). Of the 413 residents, 305 were in pharmacy practice residencies and 108 were in specialized residencies. None of the mean scores indicated disagreement (scores < 3) with the positively worded statements or agreement (scores > 3) with the negatively worded statements. The median and mode were equal to 2 (disagree) for the three negatively worded items and 4 (agree) for all but three positively worded items. Only 8% of the residents indicated that they would not accept the residency again if given the chance. Specialized residents tended to rate positively worded statements higher and negatively worded statements lower than pharmacy practice residents. Female residents indicated greater satisfaction than male residents. Pay and benefits were rated slightly better than neutral. Pharmacy residents appeared generally satisfied with their residencies. Specialized pharmacy residents were more satisfied than pharmacy practice residents, and women were more satisfied than men.

  11. Inflammatory macrophages can transdifferentiate into myofibroblasts during renal fibrosis

    PubMed Central

    Meng, Xiao-Ming; Wang, Shuang; Huang, Xiao-Ru; Yang, Chen; Xiao, Jun; Zhang, Yang; To, Ka-Fai; Nikolic-Paterson, David J; Lan, Hui-Yao

    2016-01-01

    Myofibroblasts play a central role in renal fibrosis although the origin of these cells remains controversial. We recently reported that bone marrow-derived macrophages can give rise to myofibroblasts through macrophage to myofibroblast transition (MMT). However, several important issues remain to be addressed, including whether MMT occurs in human kidney disease and verification of the MMT process through lineage tracing. Biopsies from a cohort of 58 patients with various forms of kidney disease were examined for MMT cells that co-express macrophage (CD68) and myofibroblast (α-smooth muscle actin, α-SMA) markers. MMT cells were evident in active fibrotic lesions, but were largely absent in acute inflammatory or sclerotic lesions, suggesting that MMT cells contribute to progressive renal fibrosis. Fate-mapping studies in LysMCreTomato mice identified substantial numbers of Tomato+ myeloid cells with F4/80+ macrophage phenotype expressing α-SMA and collagen I in the unilateral ureteral obstructive model of renal fibrosis, providing direct evidence for the MMT process during the development of renal fibrosis. In addition, MMT cells had a predominant M2 phenotype in both human and mouse renal fibrosis. Finally, selective depletion of myeloid cells via diphtheria toxin in LysMCreiDTR mice largely abolished macrophage infiltration and MMT cells in the obstructed kidney and substantially reduced accumulation of α-SMA+ myofibroblasts and collagen deposition, revealing a pathogenic role for inflammatory macrophages in MMT and tissue fibrosis. In conclusion, these findings provide substantial new data to support the postulate that macrophages can directly transdifferentiate into collagen-producing myofibroblasts in human and experimental kidney disease. PMID:27906172

  12. Macrophage-targeted photodynamic detection of vulnerable atherosclerotic plaque

    NASA Astrophysics Data System (ADS)

    Hamblin, Michael R.; Tawakol, Ahmed; Castano, Ana P.; Gad, Faten; Zahra, Touqir; Ahmadi, Atosa; Stern, Jeremy; Ortel, Bernhard; Chirico, Stephanie; Shirazi, Azadeh; Syed, Sakeena; Muller, James E.

    2003-06-01

    Rupture of a vulnerable atherosclerotic plaque (VP) leading to coronary thrombosis is the chief cause of sudden cardiac death. VPs are angiographically insignificant lesions, which are excessively inflamed and characterized by dense macrophage infiltration, large necrotic lipid cores, thin fibrous caps, and paucity of smooth muscle cells. We have recently shown that chlorin(e6) conjugated with maleylated albumin can target macrophages with high selectivity via the scavenger receptor. We report the potential of this macrophage-targeted fluorescent probe to localize in VPs in a rabbit model of atherosclerosis, and allow detection and/or diagnosis by fluorescence spectroscopy or imaging. Atherosclerotic lesions were induced in New Zealand White rabbit aortas by balloon injury followed by administration of a high-fat diet. 24-hours after IV injection of the conjugate into atherosclerotic or normal rabbits, the animals were sacrificed, and aortas were removed, dissected and examined for fluorescence localization in plaques by fiber-based spectrofluorimetry and confocal microscopy. Dye uptake within the aortas was also quantified by fluorescence extraction of samples from aorta segments. Biodistribution of the dye was studied in many organs of the rabbits. Surface spectrofluorimetry after conjugate injection was able to distinguish between plaque and adjacent aorta, between atherosclerotic and normal aorta, and balloon-injured and normal iliac arteries with high significance. Discrete areas of high fluorescence (up to 20 times control were detected in the balloon-injured segments, presumably corresponding to macrophage-rich plaques. Confocal microscopy showed red ce6 fluorescence localized in plaques that showed abundant foam cells and macrophages by histology. Extraction data on aortic tissue corroborated the selectivity of the conjugate for plaques. These data support the strategy of employing macrophage-targeted fluorescent dyes to detect VP by intravascular

  13. Bioelectric modulation of macrophage polarization.

    PubMed

    Li, Chunmei; Levin, Michael; Kaplan, David L

    2016-02-12

    Macrophages play a critical role in regulating wound healing and tissue regeneration by changing their polarization state in response to local microenvironmental stimuli. The native roles of polarized macrophages encompass biomaterials and tissue remodeling needs, yet harnessing or directing the polarization response has been largely absent as a potential strategy to exploit in regenerative medicine to date. Recent data have revealed that specific alteration of cells' resting potential (Vmem) is a powerful tool to direct proliferation and differentiation in a number of complex tissues, such as limb regeneration, craniofacial patterning and tumorigenesis. In this study, we explored the bioelectric modulation of macrophage polarization by targeting ATP sensitive potassium channels (KATP). Glibenclamide (KATP blocker) and pinacidil (KATP opener) treatment not only affect macrophage polarization, but also influence the phenotype of prepolarized macrophages. Furthermore, modulation of cell membrane electrical properties can fine-tune macrophage plasticity. Glibenclamide decreased the secretion and gene expression of selected M1 markers, while pinacidil augmented M1 markers. More interestingly, glibencalmide promoted macrophage alternative activation by enhancing certain M2 markers during M2 polarization. These findings suggest that control of bioelectric properties of macrophages could offer a promising approach to regulate macrophage phenotype as a useful tool in regenerative medicine.

  14. Macrophages in homeostatic immune function

    PubMed Central

    Jantsch, Jonathan; Binger, Katrina J.; Müller, Dominik N.; Titze, Jens

    2014-01-01

    Macrophages are not only involved in inflammatory and anti-infective processes, but also play an important role in maintaining tissue homeostasis. In this review, we summarize recent evidence investigating the role of macrophages in controlling angiogenesis, metabolism as well as salt and water balance. Particularly, we summarize the importance of macrophage tonicity enhancer binding protein (TonEBP, also termed nuclear factor of activated T-cells 5 [NFAT5]) expression in the regulation of salt and water homeostasis. Further understanding of homeostatic macrophage function may lead to new therapeutic approaches to treat ischemia, hypertension and metabolic disorders. PMID:24847274

  15. Bioelectric modulation of macrophage polarization

    NASA Astrophysics Data System (ADS)

    Li, Chunmei; Levin, Michael; Kaplan, David L.

    2016-02-01

    Macrophages play a critical role in regulating wound healing and tissue regeneration by changing their polarization state in response to local microenvironmental stimuli. The native roles of polarized macrophages encompass biomaterials and tissue remodeling needs, yet harnessing or directing the polarization response has been largely absent as a potential strategy to exploit in regenerative medicine to date. Recent data have revealed that specific alteration of cells’ resting potential (Vmem) is a powerful tool to direct proliferation and differentiation in a number of complex tissues, such as limb regeneration, craniofacial patterning and tumorigenesis. In this study, we explored the bioelectric modulation of macrophage polarization by targeting ATP sensitive potassium channels (KATP). Glibenclamide (KATP blocker) and pinacidil (KATP opener) treatment not only affect macrophage polarization, but also influence the phenotype of prepolarized macrophages. Furthermore, modulation of cell membrane electrical properties can fine-tune macrophage plasticity. Glibenclamide decreased the secretion and gene expression of selected M1 markers, while pinacidil augmented M1 markers. More interestingly, glibencalmide promoted macrophage alternative activation by enhancing certain M2 markers during M2 polarization. These findings suggest that control of bioelectric properties of macrophages could offer a promising approach to regulate macrophage phenotype as a useful tool in regenerative medicine.

  16. Macrophage Cryptococcus interactions: an update

    PubMed Central

    Mansour, Michael K.; Reedy, Jennifer L.; Tam, Jenny M.; Vyas, Jatin M.

    2014-01-01

    Cryptococcus species are fungal pathogens that are a leading cause of mortality. Initial inoculation is through the pulmonary route and, if disseminated, results in severe invasive infection including meningoencephalitis. Macrophages are the dominant phagocytic cell that interacts with Cryptococcus. Emerging theories suggest that Cryptococcus microevolution in macrophages is linked to survival and virulence within the host. In addition, Cryptococcus elaborates virulence factors as well as usurps host machinery to establish macrophage activation states that are permissive to intracellular survival and replication. In this review, we provide an update of the recent findings pertaining to macrophage interaction with Cryptococcus and focus on new avenues for biomedical research. PMID:24660045

  17. Genetic Control of the Innate Resistance of Mice to Salmonella typhimurium: Expression of the Ity Gene in Peritoneal Macrophages Isolated In Vitro

    DTIC Science & Technology

    1984-07-20

    Statistical Analysis 67 RESULTS Configuration of the _In Vitro Salmonella Infection Assay 68 I. Assessment of the cellular composition of resident... Salmonella Infection Assay I. Assessment of the cellular composition of resident adherent macrophages at the time of infection The methods used for...point of Salmonella infection . At that time, the macrophage cultures were overlaid with 500 pi/well of the lidocaine solution, and incubated at 37° C

  18. Burnout Syndrome During Residency

    PubMed Central

    Turgut, Namigar; Karacalar, Serap; Polat, Cengiz; Kıran, Özlem; Gültop, Fethi; Kalyon, Seray Türkmen; Sinoğlu, Betül; Zincirci, Mehmet; Kaya, Ender

    2016-01-01

    Objective The aim of this study is identified the degree of Burnout Syndrome (BOS) and find out its correlation with years of recidency and sociodemograpfic chareacteristics, training, sleeping habits, such as smoking and alcohol consumption. Methods After approval from the Hospital Ethics Committee and obtaining informed consent, First, second, third, fourth and fifth year of recidency staff (n=127) working in our hospital were involved in this study. The standardized Maslach Burnout Inventory (MBI) was used in this study. Results Fifty six male (44.1%) and seventy one female (55.9%) residents were enroled in this study (Coranbach Alfa(α)=0.873). 57% of the first year residents smokes cigaret and 54% of them use alcohol. 2% of them gets one day off after hospital night shift, 61% of them suffers from disturbed sleep. 60% of them had been stated that they willingly selected their profession. 61% of them prefers talking to friends and 32% of them prefers shopping to overcome stress. There were statistical difference acording to years of recidency in MBI, Emotional Burnout (EB) and desensitisation scale (DS) points. EB scale points of the second year of residency group was statisticaly higher than fourth year of residency group. DS points of second year of residency group was also statisticaly higher than the third and fourth year of residency group. There was no statistical difference between any groups in Personal Success. Conclusion BOS is a frequent problem during residency in anaesthesia. Appropriate definition and awareness are the first important steps to prevent this syndrome. Further administrative approaches should be evaluated with regard to their effects. PMID:27909607

  19. Highly efficient, functional engraftment of skeletal muscle stem cells in dystrophic muscles.

    PubMed

    Cerletti, Massimiliano; Jurga, Sara; Witczak, Carol A; Hirshman, Michael F; Shadrach, Jennifer L; Goodyear, Laurie J; Wagers, Amy J

    2008-07-11

    Satellite cells reside beneath the basal lamina of skeletal muscle fibers and include cells that act as precursors for muscle growth and repair. Although they share a common anatomical localization and typically are considered a homogeneous population, satellite cells actually exhibit substantial heterogeneity. We used cell-surface marker expression to purify from the satellite cell pool a distinct population of skeletal muscle precursors (SMPs) that function as muscle stem cells. When engrafted into muscle of dystrophin-deficient mdx mice, purified SMPs contributed to up to 94% of myofibers, restoring dystrophin expression and significantly improving muscle histology and contractile function. Transplanted SMPs also entered the satellite cell compartment, renewing the endogenous stem cell pool and participating in subsequent rounds of injury repair. Together, these studies indicate the presence in adult skeletal muscle of prospectively isolatable muscle-forming stem cells and directly demonstrate the efficacy of myogenic stem cell transplant for treating muscle degenerative disease.

  20. Phenotype Determines Nanoparticle Uptake by Human Macrophages from Liver and Blood.

    PubMed

    MacParland, Sonya A; Tsoi, Kim M; Ouyang, Ben; Ma, Xue-Zhong; Manuel, Justin; Fawaz, Ali; Ostrowski, Mario A; Alman, Benjamin A; Zilman, Anton; Chan, Warren C W; McGilvray, Ian D

    2017-01-17

    A significant challenge to delivering therapeutic doses of nanoparticles to targeted disease sites is the fact that most nanoparticles become trapped in the liver. Liver-resident macrophages, or Kupffer cells, are key cells in the hepatic sequestration of nanoparticles. However, the precise role that the macrophage phenotype plays in nanoparticle uptake is unknown. Here, we show that the human macrophage phenotype modulates hard nanoparticle uptake. Using gold nanoparticles, we examined uptake by human monocyte-derived macrophages that had been driven to a "regulatory" M2 phenotype or an "inflammatory" M1 phenotype and found that M2-type macrophages preferentially take up nanoparticles, with a clear hierarchy among the subtypes (M2c > M2 > M2a > M2b > M1). We also found that stimuli such as LPS/IFN-γ rather than with more "regulatory" stimuli such as TGF-β/IL-10 reduce per cell macrophage nanoparticle uptake by an average of 40%. Primary human Kupffer cells were found to display heterogeneous expression of M1 and M2 markers, and Kupffer cells expressing higher levels of M2 markers (CD163) take up significantly more nanoparticles than Kupffer cells expressing lower levels of surface CD163. Our results demonstrate that hepatic inflammatory microenvironments should be considered when studying liver sequestration of nanoparticles, and that modifying the hepatic microenvironment might offer a tool for enhancing or decreasing this sequestration. Our findings also suggest that models examining the nanoparticle/macrophage interaction should include studies with primary tissue macrophages.

  1. The angiogenic response of the aorta to injury and inflammatory cytokines requires macrophages

    PubMed Central

    Gelati, Maurizio; Aplin, Alfred C; Fogel, Eric; Smith, Kelly D; Nicosia, Roberto Francesco

    2008-01-01

    The purpose of this study was to define early events during the angiogenic response of the aortic wall to injury. Rat aortic rings produced neovessels in collagen culture but lost this capacity over time. These quiescent rings responded to vascular endothelial growth factor (VEGF) but not to a cocktail of macrophage-stimulatory cytokines and chemokines that was angiogenically active on fresh rings. Analysis of cytokine receptor expression revealed selective loss in quiescent rings of the proangiogenic chemokine receptor CXCR2, which was expressed predominantly in aortic macrophages. Pharmacologic inhibition of CXCR2 impaired angiogenesis from fresh rings but had no effect on VEGF-induced angiogenesis from quiescent explants. Angiogenesis was also impaired in cultures of aortic rings from CXCR2-deficient mice. Reduced CXCR2 expression in quiescent rat aortic rings correlated with marked macrophage depletion. Pharmacologic ablation of macrophages from aortic explants blocked formation of neovessels in vitro and reduced aortic ring-induced angiogenesis in vivo. The angiogenic response of macrophage-depleted rings was completely restored by adding exogenous macrophages. Moreover, angiogenesis from fresh rings was promoted by macrophage colony stimulating factor (CSF-1) and inhibited with anti-CSF-1 antibody. Thus aortic angiogenic sprouting following injury is strongly influenced by conditions that modulate resident macrophage numbers and function. PMID:18832730

  2. Detection of the inhibitory neurotransmitter GABA in macrophages by magnetic resonance spectroscopy.

    PubMed

    Stuckey, D J; Anthony, D C; Lowe, J P; Miller, J; Palm, W M; Styles, P; Perry, V H; Blamire, A M; Sibson, N R

    2005-08-01

    Macrophages are key components of the inflammatory response to tissue injury, but their activities can exacerbate neuropathology. High-resolution magnetic resonance spectroscopy was used to identify metabolite levels in perchloric acid extracts of cultured cells of the RAW 264.7 murine macrophage line under resting and lipopolysaccharide-activated conditions. Over 25 metabolites were identified including gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter not previously reported to be present in macrophages. The presence of GABA was also demonstrated in extracts of human peripheral blood monocyte-derived macrophages. This finding suggests that there may be communication between damaged central nervous system (CNS) tissue and recruited macrophages and resident microglia, which could help orchestrate the immune response. On activation, lactate, glutamine, glutamate, and taurine levels were elevated significantly, and GABA and alanine were reduced significantly. Strong resonances from glutathione, evident in the macrophage two-dimensional 1H spectrum, suggest that this may have potential as a noninvasive marker of macrophages recruited to the CNS, as it is only present at low levels in normal brain. Alternatively, a specific combination of spectroscopic changes, such as lactate, alanine, glutathione, and polyamines, may prove to be the most accurate means of detecting macrophage recruitment to the CNS.

  3. Apoptotic neutrophils augment the inflammatory response to Mycobacterium tuberculosis infection in human macrophages.

    PubMed

    Andersson, Henrik; Andersson, Blanka; Eklund, Daniel; Ngoh, Eyler; Persson, Alexander; Svensson, Kristoffer; Lerm, Maria; Blomgran, Robert; Stendahl, Olle

    2014-01-01

    Macrophages in the lung are the primary cells being infected by Mycobacterium tuberculosis (Mtb) during the initial manifestation of tuberculosis. Since the adaptive immune response to Mtb is delayed, innate immune cells such as macrophages and neutrophils mount the early immune protection against this intracellular pathogen. Neutrophils are short-lived cells and removal of apoptotic cells by resident macrophages is a key event in the resolution of inflammation and tissue repair. Since anti-inflammatory activity is not compatible with effective immunity to intracellular pathogens, we therefore investigated how uptake of apoptotic neutrophils modulates the function of Mtb-activated human macrophages. We show that Mtb infection exerts a potent proinflammatory activation of human macrophages with enhanced gene activation and release of proinflammatory cytokines and that this response was augmented by apoptotic neutrophils. The enhanced macrophage response is linked to apoptotic neutrophil-driven activation of the NLRP3 inflammasome and subsequent IL-1β signalling. We also demonstrate that apoptotic neutrophils not only modulate the inflammatory response, but also enhance the capacity of infected macrophages to control intracellular growth of virulent Mtb. Taken together, these results suggest a novel role for apoptotic neutrophils in the modulation of the macrophage-dependent inflammatory response contributing to the early control of Mtb infection.

  4. Proinflammatory Macrophages Enhance the Regenerative Capacity of Human Myoblasts by Modifying Their Kinetics of Proliferation and Differentiation

    PubMed Central

    Bencze, Maximilien; Negroni, Elisa; Vallese, Denis; Yacoub–Youssef, Houda; Chaouch, Soraya; Wolff, Annie; Aamiri, Ahmed; Di Santo, James P; Chazaud, Bénédicte; Butler-Browne, Gillian; Savino, Wilson; Mouly, Vincent; Riederer, Ingo

    2012-01-01

    Macrophages have been shown to be essential for muscle repair by delivering trophic cues to growing skeletal muscle precursors and young fibers. Here, we investigated whether human macrophages, either proinflammatory or anti-inflammatory, coinjected with human myoblasts into regenerating muscle of Rag2−/− γC−/− immunodeficient mice, could modify in vivo the kinetics of proliferation and differentiation of the transplanted human myogenic precursors. Our results clearly show that proinflammatory macrophages improve in vivo the participation of injected myoblasts to host muscle regeneration, extending the window of proliferation, increasing migration, and delaying differentiation. Interestingly, immunostaining of transplanted proinflammatory macrophages at different time points strongly suggests that these cells are able to switch to an anti-inflammatory phenotype in vivo, which then may stimulate differentiation during muscle regeneration. Conceptually, our data provide for the first time in vivo evidence strongly suggesting that proinflammatory macrophages play a supportive role in the regulation of myoblast behavior after transplantation into preinjured muscle, and could thus potentially optimize transplantation of myogenic progenitors in the context of cell therapy. PMID:23070116

  5. Proinflammatory macrophages enhance the regenerative capacity of human myoblasts by modifying their kinetics of proliferation and differentiation.

    PubMed

    Bencze, Maximilien; Negroni, Elisa; Vallese, Denis; Yacoub-Youssef, Houda; Chaouch, Soraya; Wolff, Annie; Aamiri, Ahmed; Di Santo, James P; Chazaud, Bénédicte; Butler-Browne, Gillian; Savino, Wilson; Mouly, Vincent; Riederer, Ingo

    2012-11-01

    Macrophages have been shown to be essential for muscle repair by delivering trophic cues to growing skeletal muscle precursors and young fibers. Here, we investigated whether human macrophages, either proinflammatory or anti-inflammatory, coinjected with human myoblasts into regenerating muscle of Rag2(-/-) γC(-/-) immunodeficient mice, could modify in vivo the kinetics of proliferation and differentiation of the transplanted human myogenic precursors. Our results clearly show that proinflammatory macrophages improve in vivo the participation of injected myoblasts to host muscle regeneration, extending the window of proliferation, increasing migration, and delaying differentiation. Interestingly, immunostaining of transplanted proinflammatory macrophages at different time points strongly suggests that these cells are able to switch to an anti-inflammatory phenotype in vivo, which then may stimulate differentiation during muscle regeneration. Conceptually, our data provide for the first time in vivo evidence strongly suggesting that proinflammatory macrophages play a supportive role in the regulation of myoblast behavior after transplantation into preinjured muscle, and could thus potentially optimize transplantation of myogenic progenitors in the context of cell therapy.

  6. IL-1α induces CD11b(low) alveolar macrophage proliferation and maturation during granuloma formation.

    PubMed

    Huaux, François; Lo Re, Sandra; Giordano, Giulia; Uwambayinema, Francine; Devosse, Raynal; Yakoub, Yousof; Panin, Nadtha; Palmai-Pallag, Mihaly; Rabolli, Virginie; Delos, Monique; Marbaix, Etienne; Dauguet, Nicolas; Couillin, Isabelle; Ryffel, Bernhard; Renauld, Jean-Christophe; Lison, Dominique

    2015-04-01

    Macrophages play a central role in immune and tissue responses of granulomatous lung diseases induced by pathogens and foreign bodies. Circulating monocytes are generally viewed as central precursors of these tissue effector macrophages. Here, we provide evidence that granulomas derive from alveolar macrophages serving as a local reservoir for the expansion of activated phagocytic macrophages. By exploring lung granulomatous responses to silica particles in IL-1-deficient mice, we found that the absence of IL-1α, but not IL-1β, was associated with reduced CD11b(high) phagocytic macrophage accumulation and fewer granulomas. This defect was associated with impaired alveolar clearance and resulted in the development of pulmonary alveolar proteinosis (PAP). Reconstitution of IL-1α(-/-) mice with recombinant IL-1α restored lung clearance functions and the pulmonary accumulation of CD11b(high) phagocytic macrophages. Mechanistically, IL-1α induced the proliferation of CD11b(low) alveolar macrophages and differentiated these cells into CD11b(high) macrophages which perform critical phagocytic functions and organize granuloma. We newly discovered here that IL-1α triggers lung responses requiring macrophage proliferation and maturation from tissue-resident macrophages.

  7. MAFB Determines Human Macrophage Anti-Inflammatory Polarization: Relevance for the Pathogenic Mechanisms Operating in Multicentric Carpotarsal Osteolysis.

    PubMed

    Cuevas, Víctor D; Anta, Laura; Samaniego, Rafael; Orta-Zavalza, Emmanuel; Vladimir de la Rosa, Juan; Baujat, Geneviève; Domínguez-Soto, Ángeles; Sánchez-Mateos, Paloma; Escribese, María M; Castrillo, Antonio; Cormier-Daire, Valérie; Vega, Miguel A; Corbí, Ángel L

    2017-03-01

    Macrophage phenotypic and functional heterogeneity derives from tissue-specific transcriptional signatures shaped by the local microenvironment. Most studies addressing the molecular basis for macrophage heterogeneity have focused on murine cells, whereas the factors controlling the functional specialization of human macrophages are less known. M-CSF drives the generation of human monocyte-derived macrophages with a potent anti-inflammatory activity upon stimulation. We now report that knockdown of MAFB impairs the acquisition of the anti-inflammatory profile of human macrophages, identify the MAFB-dependent gene signature in human macrophages and illustrate the coexpression of MAFB and MAFB-target genes in CD163(+) tissue-resident and tumor-associated macrophages. The contribution of MAFB to the homeostatic/anti-inflammatory macrophage profile is further supported by the skewed polarization of monocyte-derived macrophages from multicentric carpotarsal osteolysis (Online Mendelian Inheritance in Man #166300), a pathology caused by mutations in the MAFB gene. Our results demonstrate that MAFB critically determines the acquisition of the anti-inflammatory transcriptional and functional profiles of human macrophages.

  8. Aging impairs peritoneal but not bone marrow-derived macrophage phagocytosis.

    PubMed

    Linehan, Eimear; Dombrowski, Yvonne; Snoddy, Rachel; Fallon, Padraic G; Kissenpfennig, Adrien; Fitzgerald, Denise C

    2014-08-01

    Aging results in deterioration of the immune system, which is associated with increased susceptibility to infection and impaired wound healing in the elderly. Phagocytosis is an essential process in both wound healing and immune defence. As such, age-related impairments in phagocytosis impact on the health of the elderly population. Phagocytic efficiency in peritoneal macrophages, bone marrow-derived macrophages and bone marrow monocytes from young and old mice was investigated. Aging significantly impaired phagocytosis by peritoneal macrophages, both in vitro and in vivo. However, bone marrow-derived macrophages and bone marrow monocytes did not exhibit age-related impairments in phagocytosis, suggesting no intrinsic defect in these cells. We sought to investigate underlying mechanisms in age-related impairments in phagocytosis by peritoneal macrophages. We hypothesized that microenvironmental factors in the peritoneum of old mice impaired macrophage phagocytosis. Indeed, macrophages from young mice injected into the peritoneum of old mice exhibited impaired phagocytosis. Proportions of peritoneal immune cells were characterized, and striking increases in numbers of T cells, B1 and B2 cells were observed in the peritoneum of old mice compared with young mice. In addition, B cell-derived IL-10 was increased in resting and LPS-activated peritoneal cell cultures from old mice. These data demonstrate that aging impairs phagocytosis by tissue-resident peritoneal macrophages, but not by bone marrow-derived macrophages/monocytes, and suggest that age-related defects in macrophage phagocytosis may be due to extrinsic factors in the tissue microenvironment. As such, defects may be reversible and macrophages could be targeted therapeutically in order to boost immune function in the elderly.

  9. Financing Residency Training Redesign

    PubMed Central

    Carney, Patricia A.; Waller, Elaine; Green, Larry A.; Crane, Steven; Garvin, Roger D.; Pugno, Perry A.; Kozakowski, Stanley M.; Douglass, Alan B.; Jones, Samuel; Eiff, M. Patrice

    2014-01-01

    Background Redesign in the health care delivery system creates a need to reorganize resident education. How residency programs fund these redesign efforts is not known. Methods Family medicine residency program directors participating in the Preparing Personal Physicians for Practice (P4) project were surveyed between 2006 and 2011 on revenues and expenses associated with training redesign. Results A total of 6 university-based programs in the study collectively received $5,240,516 over the entire study period, compared with $4,718,943 received by 8 community-based programs. Most of the funding for both settings came from grants, which accounted for 57.8% and 86.9% of funding for each setting, respectively. Department revenue represented 3.4% of university-based support and 13.1% of community-based support. The total average revenue (all years combined) per program for university-based programs was just under $875,000, and the average was nearly $590,000 for community programs. The vast majority of funds were dedicated to salary support (64.8% in university settings versus 79.3% in community-based settings). Based on the estimated ratio of new funding relative to the annual costs of training using national data for a 3-year program with 7 residents per year, training redesign added 3% to budgets for university-based programs and about 2% to budgets for community-based programs. Conclusions Residencies undergoing training redesign used a variety of approaches to fund these changes. The costs of innovations marginally increased the estimated costs of training. Federal and local funding sources were most common, and costs were primarily salary related. More research is needed on the costs of transforming residency training. PMID:26140119

  10. Degradation of connective tissue matrices by macrophages. II. Influence of matrix composition on proteolysis of glycoproteins, elastin, and collagen by macrophages in culture

    SciTech Connect

    Jones, P.A.; Werb, Z.

    1980-12-01

    Thioglycollate-elicited mouse peritoneal macrophages were cultured in contact with the mixture of extracellular matrix proteins produced by rat smooth muscle cells in culture. Both live macrophages and their conditioned media hydrolyzed glycoproteins, elastin, and collagen. Live macrophages also degraded extracellular connective tissue proteins secreted by endothelial cells and fibroblasts. The glycoproteins in the matrix markedly inhibited the rate of digestion of the other macromolecules, particularly elastin. When plasminogen was added to the matrix, activation of plasminogen to plasmin resulted in the hydrolysis of the glycoprotein components, which then allowed the macrophage elastase easier access to its substrate, elastin. Thus, although plasmin has no direct elastinolytic activity, its presence accelerated the rate of hydrolysis of elastin and therefore the rate of matrix degradation. These findings may be important in an understanding of disease states, such as emphysema and atherosclerosis, that are characterized by the destruction of connective tissue.

  11. An Assigned Teaching Resident Rotation

    ERIC Educational Resources Information Center

    Daniels-Brady, Catherine; Rieder, Ronald

    2010-01-01

    Objective: The authors' adult psychiatry residency training program identified several educational needs for residents at their institution. Junior residents needed enhanced learning of clinical interviewing skills and learning connected to the inpatient psychiatry ward rotations, and senior residents needed opportunities to prepare for the…

  12. Macrophage activation and its role in repair and pathology after spinal cord injury.

    PubMed

    Gensel, John C; Zhang, Bei

    2015-09-04

    The injured spinal cord does not heal properly. In contrast, tissue repair and functional recovery occur after skin or muscle injuries. The reason for this dichotomy in wound repair is unclear but inflammation, and specifically macrophage activation, likely plays a key role. Macrophages have the ability to promote the repair of injured tissue by regulating transitions through different phase of the healing response. In the current review we compare and contrast the healing and inflammatory responses between spinal cord injuries and tissues that undergo complete wound resolution. Through this comparison, we identify key macrophage phenotypes that are inaptly triggered or absent after spinal cord injury and discuss spinal cord stimuli that contribute to this maladaptive response. Sequential activation of classic, pro-inflammatory, M1 macrophages and alternatively activated, M2a, M2b, and M2c macrophages occurs during normal healing and facilitates transitions through the inflammatory, proliferative, and remodeling phases of repair. In contrast, in the injured spinal cord, pro-inflammatory macrophages potentiate a prolonged inflammatory phase and remodeling is not properly initiated. The desynchronized macrophage activation after spinal cord injury is reminiscent of the inflammation present in chronic, non-healing wounds. By refining the role macrophages play in spinal cord injury repair we bring to light important areas for future neuroinflammation and neurotrauma research. This article is part of a Special Issue entitled SI: Spinal cord injury.

  13. Muscle biopsy

    MedlinePlus

    ... Inflammatory diseases of muscle (such as polymyositis or dermatomyositis ) Diseases of the connective tissue and blood vessels ( ... disease that involves inflammation and a skin rash ( dermatomyositis ) Inherited muscle disorder ( Duchenne muscular dystrophy ) Inflammation of ...

  14. Macrophage-to-Myofibroblast Transition Contributes to Interstitial Fibrosis in Chronic Renal Allograft Injury.

    PubMed

    Wang, Ying-Ying; Jiang, Hong; Pan, Jun; Huang, Xiao-Ru; Wang, Yu-Cheng; Huang, Hong-Feng; To, Ka-Fai; Nikolic-Paterson, David J; Lan, Hui-Yao; Chen, Jiang-Hua

    2017-02-16

    Interstitial fibrosis is an important contributor to graft loss in chronic renal allograft injury. Inflammatory macrophages are associated with fibrosis in renal allografts, but how these cells contribute to this damaging response is not clearly understood. Here, we investigated the role of macrophage-to-myofibroblast transition in interstitial fibrosis in human and experimental chronic renal allograft injury. In biopsy specimens from patients with active chronic allograft rejection, we identified cells undergoing macrophage-to-myofibroblast transition by the coexpression of macrophage (CD68) and myofibroblast (α-smooth muscle actin [α-SMA]) markers. CD68(+)/α-SMA(+) cells accounted for approximately 50% of the myofibroblast population, and the number of these cells correlated with allograft function and the severity of interstitial fibrosis. Similarly, in C57BL/6J mice with a BALB/c renal allograft, cells coexpressing macrophage markers (CD68 or F4/80) and α-SMA composed a significant population in the interstitium of allografts undergoing chronic rejection. Fate-mapping in Lyz2-Cre/Rosa26-Tomato mice showed that approximately half of α-SMA(+) myofibroblasts in renal allografts originated from recipient bone marrow-derived macrophages. Knockout of Smad3 protected against interstitial fibrosis in renal allografts and substantially reduced the number of macrophage-to-myofibroblast transition cells. Furthermore, the majority of macrophage-to-myofibroblast transition cells in human and experimental renal allograft rejection coexpressed the M2-type macrophage marker CD206, and this expression was considerably reduced in Smad3-knockout recipients. In conclusion, our studies indicate that macrophage-to-myofibroblast transition contributes to interstitial fibrosis in chronic renal allograft injury. Moreover, the transition of bone marrow-derived M2-type macrophages to myofibroblasts in the renal allograft is regulated via a Smad3-dependent mechanism.

  15. Modeling Muscles

    ERIC Educational Resources Information Center

    Goodwyn, Lauren; Salm, Sarah

    2007-01-01

    Teaching the anatomy of the muscle system to high school students can be challenging. Students often learn about muscle anatomy by memorizing information from textbooks or by observing plastic, inflexible models. Although these mediums help students learn about muscle placement, the mediums do not facilitate understanding regarding integration of…

  16. Macrophage podosomes go 3D.

    PubMed

    Van Goethem, Emeline; Guiet, Romain; Balor, Stéphanie; Charrière, Guillaume M; Poincloux, Renaud; Labrousse, Arnaud; Maridonneau-Parini, Isabelle; Le Cabec, Véronique

    2011-01-01

    Macrophage tissue infiltration is a critical step in the immune response against microorganisms and is also associated with disease progression in chronic inflammation and cancer. Macrophages are constitutively equipped with specialized structures called podosomes dedicated to extracellular matrix (ECM) degradation. We recently reported that these structures play a critical role in trans-matrix mesenchymal migration mode, a protease-dependent mechanism. Podosome molecular components and their ECM-degrading activity have been extensively studied in two dimensions (2D), but yet very little is known about their fate in three-dimensional (3D) environments. Therefore, localization of podosome markers and proteolytic activity were carefully examined in human macrophages performing mesenchymal migration. Using our gelled collagen I 3D matrix model to obligate human macrophages to perform mesenchymal migration, classical podosome markers including talin, paxillin, vinculin, gelsolin, cortactin were found to accumulate at the tip of F-actin-rich cell protrusions together with β1 integrin and CD44 but not β2 integrin. Macrophage proteolytic activity was observed at podosome-like protrusion sites using confocal fluorescence microscopy and electron microscopy. The formation of migration tunnels by macrophages inside the matrix was accomplished by degradation, engulfment and mechanic compaction of the matrix. In addition, videomicroscopy revealed that 3D F-actin-rich protrusions of migrating macrophages were as dynamic as their 2D counterparts. Overall, the specifications of 3D podosomes resembled those of 2D podosome rosettes rather than those of individual podosomes. This observation was further supported by the aspect of 3D podosomes in fibroblasts expressing Hck, a master regulator of podosome rosettes in macrophages. In conclusion, human macrophage podosomes go 3D and take the shape of spherical podosome rosettes when the cells perform mesenchymal migration. This work

  17. Isolation of satellite cells from single muscle fibers from young, aged, or dystrophic muscles.

    PubMed

    Di Foggia, Valentina; Robson, Lesley

    2012-01-01

    Skeletal muscle contains an identified resident stem cell population called the satellite cells. This cell is responsible for the majority of the postnatal growth and regenerative potential of skeletal muscle. Other cells do contribute to skeletal muscle regeneration and in cultures of minced whole muscle these cells are cultured along with the satellite cells and it is impossible to dissect out their contribution compared to the satellite cells. Therefore, a method to culture pure satellite cells has been developed to study the signaling pathways that control their proliferation and differentiation. In our studies into the role of the resident myogenic stem cells in regeneration, myopathic conditions, and aging, we have optimized the established techniques that already exist to isolate pure satellite cell cultures from single muscle fibers. We have successfully isolated satellite cells from young adults through to 24-month-old muscles and obtained populations of cells that we are studying for the signaling events that regulate their proliferative potential.

  18. Selection of Anesthesiology Residents.

    ERIC Educational Resources Information Center

    Baker, J. David, III; And Others

    1993-01-01

    Selection data for all Medical University of South Carolina anesthesiology residency applicants (about 200 per year) and the 8 selected per year were compared for 4 years. Results showed standardized test scores, grades, and class ranks of those selected were not higher than of others, but interview and recommendation scores were higher.…

  19. Observing Community Residences.

    ERIC Educational Resources Information Center

    Taylor, Steven J.; Bogdan, Robert

    The document offers guidelines effectively monitoring the quality of care provided in community residences serving people with disabilities. An initial section offers suggestions on observation and evaluation procedures. The remainder of the document lists possible questions to be asked in 19 areas: location, building and yard, relations with the…

  20. Residence Hall Fires.

    ERIC Educational Resources Information Center

    Wright, Dorothy

    1999-01-01

    Discusses how one college's experience with a tragic fire in one of its residence halls prompted a reevaluation of its fire-prevention-and-response strategies. Staff training, sprinkler installation, new alarm systems, and exit hardware to help make building exiting more efficient are discussed. (GR)

  1. A Fine Arts Residency.

    ERIC Educational Resources Information Center

    Riggs, Patricia L.

    1982-01-01

    A four-week writer-in-residence program designed to stimulate the creativity of K-5 students was held in the Briar Glen Library Media Center, Wheaton, Illinois, with poet Joan Colby. This description of the program includes information on planning, funding, and future plans. (CHC)

  2. Stable isotopes as tracers of residency for fish on inshore coral reefs

    NASA Astrophysics Data System (ADS)

    Davis, Jean P.; Pitt, Kylie A.; Fry, Brian; Connolly, Rod M.

    2015-12-01

    Understanding the migratory movements of fish between habitats is an important priority for fisheries management. Carbon (C) and nitrogen (N) stable isotopes were used to evaluate the degree of movement and residency for five fish species collected from coral reefs in Queensland, Australia. Isotope values of fish were measured and compared between slow-turnover muscle tissue and fast-turnover liver tissue, with isotopic agreement between liver and muscle generally indicating resident animals, and relatively low C isotope values in muscle indicating migrants. Three fish species, rabbitfish (Siganus fuscescens), painted sweetlips (Diagramma labiosum) and Guenther's wrasse (Pseudolabrus guentheri) showed relatively consistent carbon isotope values between muscle and liver tissue as expected for resident populations. One quarter of bream (Acanthopagrus australis) individuals showed much lower δ13C values in muscle than liver. These low values diverged from the -10 to -15‰ values of residents and were more similar to the -20‰ values of fish collected from coastal riverine habitats, the presumed migration source. Moses perch (Lutjanus russelli) also showed substantial differences between muscle and liver C isotopes for about a quarter of individuals, but the overall higher C values of these individuals indicated they may have switched diets within island habitats rather than migrating. Our results were consistent with previous studies of fish residency and indicate that measuring stable isotopes in multiple tissues provides a useful methodology for characterizing fish residency in inshore areas.

  3. Macrophages and Tissue Injury: Agents of Defense or Destruction?

    PubMed Central

    Laskin, Debra L.; Sunil, Vasanthi R.; Gardner, Carol R.; Laskin, Jeffrey D.

    2013-01-01

    The past several years have seen the accumulation of evidence demonstrating that tissue injury induced by diverse toxicants is due not only to their direct effects on target tissues but also indirectly to the actions of resident and infiltrating macrophages. These cells release an array of mediators with cytotoxic, pro- and anti-inflammatory, angiogenic, fibrogenic, and mitogenic activity, which function to fight infections, limit tissue injury, and promote wound healing. However, following exposure to toxicants, macrophages can become hyperresponsive, resulting in uncontrolled or dysregulated release of mediators that exacerbate acute tissue injury and/or promote the development of chronic diseases such as fibrosis and cancer. Evidence suggests that the diverse activity of macrophages is mediated by distinct subpopulations that develop in response to signals within their microenvironment. Understanding the precise roles of these different macrophage populations in the pathogenic response to toxicants is key to designing effective treatments for minimizing tissue damage and chronic disease and for facilitating wound repair. PMID:20887196

  4. Obesity induces a phenotypic switch in adipose tissue macrophage polarization.

    PubMed

    Lumeng, Carey N; Bodzin, Jennifer L; Saltiel, Alan R

    2007-01-01

    Adipose tissue macrophages (ATMs) infiltrate adipose tissue during obesity and contribute to insulin resistance. We hypothesized that macrophages migrating to adipose tissue upon high-fat feeding may differ from those that reside there under normal diet conditions. To this end, we found a novel F4/80(+)CD11c(+) population of ATMs in adipose tissue of obese mice that was not seen in lean mice. ATMs from lean mice expressed many genes characteristic of M2 or "alternatively activated" macrophages, including Ym1, arginase 1, and Il10. Diet-induced obesity decreased expression of these genes in ATMs while increasing expression of genes such as those encoding TNF-alpha and iNOS that are characteristic of M1 or "classically activated" macrophages. Interestingly, ATMs from obese C-C motif chemokine receptor 2-KO (Ccr2-KO) mice express M2 markers at levels similar to those from lean mice. The antiinflammatory cytokine IL-10, which was overexpressed in ATMs from lean mice, protected adipocytes from TNF-alpha-induced insulin resistance. Thus, diet-induced obesity leads to a shift in the activation state of ATMs from an M2-polarized state in lean animals that may protect adipocytes from inflammation to an M1 proinflammatory state that contributes to insulin resistance.

  5. Obesity induces a phenotypic switch in adipose tissue macrophage polarization

    PubMed Central

    Lumeng, Carey N.; Bodzin, Jennifer L.; Saltiel, Alan R.

    2007-01-01

    Adipose tissue macrophages (ATMs) infiltrate adipose tissue during obesity and contribute to insulin resistance. We hypothesized that macrophages migrating to adipose tissue upon high-fat feeding may differ from those that reside there under normal diet conditions. To this end, we found a novel F4/80+CD11c+ population of ATMs in adipose tissue of obese mice that was not seen in lean mice. ATMs from lean mice expressed many genes characteristic of M2 or “alternatively activated” macrophages, including Ym1, arginase 1, and Il10. Diet-induced obesity decreased expression of these genes in ATMs while increasing expression of genes such as those encoding TNF-α and iNOS that are characteristic of M1 or “classically activated” macrophages. Interestingly, ATMs from obese C-C motif chemokine receptor 2–KO (Ccr2-KO) mice express M2 markers at levels similar to those from lean mice. The antiinflammatory cytokine IL-10, which was overexpressed in ATMs from lean mice, protected adipocytes from TNF-α–induced insulin resistance. Thus, diet-induced obesity leads to a shift in the activation state of ATMs from an M2-polarized state in lean animals that may protect adipocytes from inflammation to an M1 proinflammatory state that contributes to insulin resistance. PMID:17200717

  6. Global Health Simulation During Residency

    PubMed Central

    Rosenman, Jane R.; Fischer, Philip R.; Arteaga, Grace M.; Hulyalkar, Manasi; Butteris, Sabrina M.; Pitt, Michael B.

    2016-01-01

    Resident participation in international health electives (IHEs) has been shown to be beneficial, yet not all residents have the opportunity to participate. We sought to determine whether participating in simulated global health cases, via the standardized Simulation Use for Global Away Rotations (SUGAR) curriculum, was useful for all pediatric residents, not merely those planning to go on an IHE. Pediatric residents in our program took part in 2 SUGAR cases and provided feedback via an online survey. Thirty-six of 40 residents participated (90%); 72% responded to the survey. Three of 10 residents not previously planning to work in resource-limited settings indicated participation in SUGAR made them more likely to do so. Nearly all residents (88%) felt SUGAR should be part of the residency curriculum. All felt better prepared for working cross-culturally. While designed to prepare trainees for work in resource-limited settings, SUGAR may be beneficial for all residents. PMID:27583300

  7. Sex-differences in resident immune cell phenotype underlies more efficient acute inflammatory responses in female mice

    PubMed Central

    Scotland, Ramona S.; Stables, Melanie J.; Madalli, Shimona; Watson, Peter; Gilroy, Derek W.

    2017-01-01

    Females are protected against mortality arising from severe sepsis. The precise mechanisms that confer this survival advantage in females over males are unclear. Resident leukocytes in resting tissues have a significant influence on circulating cytokine levels and recruitment of blood leukocytes during acute inflammatory responses. Whether the phenotype of resident leukocytes is distinct in females is unknown. Herein we show that the numbers of leukocytes occupying the naive peritoneal and pleural cavities is higher in female than in male mice and rats, comprising more T- and B-lymphocytes as well as macrophages. The altered immune cell composition of the female peritoneum is controlled by elevated tissue chemokine expression. Female resident macrophages also exhibit greater Toll-like receptor expression, as well as enhanced phagocytosis and NADPHoxidase-mediated bacterial killing. However, macrophage-derived cytokine production is diminished by proportionally more resident immunomodulatory CD4+ T-lymphocytes. Ovarian hormones regulate macrophage phenotype, function, and numbers but have no significant impact on T-lymphocyte populations in females. Thus we have identified a fundamental sex-difference in phenotype of resident leukocytes. We propose that the distinct resident leukocyte population in females allows aggressive recognition and elimination of diverse infectious stimuli without recruitment of circulating neutrophils or excessive cytokine production. PMID:21911834

  8. Metabolic Reprograming in Macrophage Polarization

    PubMed Central

    Galván-Peña, Silvia; O’Neill, Luke A. J.

    2014-01-01

    Studying the metabolism of immune cells in recent years has emphasized the tight link existing between the metabolic state and the phenotype of these cells. Macrophages in particular are a good example of this phenomenon. Whether the macrophage obtains its energy through glycolysis or through oxidative metabolism can give rise to different phenotypes. Classically activated or M1 macrophages are key players of the first line of defense against bacterial infections and are known to obtain energy through glycolysis. Alternatively activated or M2 macrophages on the other hand are involved in tissue repair and wound healing and use oxidative metabolism to fuel their longer-term functions. Metabolic intermediates, however, are not just a source of energy but can be directly implicated in a particular macrophage phenotype. In M1 macrophages, the Krebs cycle intermediate succinate regulates HIF1α, which is responsible for driving the sustained production of the pro-inflammatory cytokine IL1β. In M2 macrophages, the sedoheptulose kinase carbohydrate kinase-like protein is critical for regulating the pentose phosphate pathway. The potential to target these events and impact on disease is an exciting prospect. PMID:25228902

  9. Impairment of macrophage eicosanoid and nitric oxide production by an alkaloid from Sinomenium acutum.

    PubMed

    Liu, L; Riese, J; Resch, K; Kaever, V

    1994-11-01

    The effects of sinomenine (7,8-didehydro-4-hydroxy-3,7-dimethoxy-17-methyl- 9 alpha,13 alpha,14 alpha-morphinan-6-one), a pure alkaloid extracted from the Chinese medical plant Sinomenium acutum, on different macrophage capacities were investigated in vitro using resident mouse peritoneal macrophages and the macrophage-like cell line RAW 264.7. Sinomenine markedly decreased prostaglandin E2 and leukotriene C4 synthesis of macrophages stimulated by zymosan or calcium ionophore and also significantly inhibited the nitric oxide production of RAW 264.7 cells activated by interferon-gamma/lipopolysaccharide. It can be considered that these effects are part of the analgesic, anti-inflammatory, and antirheumatic mechanisms of sinomenine.

  10. Intravital Imaging of Axonal Interactions with Microglia and Macrophages in a Mouse Dorsal Column Crush Injury

    PubMed Central

    Evans, Teresa A.; Barkauskas, Deborah S.; Myers, Jay T.; Huang, Alex Y.

    2014-01-01

    Traumatic spinal cord injury causes an inflammatory reaction involving blood-derived macrophages and central nervous system (CNS)-resident microglia. Intra-vital two-photon microscopy enables the study of macrophages and microglia in the spinal cord lesion in the living animal. This can be performed in adult animals with a traumatic injury to the dorsal column. Here, we describe methods for distinguishing macrophages from microglia in the CNS using an irradiation bone marrow chimera to obtain animals in which only macrophages or microglia are labeled with a genetically encoded green fluorescent protein. We also describe a injury model that crushes the dorsal column of the spinal cord, thereby producing a simple, easily accessible, rectangular lesion that is easily visualized in an animal through a laminectomy. Furthermore, we will outline procedures to sequentially image the animals at the anatomical site of injury for the study of cellular interactions during the first few days to weeks after injury. PMID:25489963

  11. Bacterial phagocytosis by macrophages from lipopolysaccharide responder and nonresponder mouse strains.

    PubMed Central

    Cuffini, A; Carlone, N A; Forni, G

    1980-01-01

    The phagocytic capacity of macrophages from C3H/H3J mice was assessed against lipopolysaccharide-producing (Escherichia coli) and -nonproducing (Staphylococcus aureus) bacteria. Despite their gene-coded unresponsiveness to lipopolysaccharide endotoxin and lymphokines and their defective tumoricidal activity, proteose peptone-induced C3H/HeJ macrophages did not display a defective phagocytic capacity, but rather displayed an enhanced phagocytosis of both bacterial strains compared with macrophages from closely related C3H/HeN mice. Unstimulated peritoneal resident C3H/HeJ macrophages, on the other hand, displayed a normal phagocytic activity toward E. coli and enhanced phagocytosis toward S. aureus. PMID:6995321

  12. The transition of smooth muscle cells from a contractile to a migratory, phagocytic phenotype: direct demonstration of phenotypic modulation

    PubMed Central

    Sandison, Mairi E.; Dempster, John

    2016-01-01

    Key points Smooth muscle cell (SMC) phenotypic conversion from a contractile to a migratory phenotype is proposed to underlie cardiovascular disease but its contribution to vascular remodelling and even its existence have recently been questioned.Tracking the fate of individual SMCs is difficult as no specific markers of migratory SMCs exist.This study used a novel, prolonged time‐lapse imaging approach to continuously track the behaviour of unambiguously identified, fully differentiated SMCs.In response to serum, highly‐elongated, contractile SMCs initially rounded up, before spreading and migrating and these migratory cells displayed clear phagocytic activity.This study provides a direct demonstration of the transition of fully contractile SMCs to a non‐contractile, migratory phenotype with phagocytic capacity that may act as a macrophage‐like cell. Abstract Atherosclerotic plaques are populated with smooth muscle cells (SMCs) and macrophages. SMCs are thought to accumulate in plaques because fully differentiated, contractile SMCs reprogramme into a ‘synthetic’ migratory phenotype, so‐called phenotypic modulation, whilst plaque macrophages are thought to derive from blood‐borne myeloid cells. Recently, these views have been challenged, with reports that SMC phenotypic modulation may not occur during vascular remodelling and that plaque macrophages may not be of haematopoietic origin. Following the fate of SMCs is complicated by the lack of specific markers for the migratory phenotype and direct demonstrations of phenotypic modulation are lacking. Therefore, we employed long‐term, high‐resolution, time‐lapse microscopy to track the fate of unambiguously identified, fully‐differentiated, contractile SMCs in response to the growth factors present in serum. Phenotypic modulation was clearly observed. The highly elongated, contractile SMCs initially rounded up, for 1–3 days, before spreading outwards. Once spread, the SMCs became motile and

  13. Macrophages engulf endothelial cell membrane particles preceding pupillary membrane capillary regression.

    PubMed

    Poché, Ross A; Hsu, Chih-Wei; McElwee, Melissa L; Burns, Alan R; Dickinson, Mary E

    2015-07-01

    Programmed capillary regression and remodeling are essential developmental processes. However, the cellular and molecular mechanisms that regulate vessel regression are only the beginning to be understood. Here, using in vivo, dynamic, confocal imaging of mouse transgenic reporters as well as static confocal and electron microscopy, we studied the embryonic development and postnatal regression of the transient mouse pupillary membrane (PM) vasculature. This approach allowed us to directly observe the precise temporal sequence of cellular events preceding and during the elimination of the PM from the mouse eye. Imaging of Tcf/Lef-H2B::GFP Wnt-reporter mice uncovered that, unlike the hyaloid vasculature of the posterior eye, a PM endothelial cell (EC) Wnt/β-catenin response is unlikely to be part of the regression mechanism. Live imaging of EC and macrophage dynamics revealed highly active Csf1r-GFP+ macrophages making direct contact with the Flk1-myr::mCherry+ vessel surface and with membrane protrusions or filopodia extending from the ECs. Flk1-myr::mCherry+ EC membrane particles were observed on and around ECs as well as within macrophages. Electron microscopy studies confirmed that they were in phagosomes within macrophages, indicating that the macrophages engulfed the membrane particles. Interestingly, EC plasma membrane uptake by PM macrophages did not correlate with apoptosis and was found shortly after vessel formation at mid-gestation stages in the embryo; long before vessel regression begins during postnatal development. Additionally, genetic ablation of macrophages showed that EC membrane particles were still shed in the absence of macrophages suggesting that macrophages do not induce the formation or release of EC microparticles. These studies have uncovered a novel event during programmed capillary regression in which resident macrophages scavenge endothelial cell microparticles released from the PM vessels. This finding suggests that there may be an

  14. Macrophage recruitment and epithelial repair following hair cell injury in the mouse utricle.

    PubMed

    Kaur, Tejbeer; Hirose, Keiko; Rubel, Edwin W; Warchol, Mark E

    2015-01-01

    The sensory organs of the inner ear possess resident populations of macrophages, but the function of those cells is poorly understood. In many tissues, macrophages participate in the removal of cellular debris after injury and can also promote tissue repair. The present study examined injury-evoked macrophage activity in the mouse utricle. Experiments used transgenic mice in which the gene for the human diphtheria toxin receptor (huDTR) was inserted under regulation of the Pou4f3 promoter. Hair cells in such mice can be selectively lesioned by systemic treatment with diphtheria toxin (DT). In order to visualize macrophages, Pou4f3-huDTR mice were crossed with a second transgenic line, in which one or both copies of the gene for the fractalkine receptor CX3CR1 were replaced with a gene for GFP. Such mice expressed GFP in all macrophages, and mice that were CX3CR1(GFP/GFP) lacked the necessary receptor for fractalkine signaling. Treatment with DT resulted in the death of ∼70% of utricular hair cells within 7 days, which was accompanied by increased numbers of macrophages within the utricular sensory epithelium. Many of these macrophages appeared to be actively engulfing hair cell debris, indicating that macrophages participate in the process of 'corpse removal' in the mammalian vestibular organs. However, we observed no apparent differences in injury-evoked macrophage numbers in the utricles of CX3CR1(+/GFP) mice vs. CX3CR1(GFP/GFP) mice, suggesting that fractalkine signaling is not necessary for macrophage recruitment in these sensory organs. Finally, we found that repair of sensory epithelia at short times after DT-induced hair cell lesions was mediated by relatively thin cables of F-actin. After 56 days recovery, however, all cell-cell junctions were characterized by very thick actin cables.

  15. In vitro modulation of macrophage functions by 1,1-dimethylhydrazine (UDMH): Possible mechanism for UDMH-induced immuno-enhancement.

    PubMed

    Tarr, M J; Olsen, R G; Bowen, B L; Fertel, R H

    1988-01-01

    The in vitro effects of 1,1-dimethylhydrazine (UDMH) on prostaglandin E(2) (PGE(2)) synthesis, chemiluminescence, phagocytosis, microbicidal activity and chemotaxis in murine enriched-macrophage populations were evaluated. PGE(2) synthesis by resident peritoneal macrophages and chemiluminescence by activated macrophages were markedly suppressed in the presence of UDMH; phagocytosis and microbicidal activity were slightly to moderately suppressed, and chemotaxis was not affected. Two of these functions (PGE(2) synthesis and chemiluminescence) reflect macrophage immunoregulatory properties, and the UDMH-induced abrogation of these functions may be related to the previously reported immuno-enhancing effects of UDMH.

  16. Macrophages and the Viral Dissemination Super Highway

    PubMed Central

    Klepper, Arielle; Branch, Andrea D

    2016-01-01

    Monocytes and macrophages are key components of the innate immune system yet they are often the victims of attack by infectious agents. This review examines the significance of viral infection of macrophages. The central hypothesis is that macrophage tropism enhances viral dissemination and persistence, but these changes may come at the cost of reduced replication in cells other than macrophages. PMID:26949751

  17. Cryptococcus neoformans-induced macrophage lysosome damage crucially contributes to fungal virulence.

    PubMed

    Davis, Michael J; Eastman, Alison J; Qiu, Yafeng; Gregorka, Brian; Kozel, Thomas R; Osterholzer, John J; Curtis, Jeffrey L; Swanson, Joel A; Olszewski, Michal A

    2015-03-01

    Upon ingestion by macrophages, Cryptococcus neoformans can survive and replicate intracellularly unless the macrophages become classically activated. The mechanism enabling intracellular replication is not fully understood; neither are the mechanisms that allow classical activation to counteract replication. C. neoformans-induced lysosome damage was observed in infected murine bone marrow-derived macrophages, increased with time, and required yeast viability. To demonstrate lysosome damage in the infected host, we developed a novel flow cytometric method for measuring lysosome damage. Increased lysosome damage was found in C. neoformans-containing lung cells compared with C. neoformans-free cells. Among C. neoformans-containing myeloid cells, recently recruited cells displayed lower damage than resident cells, consistent with the protective role of recruited macrophages. The magnitude of lysosome damage correlated with increased C. neoformans replication. Experimental induction of lysosome damage increased C. neoformans replication. Activation of macrophages with IFN-γ abolished macrophage lysosome damage and enabled increased killing of C. neoformans. We conclude that induction of lysosome damage is an important C. neoformans survival strategy and that classical activation of host macrophages counters replication by preventing damage. Thus, therapeutic strategies that decrease lysosomal damage, or increase resistance to such damage, could be valuable in treating cryptococcal infections.

  18. Novel Action of Carotenoids on Non-Alcoholic Fatty Liver Disease: Macrophage Polarization and Liver Homeostasis

    PubMed Central

    Ni, Yinhua; Zhuge, Fen; Nagashimada, Mayumi; Ota, Tsuguhito

    2016-01-01

    Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. It is characterized by a wide spectrum of hepatic changes, which may progress to non-alcoholic steatohepatitis (NASH) and cirrhosis. NAFLD is considered a hepatic manifestation of metabolic syndrome; however, mechanisms underlying the onset and progression of NAFLD are still unclear. Resident and recruited macrophages are key players in the homeostatic function of the liver and in the progression of NAFLD to NASH. Progress has been made in understanding the molecular mechanisms underlying the polarized activation of macrophages. New NAFLD therapies will likely involve modification of macrophage polarization by restraining M1 activation or driving M2 activation. Carotenoids are potent antioxidants and anti-inflammatory micronutrients that have been used to prevent and treat NAFLD. In addition to their antioxidative action, carotenoids can regulate macrophage polarization and thereby halt the progression of NASH. In this review, we summarize the molecular mechanisms of macrophage polarization and the function of liver macrophages/Kupffer cells in NAFLD. From our review, we propose that dietary carotenoids, such as β-cryptoxanthin and astaxanthin, be used to prevent or treat NAFLD through the regulation of macrophage polarization and liver homeostasis. PMID:27347998

  19. Tumor-Infiltrating Macrophages in Post-Transplant, Relapsed Classical Hodgkin Lymphoma Are Donor-Derived.

    PubMed

    Crane, Genevieve M; Samols, Mark A; Morsberger, Laura A; Yonescu, Raluca; Thiess, Michele L; Batista, Denise A S; Ning, Yi; Burns, Kathleen H; Vuica-Ross, Milena; Borowitz, Michael J; Gocke, Christopher D; Ambinder, Richard F; Duffield, Amy S

    Tumor-associated inflammatory cells in classical Hodgkin lymphoma (CHL) typically outnumber the neoplastic Hodgkin/Reed-Sternberg (H/RS) cells. The composition of the inflammatory infiltrate, particularly the fraction of macrophages, has been associated with clinical behavior. Emerging work from animal models demonstrates that most tissue macrophages are maintained by a process of self-renewal under physiologic circumstances and certain inflammatory states, but the contribution from circulating monocytes may be increased in some disease states. This raises the question of the source of macrophages involved in human disease, particularly that of CHL. Patients with relapsed CHL following allogeneic bone marrow transplant (BMT) provide a unique opportunity to begin to address this issue. We identified 4 such patients in our archives. Through molecular chimerism and/or XY FISH studies, we demonstrated the DNA content in the post-BMT recurrent CHL was predominantly donor-derived, while the H/RS cells were derived from the patient. Where possible to evaluate, the cellular composition of the inflammatory infiltrate, including the percentage of macrophages, was similar to that of the original tumor. Our findings suggest that the H/RS cells themselves define the inflammatory environment. In addition, our results demonstrate that tumor-associated macrophages in CHL are predominantly derived from circulating monocytes rather than resident tissue macrophages. Given the association between tumor microenvironment and disease progression, a better understanding of macrophage recruitment to CHL may open new strategies for therapeutic intervention.

  20. Novel Action of Carotenoids on Non-Alcoholic Fatty Liver Disease: Macrophage Polarization and Liver Homeostasis.

    PubMed

    Ni, Yinhua; Zhuge, Fen; Nagashimada, Mayumi; Ota, Tsuguhito

    2016-06-24

    Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. It is characterized by a wide spectrum of hepatic changes, which may progress to non-alcoholic steatohepatitis (NASH) and cirrhosis. NAFLD is considered a hepatic manifestation of metabolic syndrome; however, mechanisms underlying the onset and progression of NAFLD are still unclear. Resident and recruited macrophages are key players in the homeostatic function of the liver and in the progression of NAFLD to NASH. Progress has been made in understanding the molecular mechanisms underlying the polarized activation of macrophages. New NAFLD therapies will likely involve modification of macrophage polarization by restraining M1 activation or driving M2 activation. Carotenoids are potent antioxidants and anti-inflammatory micronutrients that have been used to prevent and treat NAFLD. In addition to their antioxidative action, carotenoids can regulate macrophage polarization and thereby halt the progression of NASH. In this review, we summarize the molecular mechanisms of macrophage polarization and the function of liver macrophages/Kupffer cells in NAFLD. From our review, we propose that dietary carotenoids, such as β-cryptoxanthin and astaxanthin, be used to prevent or treat NAFLD through the regulation of macrophage polarization and liver homeostasis.

  1. Tumor-Infiltrating Macrophages in Post-Transplant, Relapsed Classical Hodgkin Lymphoma Are Donor-Derived

    PubMed Central

    Morsberger, Laura A.; Yonescu, Raluca; Thiess, Michele L.; Batista, Denise A. S.; Ning, Yi; Burns, Kathleen H.; Vuica-Ross, Milena; Borowitz, Michael J.; Gocke, Christopher D.; Ambinder, Richard F.; Duffield, Amy S.

    2016-01-01

    Tumor-associated inflammatory cells in classical Hodgkin lymphoma (CHL) typically outnumber the neoplastic Hodgkin/Reed-Sternberg (H/RS) cells. The composition of the inflammatory infiltrate, particularly the fraction of macrophages, has been associated with clinical behavior. Emerging work from animal models demonstrates that most tissue macrophages are maintained by a process of self-renewal under physiologic circumstances and certain inflammatory states, but the contribution from circulating monocytes may be increased in some disease states. This raises the question of the source of macrophages involved in human disease, particularly that of CHL. Patients with relapsed CHL following allogeneic bone marrow transplant (BMT) provide a unique opportunity to begin to address this issue. We identified 4 such patients in our archives. Through molecular chimerism and/or XY FISH studies, we demonstrated the DNA content in the post-BMT recurrent CHL was predominantly donor-derived, while the H/RS cells were derived from the patient. Where possible to evaluate, the cellular composition of the inflammatory infiltrate, including the percentage of macrophages, was similar to that of the original tumor. Our findings suggest that the H/RS cells themselves define the inflammatory environment. In addition, our results demonstrate that tumor-associated macrophages in CHL are predominantly derived from circulating monocytes rather than resident tissue macrophages. Given the association between tumor microenvironment and disease progression, a better understanding of macrophage recruitment to CHL may open new strategies for therapeutic intervention. PMID:27685855

  2. The Fundamentals of Resident Dismissal.

    PubMed

    Schenarts, Paul J; Langenfeld, Sean

    2017-02-01

    Residents have the rights and responsibilities of both students and employees. Dismissal of a resident from a training program is traumatic and has lasting repercussions for the program director, the faculty, the dismissed resident, and the residency. A review of English language literature was performed using PUBMED and OVID databases, using the search terms, resident dismissal, resident termination, student dismissal, student and resident evaluation, legal aspects of education, and remediation. The references of each publication were also reviewed to identify additional appropriate citations. If the Just Cause threshold has been met, educators have the absolute discretion to evaluate academic and clinical performance. Legal opinion has stated that it is not necessary to wait until a patient is harmed to dismiss a resident. Evaluations should be standard and robust. Negative evaluations are not defamatory as the resident gave consent to be evaluated. Provided departmental and institutional polices have been followed, a resident can be dismissed without a formal hearing. Residencies are entitled to modify academic requirements and dismissal is not considered a breach of contract. Although there is anxiety regarding resident dismissal, the courts have uniformly supported faculty having this role. When indicated, failure to dismiss a resident also places the program director and the faculty at risk for educational malpractice.

  3. The Macrophage Switch in Obesity Development

    PubMed Central

    Castoldi, Angela; Naffah de Souza, Cristiane; Câmara, Niels Olsen Saraiva; Moraes-Vieira, Pedro M.

    2016-01-01

    Immune cell infiltration in (white) adipose tissue (AT) during obesity is associated with the development of insulin resistance. In AT, the main population of leukocytes are macrophages. Macrophages can be classified into two major populations: M1, classically activated macrophages, and M2, alternatively activated macrophages, although recent studies have identified a broad range of macrophage subsets. During obesity, AT M1 macrophage numbers increase and correlate with AT inflammation and insulin resistance. Upon activation, pro-inflammatory M1 macrophages induce aerobic glycolysis. By contrast, in lean humans and mice, the number of M2 macrophages predominates. M2 macrophages secrete anti-inflammatory cytokines and utilize oxidative metabolism to maintain AT homeostasis. Here, we review the immunologic and metabolic functions of AT macrophages and their different facets in obesity and the metabolic syndrome. PMID:26779183

  4. ROS sets the stage for macrophage differentiation.

    PubMed

    Covarrubias, Anthony; Byles, Vanessa; Horng, Tiffany

    2013-08-01

    While M1 macrophages are highly pro-inflammatory and microbicidal, M2 macrophages and the related tumor associated macrophages (TAMs) regulate tissue remodeling and angiogenesis and can display immunomodulatory activity. In July issue of Cell Research, Zhang et al. show that ROS production, critical for the activation and functions of M1 macrophages, is necessary for the differentiation of M2 macrophages and TAMs, and that antioxidant therapy blocks TAM differentiation and tumorigenesis in mouse models of cancer.

  5. Macrophage Responses to B. Anthracis

    DTIC Science & Technology

    2006-08-14

    LPS were reflective of a profound rophage responses to close relatives like Bacillus cereus as well change in cellular signaling, and in general these...published (attached) in 2005 [Bergman, et al. Murine Macrophage Transcriptional Responses to Bacillus I Final Report anthracis Infection and Intoxication...Macrophage Transcriptional Responses to Bacillus anthracis Infection and Intoxication. Infection & Immunity. 73:1069-1079. Parallel to the mRNA data

  6. Alendronate inhalation ameliorates elastase-induced pulmonary emphysema in mice by induction of apoptosis of alveolar macrophages.

    PubMed

    Ueno, Manabu; Maeno, Toshitaka; Nishimura, Satoshi; Ogata, Fusa; Masubuchi, Hiroaki; Hara, Kenichiro; Yamaguchi, Kouichi; Aoki, Fumiaki; Suga, Tatsuo; Nagai, Ryozo; Kurabayashi, Masahiko

    2015-03-10

    Alveolar macrophages play a crucial role in the pathogenesis of emphysema, for which there is currently no effective treatment. Bisphosphonates are widely used to treat osteoclast-mediated bone diseases. Here we show that delivery of the nitrogen-containing bisphosphonate alendronate via aerosol inhalation ameliorates elastase-induced emphysema in mice. Inhaled, but not orally ingested, alendronate inhibits airspace enlargement after elastase instillation, and induces apoptosis of macrophages in bronchoalveolar fluid via caspase-3- and mevalonate-dependent pathways. Cytometric analysis indicates that the F4/80(+)CD11b(high)CD11c(mild) population characterizing inflammatory macrophages, and the F4/80(+)CD11b(mild)CD11c(high) population defining resident alveolar macrophages take up substantial amounts of the bisphosphonate imaging agent OsteoSense680 after aerosol inhalation. We further show that alendronate inhibits macrophage migratory and phagocytotic activities and blunts the inflammatory response of alveolar macrophages by inhibiting nuclear factor-κB signalling. Given that the alendronate inhalation effectively induces apoptosis in both recruited and resident alveolar macrophages, we suggest this strategy may have therapeutic potential for the treatment of emphysema.

  7. Macrophage Activation in Pediatric Nonalcoholic Fatty Liver Disease (NAFLD) Correlates with Hepatic Progenitor Cell Response via Wnt3a Pathway

    PubMed Central

    Renzi, Anastasia; De Stefanis, Cristiano; Stronati, Laura; Franchitto, Antonio; Alisi, Anna; Onori, Paolo; De Vito, Rita; Alpini, Gianfranco; Gaudio, Eugenio

    2016-01-01

    Non-alcoholic fatty liver disease is one of the most important causes of liver-related morbidity in children. In non-alcoholic fatty liver disease, the activation of liver resident macrophage pool is a central event in the progression of liver injury. The aims of the present study were to evaluate the polarization of liver macrophages and the possible role of Wnt3a production by macrophages in hepatic progenitor cell response in the progression of pediatric non-alcoholic fatty liver disease. 32 children with biopsy-proven non-alcoholic fatty liver disease were included. 20 out of 32 patients were treated with docosahexaenoic acid for 18 months and biopsies at the baseline and after 18 months were included. Hepatic progenitor cell activation, macrophage subsets and Wnt/β-catenin pathway were evaluated by immunohistochemistry and immunofluorescence. Our results indicated that in pediatric non-alcoholic fatty liver disease, pro-inflammatory macrophages were the predominant subset. Macrophage polarization was correlated with Non-alcoholic fatty liver disease Activity Score, ductular reaction, and portal fibrosis; docosahexaenoic acid treatment determined a macrophage polarization towards an anti-inflammatory phenotype in correlation with the reduction of serum inflammatory cytokines, with increased macrophage apoptosis, and with the up-regulation of macrophage Wnt3a expression; macrophage Wnt3a expression was correlated with β-catenin phosphorylation in hepatic progenitor cells and signs of commitment towards hepatocyte fate. In conclusion, macrophage polarization seems to have a key role in the progression of pediatric non-alcoholic fatty liver disease; the modulation of macrophage polarization could drive hepatic progenitor cell response by Wnt3a production. PMID:27310371

  8. Lipoprotein lipase regulates Fc receptor-mediated phagocytosis by macrophages maintained in glucose-deficient medium.

    PubMed Central

    Yin, B; Loike, J D; Kako, Y; Weinstock, P H; Breslow, J L; Silverstein, S C; Goldberg, I J

    1997-01-01

    During periods of intense activity such as phagocytosis, macrophages are thought to derive most of their energy from glucose metabolism under both aerobic and anaerobic conditions. To determine whether fatty acids released from lipoproteins by macrophage lipoprotein lipase (LPL) could substitute for glucose as a source of energy for phagocytosis, we cultured peritoneal macrophages from normal and LPL knockout (LPL-KO) mice that had been rescued from neonatal demise by expression of human LPL via the muscle creatine kinase promoter. Normal and LPL-KO macrophages were cultured in medium containing normal (5 mM) or low (1 mM) glucose, and were tested for their capacity to phagocytose IgG-opsonized sheep erythrocytes. LPL-KO macrophages maintained in 1 and 5 mM glucose phagocytosed 67 and 79% fewer IgG-opsonized erythrocytes, respectively, than macrophages from normal mice. Addition of VLDL to LPL-expressing macrophages maintained in 1 mM glucose enhanced the macrophages' phagocytosis of IgG-opsonized erythrocytes, but did not stimulate phagocytosis by LPL-KO macrophages. Inhibition of secreted LPL with a monoclonal anti-LPL antibody or with tetrahydrolipstatin blocked the ability of VLDL to enhance phagocytosis by LPL-expressing macrophages maintained in 1 mM glucose. Addition of oleic acid significantly enhanced phagocytosis by both LPL-expressing and LPL-KO macrophages maintained in 1 mM glucose. Moreover, oleic acid stimulated phagocytosis in cells cultured in non-glucose-containing medium, and increased the intracellular stores of creatine phosphate. Inhibition of oxidative phosphorylation, but not of glycolysis, blocked the capacity of oleic acid to stimulate phagocytosis. Receptor-mediated endocytosis of acetyl LDL by macrophages from LPL-expressing and LPL-KO mice was similar whether the cells were maintained in 5 or 1 mM glucose, and was not augmented by VLDL. We postulate that fatty acids derived from macrophage LPL-catalyzed hydrolysis of triglycerides and

  9. Macrophage dynamics are regulated by local macrophage proliferation and monocyte recruitment in injured pancreas.

    PubMed

    Van Gassen, Naomi; Van Overmeire, Eva; Leuckx, Gunter; Heremans, Yves; De Groef, Sofie; Cai, Ying; Elkrim, Yvon; Gysemans, Conny; Stijlemans, Benoît; Van de Casteele, Mark; De Baetselier, Patrick; De Leu, Nico; Heimberg, Harry; Van Ginderachter, Jo A

    2015-05-01

    Pancreas injury by partial duct ligation (PDL) activates a healing response, encompassing β-cell neogenesis and proliferation. Macrophages (MΦs) were recently shown to promote β-cell proliferation after PDL, but they remain poorly characterized. We assessed myeloid cell diversity and the factors driving myeloid cell dynamics following acute pancreas injury by PDL. In naive and sham-operated pancreas, the myeloid cell compartment consisted mainly of two distinct tissue-resident MΦ types, designated MHC-II(lo) and MHC-II(hi) MΦs, the latter being predominant. MHC-II(lo) and MHC-II(hi) pancreas MΦs differed at the molecular level, with MHC-II(lo) MΦs being more M2-activated. After PDL, there was an early surge of Ly6C(hi) monocyte infiltration in the pancreas, followed by a transient MHC-II(lo) MΦ peak and ultimately a restoration of the MHC-II(hi) MΦ-dominated steady-state equilibrium. These intricate MΦ dynamics in PDL pancreas depended on monocyte recruitment by C-C chemokine receptor 2 and macrophage-colony stimulating factor receptor as well as on macrophage-colony stimulating factor receptor-dependent local MΦ proliferation. Functionally, MHC-II(lo) MΦs were more angiogenic. We further demonstrated that, at least in C-C chemokine receptor 2-KO mice, tissue MΦs, rather than Ly6C(hi) monocyte-derived MΦs, contributed to β-cell proliferation. Together, our study fully characterizes the MΦ subsets in the pancreas and clarifies the complex dynamics of MΦs after PDL injury.

  10. [Resident foreigners in Spain].

    PubMed

    Solana, A M; Pascual De Sans, A

    1994-01-01

    The authors review trends in the size of the resident foreign population in Spain over time since the 1940s. A continuing growth over time, with temporal fluctuations, is noted, with a rapid rise in immigration in the 1980s, leading to new legislation designed to control immigration in 1985-1986 and 1991. The authors note that Europeans, particularly from countries of the European Union, make up a large percentage of the foreign population, but that the number of immigrants from developing countries has increased significantly in the last 10 years.

  11. In Silico and In Vivo Experiments Reveal M-CSF Injections Accelerate Regeneration Following Muscle Laceration.

    PubMed

    Martin, Kyle S; Kegelman, Christopher D; Virgilio, Kelley M; Passipieri, Julianna A; Christ, George J; Blemker, Silvia S; Peirce, Shayn M

    2017-03-01

    Numerous studies have pharmacologically modulated the muscle milieu in the hopes of promoting muscle regeneration; however, the timing and duration of these interventions are difficult to determine. This study utilized a combination of in silico and in vivo experiments to investigate how inflammation manipulation improves muscle recovery following injury. First, we measured macrophage populations following laceration injury in the rat tibialis anterior (TA). Then we calibrated an agent-based model (ABM) of muscle injury to mimic the observed inflammation profiles. The calibrated ABM was used to simulate macrophage and satellite stem cell (SC) dynamics, and suggested that delivering macrophage colony stimulating factor (M-CSF) prior to injury would promote SC-mediated injury recovery. Next, we performed an experiment wherein 1 day prior to injury, we injected M-CSF into the rat TA muscle. M-CSF increased the number of macrophages during the first 4 days post-injury. Furthermore, treated muscles experienced a swifter increase in the appearance of PAX7(+) SCs and regenerating muscle fibers. Our study suggests that computational models of muscle injury provide novel insights into cellular dynamics during regeneration, and further, that pharmacologically altering inflammation dynamics prior to injury can accelerate the muscle regeneration process.

  12. The penetration of rifampicin, pyrazinamide, and pyrazinoic acid into mouse macrophages.

    PubMed

    Acocella, G; Carlone, N A; Cuffini, A M; Cavallo, G

    1985-12-01

    The degree of penetration of rifampicin, pyrazinamide, and its metabolite pyrazinoic acid in mouse macrophages was evaluated over a period of 24 h. Cell cultures were exposed to 14C-labeled drugs at concentrations corresponding to peak, trough, and intermediate serum concentrations observed in humans after administration of therapeutic doses. The study was carried out with dead, resident, and stimulated peritoneal macrophages. The results indicated that the 3 compounds penetrate macrophages rapidly. At the lower concentrations, uptake of the 3 drugs is practically complete. With increasing concentrations, the absolute amount in the intracellular compartment increased. Comparison of the degree of penetration of the 3 drugs into dead, resident, and stimulated macrophages seems to suggest that the process of transfer through the macrophage wall is of a passive nature and not related to the metabolic state of the cells. Analysis of the binding of the 3 drugs to intracellular proteins indicated that more binding sites are probably available for rifampicin than for the other 2 drugs.

  13. Increased inflammatory properties of adipose tissue macrophages recruited during diet-induced obesity.

    PubMed

    Lumeng, Carey N; Deyoung, Stephanie M; Bodzin, Jennifer L; Saltiel, Alan R

    2007-01-01

    Although recent studies show that adipose tissue macrophages (ATMs) participate in the inflammatory changes in obesity and contribute to insulin resistance, the properties of these cells are not well understood. We hypothesized that ATMs recruited to adipose tissue during a high-fat diet have unique inflammatory properties compared with resident tissue ATMs. Using a dye (PKH26) to pulse label ATMs in vivo, we purified macrophages recruited to white adipose tissue during a high-fat diet. Comparison of gene expression in recruited and resident ATMs using real-time RT-PCR and cDNA microarrays showed that recruited ATMs overexpress genes important in macrophage migration and phagocytosis, including interleukin-6 (IL-6), inducible nitric oxide synthase (iNOS), and C-C chemokine receptor 2 (CCR2). Many of these genes were not induced in ATMs from high-fat diet-fed CCR2 knockout mice, supporting the importance of CCR2 in regulating recruitment of inflammatory ATMs during obesity. Additionally, expression of Apoe was decreased, whereas genes important in lipid metabolism, such as Pparg, Adfp, Srepf1, and Apob48r, were increased in the recruited macrophages. In agreement with this, ATMs from obese mice had increased lipid content compared with those from lean mice. These studies demonstrate that recruited ATMs in obese animals represent a subclass of macrophages with unique properties.

  14. Active macrophage-associated TGF-beta co-localizes with type I procollagen gene expression in atherosclerotic human pulmonary arteries.

    PubMed Central

    Bahadori, L.; Milder, J.; Gold, L.; Botney, M.

    1995-01-01

    Vascular remodeling in adult atherosclerotic pulmonary arteries is characterized by discrete areas of neointimal smooth muscle cell extracellular matrix gene expression in close proximity to non-foamy macrophages, suggesting regulation by local macrophage-associated factors. The purpose of these studies was to begin addressing the role of putative macrophage-associated factors such as transforming growth factor-beta (TGF-beta), by determining the spatial relationship between TGF-beta and neointimal matrix gene expression in human atherosclerotic pulmonary arteries. For example, the participation of TGF-beta in vascular remodeling could be inferred by its colocalization with non-foamy macrophages in areas of active matrix synthesis. In situ hybridization and immunohistochemistry demonstrated focal neointimal procollagen gene expression in close association with non-foamy but not foamy macrophages. Immunohistochemistry with isoform-specific anti-TGF-beta antibodies demonstrated all three isoforms of TGF-beta associated with non-foamy macrophages, but foamy macrophages were not immunoreactive. Neointimal and medial smooth muscle cells stained lightly. In contrast, intense TGF-beta immunoreactivity was also associated with medial smooth muscle cells in normal nonremodeling vessels. Immunohistochemistry with antibodies specific for latent TGF-beta was similar to immunohistochemistry for mature TGF-beta in both remodeling and nonremodeling vessels. Finally, using an antibody specific for active TGF-beta 1, immunoreactivity was only seen in non-foamy neointimal macrophages but not in foamy macrophages or medial smooth muscle cells from hypertensive or normal vessels. These observations suggest non-foamy macrophages may participate in modulating matrix gene expression in atherosclerotic remodeling via a TGF-beta-dependent mechanism. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 PMID:7747808

  15. Resident-to-Resident Violence Triggers in Nursing Homes

    PubMed Central

    Snellgrove, Susan; Beck, Cornelia; Green, Angela; McSweeney, Jean C.

    2014-01-01

    Certified nurses’ assistants (CNAs) employed by a rural nursing home in Northeast Arkansas described their perceptions of resident-to-resident violence in order to provide insight on factors, including unmet needs, that may trigger the phenomenon. Semistructured interviews were conducted with 11 CNAs. Data were analyzed using content analysis and constant comparison. Two categories of triggers emerged from the data—active and passive. Active triggers involved the actions of other residents that were intrusive in nature, such as wandering into a residents’ personal space, taking a resident’s belongings, and so forth. Passive triggers did not involve the actions of residents but related to the internal and external environment of the residents. Examples were factors such as boredom, competition for attention and communication difficulties. Results indicate that there are factors, including unmet needs within the nursing home environment that may be identified and altered to prevent violence between residents. PMID:23447361

  16. Silencing CCR2 in Macrophages Alleviates Adipose Tissue Inflammation and the Associated Metabolic Syndrome in Dietary Obese Mice.

    PubMed

    Kim, Jongkil; Chung, Kunho; Choi, Changseon; Beloor, Jagadish; Ullah, Irfan; Kim, Nahyeon; Lee, Kuen Yong; Lee, Sang-Kyung; Kumar, Priti

    2016-01-26

    Adipose tissue macrophage (ATM)-mediated inflammation is a key feature contributing to the adverse metabolic outcomes of dietary obesity. Recruitment of macrophages to obese adipose tissues (AT) can occur through the engagement of CCR2, the receptor for MCP-1 (monocyte chemoattractant protein-1), which is expressed on peripheral monocytes/macrophages. Here, we show that i.p. administration of a rabies virus glycoprotein-derived acetylcholine receptor-binding peptide effectively delivers complexed siRNA into peritoneal macrophages and ATMs in a mouse model of high-fat diet-induced obesity. Treatment with siRNA against CCR2 inhibited macrophage infiltration and accumulation in AT and, therefore, proinflammatory cytokines produced by macrophages. Consequently, the treatment significantly improved glucose tolerance and insulin sensitivity profiles, and also alleviated the associated symptoms of hepatic steatosis and reduced hepatic triglyceride production. These results demonstrate that disruption of macrophage chemotaxis to the AT through cell-targeted gene knockdown strategies can provide a therapeutic intervention for obesity-related metabolic diseases. The study also highlights a siRNA delivery approach for targeting specific monocyte subsets that contribute to obesity-associated inflammation without affecting the function of other tissue-resident macrophages that are essential for host homeostasis and survival.

  17. Silencing CCR2 in Macrophages Alleviates Adipose Tissue Inflammation and the Associated Metabolic Syndrome in Dietary Obese Mice

    PubMed Central

    Kim, Jongkil; Chung, Kunho; Choi, Changseon; Beloor, Jagadish; Ullah, Irfan; Kim, Nahyeon; Lee, Kuen Yong; Lee, Sang-Kyung; Kumar, Priti

    2016-01-01

    Adipose tissue macrophage (ATM)-mediated inflammation is a key feature contributing to the adverse metabolic outcomes of dietary obesity. Recruitment of macrophages to obese adipose tissues (AT) can occur through the engagement of CCR2, the receptor for MCP-1 (monocyte chemoattractant protein-1), which is expressed on peripheral monocytes/macrophages. Here, we show that i.p. administration of a rabies virus glycoprotein-derived acetylcholine receptor-binding peptide effectively delivers complexed siRNA into peritoneal macrophages and ATMs in a mouse model of high-fat diet-induced obesity. Treatment with siRNA against CCR2 inhibited macrophage infiltration and accumulation in AT and, therefore, proinflammatory cytokines produced by macrophages. Consequently, the treatment significantly improved glucose tolerance and insulin sensitivity profiles, and also alleviated the associated symptoms of hepatic steatosis and reduced hepatic triglyceride production. These results demonstrate that disruption of macrophage chemotaxis to the AT through cell-targeted gene knockdown strategies can provide a therapeutic intervention for obesity-related metabolic diseases. The study also highlights a siRNA delivery approach for targeting specific monocyte subsets that contribute to obesity-associated inflammation without affecting the function of other tissue-resident macrophages that are essential for host homeostasis and survival. PMID:26812653

  18. Passive transfer of interferon-γ over-expressing macrophages enhances resistance of SCID mice to Mycobacterium tuberculosis infection.

    PubMed

    Pasula, Rajamouli; Martin, William J; Kesavalu, Banu Rekha; Abdalla, Maher Y; Britigan, Bradley E

    2017-02-23

    Infection with Mycobacterium tuberculosis (M.tb) is associated with increased deaths worldwide. Alveolar macrophages (AMs) play a critical role in host defense against infection with this pathogen. In this work we tested the hypothesis that passive transfer of normal AMs, IFN-γ activated AMs, or macrophages transduced to over-express IFN-γ into the lungs of immunosuppressed SCID mice, where resident macrophages are present but not functional, would enhance alveolar immunity and increase clearance of pulmonary M.tb infection. Accordingly, SCID mice were infected with M.tb intratracheally (I.T.), following which they received either control macrophages or macrophages overexpressing IFN-γ (J774A.1). The extent of M.tb infection was assessed at 30days post-M.tb infection. SCID mice administered macrophages over-expressing IFN-γ showed a significant decrease in M.tb burden and increased survival compared to J774A.1 control macrophages or untreated mice. This was further associated with a significant increase in IFN-γ and TNF-α mRNA and protein expression, as well as NF-κB (p65) mRNA, in the lungs. The increase in IFN-γ and TNF-α lung levels was inversely proportional to the number of M.tb organisms recovered. These results provide evidence that administration of macrophages overexpressing IFN-γ inhibit M.tb growth in vivo and may enhance host defense against M.tb infection.

  19. Guidelines for resident teaching experiences.

    PubMed

    Havrda, Dawn E; Engle, Janet P; Anderson, Keri C; Ray, Shaunta' M; Haines, Seena L; Kane-Gill, Sandra L; Ballard, Stephanie L; Crannage, Andrew J; Rochester, Charmaine D; Parman, Malinda G

    2013-07-01

    Postgraduate year one (PGY1) and postgraduate year two (PGY2) residencies serve to develop pharmacists into skillful clinicians who provide advanced patient-centered care in various general and specialized areas of pharmacy practice. Pharmacy residencies are a minimum requirement for many clinical pharmacy positions, as well as for positions in academia. The role of clinical pharmacists typically includes teaching, regardless of whether they pursue an academic appointment. Common teaching duties of pharmacist-clinicians include giving continuing education or other invited presentations, providing education to colleagues regarding clinical initiatives, precepting pharmacy students (early and advanced experiences) and residents, and educating other health care professionals. Although ASHP provides accreditation standards for PGY1 and PGY2 residencies, the standards pertaining to teaching or education training are vague. Through the years, teaching certificate programs that develop residents' teaching skills and better prepare residents for a diverse pharmacy job market have increased in popularity; moreover, teaching certificate programs serve as an attractive recruitment tool. However, the consistency of requirements for teaching certificate programs is lacking, and standardization is needed. The Task Force on Residencies developed two sets of guidelines to define teaching experiences within residencies. The first guideline defines the minimum standards for teaching experiences in any residency-training program. The second guideline is for programs offering a teaching certificate program to provide standardization, ensuring similar outcomes and quality on program completion. One of the main differences between the guidelines is the recommendation that residency programs offering a teaching certificate program be affiliated with an academic institution to provide the pedagogy and variety of teaching experiences for the resident. Residency program directors should

  20. Systemic and Cardiac Depletion of M2 Macrophage through CSF-1R Signaling Inhibition Alters Cardiac Function Post Myocardial Infarction.

    PubMed

    Leblond, Anne-Laure; Klinkert, Kerstin; Martin, Kenneth; Turner, Elizebeth C; Kumar, Arun H; Browne, Tara; Caplice, Noel M

    2015-01-01

    The heart hosts tissue resident macrophages which are capable of modulating cardiac inflammation and function by multiple mechanisms. At present, the consequences of phenotypic diversity in macrophages in the heart are incompletely understood. The contribution of cardiac M2-polarized macrophages to the resolution of inflammation and repair response following myocardial infarction remains to be fully defined. In this study, the role of M2 macrophages was investigated utilising a specific CSF-1 receptor signalling inhibition strategy to achieve their depletion. In mice, oral administration of GW2580, a CSF-1R kinase inhibitor, induced significant decreases in Gr1lo and F4/80hi monocyte populations in the circulation and the spleen. GW2580 administration also induced a significant depletion of M2 macrophages in the heart after 1 week treatment as well as a reduction of cardiac arginase1 and CD206 gene expression indicative of M2 macrophage activity. In a murine myocardial infarction model, reduced M2 macrophage content was associated with increased M1-related gene expression (IL-6 and IL-1β), and decreased M2-related gene expression (Arginase1 and CD206) in the heart of GW2580-treated animals versus vehicle-treated controls. M2 depletion was also associated with a loss in left ventricular contractile function, infarct enlargement, decreased collagen staining and increased inflammatory cell infiltration into the infarct zone, specifically neutrophils and M1 macrophages. Taken together, these data indicate that CSF-1R signalling is critical for maintaining cardiac tissue resident M2-polarized macrophage population, which is required for the resolution of inflammation post myocardial infarction and, in turn, for preservation of ventricular function.

  1. Characterization of the macrophage transcriptome in glomerulonephritis-susceptible and -resistant rat strains.

    PubMed

    Maratou, K; Behmoaras, J; Fewings, C; Srivastava, P; D'Souza, Z; Smith, J; Game, L; Cook, T; Aitman, T

    2011-03-01

    Crescentic glomerulonephritis (CRGN) is a major cause of rapidly progressive renal failure for which the underlying genetic basis is unknown. Wistar-Kyoto (WKY) rats show marked susceptibility to CRGN, whereas Lewis rats are resistant. Glomerular injury and crescent formation are macrophage dependent and mainly explained by seven quantitative trait loci (Crgn1-7). Here, we used microarray analysis in basal and lipopolysaccharide (LPS)-stimulated macrophages to identify genes that reside on pathways predisposing WKY rats to CRGN. We detected 97 novel positional candidates for the uncharacterized Crgn3-7. We identified 10 additional secondary effector genes with profound differences in expression between the two strains (>5-fold change, <1% false discovery rate) for basal and LPS-stimulated macrophages. Moreover, we identified eight genes with differentially expressed alternatively spliced isoforms, by using an in-depth analysis at the probe level that allowed us to discard false positives owing to polymorphisms between the two rat strains. Pathway analysis identified several common linked pathways, enriched for differentially expressed genes, which affect macrophage activation. In summary, our results identify distinct macrophage transcriptome profiles between two rat strains that differ in susceptibility to glomerulonephritis, provide novel positional candidates for Crgn3-7 and define groups of genes that play a significant role in differential regulation of macrophage activity.

  2. Identification of atypical ether-linked glycerophospholipid species in macrophages by mass spectrometry

    PubMed Central

    Ivanova, Pavlina T.; Milne, Stephen B.; Brown, H. Alex

    2010-01-01

    A large scale profiling and analysis of glycerophospholipid species in macrophages has facilitated the identification of several rare and atypical glycerophospholipid species. By using liquid chromatography tandem mass spectrometry and comparison of the elution and fragmentation properties of the rare lipids to synthetic standards, we were able to identify an array of ether-linked phosphatidylinositols (PIs), phosphatidic acids, phosphatidylserines (PSs), very long chain phosphatidylethanolamines (PEs), and phosphatidylcholines (PCs) as well as phosphatidylthreonines (PTs) and a wide collection of odd carbon fatty acid-containing phospholipids in macrophages. A comprehensive qualitative analysis of glycerophospholipids from different macrophage cells was conducted. During the phospholipid profiling of the macrophage-like RAW 264.7 cells, we identified dozens of rare or previously uncharacterized phospholipids, including ether-linked PIs, PSs, and glycerophosphatidic acids, PTs, and PCs and PTs containing very long polyunsaturated fatty acids. Additionally, large numbers of phospholipids containing at least one odd carbon fatty acid were identified. Using the same methodology, we also identified many of the same species of glycerophospholipids in resident peritoneal macrophages, foam cells, and murine bone marrow derived macrophages. PMID:19965583

  3. A novel guinea pig macrophage-specific polymorphic molecule. I. Biochemistry, genetics, and tissue distribution.

    PubMed

    Jensen, L A; Schwartz, B D

    1988-02-15

    In the course of studying Ia molecules from strain 2 and strain 13 guinea pig macrophages, with the intent of comparing them to B cell Ia molecules, it was observed that guinea pig alloserum prepared by cross-immunization of guinea pig lymphocyte Ag non-identical inbred guinea pigs immunoprecipitated not only conventional class I and class II molecules, but also a 98,000-Da molecule, termed gp98. Two different forms of the molecule were detected, indicating it is polymorphic. The genes encoding gp98 were shown not to be linked to the guinea pig lymphocyte Ag complex. The molecule gp98 was found on macrophages within populations of peritoneal exudate cells, resident peritoneal cells, bone marrow cells, and spleen. All gp98-bearing macrophages were also Ia-positive. However, only a subpopulation of macrophages bore gp98. The gp98 was not found on Ly-1 or Ig-bearing cells, indicating that B and T cells do not bear Ia. Thus, gp98 appears to be a highly immunogenic polymorphic macrophage-specific molecule that allows the characterization of guinea pig macrophage subsets.

  4. Macrophage Heterogeneity in Respiratory Diseases

    PubMed Central

    Boorsma, Carian E.; Draijer, Christina; Melgert, Barbro N.

    2013-01-01

    Macrophages are among the most abundant cells in the respiratory tract, and they can have strikingly different phenotypes within this environment. Our knowledge of the different phenotypes and their functions in the lung is sketchy at best, but they appear to be linked to the protection of gas exchange against microbial threats and excessive tissue responses. Phenotypical changes of macrophages within the lung are found in many respiratory diseases including asthma, chronic obstructive pulmonary disease (COPD), and pulmonary fibrosis. This paper will give an overview of what macrophage phenotypes have been described, what their known functions are, what is known about their presence in the different obstructive and restrictive respiratory diseases (asthma, COPD, pulmonary fibrosis), and how they are thought to contribute to the etiology and resolution of these diseases. PMID:23533311

  5. Nitric oxide synthase inhibition reduces muscle inflammation and necrosis in modified muscle use

    NASA Technical Reports Server (NTRS)

    Pizza, F. X.; Hernandez, I. J.; Tidball, J. G.

    1998-01-01

    The objective of this study was to determine the role of nitric oxide in muscle inflammation, fiber necrosis, and apoptosis of inflammatory cells in vivo. The effects of nitric oxide synthase (NOS) inhibition on the concentrations of neutrophils, ED1+ and ED2+ macrophages, apoptotic inflammatory cells, and necrotic muscle fibers in rats subjected to 10 days of hindlimb unloading and 2 days of reloading were determined. Administration of NOS inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME) significantly reduced the concentrations of neutrophils, ED1+ and ED2+ macrophages, and necrotic fibers in soleus muscle relative to water-treated controls. The concentration of apoptotic inflammatory cells was also significantly lower for L-NAME-treated animals compared with water-treated controls. However, the proportion of the inflammatory cell population that was apoptotic did not differ between L-NAME-treated and control animals, suggesting that L-NAME treatment did not decrease inflammatory cell populations by increasing the frequency of apoptosis. Thus, nitric oxide or one of its intermediates promotes muscle inflammation and fiber necrosis during modified muscle use and plays no more than a minor role in the resolution of muscle inflammation by inducing apoptosis of inflammatory cells.

  6. Bone marrow-derived cell regulation of skeletal muscle regeneration

    PubMed Central

    Sun, Dongxu; Martinez, Carlo O.; Ochoa, Oscar; Ruiz-Willhite, Lourdes; Bonilla, Jose R.; Centonze, Victoria E.; Waite, Lindsay L.; Michalek, Joel E.; McManus, Linda M.; Shireman, Paula K.

    2009-01-01

    Limb regeneration requires the coordination of multiple stem cell populations to recapitulate the process of tissue formation. Therefore, bone marrow (BM) -derived cell regulation of skeletal muscle regeneration was examined in mice lacking the CC chemokine receptor 2 (CCR2). Myofiber size, numbers of myogenic progenitor cells (MPCs), and recruitment of BM-derived cells and macrophages were assessed after cardiotoxin-induced injury of chimeric mice produced by transplanting BM from wild-type (WT) or CCR2−/− mice into irradiated WT or CCR2−/− host mice. Regardless of the host genotype, muscle regeneration and recruitment of BM-derived cells and macrophages were similar in mice replenished with WT BM, whereas BM-derived cells and macrophage accumulation were decreased and muscle regeneration was impaired in all animals receiving CCR2−/− BM. Furthermore, numbers of MPCs (CD34+/Sca-1−/CD45− cells) were significantly increased in mice receiving CCR2−/− BM despite the decreased size of regenerated myofibers. Thus, the expression of CCR2 on BM-derived cells regulated macrophage recruitment into injured muscle, numbers of MPC, and the extent of regenerated myofiber size, all of which were independent of CCR2 expression on host-derived cells. Future studies in regenerative medicine must include consideration of the role of BM-derived cells, possibly macrophages, in CCR2-dependent events that regulate effective skeletal muscle regeneration.—Sun, D., Martinez, C. O., Ochoa, O., Ruiz-Willhite, L., Bonilla, J. R., Centonze, V. E., Waite, L. L., Michalek, J. E., McManus, L. M., Shireman, P. K. Bone marrow-derived cell regulation of skeletal muscle regeneration. PMID:18827026

  7. Evidence for particle transport between alveolar macrophages in vivo

    SciTech Connect

    Benson, J.M.; Nikula, K.J.; Guilmette, R.A.

    1995-12-01

    Recent studies at this Institute have focused on determining the role of alveolar macrophages (AMs) in the transport of particles within and form the lung. For those studies, AMs previously labeled using the nuclear stain Hoechst 33342 and polychromatic Fluoresbrite microspheres (1 {mu}m diameter, Polysciences, Inc., Warrington, PA) were instilled into lungs of recipient F344 rats. The fate of the donor particles and the doubly labeled AMs within recipient lungs was followed for 32 d. Within 2-4 d after instillation, the polychromatic microspheres were found in both donor and resident AMs, suggesting that particle transfer occurred between the donor and resident AMs. However, this may also have been an artifact resulting from phagocytosis of the microspheres form dead donor cells or from the fading or degradation of Hoechst 33342 within the donor cells leading to their misidentification as resident AMs. The results support the earlier findings that microspheres in donor AMs can be transferred to resident AMs within 2 d after instillation.

  8. Klebsiella pneumoniae survives within macrophages by avoiding delivery to lysosomes.

    PubMed

    Cano, Victoria; March, Catalina; Insua, Jose Luis; Aguiló, Nacho; Llobet, Enrique; Moranta, David; Regueiro, Verónica; Brennan, Gerard P; Millán-Lou, Maria Isabel; Martín, Carlos; Garmendia, Junkal; Bengoechea, José A

    2015-11-01

    Klebsiella pneumoniae is an important cause of community-acquired and nosocomial pneumonia. Evidence indicates that Klebsiella might be able to persist intracellularly within a vacuolar compartment. This study was designed to investigate the interaction between Klebsiella and macrophages. Engulfment of K. pneumoniae was dependent on host cytoskeleton, cell plasma membrane lipid rafts and the activation of phosphoinositide 3-kinase (PI3K). Microscopy studies revealed that K. pneumoniae resides within a vacuolar compartment, the Klebsiella-containing vacuole (KCV), which traffics within vacuoles associated with the endocytic pathway. In contrast to UV-killed bacteria, the majority of live bacteria did not co-localize with markers of the lysosomal compartment. Our data suggest that K. pneumoniae triggers a programmed cell death in macrophages displaying features of apoptosis. Our efforts to identify the mechanism(s) whereby K. pneumoniae prevents the fusion of the lysosomes to the KCV uncovered the central role of the PI3K-Akt-Rab14 axis to control the phagosome maturation. Our data revealed that the capsule is dispensable for Klebsiella intracellular survival if bacteria were not opsonized. Furthermore, the environment found by Klebsiella within the KCV triggered the down-regulation of the expression of cps. Altogether, this study proves evidence that K. pneumoniae survives killing by macrophages by manipulating phagosome maturation that may contribute to Klebsiella pathogenesis.

  9. Coculture with intraocular lens material-activated macrophages induces an inflammatory phenotype in lens epithelial cells.

    PubMed

    Pintwala, Robert; Postnikoff, Cameron; Molladavoodi, Sara; Gorbet, Maud

    2015-03-01

    Cataracts are the leading cause of blindness worldwide, requiring surgical implantation of an intraocular lens. Despite evidence of leukocyte ingress into the postoperative lens, few studies have investigated the leukocyte response to intraocular lens materials. A novel coculture model was developed to examine macrophage activation by hydrophilic acrylic (poly(2-hydroxyethyl methacrylate)) and hydrophobic acrylic (polymethylmethacrylate) commercial intraocular lens. The human monocytic cell line THP-1 was differentiated into macrophages and cocultured with human lens epithelial cell line (HLE-B3) with or without an intraocular lens for one, two, four, or six days. Using flow cytometry and confocal microscopy, expression of the macrophage activation marker CD54 (intercellular adhesion molecule-1) and production of reactive oxygen species via the fluorogenic probe 2',7'-dichlorodihydrofluorescein diacetate were examined in macrophages. α-Smooth muscle actin, a transdifferentiation marker, was characterized in lens epithelial cells. The poly(2-hydroxyethyl methacrylate) intraocular lens prevented adhesion but induced significant macrophage activation (p < 0.03) versus control (no intraocular lens), while the polymethylmethacrylate intraocular lens enabled adhesion and multinucleated fusion, but induced no significant activation. Coculture with either intraocular lens increased reactive oxygen species production in macrophages after one day (p < 0.03) and increased expression of α-smooth muscle actin in HLE B-3 after six days, although only poly(2-hydroxyethyl methacrylate) induced a significant difference versus control (p < 0.01). Our results imply that-contrary to prior uveal biocompatibility understanding-macrophage adherence is not necessary for a strong inflammatory response to an intraocular lens, with hydrophilic surfaces inducing higher activation than hydrophobic surfaces. These findings provide a new method of inquiry into uveal

  10. Muscle atrophy

    MedlinePlus

    ... damage caused by injury, diabetes, toxins, or alcohol Polio ( poliomyelitis ) Spinal cord injury Although people can adapt to ... Guillain-Barré syndrome Hypotonia Muscle cramps Muscular dystrophy Polio Review Date 1/5/2016 Updated by: Joseph ...

  11. Getting Muscles

    MedlinePlus

    ... muscular as a superhero or your favorite professional athlete? Well, the big muscles you're thinking about ... Superheroes, of course, aren't real, and professional athletes are grownups, whose bodies are different from kids' ...

  12. Muscle twitching

    MedlinePlus

    ... patient with neurologic disease. In: Goldman L, Schafer AI, eds. Goldman's Cecil Medicine . 25th ed. Philadelphia, PA: ... Selcen D. Muscle diseases. In: Goldman L, Schafer AI, eds. Goldman's Cecil Medicine . 25th ed. Philadelphia, PA: ...

  13. Sessile alveolar macrophages communicate with alveolar epithelium to modulate immunity

    NASA Astrophysics Data System (ADS)

    Westphalen, Kristin; Gusarova, Galina A.; Islam, Mohammad N.; Subramanian, Manikandan; Cohen, Taylor S.; Prince, Alice S.; Bhattacharya, Jahar

    2014-02-01

    The tissue-resident macrophages of barrier organs constitute the first line of defence against pathogens at the systemic interface with the ambient environment. In the lung, resident alveolar macrophages (AMs) provide a sentinel function against inhaled pathogens. Bacterial constituents ligate Toll-like receptors (TLRs) on AMs, causing AMs to secrete proinflammatory cytokines that activate alveolar epithelial receptors, leading to recruitment of neutrophils that engulf pathogens. Because the AM-induced response could itself cause tissue injury, it is unclear how AMs modulate the response to prevent injury. Here, using real-time alveolar imaging in situ, we show that a subset of AMs attached to the alveolar wall form connexin 43 (Cx43)-containing gap junction channels with the epithelium. During lipopolysaccharide-induced inflammation, the AMs remained sessile and attached to the alveoli, and they established intercommunication through synchronized Ca2+ waves, using the epithelium as the conducting pathway. The intercommunication was immunosuppressive, involving Ca2+-dependent activation of Akt, because AM-specific knockout of Cx43 enhanced alveolar neutrophil recruitment and secretion of proinflammatory cytokines in the bronchoalveolar lavage. A picture emerges of a novel immunomodulatory process in which a subset of alveolus-attached AMs intercommunicates immunosuppressive signals to reduce endotoxin-induced lung inflammation.

  14. Macrophages and HIV-1: An Unhealthy Constellation.

    PubMed

    Sattentau, Quentin J; Stevenson, Mario

    2016-03-09

    Lentiviruses have a long-documented association with macrophages. Abundant evidence exists for in vitro and, in a tissue-specific manner, in vivo infection of macrophages by the primate lentiviruses HIV-1 and SIV. However, macrophage contribution to aspects of HIV-1 and SIV pathogenesis, and their role in viral persistence in individuals on suppressive antiretroviral therapy, remains unclear. Here we discuss recent evidence implicating macrophages in HIV-1-mediated disease and highlight directions for further investigation.

  15. Macrophage Heterogeneity and Plasticity: Impact of Macrophage Biomarkers on Atherosclerosis

    PubMed Central

    Rojas, Joselyn; Salazar, Juan; Martínez, María Sofía; Palmar, Jim; Bautista, Jordan; Chávez-Castillo, Mervin; Gómez, Alexis; Bermúdez, Valmore

    2015-01-01

    Cardiovascular disease (CVD) is a global epidemic, currently representing the worldwide leading cause of morbidity and mortality. Atherosclerosis is the fundamental pathophysiologic component of CVD, where the immune system plays an essential role. Monocytes and macrophages are key mediators in this aspect: due to their heterogeneity and plasticity, these cells may act as either pro- or anti-inflammatory mediators. Indeed, monocytes may develop heterogeneous functional phenotypes depending on the predominating pro- or anti-inflammatory microenvironment within the lesion, resulting in classic, intermediate, and non-classic monocytes, each with strikingly differing features. Similarly, macrophages may also adopt heterogeneous profiles being mainly M1 and M2, the former showing a proinflammatory profile while the latter demonstrates anti-inflammatory traits; they are further subdivided in several subtypes with more specialized functions. Furthermore, macrophages may display plasticity by dynamically shifting between phenotypes in response to specific signals. Each of these distinct cell profiles is associated with diverse biomarkers which may be exploited for therapeutic intervention, including IL-10, IL-13, PPAR-γ, LXR, NLRP3 inflammasomes, and microRNAs. Direct modulation of the molecular pathways concerning these potential macrophage-related targets represents a promising field for new therapeutic alternatives in atherosclerosis and CVD. PMID:26491604

  16. Molecular Mechanisms Regulating Macrophage Response to Hypoxia

    PubMed Central

    Rahat, Michal A.; Bitterman, Haim; Lahat, Nitza

    2011-01-01

    Monocytes and Macrophages (Mo/Mɸ) exhibit great plasticity, as they can shift between different modes of activation and, driven by their immediate microenvironment, perform divergent functions. These include, among others, patrolling their surroundings and maintaining homeostasis (resident Mo/Mɸ), combating invading pathogens and tumor cells (classically activated or M1 Mo/Mɸ), orchestrating wound healing (alternatively activated or M2 Mo/Mɸ), and restoring homeostasis after an inflammatory response (resolution Mɸ). Hypoxia is an important factor in the Mɸ microenvironment, is prevalent in many physiological and pathological conditions, and is interdependent with the inflammatory response. Although Mo/Mɸ have been studied in hypoxia, the mechanisms by which hypoxia influences the different modes of their activation, and how it regulates the shift between them, remain unclear. Here we review the current knowledge about the molecular mechanisms that mediate this hypoxic regulation of Mɸ activation. Much is known about the hypoxic transcriptional regulatory network, which includes the master regulators hypoxia-induced factor-1 and NF-κB, as well as other transcription factors (e.g., AP-1, Erg-1), but we also highlight the role of post-transcriptional and post-translational mechanisms. These mechanisms mediate hypoxic induction of Mɸ pro-angiogenic mediators, suppress M1 Mɸ by post-transcriptionally inhibiting pro-inflammatory mediators, and help shift the classically activated Mɸ into an activation state which approximate the alternatively activated or resolution Mɸ. PMID:22566835

  17. Expression of ACAT-1 protein in human atherosclerotic lesions and cultured human monocytes-macrophages.

    PubMed

    Miyazaki, A; Sakashita, N; Lee, O; Takahashi, K; Horiuchi, S; Hakamata, H; Morganelli, P M; Chang, C C; Chang, T Y

    1998-10-01

    The acyl coenzyme A:cholesterol acyltransferase (ACAT) gene was first cloned in 1993 (Chang et al, J Biol Chem. 1993;268:20747-20755; designated ACAT-1). Using affinity-purified antibodies raised against the N-terminal portion of human ACAT-1 protein, we performed immunohistochemical localization studies and showed that the ACAT-1 protein was highly expressed in atherosclerotic lesions of the human aorta. We also performed cell-specific localization studies using double immunostaining and showed that ACAT-1 was predominantly expressed in macrophages but not in smooth muscle cells. We then used a cell culture system in vitro to monitor the ACAT-1 expression in differentiating monocytes-macrophages. The ACAT-1 protein content increased by up to 10-fold when monocytes spontaneously differentiated into macrophages. This increase occurred within the first 2 days of culturing the monocytes and reached a plateau level within 4 days of culturing, indicating that the increase in ACAT-1 protein content is an early event during the monocyte differentiation process. The ACAT-1 protein expressed in the differentiating monocytes-macrophages was shown to be active by enzyme assay in vitro. The high levels of ACAT-1 present in macrophages maintained in culture can explain the high ACAT-1 contents found in atherosclerotic lesions. Our results thus support the idea that ACAT-1 plays an important role in differentiating monocytes and in forming macrophage foam cells during the development of human atherosclerosis.

  18. Regulatory T cells and skeletal muscle regeneration.

    PubMed

    Schiaffino, Stefano; Pereira, Marcelo G; Ciciliot, Stefano; Rovere-Querini, Patrizia

    2017-02-01

    Skeletal muscle regeneration results from the activation and differentiation of myogenic stem cells, called satellite cells, located beneath the basal lamina of the muscle fibers. Inflammatory and immune cells have a crucial role in the regeneration process. Acute muscle injury causes an immediate transient wave of neutrophils followed by a more persistent infiltration of M1 (proinflammatory) and M2 (anti-inflammatory/proregenerative) macrophages. New studies show that injured muscle is also infiltrated by a specialized population of regulatory T (Treg) cells, which control both the inflammatory response, by promoting the M1-to-M2 switch, and the activation of satellite cells. Treg cells accumulate in injured muscle in response to specific cytokines, such as IL-33, and promote muscle growth by releasing growth factors, such as amphiregulin. Muscle repair during aging is impaired due to reduced number of Treg cells and can be enhanced by IL-33 supplementation. Migration of Treg cells could also contribute to explain the effect of heterochronic parabiosis, whereby muscle regeneration of aged mice can be improved by a parabiotically linked young partners. In mdx dystrophin-deficient mice, a model of human Duchenne muscular dystrophy, muscle injury, and inflammation is mitigated by expansion of the Treg-cell population but exacerbated by Treg-cell depletion. These findings support the notion that immunological mechanisms are not only essential in the response to pathogenic microbes and tumor cells but also have a wider homeostatic role in tissue repair, and open new perspectives for boosting muscle growth in chronic muscle disease and during aging.

  19. In acute experimental autoimmune encephalomyelitis, infiltrating macrophages are immune activated, whereas microglia remain immune suppressed.

    PubMed

    Vainchtein, I D; Vinet, J; Brouwer, N; Brendecke, S; Biagini, G; Biber, K; Boddeke, H W G M; Eggen, B J L

    2014-10-01

    Multiple sclerosis (MS) is an autoimmune demyelinating disorder of the central nervous system (CNS) characterized by loss of myelin accompanied by infiltration of T-lymphocytes and monocytes. Although it has been shown that these infiltrates are important for the progression of MS, the role of microglia, the resident macrophages of the CNS, remains ambiguous. Therefore, we have compared the phenotypes of microglia and macrophages in a mouse model for MS, experimental autoimmune encephalomyelitis (EAE). In order to properly discriminate between these two cell types, microglia were defined as CD11b(pos) CD45(int) Ly-6C(neg) , and infiltrated macrophages as CD11b(pos) CD45(high) Ly-6C(pos) . During clinical EAE, microglia displayed a weakly immune-activated phenotype, based on the expression of MHCII, co-stimulatory molecules (CD80, CD86, and CD40) and proinflammatory genes [interleukin-1β (IL-1β) and tumour necrosis factor- α (TNF-α)]. In contrast, CD11b(pos) CD45(high) Ly-6C(pos) infiltrated macrophages were strongly activated and could be divided into two populations Ly-6C(int) and Ly-6C(high) , respectively. Ly-6C(high) macrophages contained less myelin than Ly-6C(int) macrophages and expression levels of the proinflammatory cytokines IL-1β and TNF-α were higher in Ly-6C(int) macrophages. Together, our data show that during clinical EAE, microglia are only weakly activated whereas infiltrated macrophages are highly immune reactive.

  20. Incorporating resident research into the dermatology residency program

    PubMed Central

    Wagner, Richard F; Raimer, Sharon S; Kelly, Brent C

    2013-01-01

    Programmatic changes for the dermatology residency program at The University of Texas Medical Branch were first introduced in 2005, with the faculty goal incorporating formal dermatology research projects into the 3-year postgraduate training period. This curriculum initially developed as a recommendation for voluntary scholarly project activity by residents, but it evolved into a program requirement for all residents in 2009. Departmental support for this activity includes assignment of a faculty mentor with similar interest about the research topic, financial support from the department for needed supplies, materials, and statistical consultation with the Office of Biostatistics for study design and data analysis, a 2-week elective that provides protected time from clinical activities for the purpose of preparing research for publication and submission to a peer-reviewed medical journal, and a departmental award in recognition for the best resident scholarly project each year. Since the inception of this program, five classes have graduated a total of 16 residents. Ten residents submitted their research studies for peer review and published their scholarly projects in seven dermatology journals through the current academic year. These articles included three prospective investigations, three surveys, one article related to dermatology education, one retrospective chart review, one case series, and one article about dermatopathology. An additional article from a 2012 graduate about dermatology education has also been submitted to a journal. This new program for residents was adapted from our historically successful Dermatology Honors Research Program for medical students at The University of Texas Medical Branch. Our experience with this academic initiative to promote dermatology research by residents is outlined. It is recommended that additional residency programs should consider adopting similar research programs to enrich resident education. PMID:23901305

  1. Dysferlin-mediated phosphatidylserine sorting engages macrophages in sarcolemma repair

    PubMed Central

    Middel, Volker; Zhou, Lu; Takamiya, Masanari; Beil, Tanja; Shahid, Maryam; Roostalu, Urmas; Grabher, Clemens; Rastegar, Sepand; Reischl, Markus; Nienhaus, Gerd Ulrich; Strähle, Uwe

    2016-01-01

    Failure to repair the sarcolemma leads to muscle cell death, depletion of stem cells and myopathy. Hence, membrane lesions are instantly sealed by a repair patch consisting of lipids and proteins. It has remained elusive how this patch is removed to restore cell membrane integrity. Here we examine sarcolemmal repair in live zebrafish embryos by real-time imaging. Macrophages remove the patch. Phosphatidylserine (PS), an ‘eat-me' signal for macrophages, is rapidly sorted from adjacent sarcolemma to the repair patch in a Dysferlin (Dysf) dependent process in zebrafish and human cells. A previously unrecognized arginine-rich motif in Dysf is crucial for PS accumulation. It carries mutations in patients presenting with limb-girdle muscular dystrophy 2B. This underscores the relevance of this sequence and uncovers a novel pathophysiological mechanism underlying this class of myopathies. Our data show that membrane repair is a multi-tiered process involving immediate, cell-intrinsic mechanisms as well as myofiber/macrophage interactions. PMID:27641898

  2. Bacteriostatic and bactericidal activities of benzoxazinorifamycin KRM-1648 against Mycobacterium tuberculosis and Mycobacterium avium in human macrophages.

    PubMed Central

    Mor, N; Simon, B; Heifets, L

    1996-01-01

    Inhibitory and bactericidal activities of KRM-1648 were determined against Mycobacterium tuberculosis and M. avium residing in human monocyte-derived macrophages and extracellular M. tuberculosis and M. avium. MICs and MBCs of KRM-1648 against intracellular and extracellular bacteria were substantially lower than those of rifampin. The MICs and MBCs of either drug against the intracellular bacteria were only twofold lower than or equal to the values found for extracellular bacteria. The prolonged effect of KRM-1648 found in this study is probably associated with high ratios of intracellular accumulation, which were 50- to 100-fold higher than that found for rifampin. Further studies on intracellular distribution of KRM-1648 and on the sites of actual interaction between the drug and bacteria residing in macrophages are necessary, as well as evaluation of combined effects of KRM-1648 with other drugs in long-term macrophage culture experiments. PMID:8726023

  3. Muscle Interstitial Cells: A Brief Field Guide to Non-satellite Cell Populations in Skeletal Muscle.

    PubMed

    Tedesco, Francesco Saverio; Moyle, Louise A; Perdiguero, Eusebio

    2017-01-01

    Skeletal muscle regeneration is mainly enabled by a population of adult stem cells known as satellite cells. Satellite cells have been shown to be indispensable for adult skeletal muscle repair and regeneration. In the last two decades, other stem/progenitor cell populations resident in the skeletal muscle interstitium have been identified as "collaborators" of satellite cells during regeneration. They also appear to have a key role in replacing skeletal muscle with adipose, fibrous, or bone tissue in pathological conditions. Here, we review the role and known functions of these different interstitial skeletal muscle cell types and discuss their role in skeletal muscle tissue homeostasis, regeneration, and disease, including their therapeutic potential for cell transplantation protocols.

  4. Murine macrophages response to iron.

    PubMed

    Polati, Rita; Castagna, Annalisa; Bossi, Alessandra Maria; Alberio, Tiziana; De Domenico, Ivana; Kaplan, Jerry; Timperio, Anna Maria; Zolla, Lello; Gevi, Federica; D'Alessandro, Angelo; Brunch, Ryan; Olivieri, Oliviero; Girelli, Domenico

    2012-12-05

    Macrophages play a critical role at the crossroad between iron metabolism and immunity, being able to store and recycle iron derived from the phagocytosis of senescent erythrocytes. The way by which macrophages manage non-heme iron at physiological concentration is still not fully understood. We investigated protein changes in mouse bone marrow macrophages incubated with ferric ammonium citrate (FAC 10 μM iron). Differentially expressed spots were identified by nano RP-HPLC-ESI-MS/MS. Transcriptomic, metabolomics and western immunoblotting analyses complemented the proteomic approach. Pattern analysis was also used for identifying networks of proteins involved in iron homeostasis. FAC treatment resulted in higher abundance of several proteins including ferritins, cytoskeleton related proteins, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) at the membrane level, vimentin, arginase, galectin-3 and macrophage migration inhibitory factor (MIF). Interestingly, GAPDH has been recently proposed to act as an alternative transferrin receptor for iron acquisition through internalization of the GAPDH-transferrin complex into the early endosomes. FAC treatment also induced the up-regulation of oxidative stress-related proteins (PRDX), which was further confirmed at the metabolic level (increase in GSSG, 8-isoprostane and pentose phosphate pathway intermediates) through mass spectrometry-based targeted metabolomics approaches. This study represents an example of the potential usefulness of "integarated omics" in the field of iron biology, especially for the elucidation of the molecular mechanisms controlling iron homeostasis in normal and disease conditions. This article is part of a Special Issue entitled: Integrated omics.

  5. Modulating macrophage response to biomaterials

    NASA Astrophysics Data System (ADS)

    Zaveri, Toral

    Macrophages recruited to the site of biomaterial implantation are the primary mediators of the chronic foreign body response to implanted materials. Since foreign body response limits performance and functional life of numerous implanted biomaterials/medical devices, various approaches have been investigated to modulate macrophage interactions with biomaterial surfaces to mitigate this response. In this work we have explored two independent approaches to modulate the macrophage inflammatory response to biomaterials. The first approach targets surface integrins, cell surface receptors that mediate cell adhesion to biomaterials through adhesive proteins spontaneously adsorbed on biomaterial surfaces. The second approach involves surface modification of biomaterials using nanotopographic features since nanotopography has been reported to modulate cell adhesion and viability in a cell type-dependent manner. More specifically, Zinc Oxide (ZnO) nanorod surface was investigated for its role in modulating macrophage adhesion and survival in vitro and foreign body response in vivo. For the first approach, we have investigated the role of integrin Mac-1 and RGD-binding integrins in the in-vivo osteolysis response and macrophage inflammatory processes of phagocytosis as well as inflammatory cytokine secretion in response to particulate biomaterials. We have also investigated the in vivo foreign body response (FBR) to subcutaneously implanted biomaterials by evaluating the thickness of fibrous capsule formed around the implants after 2 weeks of implantation. The role of Mac-1 integrin was isolated using a Mac-1 KO mouse and comparing it to a WT control. The role of RGD binding integrins in FBR was investigated by coating the implanted biomaterial with ELVAX(TM) polymer loaded with Echistatin which contains the RGD sequence. For the in-vivo osteolysis study and to study the in-vitro macrophage response to particulate biomaterials, we used the RGD peptide encapsulated in ELVAX

  6. Resident Care Guide. Third Edition.

    ERIC Educational Resources Information Center

    Woodbridge State School, NJ.

    The third edition of the Woodbridge State School Cottage Life Department Resident Care Guide is explained to be a developmental status scale devised in 1969 as part of a 5-year study for the purposes of measuring the entire population's self-help training abilities. The department is said to serve 954 residents; 424 are non-ambulatory and 530 are…

  7. Substance Abuse by Anesthesiology Residents.

    ERIC Educational Resources Information Center

    Lutsky, Irving; And Others

    1991-01-01

    The analysis of 183 responses to a survey of former anesthesiology residents of the Medical College of Wisconsin found that 29 had been self-administered problematic substance abusers during their residencies, 23 had been alcohol dependent, and 6 had been drug dependent. More than 85 percent of respondents considered the drug policy information…

  8. Residence Hall Seating That Works.

    ERIC Educational Resources Information Center

    Wiens, Janet

    2003-01-01

    Describes the seating chosen for residence halls at the Massachusetts Institute of Technology and the University of New England. The seating required depends on ergonomics, aesthetics, durability, cost, and code requirements. In addition, residence halls must have a range of seating types to accommodate various uses. (SLD)

  9. The Artist-in-Residence

    ERIC Educational Resources Information Center

    Hall, James W.

    1977-01-01

    Institutions are bringing the professional artist into their instructional and cultural environments through five approaches: concert performances, extended performances, master classes, part-time residencies, and full-time residencies. The effect of each program on the artist and the college or university is examined. (Author/LBH)

  10. Medical Residency Goes to School

    ERIC Educational Resources Information Center

    Boatright, Beth; Gallucci, Chrysan; Swanson, Judy; Van Lare, Michelle; Yoon, Irene

    2009-01-01

    The Highline School District, located roughly 10 miles south of Seattle, Washington, has begun to implement a residency model for professional learning. Like the medical model, current teachers often traveled from other schools to be "in residency" at a previously selected classroom for six half-day sessions during the 2005-06 school year. Some…

  11. Monocyte/macrophage-reactive monoclonal antibody Ki-M6 recognizes an intracytoplasmic antigen.

    PubMed Central

    Parwaresch, M. R.; Radzun, H. J.; Kreipe, H.; Hansmann, M. L.; Barth, J.

    1986-01-01

    A monoclonal antibody, termed Ki-M6, is described, which shows a restricted reactivity to cells of the monocyte/macrophage system. On light- and electron-microscopic immunoperoxidase staining Ki-M6 recognizes monocytes and the phagocytosing compartment of macrophages residing in different tissue sites; granulocytes and the so-called immune accessories of B- and T-cell immune response as closely monocyte/macrophage related cell populations do not reveal any reactivity. This is shown by comparison with the monoclonal antibodies Ki-M4 and Ki-M1 or OKT6 recognizing immune accessory cells by immunohistochemical methods. Ki-M6 binds to a lysosomal membrane-restricted antigen of 60,000 daltons without influencing significantly lysosome-related functions as far as the chemiluminescence response is concerned. Images Figure 2 Figure 4 Figure 1 Figure 3 Figure 6 PMID:3777131

  12. Mycobacterial escape from macrophage phagosomes to the cytoplasm represents an alternate adaptation mechanism

    PubMed Central

    Jamwal, Shilpa V.; Mehrotra, Parul; Singh, Archana; Siddiqui, Zaved; Basu, Atanu; Rao, Kanury V.S.

    2016-01-01

    Survival of Mycobacterium tuberculosis (Mtb) within the host macrophage is mediated through pathogen-dependent inhibition of phagosome-lysosome fusion, which enables bacteria to persist within the immature phagosomal compartment. By employing ultrastructural examination of different field isolates supported by biochemical analysis, we found that some of the Mtb strains were in fact poorly adapted for subsistence within endocytic vesicles of infected macrophages. Instead, through a mechanism involving activation of host cytosolic phospholipase A2, these bacteria rapidly escaped from phagosomes, and established residence in the cytoplasm of the host cell. Interestingly, by facilitating an enhanced suppression of host cellular autophagy, this translocation served as an alternate virulence acquisition mechanism. Thus, our studies reveal plasticity in the adaptation strategies employed by Mtb, for survival in the host macrophage. PMID:26980157

  13. Lineage-specific enhancers activate self-renewal genes in macrophages and embryonic stem cells

    PubMed Central

    Soucie, Erinn L.; Weng, Ziming; Geirsdóttir, Laufey; Molawi, Kaaweh; Maurizio, Julien; Fenouil, Romain; Mossadegh-Keller, Noushine; Gimenez, Gregory; VanHille, Laurent; Beniazza, Meryam; Favret, Jeremy; Berruyer, Carole; Perrin, Pierre; Hacohen, Nir; Andrau, J.-C.; Ferrier, Pierre; Dubreuil, Patrice; Sidow, Arend; Sieweke, Michael H.

    2016-01-01

    Differentiated macrophages can self-renew in tissues and expand long-term in culture, but the gene regulatory mechanisms that accomplish self-renewal in the differentiated state have remained unknown. Here we show that in mice, the transcription factors MafB and c-Maf repress a macrophage-specific enhancer repertoire associated with a gene network controlling self-renewal. Single cell analysis revealed that, in vivo, proliferating resident macrophages can access this network by transient down-regulation of Maf transcription factors. The network also controls embryonic stem cell self-renewal but is associated with distinct embryonic stem cell-specific enhancers. This indicates that distinct lineage-specific enhancer platforms regulate a shared network of genes that control self-renewal potential in both stem and mature cells. PMID:26797145

  14. Contrasting regulation of macrophage iron homeostasis in response to infection with Listeria monocytogenes depending on localization of bacteria.

    PubMed

    Haschka, David; Nairz, Manfred; Demetz, Egon; Wienerroither, Sebastian; Decker, Thomas; Weiss, Günter

    2015-06-01

    Due to its multiple roles for the proliferation and pathogenicity of many microbes on the one hand and via modulation of immune effector functions on the other hand the control over iron homeostasis is thought to play a decisive role in the course of infections. Diversion of cellular iron traffic is considered as an important defense mechanism of macrophages to reduce metal availability for intracellular bacteria residing in the phagosome. However, evidence is lacking whether such alterations of iron homeostasis also become evident upon infection with bacteria gaining access to the cytosol like Listeria monocytogenes. Here we show that infection of macrophages with L. monocytogenes triggers the expression of the major cellular iron exporter ferroportin1 and induces cellular iron egress. As the growth of Listeria within macrophages is promoted by iron, stimulation of ferroportin1 functionality limits the availability of the metal for Listeria residing in the cytoplasm, whereas ferroportin1 degradation upon hepcidin treatment increases intracellular bacterial growth. In parallel to an increase of ferroportin1 expression, infected macrophages induce anti-microbial immune effector mechanisms such as TNFα formation or NO expression which are aggravated upon iron deficiency. These adaptive changes of iron homeostasis and immune response pathways are only found in macrophages infected with Listeria which express listeriolysin O and are therefore able to escape from the phagosome to the cytoplasm. Listeriolysin O deficient Listeria which are restricted to the phagosome are even killed by excess iron which may be based on "iron intoxification" via macrophage radical formation, because iron supplementation in that setting is paralleled by increased ROS formation. Our results indicate that ferroportin1 mediated iron export is a nutritional immune effector pathway to control infection with Listeria residing in the cytoplasm, whereas a different strategy is observed in mutant

  15. The journey from stem cell to macrophage

    PubMed Central

    Pittet, Mikael J.; Nahrendorf, Matthias; Swirski, Filip K.

    2014-01-01

    Essential protectors against infection and injury, macrophages can also contribute to many common and fatal diseases. Here we discuss the mechanisms that control different types of macrophage activities in mice. We follow the cells’ maturational pathways over time and space, and elaborate on events that influence the type of macrophage eventually settling a particular destination. The nature of the precursor cells, developmental niches, tissues, environmental cues, and other connecting processes appear to contribute to the identity of macrophage type. Together, the spatial and developmental relationships of macrophages comprise a topo-ontogenic map that can guide our understanding of their biology. PMID:24673186

  16. Early resident-to-resident physics education in diagnostic radiology.

    PubMed

    Kansagra, Akash P

    2014-01-01

    The revised ABR board certification process has updated the method by which diagnostic radiology residents are evaluated for competency in clinical radiologic physics. In this work, the author reports the successful design and implementation of a resident-taught physics course consisting of 5 weekly, hour-long lectures intended for incoming first-year radiology residents in their first month of training. To the author's knowledge, this is the first description of a course designed to provide a very early framework for ongoing physics education throughout residency without increasing the didactic burden on faculty members. Twenty-six first-year residents spanning 2 academic years took the course and reported subjective improvement in their knowledge (90%) and interest (75%) in imaging physics and a high level of satisfaction with the use of senior residents as physics educators. Based on the success of this course and the minimal resources required for implementation, this work may serve as a blueprint for other radiology residency programs seeking to develop revised physics curricula.

  17. T3 Regulates a Human Macrophage-Derived TSH-β Splice Variant: Implications for Human Bone Biology.

    PubMed

    Baliram, R; Latif, R; Morshed, S A; Zaidi, M; Davies, T F

    2016-09-01

    TSH and thyroid hormones (T3 and T4) are intimately involved in bone biology. We have previously reported the presence of a murine TSH-β splice variant (TSH-βv) expressed specifically in bone marrow-derived macrophages and that exerted an osteoprotective effect by inducing osteoblastogenesis. To extend this observation and its relevance to human bone biology, we set out to identify and characterize a TSH-β variant in human macrophages. Real-time PCR analyses using human TSH-β-specific primers identified a 364-bp product in macrophages, bone marrow, and peripheral blood mononuclear cells that was sequence verified and was homologous to a human TSH-βv previously reported. We then examined TSH-βv regulation using the THP-1 human monocyte cell line matured into macrophages. After 4 days, 46.1% of the THP-1 cells expressed the macrophage markers CD-14 and macrophage colony-stimulating factor and exhibited typical morphological characteristics of macrophages. Real-time PCR analyses of these cells treated in a dose-dependent manner with T3 showed a 14-fold induction of human TSH-βv mRNA and variant protein. Furthermore, these human TSH-βv-positive cells, induced by T3 exposure, had categorized into both M1 and M2 macrophage phenotypes as evidenced by the expression of macrophage colony-stimulating factor for M1 and CCL-22 for M2. These data indicate that in hyperthyroidism, bone marrow resident macrophages have the potential to exert enhanced osteoprotective effects by oversecreting human TSH-βv, which may exert its local osteoprotective role via osteoblast and osteoclast TSH receptors.

  18. Hepatocellular carcinoma is accelerated by NASH involving M2 macrophage polarization mediated by hif-1αinduced IL-10.

    PubMed

    Ambade, Aditya; Satishchandran, Abhishek; Saha, Banishree; Gyongyosi, Benedek; Lowe, Patrick; Kodys, Karen; Catalano, Donna; Szabo, Gyongyi

    2016-01-01

    Obesity-related inflammation promotes cancer development. Tissue resident macrophages affect tumor progression and the tumor micro-environment favors polarization into alternatively activated macrophages (M2) that facilitate tumor invasiveness. Here, we dissected the role of western diet-induced NASH in inducing macrophage polarization in a carcinogen initiated model of hepatocellular carcinoma (HCC). Adult C57BL/6 male mice received diethyl nitrosamine (DEN) followed by 24 weeks of high fat-high cholesterol-high sugar diet (HF-HC-HSD). We assessed liver MRI and histology, serum ALT, AFP, liver triglycerides, and cytokines. Macrophage polarization was determined by IL-12/TNFα (M1) and CD163/CD206 (M2) expression using flow cytometry. Role of hif-1α-induced IL-10 was dissected in hepatocyte specific hif-1αKO and hif-1αdPA (over-expression) mice. The western diet-induced features of NASH and accelerated HCC development after carcinogen exposure. Liver fibrosis and serum AFP were significantly increased in DEN + HF-HC-HSD mice compared to controls. Western diet resulted in macrophage (F4/80(+)CD11b(+)) infiltration to liver and DEN + HF-HC-HSD mice showed preferential increase in M2 macrophages. Isolated hepatocytes from western diet fed mice showed significant upregulation of the hypoxia-inducible transcription factor, hif-1α, and livers from hif-1α over-expressing mice had increased proportion of M2 macrophages. Primary hepatocytes from wild-type mice treated with DEN and palmitic acid in vitro showed activation of hif-1α and induction of IL-10, a M2 polarizing cytokine. IL-10 neutralization in hepatocyte-derived culture supernatant prevented M2 macrophage polarization and silencing hif-1α in macrophages blocked their M2 polarization. Therefore, our data demonstrate that NASH accelerates HCC progression via upregulation of hif-1α mediated IL-10 polarizing M2 macrophages.

  19. Identification of polarized macrophage subsets in zebrafish.

    PubMed

    Nguyen-Chi, Mai; Laplace-Builhe, Béryl; Travnickova, Jana; Luz-Crawford, Patricia; Tejedor, Gautier; Phan, Quang Tien; Duroux-Richard, Isabelle; Levraud, Jean-Pierre; Kissa, Karima; Lutfalla, Georges; Jorgensen, Christian; Djouad, Farida

    2015-07-08

    While the mammalian macrophage phenotypes have been intensively studied in vitro, the dynamic of their phenotypic polarization has never been investigated in live vertebrates. We used the zebrafish as a live model to identify and trail macrophage subtypes. We generated a transgenic line whose macrophages expressing tumour necrosis factor alpha (tnfa), a key feature of classically activated (M1) macrophages, express fluorescent proteins Tg(mpeg1:mCherryF/tnfa:eGFP-F). Using 4D-confocal microscopy, we showed that both aseptic wounding and Escherichia coli inoculation triggered macrophage recruitment, some of which started to express tnfa. RT-qPCR on Fluorescence Activated Cell Sorting (FACS)-sorted tnfa(+) and tnfa(-) macrophages showed that they, respectively, expressed M1 and alternatively activated (M2) mammalian markers. Fate tracing of tnfa(+) macrophages during the time-course of inflammation demonstrated that pro-inflammatory macrophages converted into M2-like phenotype during the resolution step. Our results reveal the diversity and plasticity of zebrafish macrophage subsets and underline the similarities with mammalian macrophages proposing a new system to study macrophage functional dynamic.

  20. Identification of polarized macrophage subsets in zebrafish

    PubMed Central

    Nguyen-Chi, Mai; Laplace-Builhe, Béryl; Travnickova, Jana; Luz-Crawford, Patricia; Tejedor, Gautier; Phan, Quang Tien; Duroux-Richard, Isabelle; Levraud, Jean-Pierre; Kissa, Karima; Lutfalla, Georges

    2015-01-01

    While the mammalian macrophage phenotypes have been intensively studied in vitro, the dynamic of their phenotypic polarization has never been investigated in live vertebrates. We used the zebrafish as a live model to identify and trail macrophage subtypes. We generated a transgenic line whose macrophages expressing tumour necrosis factor alpha (tnfa), a key feature of classically activated (M1) macrophages, express fluorescent proteins Tg(mpeg1:mCherryF/tnfa:eGFP-F). Using 4D-confocal microscopy, we showed that both aseptic wounding and Escherichia coli inoculation triggered macrophage recruitment, some of which started to express tnfa. RT-qPCR on Fluorescence Activated Cell Sorting (FACS)-sorted tnfa+ and tnfa− macrophages showed that they, respectively, expressed M1 and alternatively activated (M2) mammalian markers. Fate tracing of tnfa+ macrophages during the time-course of inflammation demonstrated that pro-inflammatory macrophages converted into M2-like phenotype during the resolution step. Our results reveal the diversity and plasticity of zebrafish macrophage subsets and underline the similarities with mammalian macrophages proposing a new system to study macrophage functional dynamic. DOI: http://dx.doi.org/10.7554/eLife.07288.001 PMID:26154973

  1. Inhibiting macrophage proliferation suppresses atherosclerotic plaque inflammation.

    PubMed

    Tang, Jun; Lobatto, Mark E; Hassing, Laurien; van der Staay, Susanne; van Rijs, Sarian M; Calcagno, Claudia; Braza, Mounia S; Baxter, Samantha; Fay, Francois; Sanchez-Gaytan, Brenda L; Duivenvoorden, Raphaël; Sager, Hendrik; Astudillo, Yaritzy M; Leong, Wei; Ramachandran, Sarayu; Storm, Gert; Pérez-Medina, Carlos; Reiner, Thomas; Cormode, David P; Strijkers, Gustav J; Stroes, Erik S G; Swirski, Filip K; Nahrendorf, Matthias; Fisher, Edward A; Fayad, Zahi A; Mulder, Willem J M

    2015-04-01

    Inflammation drives atherosclerotic plaque progression and rupture, and is a compelling therapeutic target. Consequently, attenuating inflammation by reducing local macrophage accumulation is an appealing approach. This can potentially be accomplished by either blocking blood monocyte recruitment to the plaque or increasing macrophage apoptosis and emigration. Because macrophage proliferation was recently shown to dominate macrophage accumulation in advanced plaques, locally inhibiting macrophage proliferation may reduce plaque inflammation and produce long-term therapeutic benefits. To test this hypothesis, we used nanoparticle-based delivery of simvastatin to inhibit plaque macrophage proliferation in apolipoprotein E deficient mice (Apoe(-/-) ) with advanced atherosclerotic plaques. This resulted in rapid reduction of plaque inflammation and favorable phenotype remodeling. We then combined this short-term nanoparticle intervention with an eight-week oral statin treatment, and this regimen rapidly reduced and continuously suppressed plaque inflammation. Our results demonstrate that pharmacologically inhibiting local macrophage proliferation can effectively treat inflammation in atherosclerosis.

  2. Inhibiting macrophage proliferation suppresses atherosclerotic plaque inflammation

    PubMed Central

    Tang, Jun; Lobatto, Mark E.; Hassing, Laurien; van der Staay, Susanne; van Rijs, Sarian M.; Calcagno, Claudia; Braza, Mounia S.; Baxter, Samantha; Fay, Francois; Sanchez-Gaytan, Brenda L.; Duivenvoorden, Raphaël; Sager, Hendrik B.; Astudillo, Yaritzy M.; Leong, Wei; Ramachandran, Sarayu; Storm, Gert; Pérez-Medina, Carlos; Reiner, Thomas; Cormode, David P.; Strijkers, Gustav J.; Stroes, Erik S. G.; Swirski, Filip K.; Nahrendorf, Matthias; Fisher, Edward A.; Fayad, Zahi A.; Mulder, Willem J. M.

    2015-01-01

    Inflammation drives atherosclerotic plaque progression and rupture, and is a compelling therapeutic target. Consequently, attenuating inflammation by reducing local macrophage accumulation is an appealing approach. This can potentially be accomplished by either blocking blood monocyte recruitment to the plaque or increasing macrophage apoptosis and emigration. Because macrophage proliferation was recently shown to dominate macrophage accumulation in advanced plaques, locally inhibiting macrophage proliferation may reduce plaque inflammation and produce long-term therapeutic benefits. To test this hypothesis, we used nanoparticle-based delivery of simvastatin to inhibit plaque macrophage proliferation in apolipoprotein E–deficient mice (Apoe−/−) with advanced atherosclerotic plaques. This resulted in the rapid reduction of plaque inflammation and favorable phenotype remodeling. We then combined this short-term nanoparticle intervention with an 8-week oral statin treatment, and this regimen rapidly reduced and continuously suppressed plaque inflammation. Our results demonstrate that pharmacologically inhibiting local macrophage proliferation can effectively treat inflammation in atherosclerosis. PMID:26295063

  3. Differential effects of chronic monocyte depletion on macrophage populations

    SciTech Connect

    Volkman, A.; Chang, N.C.; Strausbauch, P.H.; Morahan, P.S.

    1983-09-01

    The administration of the bone-seeking isotope, /sup 89/Sr, to mice results in severe monocytopenia without any apparent effect on the numbers of resident peritoneal macrophages (M luminal diameter). An explanation for this dichotomy was sought by determining whether the residual blood monocytes were still an effective source of M luminal diameter after /sup 89/Sr treatment. Stem cell enumeration showed that a 90% fall in bone marrow macrophage colony-forming cells after /sup 89/Sr was accompanied by a 10-fold rise in splenic M-CFC. Splenectomy performed before /sup 89/Sr treatment, however, resulted in little additional monocytopenia and had no affect on the numbers of resident peritoneal M luminal diameter even when sampling was extended to 31 days, an interval beyond the accepted half-time for peritoneal M luminal diameter. Intraperitoneal injections of thioglycollate or Corynebacterium parvum elicited few or no monocyte-M luminal diameter during respective intervals of 4 and 7 days. Elicitation with thioglycollate was attempted in tritiated thymidine-labeled mice 26 days after /sup 89/Sr. Four days later only a 2-fold increase in labeled peritoneal M luminal diameter was found in the /sup 89/Sr-treated mice compared with a 150-fold increase in the controls. Studies of the ectoenzymes 5'-nucleotidase, alkaline phosphodiesterase I, and leucine aminopeptidase in such elicitation experiments suggested that the observed changes in activities reflected the direct stimulation of resident M luminal diameter rather than monocyte immigration. Overall, the results indicate that treatment with /sup 89/Sr distinguishes two large populations of M luminal diameter on the basis of their dependence on bone marrow. M luminal diameter of inflammation reflect the monocytopenia and are severely and rapidly depleted by such treatment.

  4. Extracellular matrix components direct porcine muscle stem cell behavior

    SciTech Connect

    Wilschut, Karlijn J.; Haagsman, Henk P.; Roelen, Bernard A.J.

    2010-02-01

    In muscle tissue, extracellular matrix proteins, together with the vasculature system, muscle-residence cells and muscle fibers, create the niche for muscle stem cells. The niche is important in controlling proliferation and directing differentiation of muscle stem cells to sustain muscle tissue. Mimicking the extracellular muscle environment improves tools exploring the behavior of primary muscle cells. Optimizing cell culture conditions to maintain muscle commitment is important in stem cell-based studies concerning toxicology screening, ex vivo skeletal muscle tissue engineering and in the enhancement of clinical efficiency. We used the muscle extracellular matrix proteins collagen type I, fibronectin, laminin, and also gelatin and Matrigel as surface coatings of tissue culture plastic to resemble the muscle extracellular matrix. Several important factors that determine myogenic commitment of the primary muscle cells were characterized by quantitative real-time RT-PCR and immunofluorescence. Adhesion of high PAX7 expressing satellite cells was improved if the cells were cultured on fibronectin or laminin coatings. Cells cultured on Matrigel and laminin coatings showed dominant integrin expression levels and exhibited an activated Wnt pathway. Under these conditions both stem cell proliferation and myogenic differentiation capacity were superior if compared to cells cultured on collagen type I, fibronectin and gelatin. In conclusion, Matrigel and laminin are the preferred coatings to sustain the proliferation and myogenic differentiation capacity of the primary porcine muscle stem cells, when cells are removed from their natural environment for in vitro culture.

  5. Applying Expectancy Theory to residency training: proposing opportunities to understand resident motivation and enhance residency training.

    PubMed

    Shweiki, Ehyal; Martin, Niels D; Beekley, Alec C; Jenoff, Jay S; Koenig, George J; Kaulback, Kris R; Lindenbaum, Gary A; Patel, Pankaj H; Rosen, Matthew M; Weinstein, Michael S; Zubair, Muhammad H; Cohen, Murray J

    2015-01-01

    Medical resident education in the United States has been a matter of national priority for decades, exemplified initially through the Liaison Committee for Graduate Medical Education and then superseded by the Accreditation Council for Graduate Medical Education. A recent Special Report in the New England Journal of Medicine, however, has described resident educational programs to date as prescriptive, noting an absence of innovation in education. Current aims of contemporary medical resident education are thus being directed at ensuring quality in learning as well as in patient care. Achievement and work-motivation theories attempt to explain people's choice, performance, and persistence in tasks. Expectancy Theory as one such theory was reviewed in detail, appearing particularly applicable to surgical residency training. Correlations between Expectancy Theory as a work-motivation theory and residency education were explored. Understanding achievement and work-motivation theories affords an opportunity to gain insight into resident motivation in training. The application of Expectancy Theory in particular provides an innovative perspective into residency education. Afforded are opportunities to promote the development of programmatic methods facilitating surgical resident motivation in education.

  6. Function of microglia and macrophages in secondary damage after spinal cord injury

    PubMed Central

    Zhou, Xiang; He, Xijing; Ren, Yi

    2014-01-01

    Spinal cord injury (SCI) is a devastating type of neurological trauma with limited therapeutic opportunities. The pathophysiology of SCI involves primary and secondary mechanisms of injury. Among all the secondary injury mechanisms, the inflammatory response is the major contributor and results in expansion of the lesion and further loss of neurologic function. Meanwhile, the inflammation directly and indirectly dominates the outcomes of SCI, including not only pain and motor dysfunction, but also preventingneuronal regeneration. Microglia and macrophages play very important roles in secondary injury. Microglia reside in spinal parenchyma and survey the microenvironment through the signals of injury or infection. Macrophages are derived from monocytes recruited to injured sites from the peripheral circulation. Activated resident microglia and monocyte-derived macrophages induce and magnify immune and inflammatory responses not only by means of their secretory moleculesand phagocytosis, but also through their influence on astrocytes, oligodendrocytes and demyelination. In this review, we focus on the roles of microglia and macrophages in secondary injury and how they contribute to the sequelae of SCI. PMID:25422640

  7. Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis

    PubMed Central

    Yona, Simon; Kim, Ki-Wook; Wolf, Yochai; Mildner, Alexander; Varol, Diana; Breker, Michal; Strauss-Ayali, Dalit; Viukov, Sergey; Guilliams, Martin; Misharin, Alexander; Hume, David A.; Perlman, Harris; Malissen, Bernard; Zelzer, Elazar; Jung, Steffen

    2013-01-01

    SUMMARY Mononuclear phagocytes, including monocytes, macrophages and dendritic cells, contribute to tissue integrity, as well as innate and adaptive immune defense. Emerging evidence for labour division indicates that manipulation of these cells could bear therapeutic potential. However, specific ontogenies of individual populations and the overall functional organisation of the cellular network are not well-defined. Here we report a fate mapping study of the murine monocyte and macrophage compartment taking advantage of constitutive and conditional CX3CR1 promoter-driven Cre recombinase expression. We have demonstrated that major tissue resident macrophage populations, including liver Kupffer cells, lung alveolar, splenic and peritoneal macrophages, are established prior to birth and maintain themselves subsequently during adulthood independent of replenishment by blood monocytes. Furthermore, we have established that the short-lived Ly6C+ monocytes constitute obligatory steady state precursors of blood-resident Ly6C− cells and that the abundance of Ly6C+ blood monocytes dynamically controls the circulation life span of their progeny. PMID:23273845

  8. Adipocyte SIRT1 controls systemic insulin sensitivity by modulating macrophages in adipose tissue.

    PubMed

    Hui, Xiaoyan; Zhang, Mingliang; Gu, Ping; Li, Kuai; Gao, Yuan; Wu, Donghai; Wang, Yu; Xu, Aimin

    2017-03-07

    Adipose tissue inflammation, characterized by augmented infiltration and altered polarization of macrophages, contributes to insulin resistance and its associated metabolic diseases. The NAD(+)-dependent deacetylase SIRT1 serves as a guardian against metabolic disorders in multiple tissues. To dissect the roles of SIRT1 in adipose tissues, metabolic phenotypes of mice with selective ablation of SIRT1 in adipocytes and myeloid cells were monitored. Compared to myeloid-specific SIRT1 depletion, mice with adipocyte-selective deletion of SIRT1 are more susceptible to diet-induced insulin resistance. The phenotypic changes in adipocyte-selective SIRT1 knockout mice are associated with an increased number of adipose-resident macrophages and their polarization toward the pro-inflammatory M1 subtype. Mechanistically, SIRT1 in adipocytes modulates expression and secretion of several adipokines, including adiponectin, MCP-1, and interleukin 4, which in turn alters recruitment and polarization of the macrophages in adipose tissues. In adipocytes, SIRT1 deacetylates the transcription factor NFATc1 and thereby enhances the binding of NFATc1 to the Il4 gene promoter. These findings suggest that adipocyte SIRT1 controls systemic glucose homeostasis and insulin sensitivity via the cross talk with adipose-resident macrophages.

  9. Macrophage-mediated inflammatory response decreases mycobacterial survival in mouse MSCs by augmenting NO production

    PubMed Central

    Yang, Kun; Wu, Yongjian; Xie, Heping; Li, Miao; Ming, Siqi; Li, Liyan; Li, Meiyu; Wu, Minhao; Gong, Sitang; Huang, Xi

    2016-01-01

    Mycobacterium tuberculosis (MTB) is a hard-to-eradicate intracellular microbe, which escapes host immune attack during latent infection. Recent studies reveal that mesenchymal stem cells (MSCs) provide a protective niche for MTB to maintain latency. However, the regulation of mycobacterial residency in MSCs in the infectious microenvironment remains largely unknown. Here, we found that macrophage-mediated inflammatory response during MTB infection facilitated the clearance of bacilli residing in mouse MSCs. Higher inducible nitric oxide synthase (iNOS) expression and nitric oxide (NO) production were observed in mouse MSCs under macrophage-mediated inflammatory circumstance. Blocking NO production in MSCs increased the survival of intracellular mycobacteria, indicating NO-mediated antimycobacterial activity. Moreover, both nuclear factor κB (NF-κB) and Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathways were involved in iNOS expression and NO production in inflammatory microenvironment. Furthermore, pro-inflammatory cytokine interleukin-1β could trigger NO production in MSCs and exert anti-mycobacterial activity via NF-κB signaling pathway. Neutralization of interleukin-1β in macrophage-mediated inflammatory microenvironment dampened the ability of mouse MSCs to produce NO. Together, our findings demonstrated that macrophage-mediated inflammatory response during mycobacterial infection promotes the clearance of bacilli in mouse MSCs by increasing NO production, which may provide a better understanding of latent MTB infection. PMID:27251437

  10. Learning styles of orthodontic residents.

    PubMed

    Hughes, Janeen M; Fallis, Drew W; Peel, Jennifer L; Murchison, David F

    2009-03-01

    Significant challenges face many orthodontic residency programs, particularly a shortage of full-time experienced faculty members. Due to this shortage, it is critical that program directors design comprehensive curricula that incorporate the most effective and efficient teaching methods. It is theorized that teaching effectiveness and efficiency are optimized when the course design and content closely match students' learning preferences. This survey study was designed to distinguish the learning preferences of orthodontic residents utilizing Felder and Soloman's Index of Learning Styles, which assesses student learning preferences in four dimensions using dichotomous scales, thereby providing insight into how teaching strategies can best be structured. As a secondary focus, additional questions on the survey were asked to gain information about residents' access to the Internet and comfort level with online learning so as to address acceptance of web-based courses in response to the shortage of full-time faculty members. Orthodontic residents, contacted via email, were requested to complete an online survey; 261 responses were collected. The results indicate that orthodontic residents are highly visual learners and show a preference for sensing and sequential learning strategies. In terms of information technology, the residents are comfortable with and have adequate access to current technological assets; therefore, they may be well suited for inclusion of computer-based teaching modules and other multimedia devices in their residency curriculum.

  11. DAP12 expression in lung macrophages mediates ischemia reperfusion injury by promoting neutrophil extravasation

    PubMed Central

    Spahn, Jessica H.; Li, Wenjun; Bribriesco, Alejandro C.; Liu, Jie; Shen, Hua; Ibricevic, Aida; Pan, Jiehong; Zinselmeyer, Bernd H.; Brody, Steven L.; Goldstein, Daniel R.; Krupnick, Alexander S.; Gelman, Andrew E.; Miller, Mark J.; Kreisel, Daniel

    2015-01-01

    Neutrophils are critical mediators of innate immune responses and contribute to tissue injury. However, immune pathways that regulate neutrophil recruitment to injured tissues during noninfectious inflammation remain poorly understood. DAP12 is a cell-membrane associated protein that is expressed in myeloid cells and can either augment or dampen innate inflammatory responses during infections. To elucidate the role of DAP12 in pulmonary ischemia-reperfusion injury, we took advantage of a clinically relevant mouse model of transplant-mediated lung ischemia reperfusion injury. This technique allowed us to dissect the importance of DAP12 in tissue-resident cells and those that infiltrate injured tissue from the periphery during noninfectious inflammation. Macrophages in both mouse and human lungs that have been subjected to cold ischemic storage express DAP12. We found that donor, but not recipient deficiency in DAP12 protected against pulmonary ischemia reperfusion injury. Analysis of the immune response showed that DAP12 promotes the survival of tissue-resident alveolar macrophages and contributes to local production of neutrophil chemoattractants. Intravital imaging demonstrated a transendothelial migration defect into DAP12-deficient lungs, which can be rescued by local administration of the neutrophil chemokine CXCL2. We have uncovered a previously unrecognized role for DAP12 expression in tissue-resident alveolar macrophages in mediating acute noninfectious tissue injury through regulation of neutrophil trafficking. PMID:25762783

  12. Muscle strain (image)

    MedlinePlus

    A muscle strain is the stretching or tearing of muscle fibers. A muscle strain can be caused by sports, exercise, a ... something that is too heavy. Symptoms of a muscle strain include pain, tightness, swelling, tenderness, and the ...

  13. Dual origin of mouse spleen macrophages

    PubMed Central

    1984-01-01

    The present study concerns the isolation, characterization, origin, and kinetics of spleen macrophages. The spleen was first perfused in situ to remove monocytes from the vascular bed and then dissected and treated with collagenase. The macrophages in the cell suspension thus obtained were characterized morphologically and cytochemically and then quantitated. The spleen cell suspension was incubated for 24 h in Leighton tubes to obtain an enriched glass-adherent population of macrophages for characterization and [3H]thymidine-labeling studies. Almost all of the adhering macrophages were esterase positive, had Fc and C3b receptors, and ingested EIgG and opsonized bacteria. In vitro labeling with [3H]thymidine showed that approximately 5% of the mononuclear phagocytes in the spleen synthesize DNA and must be considered to be dividing cells. The course of the number of labeled monocytes and macrophages after a single injection of [3H]thymidine indicates migration of monocytes into the spleen, where they become macrophages. Calculation of the influx of monocytes into the spleen and of the local production of macrophages by DNA-synthesizing mononuclear phagocytes showed that under steady-state conditions, 55% of the population of spleen macrophages is supplied by monocyte influx and 45% by local production. This means that there is a dual origin of spleen macrophages. The mean turnover time calculated with the value for the efflux of spleen macrophages is 6.0 d. PMID:6491600

  14. The influence of aging and estradiol to progesterone ratio on rat macrophage phenotypic profile and NO and TNF-α production.

    PubMed

    Dimitrijević, Mirjana; Stanojević, Stanislava; Kuštrimović, Nataša; Mitić, Katarina; Vujić, Vesna; Aleksić, Iva; Radojević, Katarina; Leposavić, Gordana

    2013-11-01

    The phenotype and function of tissue macrophages substantially depend on the cellular milieu and biological effector molecules, such as steroid hormones, to which they are exposed. Furthermore, in female rats, aging is associated with the altered macrophage functioning and the increased estrogen level is followed by a decrease in that of progesterone. Therefore, the present study aimed to investigate the influence of estradiol/progesterone balance on rat macrophage function and phenotype throughout whole adult lifespan. We ovariectomized rats at the late prepubertal age or at the very end of reproductive lifespan, and examined the expression of ED2 (CD163, a marker of mature resident macrophages related to secretion of inflammatory mediators) on peritoneal macrophages and their ability to produce TNF-α and NO upon LPS-stimulation at different age points. In addition, to delineate direct and indirect effects of estrogen, we assessed the in vitro influence of different concentrations of 17β-estradiol on LPS-induced macrophage TNF-α and NO production. Results showed that: (a) the low frequency of ED2(high) cells amongst peritoneal macrophages of aged rats was accompanied with the reduced TNF-α, but not NO production; (b) estradiol level gradually increased following ovariectomy; (c) macrophage ED2 expression and TNF-α production were dependent on estradiol/progesterone balance and they changed in the same direction; (d) changes in estradiol/progesterone balance differentially affected macrophages TNF-α and NO production; and (e) estradiol exerted pro-inflammatory and anti-inflammatory effects on macrophages in vivo and in vitro, respectively. Overall, our study discloses that estradiol/progesterone balance contributes to the fine-tuning of rat macrophage secretory capacity, and adds to a better understanding of the ovarian steroid hormone role in the regulation of macrophage function, and its significance for the age-associated changes in innate immunity.

  15. Macrophage Biochemistry, Activation and Function

    DTIC Science & Technology

    1981-01-01

    glucoeidase +8 . . Sulfatase c +8 Modified from Morahan, 1980. b(+)Exhibit@ activity; (-) lacks activity; (+) weak or marginal activity. ’References: (1...endoplasmic reticulum enzymes, sulfatase c and alkaline a-glucosidase. Dissociation of the lysosomal enzyme patterns from sulfatase c and alkaline r...1974; Beaufay et al., 1974). Peritoneal macrophages are deficient or contain inauf- • -𔃼 :’- 41 ficient quantities of the classical constituents to be

  16. Targeted depletion of tumour-associated macrophages by an alendronate-glucomannan conjugate for cancer immunotherapy.

    PubMed

    Zhan, Xiudan; Jia, Lixin; Niu, Yiming; Qi, Haixia; Chen, Xiuping; Zhang, Qingwen; Zhang, Junfeng; Wang, Yitao; Dong, Lei; Wang, Chunming

    2014-12-01

    Tumour-associated macrophages (TAMs) are a set of macrophages residing in the tumour microenvironment. They play essential roles in mediating tumour angiogenesis, metastasis and immune evasion. Delivery of therapeutic agents to eliminate TAMs can be a promising strategy for cancer immunotherapy but an efficient vehicle to target these cells is still in pressing need. In this study, we developed a bisphosphonate-glucomannan conjugate that could efficiently target and specifically eliminate TAMs in the tumour microenvironment. We employed the polysaccharide from Bletilla striata (BSP), a glucomannan affinitive for macrophages that express abundant mannose receptors, to conjugate alendronate (ALN), a bisphosphonate compound with in vitro macrophage-inhibiting activities. In both in vitro and in vivo tests, the prepared ALN-BSP conjugate could preferentially accumulate in macrophages and induced them into apoptosis. In the subcutaneous S180 tumour-bearing mice model, the treatment using ALN-BSP effectively eliminated TAMs, remarkably inhibited angiogenesis, recovered local immune surveillance, and eventually suppressed tumour progression, without eliciting any unwanted effect such as systematic immune response. Interestingly, ALN alone failed to exhibit any anti-TAM activity in vivo, probably because this compound was susceptible to the mildly acidic tumour microenvironment. Taken together, these results demonstrate the potential of ALN-BSP as a safe and efficient tool targeted at direct depletion of TAMs for cancer immunotherapy.

  17. Infiltrating macrophages are key to the development of seizures following virus infection.

    PubMed

    Cusick, Matthew F; Libbey, Jane E; Patel, Dipan C; Doty, Daniel J; Fujinami, Robert S

    2013-02-01

    Viral infections of the central nervous system (CNS) can trigger an antiviral immune response, which initiates an inflammatory cascade to control viral replication and dissemination. The extent of the proinflammatory response in the CNS and the timing of the release of proinflammatory cytokines can lead to neuronal excitability. Tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6), two proinflammatory cytokines, have been linked to the development of acute seizures in Theiler's murine encephalomyelitis virus-induced encephalitis. It is unclear the extent to which the infiltrating macrophages versus resident CNS cells, such as microglia, contribute to acute seizures, as both cell types produce TNF-α and IL-6. In this study, we show that following infection a significantly higher number of microglia produced TNF-α than did infiltrating macrophages. In contrast, infiltrating macrophages produced significantly more IL-6. Mice treated with minocycline or wogonin, both of which limit infiltration of immune cells into the CNS and their activation, had significantly fewer macrophages infiltrating the brain, and significantly fewer mice had seizures. Therefore, our studies implicate infiltrating macrophages as an important source of IL-6 that contributes to the development of acute seizures.

  18. IRF5 governs liver macrophage activation that promotes hepatic fibrosis in mice and humans

    PubMed Central

    Alzaid, Fawaz; Lagadec, Floriane; Albuquerque, Miguel; Ballaire, Raphaëlle; Orliaguet, Lucie; Hainault, Isabelle; Blugeon, Corinne; Lemoine, Sophie; Lehuen, Agnès; Saliba, David G.; Udalova, Irina A.; Paradis, Valérie; Foufelle, Fabienne

    2016-01-01

    Hepatic fibrosis arises from inflammation in the liver initiated by resident macrophage activation and massive leukocyte accumulation. Hepatic macrophages hold a central position in maintaining homeostasis in the liver and in the pathogenesis of acute and chronic liver injury linked to fibrogenesis. Interferon regulatory factor 5 (IRF5) has recently emerged as an important proinflammatory transcription factor involved in macrophage activation under acute and chronic inflammation. Here, we revealed that IRF5 is significantly induced in liver macrophages from human subjects developing liver fibrosis from nonalcoholic fatty liver disease or hepatitis C virus infection. Furthermore, IRF5 expression positively correlated with clinical markers of liver damage, such as plasma transaminase and bilirubin levels. Interestingly, mice lacking IRF5 in myeloid cells (MKO) were protected from hepatic fibrosis induced by metabolic or toxic stresses. Transcriptional reprogramming of macrophages lacking IRF5 was characterized by immunosuppressive and antiapoptotic properties. Consequently, IRF5 MKO mice respond to hepatocellular stress by promoting hepatocyte survival, leading to complete protection from hepatic fibrogenesis. Our findings reveal a regulatory network, governed by IRF5, that mediates hepatocyte death and liver fibrosis in mice and humans. Therefore, modulating IRF5 function may be an attractive approach to experimental therapeutics in fibroinflammatory liver disease. PMID:27942586

  19. Human Cord Blood and Bone Marrow CD34+ Cells Generate Macrophages That Support Erythroid Islands

    PubMed Central

    Belay, Eyayu; Hayes, Brian J.; Blau, C. Anthony; Torok-Storb, Beverly

    2017-01-01

    Recently, we developed a small molecule responsive hyperactive Mpl-based Cell Growth Switch (CGS) that drives erythropoiesis associated with macrophages in the absence of exogenous cytokines. Here, we compare the physical, cellular and molecular interaction between the macrophages and erythroid cells in CGS expanded CD34+ cells harvested from cord blood, marrow or G-CSF-mobilized peripheral blood. Results indicated that macrophage based erythroid islands could be generated from cord blood and marrow CD34+ cells but not from G-CSF-mobilized CD34+ cells. Additional studies suggest that the deficiency resides with the G-CSF-mobilized CD34+ derived monocytes. Gene expression and proteomics studies of the in vitro generated erythroid islands detected the expression of erythroblast macrophage protein (EMP), intercellular adhesion molecule 4 (ICAM-4), CD163 and DNASE2. 78% of the erythroblasts in contact with macrophages reached the pre reticulocyte orthochromatic stage of differentiation within 14 days of culture. The addition of conditioned medium from cultures of CD146+ marrow fibroblasts resulted in a 700-fold increase in total cell number and a 90-fold increase in erythroid cell number. This novel CD34+ cell derived erythroid island may serve as a platform to explore the molecular basis of red cell maturation and production under normal, stress and pathological conditions. PMID:28135323

  20. Infiltrating Macrophages Are Key to the Development of Seizures following Virus Infection

    PubMed Central

    Cusick, Matthew F.; Libbey, Jane E.; Patel, Dipan C.; Doty, Daniel J.

    2013-01-01

    Viral infections of the central nervous system (CNS) can trigger an antiviral immune response, which initiates an inflammatory cascade to control viral replication and dissemination. The extent of the proinflammatory response in the CNS and the timing of the release of proinflammatory cytokines can lead to neuronal excitability. Tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6), two proinflammatory cytokines, have been linked to the development of acute seizures in Theiler's murine encephalomyelitis virus-induced encephalitis. It is unclear the extent to which the infiltrating macrophages versus resident CNS cells, such as microglia, contribute to acute seizures, as both cell types produce TNF-α and IL-6. In this study, we show that following infection a significantly higher number of microglia produced TNF-α than did infiltrating macrophages. In contrast, infiltrating macrophages produced significantly more IL-6. Mice treated with minocycline or wogonin, both of which limit infiltration of immune cells into the CNS and their activation, had significantly fewer macrophages infiltrating the brain, and significantly fewer mice had seizures. Therefore, our studies implicate infiltrating macrophages as an important source of IL-6 that contributes to the development of acute seizures. PMID:23236075

  1. The Cannabinoid Receptor 2 Protects Against Alcoholic Liver Disease Via a Macrophage Autophagy-Dependent Pathway.

    PubMed

    Denaës, Timothé; Lodder, Jasper; Chobert, Marie-Noële; Ruiz, Isaac; Pawlotsky, Jean-Michel; Lotersztajn, Sophie; Teixeira-Clerc, Fatima

    2016-06-27

    Kupffer cells, the resident macrophages of the liver, play a major role in the pathogenesis of alcoholic liver disease. We have previously demonstrated that CB2 receptor protects against alcoholic liver disease by inhibiting alcohol-induced inflammation and steatosis via the regulation of Kupffer cell activation. Here, we explored the mechanism underlying these effects and hypothesized that the anti-inflammatory properties of CB2 receptor in Kupffer cells rely on activation of autophagy. For this purpose, mice invalidated for CB2 receptor (CB2(Mye-/-) mice) or for the autophagy gene ATG5 (ATG5(Mye-/-) mice) in the myeloid lineage, and their littermate wild-type mice were subjected to chronic-plus-binge ethanol feeding. CB2(Mye-/-) mice showed exacerbated alcohol-induced pro-inflammatory gene expression and steatosis. Studies in cultured macrophages demonstrated that CB2 receptor activation by JWH-133 stimulated autophagy via a heme oxygenase-1 dependent pathway. Moreover, JWH-133 reduced the induction of inflammatory genes by lipopolysaccharide in wild-type macrophages, but not in ATG5-deficient cells. The CB2 agonist also protected from alcohol-induced liver inflammation and steatosis in wild-type mice, but not in ATG5(Mye-/-) mice demonstrating that macrophage autophagy mediates the anti-inflammatory and anti-steatogenic effects of CB2 receptor. Altogether these results demonstrate that CB2 receptor activation in macrophages protects from alcohol-induced steatosis by inhibiting hepatic inflammation through an autophagy-dependent pathway.

  2. Expression of monocyte chemoattractant protein 1 in macrophage-rich areas of human and rabbit atherosclerotic lesions.

    PubMed Central

    Ylä-Herttuala, S; Lipton, B A; Rosenfeld, M E; Särkioja, T; Yoshimura, T; Leonard, E J; Witztum, J L; Steinberg, D

    1991-01-01

    The recruitment of monocyte-macrophages into the artery wall is one of the earliest events in the pathogenesis of atherosclerosis. Monocyte chemoattractant protein 1 (MCP-1) is a potent monocyte chemoattractant secreted by many cells in vitro, including vascular smooth muscle and endothelial cells. To test whether it is expressed in the artery in vivo, we used Northern blot analysis, in situ hybridization, and immunocytochemistry to study the expression of MCP-1 in normal and atherosclerotic human and rabbit arteries. Northern blot analysis showed that MCP-1 mRNA could be isolated from rabbit atherosclerotic lesions but not from the intima media of normal animals. Furthermore, MCP-1 mRNA was extracted from macrophage-derived foam cells isolated from arterial lesions of ballooned cholesterol-fed rabbits, whereas alveolar macrophages isolated simultaneously from the same rabbits did not express MCP-1 mRNA. MCP-1 mRNA was detected by in situ hybridization in macrophage-rich regions of both human and rabbit atherosclerotic lesions. No MCP-1 mRNA was found in sublesional medial smooth muscle cells or in normal arteries. By using immunocytochemistry, MCP-1 protein was demonstrated in human lesions, again only in macrophage-rich regions. Immunostaining of the serial sections with an antiserum against malondialdehyde-modified low density lipoprotein indicated the presence of oxidized low density lipoprotein indicated the presence of oxidized low density lipoprotein and/or other oxidation-specific lipid-protein adducts in the same areas that contained macrophages and MCP-1. We conclude that (i) MCP-1 is strongly expressed in a small subset of cells in macrophage-rich regions of human and rabbit atherosclerotic lesions and (ii) MCP-1 may, therefore, play an important role in the ongoing recruitment of monocyte-macrophages into developing lesions in vivo. Images PMID:2052604

  3. Helping Residents Protect Water Sources

    EPA Pesticide Factsheets

    Building on the successful early engagement of the Plain Sect agricultural community, the Eastern Lancaster County Source Water Protection Collaborative is expanding its efforts to involve local residents in the work of protecting drinking water sources.

  4. US dermatology residency program rankings.

    PubMed

    Aquino, Lisa L; Wen, Ge; Wu, Jashin J

    2014-10-01

    Unlike many other adult specialties, US News & World Report does not rank dermatology residency programs annually. We conducted a study to rank individual US dermatology residency programs based on set criteria. For each residency program, data from 2008 related to a number of factors were collected, including annual amount of National Institutes of Health (NIH) and Dermatology Foundation (DF) funding received; number of publications from full-time faculty members; number of faculty lectures given at 5 annual society meetings; and number of full-time faculty members who were on the editorial boards of 6 dermatology journals with the highest impact factors. Most of the data were obtained through extensive Internet searches, and missing data were obtained by contacting individual residency programs. The programs were ranked based on the prior factors according to a weighted ranking algorithm. A list of overall rankings also was created.

  5. Center Gets Commuters, Residents Together.

    ERIC Educational Resources Information Center

    American School and University, 1979

    1979-01-01

    The new student center at Trenton State College is situated on the walkway between the central campus and the commuter parking areas. The location brings resident and commuter students together. (Author/MLF)

  6. The Optometric Residency: Its Bloom.

    ERIC Educational Resources Information Center

    Bleything, Willard B.

    1979-01-01

    Guidelines for proposed residencies in optometry are presented for pediatric, rehabilitative, and hospital optometry. Their significance in terms of costs, patient population, faculty expertise, and critical mass are discussed. (JMF)

  7. Nontypeable Haemophilus influenzae clearance by alveolar macrophages is impaired by exposure to cigarette smoke.

    PubMed

    Martí-Lliteras, Pau; Regueiro, Verónica; Morey, Pau; Hood, Derek W; Saus, Carles; Sauleda, Jaume; Agustí, Alvar G N; Bengoechea, José Antonio; Garmendia, Junkal

    2009-10-01

    Nontypeable Haemophilus influenzae (NTHI) is an opportunistic gram-negative pathogen that causes respiratory infections and is associated with progression of respiratory diseases. Cigarette smoke is a main risk factor for development of respiratory infections and chronic respiratory diseases. Glucocorticoids, which are anti-inflammatory drugs, are still the most common therapy for these diseases. Alveolar macrophages are professional phagocytes that reside in the lung and are responsible for clearing infections by the action of their phagolysosomal machinery and promotion of local inflammation. In this study, we dissected the interaction between NTHI and alveolar macrophages and the effect of cigarette smoke on this interaction. We showed that alveolar macrophages clear NTHI infections by adhesion, phagocytosis, and phagolysosomal processing of the pathogen. Bacterial uptake requires host actin polymerization, the integrity of plasma membrane lipid rafts, and activation of the phosphatidylinositol 3-kinase (PI3K) signaling cascade. Parallel to bacterial clearance, macrophages secrete tumor necrosis factor alpha (TNF-alpha) upon NTHI infection. In contrast, exposure to cigarette smoke extract (CSE) impaired alveolar macrophage phagocytosis, although NTHI-induced TNF-alpha secretion was not abrogated. Mechanistically, our data showed that CSE reduced PI3K signaling activation triggered by NTHI. Treatment of CSE-exposed cells with the glucocorticoid dexamethasone reduced the amount of TNF-alpha secreted upon NTHI infection but did not compensate for CSE-dependent phagocytic impairment. The deleterious effect of cigarette smoke was observed in macrophage cell lines and in human alveolar macrophages obtained from smokers and from patients with chronic obstructive pulmonary disease.

  8. Increased production of superoxide anion by macrophages exposed in vitro to muramyl dipeptide or lipopolysaccharide

    PubMed Central

    1980-01-01

    After in vitro exposure to lipopolysaccharide (LPS) or muramyl dipeptide (MDP), cultured resident mouse peritoneal macrophages were primed to display enhanced generation of superoxide anion (O2-) in response to stimulation by phorbol myristate acetate (PMA) or opsonized zymosan. Priming with LPS (1 microgram/ml) produced a sevenfold enhancement of PMA-stimulated O2- generation; priming was detected within 30 min and persisted for at least 4 d. Exposure to MDP (1 muM) primed the macrophages to double their O2- release; the response was first observed after 4 h and persisted for at least 3 d. The priming response was not observed with stereoisomers of MDP, which are inactive as adjuvants. LPS and MDP appeared to work directly on the macrophages rather than indirectly by interacting with adherent lymphocytes: (a) Addition of nonadherent cell populations that contained lymphocytes had no effect on the response. (b) The response was normal with cells from nude mice, which lack mature T lymphocytes. (c) Macrophages from C3H/HeJ mice, whose B lymphocytes fail to respond to LPS, were weak in their response to priming LPS; the addition of normal (C3Heb/FeJ) nonadherent cells had no effect on this weak response. (d) The macrophage-like cell line J774.1 also showed enhanced O2--generating capacity after a 4-h exposure to LPS or MDP. The O2--generating capacity of macrophages primed with LPS in vitro was equivalent to that previously observed with cells elicited in vivo by injection of LPS or activated by infection with Bacille Calmette-Guerin. The data suggest that previous exposure to bacterial products could prime macrophages to respond with increased production of toxic oxygen metabolites on contact with invading microorganisms or tumor cells. PMID:7350246

  9. 24 CFR 964.140 - Resident training.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... training. (a) Resident training opportunities. HUD encourages a partnership between the residents, the HA...: (1) Community organization and leadership training; (2) Organizational development training for... training resources may include: (1) Resident organizations; (2) Housing authorities; (3) Local...

  10. 38 CFR 51.70 - Resident rights.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... FOR NURSING HOME CARE OF VETERANS IN STATE HOMES Standards § 51.70 Resident rights. The resident has a...; (iii) Physicians of the resident's choice (to provide care in the nursing home, physicians must...

  11. 38 CFR 51.70 - Resident rights.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... FOR NURSING HOME CARE OF VETERANS IN STATE HOMES Standards § 51.70 Resident rights. The resident has a...; (iii) Physicians of the resident's choice (to provide care in the nursing home, physicians must...

  12. 38 CFR 51.70 - Resident rights.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... FOR NURSING HOME CARE OF VETERANS IN STATE HOMES Standards § 51.70 Resident rights. The resident has a...; (iii) Physicians of the resident's choice (to provide care in the nursing home, physicians must...

  13. 38 CFR 51.70 - Resident rights.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... FOR NURSING HOME CARE OF VETERANS IN STATE HOMES Standards § 51.70 Resident rights. The resident has a...; (iii) Physicians of the resident's choice (to provide care in the nursing home, physicians must...

  14. Transduction of skeletal muscles with common reporter genes can promote muscle fiber degeneration and inflammation.

    PubMed

    Winbanks, Catherine E; Beyer, Claudia; Qian, Hongwei; Gregorevic, Paul

    2012-01-01

    Recombinant adeno-associated viral vectors (rAAV vectors) are promising tools for delivering transgenes to skeletal muscle, in order to study the mechanisms that control the muscle phenotype, and to ameliorate diseases that perturb muscle homeostasis. Many studies have employed rAAV vectors carrying reporter genes encoding for β-galactosidase (β-gal), human placental alkaline phosphatase (hPLAP), and green fluorescent protein (GFP) as experimental controls when studying the effects of manipulating other genes. However, it is not clear to what extent these reporter genes can influence signaling and gene expression signatures in skeletal muscle, which may confound the interpretation of results obtained in experimentally manipulated muscles. Herein, we report a strong pro-inflammatory effect of expressing reporter genes in skeletal muscle. Specifically, we show that the administration of rAAV6:hPLAP vectors to the hind limb muscles of mice is associated with dose- and time-dependent macrophage recruitment, and skeletal muscle damage. Dose-dependent expression of hPLAP also led to marked activity of established pro-inflammatory IL-6/Stat3, TNFα, IKKβ and JNK signaling in lysates obtained from homogenized muscles. These effects were independent of promoter type, as expression cassettes featuring hPLAP under the control of constitutive CMV and muscle-specific CK6 promoters both drove cellular responses when matched for vector dose. Importantly, the administration of rAAV6:GFP vectors did not induce muscle damage or inflammation except at the highest doses we examined, and administration of a transgene-null vector (rAAV6:MCS) did not cause damage or inflammation at any of the doses tested, demonstrating that GFP-expressing, or transgene-null vectors may be more suitable as experimental controls. The studies highlight the importance of considering the potential effects of reporter genes when designing experiments that examine gene manipulation in vivo.

  15. Dendritic cells and macrophages in the uveal tract of the normal mouse eye

    PubMed Central

    McMenamin, P.

    1999-01-01

    BACKGROUND/AIMS—Dendritic cells (DC) and macrophages are components of the immune cell populations in the uveal tract whose density, distribution, turnover, and function may play a role in the maintenance of immunological homeostasis in the eye. Little is known of these cells in the mouse eye despite this being the predominant experimental model in many studies of ocular immune responses and immunoinflammatory mediated eye diseases. The aim of the present study was to obtain further immunophenotypic data on resident tissue macrophages and DC populations in the mouse uveal tract.
METHODS—Pieces of iris, ciliary body, and choroid dissected from perfusion fixed BALB/c mice were incubated whole in a variety of anti-macrophage and DC monoclonal antibodies (mAbs). Labelled cells were visualised using either single or double immunoperoxidase techniques.
RESULTS—Quantitative analysis and double immunolabelling revealed that 80% of F4/80+ cells (a mAb that recognises both DC and macrophages) in the iris are macrophages (SER4+). The iris contained a network of Ia+ cells (412 (SD 130) cells/mm2) of which two thirds appear to be DC. A similar pattern was observed in the ciliary body and choroid. Only a few DC in the uveal tract were very weakly reactive for mAbs which recognise B7-1 (CD80), B7-2 (CD86), β2 integrin (mAb N418), and multivesicular bodies associated with antigen presentation (mAb M342).
CONCLUSIONS—The present study reveals that the mouse uveal tract, like the rat, contains rich networks of DC and resident tissue macrophages. The networks of resident tissue macrophages in the mouse uveal tract closely resemble similar networks in non-ocular tissues. The phenotype of uveal tract DC suggests they are in the "immature" phase of their life cycle, similar to Langerhans cells of the skin, thus implying their role in situ within the eye is antigen capture and not antigen presentation.

 PMID:10216062

  16. Muscle satellite cells are a functionally heterogeneous population in both somite-derived and branchiomeric muscles.

    PubMed

    Ono, Yusuke; Boldrin, Luisa; Knopp, Paul; Morgan, Jennifer E; Zammit, Peter S

    2010-01-01

    Skeletal muscles of body and limb are derived from somites, but most head muscles originate from cranial mesoderm. The resident stem cells of muscle are satellite cells, which have the same embryonic origin as the muscle in which they reside. Here, we analysed satellite cells with a different ontology, comparing those of the extensor digitorum longus (EDL) of the limb with satellite cells from the masseter of the head. Satellite cell-derived myoblasts from MAS and EDL muscles had distinct gene expression profiles and masseter cells usually proliferated more and differentiated later than those from EDL. When transplanted, however, masseter-derived satellite cells regenerated limb muscles as efficiently as those from EDL. Clonal analysis showed that functional properties differed markedly between satellite cells: ranging from clones that proliferated extensively and gave rise to both differentiated and self-renewed progeny, to others that divided minimally before differentiating completely. Generally, masseter-derived clones were larger and took longer to differentiate than those from EDL. This distribution in cell properties was preserved in both EDL-derived and masseter-derived satellite cells from old mice, although clones were generally less proliferative. Satellite cells, therefore, are a functionally heterogeneous population, with many occupants of the niche exhibiting stem cell characteristics in both somite-derived and branchiomeric muscles.

  17. Aortic smooth muscle cell proteoglycan synthesis in relation to atherosclerosis

    SciTech Connect

    Edwards, I.J.

    1989-01-01

    Proteoglycans (PG) are implicated in atherogenesis by their effects on tissue permeability and cell proliferation and their interaction with plasma low density lipoproteins. Using the pigeon model in which an atherosclerosis-susceptible (WC) and -resistant (SR) breed can be compared, PG synthesis by cultured aortic smooth muscle cells was examined by the use of ({sup 35}S)-sodium sulfate and ({sup 3}H)-serine or ({sup 3}H)-glucosamine as labeling precursors. In both SR and WC cells, the majority of newly synthesized PG were secreted into the media. Chondroitin sulfate (CS) PG and dermatan sulfate (DS) PG were the major PG produced. Total PG production was consistently lower in WC compared to SR cultures due in part to reduce PG synthesis but also to degradation of newly synthesized PG. Since increased DS-PG accompanines atherosclerosis progression, experiments were designed to test the hypothesis that macrophages modulate smooth muscle cell metabolism to cause increase DS-PG production. Cultured WC aortic smooth muscle cells were exposed to the media of cholesteryl ester-loaded pigeon peritoneal macrophages or a macrophage cell line P388D1 and the production of PG examined. Increasing concentration of conditioned media from both types of macrophages caused increased incorporation of {sup 35}S-sulfate into secreted PG, but no change in cell-associated PG. Lipopolysaccharide activation of P388D1 cells enhanced the effect.

  18. Diverse macrophages polarization in tumor microenvironment.

    PubMed

    Rhee, Inmoo

    2016-11-01

    Macrophages are traditional innate immune cells that play critical roles in the clearance of pathogens and the maintenance of tissue homeostasis. Accumulating evidence proves that macrophages affect cancer initiation and malignancy. Macrophages can be categorized into two extreme subsets, classically activated (M1) and alternatively activated (M2) macrophages based on their distinct functional abilities in response to microenvironmental stimuli. In a tumor microenvironment, tumor associated macrophages (TAMs) are considered to be of the polarized M2 phenotype that enhances tumor progression and represent a poor prognosis. Furthermore, TAMs enhance tumor angiogenesis, growth, metastasis, and immunosuppression by secreting a series of cytokines, chemokines, and proteases. The regulation of macrophage polarization is considered to be a potential future therapy for cancer management.

  19. Macrophage-mediated tumor cytotoxicity: role of macrophage surface sialic acid.

    PubMed

    Cameron, D J

    1983-02-01

    Cell surface sialic acid levels were compared for monocytes and macrophages obtained from normal volunteers and breast cancer patients. Equal quantities of sialic acid were found on the monocytes obtained from normal volunteers and breast cancer patients. Approximately 60% more cell surface sialic acid was found on the macrophages from breast cancer patients than was found on the macrophages from normal volunteers. In order to determine whether cell surface sialic acid had any effect on macrophage-mediated cytotoxicity, macrophages were pretreated with neuraminidase (NANAse) prior to co-cultivation with tumor cells. The normal macrophages, after neuraminidase treatment, no longer retained their ability to kill tumor cells. However, when macrophages from breast cancer patients were treated with NANAse, no difference was observed in the ability of untreated and NANAse treated macrophages to kill tumor cells.

  20. The myeloid 7/4-antigen defines recently generated inflammatory macrophages and is synonymous with Ly-6B

    PubMed Central

    Rosas, Marcela; Thomas, Benjamin; Stacey, Martin; Gordon, Siamon; Taylor, Philip R.

    2010-01-01

    This study aimed to identify the inflammation-associated 7/4-antigen, which is highly expressed on neutrophils, inflammatory monocytes, some activated macrophages, as well as on bone marrow myeloid-restricted progenitors. The high expression on inflammatory cells is suggestive of a role in inflammation and makes the 7/4-antigen a potential target for the manipulation of inflammatory cells. Consistent with this, the 7/4-antibody mediates specific depletion of 7/4-expressing neutrophils and monocytes. We have identified the 7/4-antigen as a 25- to 30-kDa GPI-anchored glycoprotein synonymous with the Ly-6B.2 alloantigen. We characterized the expression of Ly-6B during the inflammatory reaction induced by zymosan. During the later stages of an experimental, acute, self-resolving inflammatory response, we found that Ly-6B is differentially expressed on macrophages. Ly-6B-expressing macrophages also express more MHCII, CIITA, CCR2, Ly-6C, and CD62L than the Ly-6B-negative macrophages, which in turn, express more of the resident tissue macrophage marker SIGN-R1 and higher CD11b and F4/80. Ly-6B-expressing macrophages incorporate more BrdU than their Ly-6B-negative contemporaries when fed during the resolution phase of the acute inflammatory response. Thus, Ly-6B expression on mature macrophages defines a subset of recently generated inflammatory macrophages that retain monocytic markers and is hence a surrogate marker of macrophage turnover in inflammatory lesions. The definition of the 7/4:Ly-6B antigen will allow further characterization and specific modulation of Ly-6B-expressing cells in vivo. PMID:20400676

  1. 24 CFR 964.140 - Resident training.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... Resident Management Corporations and duly elected Resident Councils; (3) Public housing policies, programs, rights and responsibilities training; and (4) Business entrepreneurial training, planning and job...

  2. 24 CFR 964.140 - Resident training.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... Resident Management Corporations and duly elected Resident Councils; (3) Public housing policies, programs, rights and responsibilities training; and (4) Business entrepreneurial training, planning and job...

  3. Macrophage heterogeneity in liver injury and fibrosis.

    PubMed

    Tacke, Frank; Zimmermann, Henning W

    2014-05-01

    Hepatic macrophages are central in the pathogenesis of chronic liver injury and have been proposed as potential targets in combatting fibrosis. Recent experimental studies in animal models revealed that hepatic macrophages are a remarkably heterogeneous population of immune cells that fulfill diverse functions in homeostasis, disease progression, and regression from injury. These range from clearance of pathogens or cellular debris and maintenance of immunological tolerance in steady state conditions; central roles in initiating and perpetuating inflammation in response to injury; promoting liver fibrosis via activating hepatic stellate cells in chronic liver damage; and, finally, resolution of inflammation and fibrosis by degradation of extracellular matrix and release of anti-inflammatory cytokines. Cellular heterogeneity in the liver is partly explained by the origin of macrophages. Hepatic macrophages can either arise from circulating monocytes, which are recruited to the injured liver via chemokine signals, or from self-renewing embryo-derived local macrophages, termed Kupffer cells. Kupffer cells appear essential for sensing tissue injury and initiating inflammatory responses, while infiltrating Ly-6C(+) monocyte-derived macrophages are linked to chronic inflammation and fibrogenesis. In addition, proliferation of local or recruited macrophages may possibly further contribute to their accumulation in injured liver. During fibrosis regression, monocyte-derived cells differentiate into Ly-6C (Ly6C, Gr1) low expressing 'restorative' macrophages and promote resolution from injury. Understanding the mechanisms that regulate hepatic macrophage heterogeneity, either by monocyte subset recruitment, by promoting restorative macrophage polarization or by impacting distinctive macrophage effector functions, may help to develop novel macrophage subset-targeted therapies for liver injury and fibrosis.

  4. Dystrophic muscle environment induces changes in cell plasticity.

    PubMed

    Faralli, Herve; Dilworth, F Jeffrey

    2014-04-15

    Fibro-adipogenic progenitors (FAPs) reside in the muscle, where they facilitate myofiber regeneration. Under normal conditions, FAPs lack myogenic potential and thus do not directly contribute to regenerated myofibers. Surprisingly, Saccone and colleagues (pp. 841-857) demonstrated that the dystrophic muscle environment causes FAPs to adopt a chromatin state that imparts these cells with myogenic potential. In this context, treatment of muscle with deacetylase inhibitors activates a BAF60c-myomiR transcriptional network in FAPs, blocking adipogenesis and driving muscle differentiation.

  5. Macrophage Polarization in Virus-Host Interactions

    PubMed Central

    Sang, Yongming; Miller, Laura C; Blecha, Frank

    2015-01-01

    Macrophage involvement in viral infections and antiviral states is common. However, this involvement has not been well-studied in the paradigm of macrophage polarization, which typically has been categorized by the dichotomy of classical (M1) and alternative (M2) statuses. Recent studies have revealed the complexity of macrophage polarization in response to various cellular mediators and exogenous stimuli by adopting a multipolar view to revisit the differential process of macrophages, especially those re-polarized during viral infections. Here, through examination of viral infections targeting macrophages/monocytic cells, we focus on the direct involvement of macrophage polarization during viral infections. Type I and type III interferons (IFNs) are critical in regulation of viral pathogenesis and host antiviral infection; thus, we propose to incorporate IFN-mediated antiviral states into the framework of macrophage polarization. This view is supported by the multifunctional properties of type I IFNs, which potentially elicit and regulate both M1- and M2-polarization in addition to inducing the antiviral state, and by the discoveries of viral mechanisms to adapt and modulate macrophage polarization. Indeed, several recent studies have demonstrated effective prevention of viral diseases through manipulation of macrophage immune statuses. PMID:26213635

  6. Changes in transcriptome of macrophages in atherosclerosis

    PubMed Central

    Chistiakov, Dimitry A; Bobryshev, Yuri V; Orekhov, Alexander N

    2015-01-01

    Macrophages display significant phenotypic heterogeneity. Two growth factors, macrophage colony-stimulating factor and chemokine (C-X-C motif) ligand 4, drive terminal differentiation of monocytes to M0 and M4 macrophages respectively. Compared to M0 macrophages, M4 cells have a unique transcriptome, with expression of surface markers such as S100A8, mannose receptor CD206 and matrix metalloproteinase 7. M4 macrophages did not express CD163, a scavenger receptor for haemoglobin/haptoglobin complex. Depending on the stimuli, M0 macrophages could polarize towards the proinflammatory M1 subset by treatment with lipopolysaccharide or interferon-γ. These macrophages produce a range of proinflammatory cytokines, nitric oxide, reactive oxygen species and exhibit high chemotactic and phagocytic activity. The alternative M2 type could be induced from M0 macrophage by stimulation with interleukin (IL)-4. M2 macrophages express high levels of CD206 and produce anti-inflammatory cytokines IL-10 and transforming growth factor-β. M1, M2 and M4 macrophages could be found in atherosclerotic plaques. In the plaque, macrophages are subjected to the intensive influence not only by cytokines and chemokines but also with bioactive lipids such as cholesterol and oxidized phospholipids. Oxidized phospholipids induce a distinct Mox phenotype in murine macrophages that express a unique panel of antioxidant enzymes under control of the redox-regulated transcription factor Klf2, resistant to lipid accumulation. In unstable human lesions, atheroprotective M(Hb) and HA-mac macrophage subsets could be found. These two subsets are induced by the haemoglobin/haptoglobin complex, highly express haeme oxygenase 1 and CD163, and are implicated in clearance of haemoglobin and erythrocyte remnants. In atherogenesis, the macrophage phenotype is plastic and could therefore be switched to proinflammatory (i.e. proatherogenic) and anti-inflammatory (i.e. atheroprotective). The aim of this review was to

  7. Macrophages in atherosclerosis: a dynamic balance

    PubMed Central

    Moore, Kathryn; Sheedy, Frederick; Fisher, Edward

    2015-01-01

    Preface Atherosclerosis is a chronic inflammatory disease arising from an imbalance in lipid metabolism and a maladaptive immune response driven by the accumulation of cholesterol-laden macrophages in the artery wall. Through the analysis of animal models of atherosclerosis progression and regression, there is a growing understanding that the balance of macrophages in the plaque is dynamic, with both macrophage numbers and an inflammatory phenotype influencing plaque fate. Here we summarize recently identified pro- and anti-inflammatory pathways linking lipid and inflammation biology with the retention of macrophages in plaques, as well as factors with the potential to promote their egress from these sites. PMID:23995626

  8. Collagenase Production by Endotoxin-Activated Macrophages

    PubMed Central

    Wahl, Larry M.; Wahl, Sharon M.; Mergenhagen, Stephan E.; Martin, George R.

    1974-01-01

    Peritoneal exudate macrophages, when exposed to bacterial lipopolysaccharide in culture, were found to produce collagenase (EC 3.4.24.3). This enzyme was not detected in extracts of the macrophages or in media from nonstimulated macrophage cultures. Lipidcontaining fractions of the lipopolysaccharide, including a glycolipid from the rough mutant of Salmonella minnesota (R595) and lipid A, were potent stimulators of collagenase production. The lipid-free polysaccharide fraction had no effect. Cycloheximide prevented the production of collagenase by endotoxin-treated macrophages, suggesting that it was newly synthesized. Images PMID:4372628

  9. Crossing the Rubicon. Preparing residents for professional life after residency.

    PubMed

    McCombs, Peter R

    2004-01-01

    In addition to clinical skill and knowledge of basic science, graduating residents need decision-making and communication skills, and an understanding of the cultural and prejudicial divides that sometimes create conflicts and misunderstandings in the clinical arena. This paper summarizes a program that one institution has adopted, which attempts to introduce topics in the humanities into the conventional curriculum. The goal is to enable graduating residents to think and to express their views more creatively and assertively, and to give them a greater understanding of some of the individual and cultural attitudes they are certain to encounter in practice.

  10. Phenotypic and functional characterization of macrophages with therapeutic potential generated from human cirrhotic monocytes in a cohort study

    PubMed Central

    Moore, Joanna K.; Mackinnon, Alison C.; Wojtacha, Dvina; Pope, Caroline; Fraser, Alasdair R.; Burgoyne, Paul; Bailey, Laura; Pass, Chloe; Atkinson, Anne; Mcgowan, Neil W.A.; Manson, Lynn; Turner, Mark L.; Campbell, John D.M.; Forbes, Stuart J.

    2015-01-01

    Background aims Macrophages have complex roles in the liver. The aim of this study was to compare profiles of human monocyte-derived macrophages between controls and cirrhotic patients, to determine whether chronic inflammation affects precursor number or the phenotype, with the eventual aim to develop a cell therapy for cirrhosis. Methods Infusion of human macrophages in a murine liver fibrosis model demonstrated a decrease in markers of liver injury (alanine transaminase, bilirubin, aspartate transaminase) and fibrosis (transforming growth factor-β, α-smooth muscle actin, phosphatidylserine receptor) and an increase in markers of liver regeneration (matrix metalloproteinases [MMP]-9, MMP-12 and TNF-related weak inducer of apoptosis). CD14+ monocytes were then isolated from controls. Monocytes were matured into macrophages for 7 days using a Good Manufacturing Practice–compatible technique. Results There was no significant difference between the mean number of CD14+ monocytes isolated from cirrhotic patients (n = 9) and controls (n = 10); 2.8 ± SEM 0.54 × 108 and 2.5 ± 0.56 × 108, respectively. The mean yield of mature macrophages cultured was also not significantly different between cirrhotic patients and controls (0.9 × 108 ± 0.38 × 108, with more than 90% viability and 0.65 × 108 ± 0.16 × 108, respectively. Maturation to macrophages resulted in up-regulation of a number of genes (MMP-9, CCL2, interleukin [IL]-10 and TNF-related weak inducer of apoptosis). A cytokine and chemokine polymerase chain reaction array, comparing the control and cirrhotic macrophages, revealed no statistically significant differences. Conclusions Macrophages can be differentiated from cirrhotic patients' apheresis-derived CD14 monocytes and develop the same pro-resolution phenotype as control macrophages, indicating their suitability for clinical therapy. PMID:26342993

  11. Tumor-associated macrophages: effectors of angiogenesis and tumor progression.

    PubMed

    Coffelt, Seth B; Hughes, Russell; Lewis, Claire E

    2009-08-01

    Tumor-associated macrophages (TAMs) are a prominent inflammatory cell population in many tumor types residing in both perivascular and avascular, hypoxic regions of these tissues. Analysis of TAMs in human tumor biopsies has shown that they express a variety of tumor-promoting factors and evidence from transgenic murine tumor models has provided unequivocal evidence for the importance of these cells in driving angiogenesis, lymphangiogenesis, immunosuppression, and metastasis. This review will summarize the mechanisms by which monocytes are recruited into tumors, their myriad, tumor-promoting functions within tumors, and the influence of the tumor microenvironment in driving these activities. We also discuss recent attempts to both target/destroy TAMs and exploit them as delivery vehicles for anti-cancer gene therapy.

  12. THE ROLE OF MACROPHAGES IN OPTIC NERVE REGENERATION

    PubMed Central

    CUI, Q.; YIN, Y.; BENOWITZ, L. I.

    2009-01-01

    Following injury to the nervous system, the activation of macrophages, microglia, and T-cells profoundly affects the ability of neurons to survive and to regenerate damaged axons. The primary visual pathway provides a well-defined model system for investigating the interactions between the immune system and the nervous system after neural injury. Following damage to the optic nerve in mice and rats, retinal ganglion cells, the projection neurons of the eye, normally fail to regenerate their axons and soon begin to die. Induction of an inflammatory response in the vitreous strongly enhances the survival of retinal ganglion cells and enables these cells to regenerate lengthy axons beyond the injury site. T cells modulate this response, whereas microglia are thought to contribute to the loss of retinal ganglion cells in this model and in certain ocular diseases. This review discusses the complex and sometimes paradoxical actions of blood-borne macrophages, resident microglia, and T-cells in determining the outcome of injury in the primary visual pathway. PMID:18708126

  13. Actions of Interferons on Macrophages

    DTIC Science & Technology

    2007-11-02

    host’s defense against bacterial infection. 1. IFN Responses of Listeria -Infected Mice The serum IFN titers in endotoxin-injected and non-injected... Listeria monocytogenes, macrophages, T cells, antiviral activity, purifi- cation. 1.5. A 9TRACT (Cootew o m- w󈨚 &ode M nwe~em en fd"M1..Asaa Mice...pase of the anti- Listeria immue S o In addit 0 S inducing M I , the Listeria also dramatically altered e at’s responsiv us t( IFIin cng ageniT._ Within

  14. Satellite cells from dystrophic muscle retain regenerative capacity.

    PubMed

    Boldrin, Luisa; Zammit, Peter S; Morgan, Jennifer E

    2015-01-01

    Duchenne muscular dystrophy is an inherited disorder that is characterized by progressive skeletal muscle weakness and wasting, with a failure of muscle maintenance/repair mediated by satellite cells (muscle stem cells). The function of skeletal muscle stem cells resident in dystrophic muscle may be perturbed by being in an increasing pathogenic environment, coupled with constant demands for repairing muscle. To investigate the contribution of satellite cell exhaustion to this process, we tested the functionality of satellite cells isolated from the mdx mouse model of Duchenne muscular dystrophy. We found that satellite cells derived from young mdx mice contributed efficiently to muscle regeneration within our in vivo mouse model. To then test the effects of long-term residence in a dystrophic environment, satellite cells were isolated from aged mdx muscle. Surprisingly, they were as functional as those derived from young or aged wild type donors. Removing satellite cells from a dystrophic milieu reveals that their regenerative capacity remains both intact and similar to satellite cells derived from healthy muscle, indicating that the host environment is critical for controlling satellite cell function.

  15. Sleep Quality Among Psychiatry Residents

    PubMed Central

    das Chagas Medeiros, Francisco; Meireles Sales de Bruin, Veralice; Pinheiro Santana, José Abraão; Bastos Lima, Alexandre; De Francesco Daher, Elizabeth

    2016-01-01

    Objective: Medical residency programs are traditionally known for long working hours, which can be associated with a poor quality of sleep and daytime sleepiness. However, few studies have focused on this theme. Our objective was to investigate sleep quality, daytime sleepiness, and their relation with anxiety, social phobia, and depressive symptoms. Methods: This cross-sectional observational study involved 59 psychiatry residents. The Pittsburgh Sleep Quality Index (PSQI) and the Epworth Sleepiness Scale (ESS) were used to measure the quality of sleep and excessive daytime sleepiness ([EDS] and ESS > 10), respectively. Results: Among the 59 psychiatry residents, 59.3% had poor sleep quality (PSQI > 5) and 28.8% had EDS. Poor sleep quality was associated with higher EDS (P = 0.03) and the year of residency program (P = 0.03). Only 20% of residents with poor sleep had consulted at least once for sleep problems; 54.2% had used medications for sleep; and 16.9% were using medications at the time of interview. Only 30% obtained medication during medical consultations. Poor sleep was associated with irregular sleep hours (P = 0.001) and long periods lying down without sleep (P = 0.03). Poor sleep quality was also associated with high scores of anxiety symptoms (P < 0.001) and social phobia symptoms (P = 0.02). Conclusion: Psychiatry residents frequently have poor sleep quality and EDS. Considering that sleep disorders can affect quality of life, predispose to metabolic syndrome, and be associated with worse performance at work, attention to this clinical problem is needed. PMID:27582452

  16. Enhancing Mutual Respect among Nursing Assistants, Residents, and Residents' Families.

    ERIC Educational Resources Information Center

    Heiselman, Terry; Noelker, Linda S.

    1991-01-01

    Interviewed nursing assistants (n=40) and nursing facility residents (n=37) regarding ways they experienced respect, disrespect, attachment, and distancing in their relationships with each other. As a result of finding evidence of disrespect, an inservice session on gaining respect as a nursing assistant was presented. (ABL)

  17. Restructuring Residence Hall Programming: Residence Hall Educators with a Curriculum

    ERIC Educational Resources Information Center

    Buckner, Donald R.

    1977-01-01

    Development of residence hall learning environments through comprehensive educational programming has been inhibited by both the generalist nature of live-in professional staff positions and the retention of a student committee-centered programming philosophy. A rationale is developed in this article for a revised staffing pattern and a different…

  18. Resting and injury-induced inflamed periosteum contain multiple macrophage subsets that are located at sites of bone growth and regeneration.

    PubMed

    Alexander, Kylie Anne; Raggatt, Liza-Jane; Millard, Susan; Batoon, Lena; Chiu-Ku Wu, Andy; Chang, Ming-Kang; Hume, David Arthur; Pettit, Allison Robyn

    2017-01-01

    Better understanding of bone growth and regeneration mechanisms within periosteal tissues will improve understanding of bone physiology and pathology. Macrophage contributions to bone biology and repair have been established but specific investigation of periosteal macrophages has not been undertaken. We used an immunohistochemistry approach to characterize macrophages in growing murine bone and within activated periosteum induced in a mouse model of bone injury. Osteal tissue macrophages (osteomacs) and resident macrophages were distributed throughout resting periosteum. In tissues collected from 4-week-old mice, osteomacs were observed intimately associated with sites of periosteal diaphyseal and metaphyseal bone dynamics associated with normal growth. This included F4/80(+)Mac-2(-/low) osteomac association with extended tracks of bone formation (modeling) on diphyseal periosteal surfaces. Although this recapitulated endosteal osteomac characteristics, there was subtle variance in the morphology and spatial organization of periosteal modeling-associated osteomacs, which likely reflects the greater structural complexity of periosteum. Osteomacs, resident macrophages and inflammatory macrophages (F4/80(+)Mac-2(hi)) were associated with the complex bone dynamics occurring within the periosteum at the metaphyseal corticalization zone. These three macrophage subsets were also present within activated native periosteum after bone injury across a 9-day time course that spanned the inflammatory through remodeling bone healing phases. This included osteomac association with foci of endochondral ossification within the activated native periosteum. These observations confirm that osteomacs are key components of both osteal tissues, in spite of salient differences between endosteal and periosteal structure and that multiple macrophage subsets are involved in periosteal bone dynamics.

  19. Microarray analysis of long noncoding RNA and mRNA expression profiles in human macrophages infected with Mycobacterium tuberculosis

    PubMed Central

    Yang, Xiaofan; Yang, Jiahui; Wang, Jinli; Wen, Qian; Wang, Hui; He, Jianchun; Hu, Shengfeng; He, Wenting; Du, Xialin; Liu, Sudong; Ma, Li

    2016-01-01

    Macrophages play a crucial role in the control and elimination of invading Mycobacterium tuberculosis (Mtb), and also serve as the major residence for Mtb. However, the interaction between macrophages and Mtb remains to be clearly determined. Although long noncoding RNAs (lncRNAs) have emerged as key regulators in many biological processes, their roles in anti-mycobacterial responses of macrophages remain to be elucidated. Here, we applied microarray analysis to examine lncRNA and mRNA expression profiles in human primary macrophages after 72 h of infection with H37Ra or H37Rv. Our results revealed that many lncRNAs were differentially expressed in macrophages after H37Ra or H37Rv infection, indicating a possible role for lncRNAs in immune responses induced by Mtb infection and providing important cues for further functional studies. Furthermore, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) biological pathway analysis of the differentially expressed mRNAs showed the potential functions and pathways related to the pathogenesis of Mtb infection. Finally, two lncRNAs, MIR3945HG V1 and MIR3945HG V2, were identified as novel candidate diagnostic markers for tuberculosis. Our results provide novel insight into the mechanisms of the pivotal Mtb-macrophage interactions, and reveal potential targets for diagnostics and the treatment of tuberculosis. PMID:27966580

  20. Functional TRAIL receptors in monocytes and tumor-associated macrophages: A possible targeting pathway in the tumor microenvironment

    PubMed Central

    Liguori, Manuela; Buracchi, Chiara; Pasqualini, Fabio; Bergomas, Francesca; Pesce, Samantha; Sironi, Marina; Grizzi, Fabio; Mantovani, Alberto

    2016-01-01

    Despite the accepted dogma that TRAIL kills only tumor cells and spares normal ones, we show in this study that mononuclear phagocytes are susceptible to recombinant TRAIL via caspase-dependent apoptosis. Human resting monocytes and in vitro-differentiated macrophages expressed substantial levels of the functional TRAIL receptors (TRAIL-R1 and TRAIL-R2), while neutrophils and lymphocytes mostly expressed the non-signaling decoy receptor (TRAIL-R3). Accordingly, exclusively monocytes and macrophages activated caspase-8 and underwent apoptosis upon recombinant TRAIL treatment. TRAIL-Rs were up-regulated by anti-inflammatory agents (IL-10, glucocorticoids) and by natural compounds (Apigenin, Quercetin, Palmitate) and their treatment resulted in increased TRAIL-induced apoptosis. In mice, the only signaling TRAIL-R (DR5) was preferentially expressed by blood monocytes rather than neutrophils or lymphocytes. In both mice and humans, Tumor-Associated Macrophages (TAM) expressed functional TRAIL-R, while resident macrophages in normal tissues did not. As a proof of principle, we treated mice bearing a murine TRAIL-resistant fibrosarcoma with recombinant TRAIL. We observed significant decrease of circulating monocytes and infiltrating TAM, as well as reduced tumor growth and lower metastasis formation. Overall, these findings demonstrate that human and murine monocytes/macrophages are, among leukocytes, uniquely susceptible to TRAIL-mediated killing. This differential susceptibility to TRAIL could be exploited to selectively target macrophages in tumors. PMID:27191500

  1. Conversations with Holocaust survivor residents.

    PubMed

    Hirst, Sandra P; LeNavenec, Carole Lynne; Aldiabat, Khaldoun

    2011-03-01

    Traumatic events in one's younger years can have an impact on how an individual copes with later life. One traumatic experience for Jewish individuals was the Holocaust. Some of these people are moving into long-term care facilities. It was within this context that the research question emerged: What are Holocaust survivor residents' perceptions of a life lived as they move into a long-term care facility? For this qualitative study, Holocaust survivors were individually interviewed. Findings emphasize that nursing care needs to ensure that Holocaust survivor residents participate in activities, receive timely health care, and receive recognition of their life experiences.

  2. Predictors of Success in an Anesthesiology Residency.

    ERIC Educational Resources Information Center

    Warrick, Shirley S.; Crumrine, Robert S.

    1986-01-01

    Factors that contributed to successful residency performance by anesthesiology residents were examined in order to assist the program's selection committee in developing selection criteria. The best predictor of a resident's academic average in the anethesiology program was the number of years the resident had spent in other specialities.…

  3. 28 CFR 115.233 - Resident education.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 28 Judicial Administration 2 2014-07-01 2014-07-01 false Resident education. 115.233 Section 115... STANDARDS Standards for Community Confinement Facilities Training and Education § 115.233 Resident education... resident is transferred to a different facility. (c) The agency shall provide resident education in...

  4. 28 CFR 115.233 - Resident education.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 28 Judicial Administration 2 2012-07-01 2012-07-01 false Resident education. 115.233 Section 115... STANDARDS Standards for Community Confinement Facilities Training and Education § 115.233 Resident education... resident is transferred to a different facility. (c) The agency shall provide resident education in...

  5. 28 CFR 115.233 - Resident education.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 28 Judicial Administration 2 2013-07-01 2013-07-01 false Resident education. 115.233 Section 115... STANDARDS Standards for Community Confinement Facilities Training and Education § 115.233 Resident education... resident is transferred to a different facility. (c) The agency shall provide resident education in...

  6. Resident microglia from adult mice are refractory to nitric oxide-inducing stimuli due to impaired NOS2 gene expression.

    PubMed

    Brannan, Courtney A; Roberts, Margo R

    2004-11-01

    Microglia are the immunoregulatory cells of the central nervous system (CNS) and share many characteristics with resident macrophages in extracerebral tissues. Nitric oxide (NO) is secreted by macrophages following induction of the NO synthase gene NOS2 by stimuli elicited during a T-cell response and/or by microbial products. NO regulates both innate and adaptive immune responses, such as killing intracellular pathogens and inhibiting T-cell proliferation. Regulation of NO production by microglia, however, is poorly understood. We find that microglia from healthy adult mice produce negligible amounts of NO compared with resident macrophages during restimulation of peptide-specific CD8 T cells, and therefore cannot block T-cell proliferation. The impaired NO response extends to exogenous NOS2-inducing stimuli, including cytokines, CD40 ligation, and lipopolysaccharide. In contrast, microglia produce proinflammatory cytokines in response to these same stimuli, and therefore possess a relatively selective block in NO production. We go on to show that resident microglia fail to produce detectable levels of either the NOS2 enzyme or NOS2 RNA in response to NO-inducing stimuli. We therefore propose that microglia in the healthy adult brain exist in an "NO-incompetent" state in which NO production is blocked at the level of NOS2 RNA. The inability of resident microglia in the healthy CNS to produce NO may allow these immunoregulatory cells to modulate immune processes temporally, and may serve to protect the CNS from irreparable damage at the onset of infection or injury.

  7. Arterial foam cells with distinctive immunomorphologic and histochemical features of macrophages.

    PubMed Central

    Schaffner, T.; Taylor, K.; Bartucci, E. J.; Fischer-Dzoga, K.; Beeson, J. H.; Glagov, S.; Wissler, R. W.

    1980-01-01

    A variable population of fat-filled "foam" cells in diet-induced experimental arterial intimal plaques of rabbits and monkeys were analyzed for several features characteristic of macrophages. These included: 1) surface binding and phagocytosis of antibody-coated or complement-coated erythrocytes to detect specific surface receptors; 2) cytochemical tests and ultrastructural features to evaluate cell function and structure; and 3) rapid adherence to glass, a feature of macrophage activity, to isolate and identify a homogeneous population of fat-filled foam cells from excised and disrupted arterial lesions. Mixed populations of cells grown in culture from explants of lesions were also analyzed and lipid-filled cells were studied in histologic sections of adjacent lesions. Eighty to ninety percent of the easily dislodged glass-adherent cells from lesions had surface receptors for the Fc portion of immunoglobulin G and for the third component of complement. Coated red blood cells were readily phagocytized, but noncoated cells were not. Acid lipase activity was demonstrated in the Fc-receptor-positive cells. These cells were also devoid of ultrastructural features of smooth muscle. Among the cells growing or migrating out of explants, a population of large round foam cells possessed all of the macrophage features found in the glass-adherent cells from lesions and lacked ultrastructural characteristics of smooth muscle. Fusiform lipid vacuolated cells also grew out of the explants but did not exhibit surface receptors, failed to phagocytize coated or noncoated erythrocytes and did not stain for acid lipase activity; these cells showed distinctive morphologic features of smooth muscle. In histologic sections of nearby lesions foam cells that showed macrophage characteristics, ie, acid lipase activity and the presence of lysozymelike antigen, lacked ultrastructural smooth muscle features. Smooth muscle cells in lesion sections often contained lipid but demonstrated no

  8. A broken krebs cycle in macrophages.

    PubMed

    O'Neill, Luke A J

    2015-03-17

    Macrophages undergo metabolic rewiring during polarization but details of this process are unclear. In this issue of Immunity, Jha et al. (2015) report a systems approach for unbiased analysis of cellular metabolism that reveals key metabolites and metabolic pathways required for distinct macrophage polarization states.

  9. Macrophage subpopulations in systemic lupus erythematosus.

    PubMed

    Orme, Jacob; Mohan, Chandra

    2012-02-01

    Systemic lupus erythematosus (SLE) is a heterogeneous group of autoimmune disorders defined by a consensus of clinical and laboratory criteria. Much of the pathophysiology and therapy of SLE has focused on autoimmune B and T cells of the adaptive immune system. Recently, the role of macrophages, part of the innate immune system, in SLE pathogenesis has gained attention. The field of immunology in general has recently changed in the way that it approaches macrophages. Rather than viewing them as a single, concrete whole, it has become clear that different subpopulations of macrophages contribute to various immune and non-immune processes. Such a nomenclature may provide an ideal framework from which to study macrophage pathogenesis in SLE. Studies suggest that M1 subtype macrophages play an important inflammatory role in SLE pathogenesis. Further, apparently reduced populations of M2a and M2c subtype macrophages may contribute to the lack of anti-inflammatory activity apparent in the disease. M2b subtype macrophages may actually have a role in causing disease directly. Regulatory macrophages have yet to be explored thoroughly in SLE, though the presence of a few of their markers may mean that they are active in suppressing SLE-related inflammation.

  10. Macrophage polarization in virus-host interactions

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Macrophage involvement in viral infections and antiviral states is common. However, this involvement has not been well-studied in the paradigm of macrophage polarization, which typically has been categorized by the dichotomy of classical (M1) and alternative (M2) statuses. Recent studies have reveal...

  11. Mycobacterium tuberculosis replicates within necrotic human macrophages

    PubMed Central

    Lerner, Thomas R.; Repnik, Urska; Herbst, Susanne; Collinson, Lucy M.; Griffiths, Gareth

    2017-01-01

    Mycobacterium tuberculosis modulation of macrophage cell death is a well-documented phenomenon, but its role during bacterial replication is less characterized. In this study, we investigate the impact of plasma membrane (PM) integrity on bacterial replication in different functional populations of human primary macrophages. We discovered that IFN-γ enhanced bacterial replication in macrophage colony-stimulating factor–differentiated macrophages more than in granulocyte–macrophage colony-stimulating factor–differentiated macrophages. We show that permissiveness in the different populations of macrophages to bacterial growth is the result of a differential ability to preserve PM integrity. By combining live-cell imaging, correlative light electron microscopy, and single-cell analysis, we found that after infection, a population of macrophages became necrotic, providing a niche for M. tuberculosis replication before escaping into the extracellular milieu. Thus, in addition to bacterial dissemination, necrotic cells provide first a niche for bacterial replication. Our results are relevant to understanding the environment of M. tuberculosis replication in the host. PMID:28242744

  12. Macrophage Phenotype in Liver Injury and Repair.

    PubMed

    Sun, Y-Y; Li, X-F; Meng, X-M; Huang, C; Zhang, L; Li, J

    2017-03-01

    Macrophages hold a critical position in the pathogenesis of liver injury and repair, in which their infiltrations is regarded as a main feature for both acute and chronic liver diseases. It is noted that, based on the distinct phenotypes and origins, hepatic macrophages are capable of clearing pathogens, promoting/or inhibiting liver inflammation, while regulating liver fibrosis and fibrolysis through interplaying with hepatocytes and hepatic stellate cells (HSC) via releasing different types of pro- or anti-inflammatory cytokines and growth factors. Macrophages are typically categorized into M1 or M2 phenotypes by adapting to local microenvironment during the progression of liver injury. In most occasions, M1 macrophages play a pro-inflammatory role in liver injury, while M2 macrophages exert an anti-inflammatory or pro-fibrotic role during liver repair and fibrosis. In this review, we focused on the up-to-date information about the phenotypic and functional plasticity of the macrophages and discussed the detailed mechanisms through which the phenotypes and functions of macrophages are regulated in different stages of liver injury and repair. Moreover, their roles in determining the fate of liver diseases were also summarized. Finally, the macrophage-targeted therapies against liver diseases were also be evaluated.

  13. Macrophagic myofasciitis: characterization and pathophysiology

    PubMed Central

    Gherardi, Romain K.; Authier, François-Jérôme

    2012-01-01

    Summary Aluminium oxyhydroxide (alum), a nano-crystaline compound forming agglomerates, has been introduced in vaccine for its immunologic adjuvant effect in 1927. Alum is the most commonly used adjuvant in human and veterinary vaccines but mechanisms by which it stimulates immune responses remains incompletely understood. Although generally well tolerated, alum may occasionally cause disabling health problems in presumably susceptible individuals. A small proportion of vaccinated people present with delayed onset of diffuse myalgia, chronic fatigue and cognitive dysfunction, and exhibit very long-term persistence of alum-loaded macrophages at site of previous intra-muscular (i.m.) immunization, forming a granulomatous lesion called macrophagic myofasciitis (MMF). Clinical symptoms associated with MMF are paradigmatic of the recently delineated “autoimmune/inflammatory syndrome induced by adjuvants” (ASIA). The stereotyped cognitive dysfunction is reminiscent of cognitive deficits described in foundry workers exposed to inhaled Al particles. Alum safety concerns will largely depend on whether the compound remains localized at site of injection or may diffuse and accumulate in distant organs. Animal experiments indicate that biopersistent nanomaterials taken-up by monocytes-lineage cells in tissues, e.g. fluorescent alum surrogates, can first translocate to draining lymph nodes, and thereafter circulate in blood within phagocytes and reach the spleen, and, eventually, slowly accumulate in brain. PMID:22235051

  14. Mycobacteria, Metals, and the Macrophage

    PubMed Central

    Niederweis, Michael; Wolschendorf, Frank; Mitra, Avishek; Neyrolles, Olivier

    2015-01-01

    Summary Mycobacterium tuberculosis is a facultative intracellular pathogen that thrives inside host macrophages. A key trait of M. tuberculosis is to exploit and manipulate metal cation trafficking inside infected macrophages to ensure survival and replication inside the phagosome. Here we describe the recent fascinating discoveries that the mammalian immune system responds to infections with M. tuberculosis by overloading the phagosome with copper and zinc, two metals which are essential nutrients in small quantities but are toxic in excess. M. tuberculosis has developed multi-faceted resistance mechanisms to protect itself from metal toxicity including control of uptake, sequestration inside the cell, oxidation, and efflux. The host response to infections combines this metal poisoning strategy with nutritional immunity mechanisms that deprive M. tuberculosis from metals such as iron and manganese to prevent bacterial replication. Both immune mechanisms rely on the translocation of metal transporter proteins to the phagosomal membrane during the maturation process of the phagosome. This review summarizes these recent findings and discusses how metal-targeted approaches might complement existing TB chemotherapeutic regimens with novel anti-infective therapies. PMID:25703564

  15. Progression of inflammation during immunodeficient mouse skeletal muscle regeneration.

    PubMed

    Grabowska, Iwona; Mazur, Magdalena A; Kowalski, K; Helinska, A; Moraczewski, Jerzy; Stremińska, Władysława; Hoser, Grażyna; Kawiak, Jerzy; Ciemerych, Maria A; Brzoska, Edyta

    2015-12-01

    The skeletal muscle injury triggers the inflammatory response which is crucial for damaged muscle fiber degradation and satellite cell activation. Immunodeficient mice are often used as a model to study the myogenic potential of transplanted human stem cells. Therefore, it is crucial to elucidate whether such model truly reflects processes occurring under physiological conditions. To answer this question we compared skeletal muscle regeneration of BALB/c, i.e. animals producing all types of inflammatory cells, and SCID mice. Results of our study documented that initial stages of muscles regeneration in both strains of mice were comparable. However, lower number of mononucleated cells was noticed in regenerating SCID mouse muscles. Significant differences in the number of CD14-/CD45+ and CD14+/CD45+ cells between BALB/c and SCID muscles were also observed. In addition, we found important differences in M1 and M2 macrophage levels of BALB/c and SCID mouse muscles identified by CD68 and CD163 markers. Thus, our data show that differences in inflammatory response during muscle regeneration, were not translated into significant modifications in muscle regeneration.

  16. Quantitation of Productively Infected Monocytes and Macrophages of Simian Immunodeficiency Virus-Infected Macaques

    PubMed Central

    Avalos, Claudia R.; Price, Sarah L.; Forsyth, Ellen R.; Pin, Julia N.; Shirk, Erin N.; Bullock, Brandon T.; Queen, Suzanne E.; Li, Ming; Gellerup, Dane; O'Connor, Shelby L.; Zink, M. Christine; Mankowski, Joseph L.; Gama, Lucio

    2016-01-01

    ABSTRACT Despite the success of combined antiretroviral therapy (ART), human immunodeficiency virus (HIV) infection remains a lifelong infection because of latent viral reservoirs in infected patients. The contribution of CD4+ T cells to infection and disease progression has been extensively studied. However, during early HIV infection, macrophages in brain and other tissues are infected and contribute to tissue-specific diseases, such as encephalitis and dementia in brain and pneumonia in lung. The extent of infection of monocytes and macrophages has not been rigorously assessed with assays comparable to those used to study infection of CD4+ T cells and to evaluate the number of CD4+ T cells that harbor infectious viral genomes. To assess the contribution of productively infected monocytes and macrophages to HIV- and simian immunodeficiency virus (SIV)-infected cells in vivo, we developed a quantitative virus outgrowth assay (QVOA) based on similar assays used to quantitate CD4+ T cell latent reservoirs in HIV- and SIV-infected individuals in whom the infection is suppressed by ART. Myeloid cells expressing CD11b were serially diluted and cocultured with susceptible cells to amplify virus. T cell receptor β RNA was measured as a control to assess the potential contribution of CD4+ T cells in the assay. Virus production in the supernatant was quantitated by quantitative reverse transcription-PCR. Productively infected myeloid cells were detected in blood, bronchoalveolar lavage fluid, lungs, spleen, and brain, demonstrating that these cells persist throughout SIV infection and have the potential to contribute to the viral reservoir during ART. IMPORTANCE Infection of CD4+ T cells and their role as latent reservoirs have been rigorously assessed; however, the frequency of productively infected monocytes and macrophages in vivo has not been similarly studied. Myeloid cells, unlike lymphocytes, are resistant to the cytopathic effects of HIV. Moreover, tissue-resident

  17. Real-time high-resolution magnetic resonance tracking of macrophage subpopulations in a murine inflammation model: a pilot study with a commercially available cryogenic probe.

    PubMed

    Al Faraj, Achraf; Luciani, Nathalie; Kolosnjaj-Tabi, Jelena; Mattar, Essam; Clement, Olivier; Wilhelm, Claire; Gazeau, Florence

    2013-01-01

    Macrophages present different polarization states exhibiting distinct functions in response to environmental stimuli. However, the dynamic of their migration to sites of inflammation is not fully elucidated. Here we propose a real-time in vivo cell tracking approach, using high-resolution (HR)-MRI obtained with a commercially available cryogenic probe (Cryoprobe™), to monitor trafficking of differently polarized macrophages after systemic injection into mice. Murine bone marrow-derived mononuclear cells were differentiated ex vivo into nonpolarized M0, pro-inflammatory M1 and immunomodulator M2 macrophage subsets and labeled with citrate-coated anionic iron oxide nanoparticles (AMNP). These cells were subsequently intravenously injected to mice bearing calf muscle inflammation. Whole body migration dynamics of macrophage subsets was monitored by MRI at 4.7 T with a volume transmission/reception radiofrequency coil and macrophage infiltration to the inflamed paw was monitored with the cryogenic probe, allowing 3D spatial resolution of 50 µm with a scan time of only 10 min. Capture of AMNP was rapid and efficient regardless of macrophage polarization, with the highest uptake in M2 macrophages. Flow cytometry confirmed that macrophages preserved their polarization hallmarks after labeling. Migration kinetics of labeled cells differed from that of free AMNP. A preferential homing of M2-polarized macrophages to inflammation sites was observed. Our in vivo HR-MRI protocol highlights the extent of macrophage infiltration to the inflammation site. Coupled to whole body imaging, HR-MRI provides quantitative information on the time course of migration of ex vivo-polarized intravenously injected macrophages.

  18. Disruption of TGF-β signaling in smooth muscle cell prevents flow-induced vascular remodeling

    SciTech Connect

    Gao, Fu; Chambon, Pierre; Tellides, George; Kong, Wei; Zhang, Xiaoming; Li, Wei

    2014-11-07

    Highlights: • TGF-β signaling in SMC contributes to the flow-induced vascular remodeling. • Disruption of TGF-β signaling in SMC can prevent this process. • Targeting SM-specific Tgfbr2 could be a novel therapeutic strategy for vascular remodeling. - Abstract: Transforming growth factor-β (TGF-β) signaling has been prominently implicated in the pathogenesis of vascular remodeling, especially the initiation and progression of flow-induced vascular remodeling. Smooth muscle cells (SMCs) are the principal resident cells in arterial wall and are critical for arterial remodeling. However, the role of TGF-β signaling in SMC for flow-induced vascular remodeling remains unknown. Therefore, the goal of our study was to determine the effect of TGF-β pathway in SMC for vascular remodeling, by using a genetical smooth muscle-specific (SM-specific) TGF-β type II receptor (Tgfbr2) deletion mice model. Mice deficient in the expression of Tgfbr2 (MyhCre.Tgfbr2{sup f/f}) and their corresponding wild-type background mice (MyhCre.Tgfbr2{sup WT/WT}) underwent partial ligation of left common carotid artery for 1, 2, or 4 weeks. Then the carotid arteries were harvested and indicated that the disruption of Tgfbr2 in SMC provided prominent inhibition of vascular remodeling. And the thickening of carotid media, proliferation of SMC, infiltration of macrophage, and expression of matrix metalloproteinase (MMP) were all significantly attenuated in Tgfbr2 disruption mice. Our study demonstrated, for the first time, that the TGF-β signaling in SMC plays an essential role in flow-induced vascular remodeling and disruption can prevent this process.

  19. The Salmonella virulence plasmid enhances Salmonella-induced lysis of macrophages and influences inflammatory responses.

    PubMed Central

    Guilloteau, L A; Wallis, T S; Gautier, A V; MacIntyre, S; Platt, D J; Lax, A J

    1996-01-01

    The Salmonella dublin virulence plasmid mediates systemic infection in mice and cattle. Here, we analyze the interaction between wild-type and plasmid-cured Salmonella strains with phagocytes in vitro and in vivo. The intracellular recovery of S. dublin from murine peritoneal and bovine alveolar macrophages cultured in the presence of gentamicin in vitro was not related to virulence plasmid carriage. However, the virulence plasmid increased the lytic activity of S. dublin, Salmonella typhimurium, and Salmonella choleraesuis for resident or activated mouse peritoneal macrophages. Lysis was not mediated by spv genes and was abolished by cytochalasin D treatment. Peritoneal and splenic macrophages were isolated from mice 4 days after intraperitoneal infection with wild-type or plasmid-cured S. dublin strains. The wild-type strain was recovered in significantly higher numbers than the plasmid-cured strain. However, the intracellular killing rates of such cells cultured in vitro for both S. dublin strains were not significantly different. Four days after infection, there was a lower increase of phagocyte numbers in the peritoneal cavities and spleens of mice infected with the wild-type strain compared with the plasmid-cured strain. The virulence plasmid influenced the survival of macrophages in vitro following infection in vivo as assessed by microscopy. Cells from mice infected with the plasmid-cured strain survived better than those from mice infected with the wild-type strain. This is the first report demonstrating an effect of the virulence plasmid on the interaction of Salmonella strains with macrophages. Plasmid-mediated macrophage dysfunction could influence the recruitment and/or the activation of phagocytic cells and consequently the net growth of Salmonella strains during infection. PMID:8757880

  20. Teaching Medical Ethics during Residency.

    ERIC Educational Resources Information Center

    Perkins, Henry S.

    1989-01-01

    Three reasons for teaching medical ethics during residency are presented. Key ethical concepts to be addressed include moral aspects of medical practice, obtaining informed consent, dealing with incompetent patients and those who refuse treatment, knowing when to withhold or disclose clinical information, and using medical resources properly. (MSE)

  1. Predictors of Residence Hall Involvement

    ERIC Educational Resources Information Center

    Arboleda, Ana; Wang, Yongyi; Shelley, Mack C., II; Whalen, Donald F.

    2003-01-01

    Residence hall students' (N = 1,186, 52% male, 90% White, 66% freshmen) involvement in their living community is influenced significantly by precollege student characteristics (gender, ethnicity), classification, attitudes (toward hall director, house cabinet, academic comfort, social environment, group study), and environmental variables (noise,…

  2. Akirin1 (Mighty), a novel promyogenic factor regulates muscle regeneration and cell chemotaxis

    SciTech Connect

    Salerno, Monica Senna; Dyer, Kelly; Bracegirdle, Jeremy; Platt, Leanne; Thomas, Mark; Siriett, Victoria; Kambadur, Ravi; Sharma, Mridula

    2009-07-15

    Akirin1 (Mighty) is a downstream target gene of myostatin and has been shown to be a promyogenic factor. Although expressed in many tissues, akirin1 is negatively regulated by myostatin specifically in skeletal muscle tissue. In this manuscript we have characterized the possible function of akirin1 in postnatal muscle growth. Molecular and immunohistological analyses indicated that while low levels of akirin1 are associated with quiescent satellite cells (SC), higher levels of akirin1 are detected in activated proliferating SC indicating that akirin1 could be associated with satellite cell activation. In addition to SC, macrophages also express akirin1, and increased expression of akirin1 resulted in more efficient chemotaxis of both macrophages and myoblasts. Akirin1 appears to regulate chemotaxis of both macrophages and myoblasts by reorganising actin cytoskeleton, leading to more efficient lamellipodia formation via a PI3 kinase dependent pathway. Expression analysis during muscle regeneration also indicated that akirin1 expression is detected very early (day 2) in regenerating muscle, and expression gradually peaks to coincide the nascent myotube formation stage of muscle regeneration. Based on these results we propose that akirin1 could be acting as a transducer of early signals of muscle regeneration. Thus, we speculate that myostatin regulates key steps of muscle regeneration including chemotaxis of inflammatory cells, SC activation and migration through akirin1.

  3. Myonuclear apoptosis in dystrophic mdx muscle occurs by perforin-mediated cytotoxicity.

    PubMed Central

    Spencer, M J; Walsh, C M; Dorshkind, K A; Rodriguez, E M; Tidball, J G

    1997-01-01

    Myonuclear apoptosis is an early event in the pathology of dystrophin-deficient muscular dystrophy in the mdx mouse. However, events that initiate apoptosis in muscular dystrophy are unknown, and whether elimination of apoptosis can ameliorate subsequent muscle wasting remains a major question. We have tested the hypothesis that cytotoxic T-lymphocytes initiate myonuclear apoptosis in dystrophic muscle, and examined whether perforin-mediated cytotoxicity plays a role in the pathophysiology of muscular dystrophy. Mdx mice showed muscle invasion by cytotoxic T cells and helper T cells at the onset of histologically detectable muscle fiber pathology. At this time, perforin-expressing cells were also present at elevated concentration. Mdx mice depleted of CD8(+) cells showed a significant reduction of apoptotic myonuclei concentration and a reduction in necrosis, judged by macrophage invasion of muscle fibers. Double-mutant mice, deficient in dystrophin and perforin, showed nearly complete absence of myonuclear apoptosis, and a significant reduction in the concentration of macrophages in the connective tissue surrounding muscle fibers. However, muscle fiber invasion by macrophages was not reduced significantly in double mutant mice. Thus, cytotoxic T-lymphocytes contribute significantly to apoptosis and necrosis in mdx dystrophy, and perforin-mediated killing is primarily responsible for myonuclear apoptosis. PMID:9169505

  4. Suppressive effects of ketamine on macrophage functions

    SciTech Connect

    Chang Yi; Chen, T.-L.; Sheu, J.-R.; Chen, R.-M. . E-mail: rmchen@tmu.edu.tw

    2005-04-01

    Ketamine is an intravenous anesthetic agent. Clinically, induction of anesthesia with ketamine can cause immunosuppression. Macrophages play important roles in host defense. In this study, we attempted to evaluate the effects of ketamine on macrophage functions and its possible mechanism using mouse macrophage-like Raw 264.7 cells as the experimental model. Exposure of macrophages to 10 and 100 {mu}M ketamine, which correspond to 0.1 and 1 times the clinically relevant concentration, for 1, 6, and 24 h had no effect on cell viability or lactate dehydrogenase release. When the administered concentration reached 1000 {mu}M, ketamine caused a release of lactate dehydrogenase and cell death. Ketamine, at 10 and 100 {mu}M, did not affect the chemotactic activity of macrophages. Administration of 1000 {mu}M ketamine in macrophages resulted in a decrease in cell migration. Treatment of macrophages with ketamine reduced phagocytic activities. The oxidative ability of macrophages was suppressed by ketamine. Treatment with lipopolysaccharide induced TNF-{alpha}, IL-1{beta}, and IL-6 mRNA in macrophages. Administration of ketamine alone did not influence TNF-{alpha}, IL-1{beta}, or IL-6 mRNA production. Meanwhile, cotreatment with ketamine and lipopolysaccharide significantly inhibited lipopolysaccharide-induced TNF-{alpha}, IL-1{beta}, and IL-6 mRNA levels. Exposure to ketamine led to a decrease in the mitochondrial membrane potential. However, the activity of mitochondrial complex I NADH dehydrogenase was not affected by ketamine. This study shows that a clinically relevant concentration of ketamine (100 {mu}M) can suppress macrophage function of phagocytosis, its oxidative ability, and inflammatory cytokine production possibly via reduction of the mitochondrial membrane potential instead of direct cellular toxicity.

  5. Role of resident macrophages, peripheral neutrophils, and translymphatic absorption in bacterial clearance from the peritoneal cavity

    SciTech Connect

    Dunn, D.L.; Barke, R.A.; Knight, N.B.; Humphrey, E.W.; Simmons, R.L.

    1985-08-01

    Microbial pathogens within the peritoneal cavity are thought to encounter three categories of host defense mechanisms: (i) removal mechanisms, which occur via diaphragmatic lymphatic absorption; (ii) killing mechanisms, in which host phagocytes act as effector cells; and (iii) sequestration mechanisms due to fibrin trapping and the formation of adhesions between visceral surfaces. The authors sought to define and quantitate the relative role of the first two components in an experimental rat model of Escherichia coli peritonitis in which fibrinous adhesions do not form. Intraperitoneal challenge with greater than or equal to 2 X 10(8) CFU of viable E. coli led to an initial decline in bacterial numbers followed by ongoing proliferation and greater than 50% mortality. With inocula of less than or equal to 5 X 10(7) CFU, elimination of bacteria occurred after moderate initial proliferation, and no mortality ensued. Nonviable, radiolabeled E. coli organisms were utilized to examine bacterial clearance via translymphatic absorption and phagocytosis. Both processes were extremely rapid, serving to eliminate free bacteria rapidly within the peritoneal cavity.

  6. Expression Profiling of Macrophages Reveals Multiple Populations with Distinct Biological Roles in an Immunocompetent Orthotopic Model of Lung Cancer

    PubMed Central

    Poczobutt, Joanna M.; De, Subhajyoti; Yadav, Vinod K.; Nguyen, Teresa T.; Li, Howard; Sippel, Trisha R.; Weiser-Evans, Mary C.M.; Nemenoff, Raphael A.

    2016-01-01

    Macrophages represent an important component of the tumor microenvironment and play a complex role in cancer progression. These cells are characterized by a high degree of plasticity, and alter their phenotype in response to local environmental cues. While the M1/M2 classification of macrophages has been widely used, the complexity of macrophage phenotypes has not been well studied, particularly in lung cancer. In this study we employed an orthotopic immunocompetent model of lung adenocarcinoma in which murine lung cancer cells are directly implanted into the left lobe of syngeneic mice. Using multi-marker flow cytometry, we defined and recovered several distinct populations of monocytes/macrophages from tumors at different stages of progression. We used RNA-seq transcriptional profiling to define distinct features of each population and determine how they change during tumor progression. We defined an alveolar resident macrophage population that does not change in number and expresses multiple genes related to lipid metabolism and lipid signaling. We also defined a population of tumor-associated macrophages that increase dramatically with tumor, and selectively expresses a panel of chemokine genes. A third population, which resembles tumor-associated monocytes, expresses a large number of genes involved in matrix remodeling. By correlating transcriptional profiles with clinically prognostic genes, we show that specific monocyte/macrophage populations are enriched in genes that predict outcomes in lung adenocarcinoma, implicating these subpopulations as critical determinants of patient survival. Our data underscore the complexity of monocytes/macrophages in the tumor microenvironment, and suggest that distinct populations play specific roles in tumor progression. PMID:26873985

  7. Macrophage cell lines P388D1 and IC-21 stimulated with gamma interferon fail to inhibit the intracellular growth of Histoplasma capsulatum.

    PubMed Central

    Wu-Hsieh, B; Howard, D H

    1989-01-01

    Histoplasma capsulatum, a facultative intracellular parasite of macrophages, grows within mononuclear cells of the P388D1 and IC-21 cell lines with a generation time comparable to that with which it grows in normal resident peritoneal macrophages (10 +/- 2 h). Recombinant murine gamma interferon (rMuIFN-gamma) activates P388D1 cells to express la antigens but not to inhibit the intracellular growth of H. capsulatum, alone or in combination with lipopolysaccharide. IC-21 cells also could not be activated to fungistasis with rMuIFN-gamma. Explanted resident peritoneal macrophages of the C57BL/6 (from which the IC-21 cell line derives), C3H/HeJ, DBA/2 (from which the P388D1 cell line derives), A/J, and SJL/J strains of mice were all stimulated by rMuIFN-gamma to inhibit the fungus. PMID:2503448

  8. 28 CFR 115.216 - Residents with disabilities and residents who are limited English proficient.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 28 Judicial Administration 2 2012-07-01 2012-07-01 false Residents with disabilities and residents... Facilities Prevention Planning § 115.216 Residents with disabilities and residents who are limited English proficient. (a) The agency shall take appropriate steps to ensure that residents with disabilities...

  9. 28 CFR 115.216 - Residents with disabilities and residents who are limited English proficient.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 28 Judicial Administration 2 2014-07-01 2014-07-01 false Residents with disabilities and residents... Facilities Prevention Planning § 115.216 Residents with disabilities and residents who are limited English proficient. (a) The agency shall take appropriate steps to ensure that residents with disabilities...

  10. Muscle strain treatment

    MedlinePlus

    Treatment - muscle strain ... Question: How do you treat a muscle strain ? Answer: Rest the strained muscle and apply ice for the first few days after the injury. Anti-inflammatory medicines or acetaminophen ( ...

  11. Eye muscle repair - discharge

    MedlinePlus

    ... Lazy eye repair - discharge; Strabismus repair - discharge; Extraocular muscle surgery - discharge ... You or your child had eye muscle repair surgery to correct eye muscle ... term for crossed eyes is strabismus. Children most often ...

  12. Skeletal muscle-melanocyte association during tadpole tail resorption in a tropical frog, Clinotarsus curtipes Jerdon (Anura, Ranoidea).

    PubMed

    Divya, Lekha; Beyo, Reston S; Sreejith, Parameswaran; Akbarsha, Mohammad A; Oommen, Oommen V

    2010-05-01

    We tested the hypothesis that melanin has a role as a molecule within the thyroid-mediated cascade. Light microscopic and ultrastructural changes in the skeletal muscle during tail resorption in tadpoles of the tropical frog Clinotarsus curtipes Jerdon (Anura: Ranoidea) were observed. Light microscopic analysis at metamorphic stage XVIII showed a melanized epidermis. A gradual migration of melanocytes from the epidermis to the dermis and filopodia of melanocytes pervading the skeletal muscle preceded tail resorption. The invasion of melanocytes into the muscle bundles coincided with the breakdown of the muscle bundles into sarcolytes and the arrival of macrophages at this site. This would suggest that the melanocyte-sarcolyte association signals the arrival of macrophages at these sites as metamorphosis progressed. Melanophages, macrophages with melanin granules, were observed at the climax stage of XXIII. The sarcolytes and the melanin granules were phagocytosed by macrophages so as to completely cleanse the exocytic muscle debris and the melanin granules. The presence of large melanomacrophage centers in the tadpole liver at metamorphic climax suggests that these phagocytic macrophages were further processed in the liver and, likely, in the spleen. It is proposed that melanin, a byzantine molecule, has a role in the cascade of events leading to tail resorption in anuran tadpoles.

  13. Monocytes and macrophages in tissue repair: Implications for immunoregenerative biomaterial design

    PubMed Central

    Segar, Claire E; Sridhar, Sraeyes; Botchwey, Edward A

    2016-01-01

    Monocytes and macrophages play a critical role in tissue development, homeostasis, and injury repair. These innate immune cells participate in guiding vascular remodeling, stimulation of local stem and progenitor cells, and structural repair of tissues such as muscle and bone. Therefore, there is a great interest in harnessing this powerful endogenous cell source for therapeutic regeneration through immunoregenerative biomaterial engineering. These materials seek to harness specific subpopulations of monocytes/macrophages to promote repair by influencing their recruitment, positioning, differentiation, and function within a damaged tissue. Monocyte and macrophage phenotypes span a continuum of inflammatory (M1) to anti-inflammatory or pro-regenerative cells (M2), and their heterogeneous functions are highly dependent on microenvironmental cues within the injury niche. Increasing evidence suggests that division of labor among subpopulations of monocytes and macrophages could allow for harnessing regenerative functions over inflammatory functions of myeloid cells; however, the complex balance between necessary functions of inflammatory versus regenerative myeloid cells remains to be fully elucidated. Historically, biomaterial-based therapies for promoting tissue regeneration were designed to minimize the host inflammatory response; although, recent appreciation for the roles that innate immune cells play in tissue repair and material integration has shifted this paradigm. A number of opportunities exist to exploit known signaling systems of specific populations of monocytes/macrophages to promote repair and to better understand the biological and pathological roles of myeloid cells. This review seeks to outline the characteristics of distinct populations of monocytes and macrophages, identify the role of these cells within diverse tissue injury niches, and offer design criteria for immunoregenerative biomaterials given the intrinsic inflammatory response to their

  14. Chloral Hydrate Treatment Induced Apoptosis of Macrophages via Fas Signaling Pathway

    PubMed Central

    Cai, Jun; Peng, Yanxia; Chen, Ting; Liao, Huanjin; Zhang, Lifang; Chen, Qiuhua; He, Yiming; Wu, Ping; Xie, Tong; Pan, Qingjun

    2016-01-01

    Background There are recent reports on several anesthetics that have anti-inflammatory and anti-infective effects apart from their uses for pain relief and muscle relaxation. Chloral hydrate is a clinical anesthetic drug and sedative that has also been reported to attenuate inflammatory response, but the mechanisms are not clearly understood. Material/Methods This study investigated the effect of chloral hydrate treatment on the apoptosis of macrophages and explored the underlying mechanisms. RAW264.7 macrophages were treated with various concentrations of chloral hydrate for various lengths of time. Morphological changes were observed under a light microscope and apoptosis was detected with annexin-V-FITC/PI double-staining assay, Hochest 33258 and DNA ladder assay, the expression of Fas/FasL was detected with a flow cytometer, and the Fas signaling pathway was assessed by Western blotting. Results The results showed that chloral hydrate treatment induced the morphology of RAW264.7 macrophages to change shape from typical fusiform to round in a concentration- and time-dependent manner, and was finally suspended in the supernatant. For the induction of apoptosis, chloral hydrate treatment induced the apoptosis of RAW264.7 macrophages from early-to-late stage apoptosis in a concentration- and time-dependent manner. For the mechanism, chloral hydrate treatment induced higher expression of Fas on RAW264.7 macrophages, and was also associated with changes in the expression of proteins involved in Fas signaling pathways. Conclusions Chloral hydrate treatment can induce the apoptosis of RAW264.7 macrophages through the Fas signaling pathway, which may provide new options for adjunctive treatment of acute inflammation. PMID:27941708

  15. Chloral Hydrate Treatment Induced Apoptosis of Macrophages via Fas Signaling Pathway.

    PubMed

    Cai, Jun; Peng, Yanxia; Chen, Ting; Liao, Huanjin; Zhang, Lifang; Chen, Qiuhua; He, Yiming; Wu, Ping; Xie, Tong; Pan, Qingjun

    2016-12-10

    BACKGROUND There are recent reports on several anesthetics that have anti-inflammatory and anti-infective effects apart from their uses for pain relief and muscle relaxation. Chloral hydrate is a clinical anesthetic drug and sedative that has also been reported to attenuate inflammatory response, but the mechanisms are not clearly understood. MATERIAL AND METHODS This study investigated the effect of chloral hydrate treatment on the apoptosis of macrophages and explored the underlying mechanisms. RAW264.7 macrophages were treated with various concentrations of chloral hydrate for various lengths of time. Morphological changes were observed under a light microscope and apoptosis was detected with annexin-V-FITC/PI double-staining assay, Hochest 33258 and DNA ladder assay, the expression of Fas/FasL was detected with a flow cytometer, and the Fas signaling pathway was assessed by Western blotting. RESULTS The results showed that chloral hydrate treatment induced the morphology of RAW264.7 macrophages to change shape from typical fusiform to round in a concentration- and time-dependent manner, and was finally suspended in the supernatant. For the induction of apoptosis, chloral hydrate treatment induced the apoptosis of RAW264.7 macrophages from early-to-late stage apoptosis in a concentration- and time-dependent manner. For the mechanism, chloral hydrate treatment induced higher expression of Fas on RAW264.7 macrophages, and was also associated with changes in the expression of proteins involved in Fas signaling pathways. CONCLUSIONS Chloral hydrate treatment can induce the apoptosis of RAW264.7 macrophages through the Fas signaling pathway, which may provide new options for adjunctive treatment of acute inflammation.

  16. Impaired macrophage autophagy increases the immune response in obese mice by promoting proinflammatory macrophage polarization

    PubMed Central

    Liu, Kun; Zhao, Enpeng; Ilyas, Ghulam; Lalazar, Gadi; Lin, Yu; Haseeb, Muhammad; Tanaka, Kathryn E; Czaja, Mark J

    2015-01-01

    Recent evidence that excessive lipid accumulation can decrease cellular levels of autophagy and that autophagy regulates immune responsiveness suggested that impaired macrophage autophagy may promote the increased innate immune activation that underlies obesity. Primary bone marrow-derived macrophages (BMDM) and peritoneal macrophages from high-fat diet (HFD)-fed mice had decreased levels of autophagic flux indicating a generalized impairment of macrophage autophagy in obese mice. To assess the effects of decreased macrophage autophagy on inflammation, mice with a Lyz2-Cre-mediated knockout of Atg5 in macrophages were fed a HFD and treated with low-dose lipopolysaccharide (LPS). Knockout mice developed systemic and hepatic inflammation with HFD feeding and LPS. This effect was liver specific as knockout mice did not have increased adipose tissue inflammation. The mechanism by which the loss of autophagy promoted inflammation was through the regulation of macrophage polarization. BMDM and Kupffer cells from knockout mice exhibited abnormalities in polarization with both increased proinflammatory M1 and decreased anti-inflammatory M2 polarization as determined by measures of genes and proteins. The heightened hepatic inflammatory response in HFD-fed, LPS-treated knockout mice led to liver injury without affecting steatosis. These findings demonstrate that autophagy has a critical regulatory function in macrophage polarization that downregulates inflammation. Defects in macrophage autophagy may underlie inflammatory disease states such as the decrease in macrophage autophagy with obesity that leads to hepatic inflammation and the progression to liver injury. PMID:25650776

  17. Impaired macrophage autophagy increases the immune response in obese mice by promoting proinflammatory macrophage polarization.

    PubMed

    Liu, Kun; Zhao, Enpeng; Ilyas, Ghulam; Lalazar, Gadi; Lin, Yu; Haseeb, Muhammad; Tanaka, Kathryn E; Czaja, Mark J

    2015-01-01

    Recent evidence that excessive lipid accumulation can decrease cellular levels of autophagy and that autophagy regulates immune responsiveness suggested that impaired macrophage autophagy may promote the increased innate immune activation that underlies obesity. Primary bone marrow-derived macrophages (BMDM) and peritoneal macrophages from high-fat diet (HFD)-fed mice had decreased levels of autophagic flux indicating a generalized impairment of macrophage autophagy in obese mice. To assess the effects of decreased macrophage autophagy on inflammation, mice with a Lyz2-Cre-mediated knockout of Atg5 in macrophages were fed a HFD and treated with low-dose lipopolysaccharide (LPS). Knockout mice developed systemic and hepatic inflammation with HFD feeding and LPS. This effect was liver specific as knockout mice did not have increased adipose tissue inflammation. The mechanism by which the loss of autophagy promoted inflammation was through the regulation of macrophage polarization. BMDM and Kupffer cells from knockout mice exhibited abnormalities in polarization with both increased proinflammatory M1 and decreased anti-inflammatory M2 polarization as determined by measures of genes and proteins. The heightened hepatic inflammatory response in HFD-fed, LPS-treated knockout mice led to liver injury without affecting steatosis. These findings demonstrate that autophagy has a critical regulatory function in macrophage polarization that downregulates inflammation. Defects in macrophage autophagy may underlie inflammatory disease states such as the decrease in macrophage autophagy with obesity that leads to hepatic inflammation and the progression to liver injury.

  18. NMAAP1 Expressed in BCG-Activated Macrophage Promotes M1 Macrophage Polarization.

    PubMed

    Liu, Qihui; Tian, Yuan; Zhao, Xiangfeng; Jing, Haifeng; Xie, Qi; Li, Peng; Li, Dong; Yan, Dongmei; Zhu, Xun

    2015-10-01

    Macrophages are divided into two subpopulations: classically activated macrophages (M1) and alternatively activated macrophages (M2). BCG (Bacilli Calmette-GuC)rin) activates disabled naC/ve macrophages to M1 macrophages, which act as inflammatory, microbicidal and tumoricidal cells through cell-cell contact and/or the release of soluble factors. Various transcription factors and signaling pathways are involved in the regulation of macrophage activation and polarization. We discovered that BCG-activated macrophages (BAM) expressed a new molecule, and we named it Novel Macrophage Activated Associated Protein 1 (NMAAP1). The current study found that the overexpression of NMAAP1 in macrophages results in M1 polarization with increased expression levels of M1 genes, such as inducible nitric oxide synthase (iNOS), tumor necrosis factor alpha (TNF-N1), Interleukin 6 (IL-6), Interleukin 12 (IL-12), Monocyte chemoattractant protein-1 (MCP-1) and Interleukin-1 beta (IL-1N2), and decreased expression of some M2 genes, such as Kruppel-like factor 4 (KLF4) and suppressor of cytokine signaling 1 (SOCS1), but not other M2 genes, including arginase-1 (Arg-1), Interleukin (IL-10), transforming growth factor beta (TGF-N2) and found in inflammatory zone 1 (Fizz1). Moreover, NMAAP1 overexpression in the RAW264.7 cell line increased cytotoxicity against MCA207 tumor cells, which depends on increased inflammatory cytokines rather than cell-cell contact. NMAAP1 also substantially enhanced the phagocytic ability of macrophages, which implies that NMAAP1 promoted macrophage adhesive and clearance activities. Our results indicate that NMAAP1 is an essential molecule that modulates macrophages phenotype and plays an important role in macrophage tumoricidal functions.

  19. Susceptibility of bone marrow-derived macrophages to influenza virus infection is dependent on macrophage phenotype.

    PubMed

    Campbell, Gillian M; Nicol, Marlynne Q; Dransfield, Ian; Shaw, Darren J; Nash, Anthony A; Dutia, Bernadette M

    2015-10-01

    The role of the macrophage in influenza virus infection is complex. Macrophages are critical for resolution of influenza virus infections but implicated in morbidity and mortality in severe infections. They can be infected with influenza virus and consequently macrophage infection is likely to have an impact on the host immune response. Macrophages display a range of functional phenotypes, from the prototypical pro-inflammatory classically activated cell to alternatively activated anti-inflammatory macrophages involved in immune regulation and wound healing. We were interested in how macrophages of different phenotype respond to influenza virus infection and therefore studied the infection of bone marrow-derived macrophages (BMDMs) of classical and alternative phenotype in vitro. Our results show that alternatively activated macrophages are more readily infected and killed by the virus than classically activated. Classically activated BMDMs express the pro-inflammatory markers inducible nitric oxide synthase (iNOS) and TNF-α, and TNF-α expression was further upregulated following infection. Alternatively activated macrophages express Arginase-1 and CD206; however, following infection, expression of these markers was downregulated whilst expression of iNOS and TNF-α was upregulated. Thus, infection can override the anti-inflammatory state of alternatively activated macrophages. Importantly, however, this results in lower levels of pro-inflammatory markers than those produced by classically activated cells. Our results showed that macrophage phenotype affects the inflammatory macrophage response following infection, and indicated that modulating the macrophage phenotype may provide a route to develop novel strategies to prevent and treat influenza virus infection.

  20. Characterization of lung inflammation and its impact on macrophage function in aging

    PubMed Central

    Canan, Cynthia H.; Gokhale, Nandan S.; Carruthers, Bridget; Lafuse, William P.; Schlesinger, Larry S.; Torrelles, Jordi B.; Turner, Joanne

    2014-01-01

    Systemic inflammation that occurs with increasing age (inflammaging) is thought to contribute to the increased susceptibility of the elderly to several disease states. The elderly are at significant risk for developing pulmonary disorders and infectious diseases, but the contribution of inflammation in the pulmonary environment has received little attention. In this study, we demonstrate that the lungs of old mice have elevated levels of proinflammatory cytokines and a resident population of highly activated pulmonary macrophages that are refractory to further activation by IFN-γ. The impact of this inflammatory state on macrophage function was determined in vitro in response to infection with M.tb. Macrophages from the lungs of old mice secreted more proinflammatory cytokines in response to M.tb infection than similar cells from young mice and also demonstrated enhanced M.tb uptake and P-L fusion. Supplementation of mouse chow with the NSAID ibuprofen led to a reversal of lung and macrophage inflammatory signatures. These data indicate that the pulmonary environment becomes inflammatory with increasing age and that this inflammatory environment can be reversed with ibuprofen. PMID:24935957

  1. Mycobacterial p(1)-type ATPases mediate resistance to zinc poisoning in human macrophages.

    PubMed

    Botella, Hélène; Peyron, Pascale; Levillain, Florence; Poincloux, Renaud; Poquet, Yannick; Brandli, Irène; Wang, Chuan; Tailleux, Ludovic; Tilleul, Sylvain; Charrière, Guillaume M; Waddell, Simon J; Foti, Maria; Lugo-Villarino, Geanncarlo; Gao, Qian; Maridonneau-Parini, Isabelle; Butcher, Philip D; Castagnoli, Paola Ricciardi; Gicquel, Brigitte; de Chastellier, Chantal; Neyrolles, Olivier

    2011-09-15

    Mycobacterium tuberculosis thrives within macrophages by residing in phagosomes and preventing them from maturing and fusing with lysosomes. A parallel transcriptional survey of intracellular mycobacteria and their host macrophages revealed signatures of heavy metal poisoning. In particular, mycobacterial genes encoding heavy metal efflux P-type ATPases CtpC, CtpG, and CtpV, and host cell metallothioneins and zinc exporter ZnT1, were induced during infection. Consistent with this pattern of gene modulation, we observed a burst of free zinc inside macrophages, and intraphagosomal zinc accumulation within a few hours postinfection. Zinc exposure led to rapid CtpC induction, and ctpC deficiency caused zinc retention within the mycobacterial cytoplasm, leading to impaired intracellular growth of the bacilli. Thus, the use of P(1)-type ATPases represents a M. tuberculosis strategy to neutralize the toxic effects of zinc in macrophages. We propose that heavy metal toxicity and its counteraction might represent yet another chapter in the host-microbe arms race.

  2. Involvement of lipoprotein PpiA of Streptococcus gordonii in evasion of phagocytosis by macrophages.

    PubMed

    Cho, K; Arimoto, T; Igarashi, T; Yamamoto, M

    2013-10-01

    Streptococcus gordonii is a commensal gram-positive bacterium that resides in the human oral cavity, and is one of the most common causes of infective endocarditis (IE). Bacterial surface molecules play an important role in establishing IE, and several S. gordonii proteins have been implicated in binding to host cells during the establishment of IE. In this study, we identified a putative lipoprotein, peptidyl-prolyl cis/trans isomerase (PpiA), and clarified its role in evasion of phagocytosis by macrophages. Attenuation of the gene encoding prolipoprotein diacylglyceryl transferase (Lgt) altered the localization of PpiA from the cell surface to the culture supernatant, indicating that PpiA is lipid-anchored in the cell membrane by Lgt. Both human and murine macrophages showed higher phagocytic activity towards ppiA and lgt mutants than the wild-type, indicating that the presence of PpiA suppresses phagocytosis of S. gordonii. Human macrophages treated with dextran sulfate had significantly impaired phagocytosis of S. gordonii, suggesting that class A scavenger receptors in human macrophages are involved in the phagocytosis of S. gordonii. These results provide evidence that S. gordonii lipoprotein PpiA plays an important role in inhibiting phagocytic engulfment and in evasion of the host immune response.

  3. Unmodified low density lipoprotein causes cholesteryl ester accumulation in J774 macrophages.

    PubMed

    Tabas, I; Weiland, D A; Tall, A R

    1985-01-01

    Cholesteryl ester (CE)-loaded macrophages (foam cells) are a prominent feature of atherosclerotic plaques. Previous studies have shown that human monocytes or resident mouse peritoneal macrophages accumulate CE in response to low density lipoprotein (LDL) only when the LDL has been appropriately chemically modified. By contrast, we report here that J774 macrophages accumulate large amounts of CE when incubated with unmodified LDL. The CE is stored in oil red O-positive droplets, which have the typical appearance of foam cell inclusions by electron microscopy. The fatty acid moieties of the cellular CE are enriched in oleate unlike those of LDL-CE, which are enriched in linoleate, indicating that the LDL-CE undergoes hydrolysis and reesterification by acyl CoA:cholesterol acyltransferase. Studies with 125I-labeled LDL at both 4 degrees C and 37 degrees C indicate that the LDL is internalized by a specific receptor that has several characteristics in common with the apolipoprotein B/E (apo B/E) receptor. However, in comparison with fibroblasts, the LDL receptor and 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase activity in J774 cells are relatively resistant to down-regulation by LDL or 25-hydroxycholesterol, leading to receptor-mediated CE storage. In addition, J774 cells appear to accumulate CE from LDL internalized by nonspecific means. Thus, macrophage-like cells can accumulate CE in response to unmodified LDL by both nonspecific and receptor-mediated processes.

  4. Phagocytic and chemiluminescent responses of mouse peritoneal macrophages to living and killed Salmonella typhimurium and other bacteria

    SciTech Connect

    Tomita, T.; Blumenstock, E.; Kanegasaki, S.

    1981-06-01

    In the presence of luminol, resident as well as thioglycolate-induced and immunized macrophages emitted chemiluminescence more efficiently when the cells were exposed to living Salmonella typhimurium than when they were exposed to the same bacterium killed by ultraviolet light or heat. This phenomenon was observed whether or not the bacterium was opsonized. The different response to living and killed bacteria was also found with Escherichia coli, Pseudomonas aeruginosa, Proteus morganii, and Enterobacter aerogenes, but not with Shigella sonnei, Klebsiella pneumoniae, and Propionibacterium acnes. The results suggest that macrophages respond better to living, motile bacteria than to nonmotile or killed bacteria. The experimental results obtained with motility mutants of S. typhimurium, E. coli, and P. aeruginosa confirm that macrophages exposed to the motile bacteria emit chemiluminescence more efficiently and ingest the motile bacteria at a much faster rate than the nonmotile bacteria.

  5. Lung Macrophage Diversity and Asthma

    PubMed Central

    2016-01-01

    Macrophages (MPs) are one of the most prominent leukocyte populations in the lung and, in many ways, a forgotten player in asthma pathogenesis. Diverse functions in asthma initiation and maintenance in chronic disease have been demonstrated, which has led to confusion as to if pulmonary MPs are agents of good or evil in asthma. Much of this is due to the wide diversity of MP populations in the lung, many of which are inaccessible experimentally in most clinical studies. This review frames lung MP biology in the context of location, phenotype, function, and response phase in asthma pathogenesis. It also assesses new findings regarding MP diversity that have challenged old dogmas and generates new ways to understand how MPs function. PMID:27027949

  6. Schistosoma japonicum infection induces macrophage polarization

    PubMed Central

    Xu, Jingwei; Zhang, Hao; Chen, Lin; Zhang, Donghui; Ji, Minjun; Wu, Haiwei; Wu, Guanling

    2014-01-01

    Abstract The role of macrophages (Mφ) as the first line of host defense is well accepted. These cells play a central role in orchestrating crucial functions during schistosomal infection. Thus, understanding the functional diversity of these cells in the process of infection as well as the mechanisms underlying these events is crucial for developing disease control strategies. In this study, we adopted a Mφ polarization recognition system. M1 macrophage was characterized by expressing CD16/32, IL-12 and iNOS. M2 macrophage was characterized by expressing CD206, IL-10 and arg-1. In vivo (mouse peritoneal macrophages of different infection stages were obtained) and in vitro (different S. japonicum antigens were used to stimulate RAW264.7) were characterized by using the above mentioned system. NCA and ACA stimulated RAW264.7 express significantly higher levels of IL-12 while significantly higher levels of IL-10 were detected after soluble egg antigen (SEA) stimulation. The results showed that dramatic changes of antigen in the microenvironment before and after egg production led to macrophage polarization. Furthermore, through TLR blocking experiments, the TLR4 signaling pathway was found to play a role in the process of macrophage polarization toward M1. Our data suggest that macrophage polarization during S. japonicum infection had significant effects on host immune responses to S. japonicum. PMID:25050114

  7. Macrophages and Dendritic Cells: Partners in Atherogenesis.

    PubMed

    Cybulsky, Myron I; Cheong, Cheolho; Robbins, Clinton S

    2016-02-19

    Atherosclerosis is a complex chronic disease. The accumulation of myeloid cells in the arterial intima, including macrophages and dendritic cells (DCs), is a feature of early stages of disease. For decades, it has been known that monocyte recruitment to the intima contributes to the burden of lesion macrophages. Yet, this paradigm may require reevaluation in light of recent advances in understanding of tissue macrophage ontogeny, their capacity for self-renewal, as well as observations that macrophages proliferate throughout atherogenesis and that self-renewal is critical for maintenance of macrophages in advanced lesions. The rate of atherosclerotic lesion formation is profoundly influenced by innate and adaptive immunity, which can be regulated locally within atherosclerotic lesions, as well as in secondary lymphoid organs, the bone marrow and the blood. DCs are important modulators of immunity. Advances in the past decade have cemented our understanding of DC subsets, functions, hematopoietic origin, gene expression patterns, transcription factors critical for differentiation, and provided new tools for study of DC biology. The functions of macrophages and DCs overlap to some extent, thus it is important to reassess the contributions of each of these myeloid cells taking into account strict criteria of cell identification, ontogeny, and determine whether their key roles are within atherosclerotic lesions or secondary lymphoid organs. This review will highlight key aspect of macrophage and DC biology, summarize how these cells participate in different stages of atherogenesis and comment on complexities, controversies, and gaps in knowledge in the field.

  8. Visualization and genetic modification of resident brain microglia using lentiviral vectors regulated by microRNA-9.

    PubMed

    Åkerblom, Malin; Sachdeva, Rohit; Quintino, Luis; Wettergren, Erika Elgstrand; Chapman, Katie Z; Manfre, Giuseppe; Lindvall, Olle; Lundberg, Cecilia; Jakobsson, Johan

    2013-01-01

    Functional studies of resident microglia require molecular tools for their genetic manipulation. Here we show that microRNA-9-regulated lentiviral vectors can be used for the targeted genetic modification of resident microglia in the rodent brain. Using transgenic reporter mice, we demonstrate that murine microglia lack microRNA-9 activity, whereas most other cells in the brain express microRNA-9. Injection of microRNA-9-regulated vectors into the adult rat brain induces transgene expression specifically in cells with morphological features typical of ramified microglia. The majority of transgene-expressing cells colabels with the microglia marker Iba1. We use this approach to visualize and isolate activated resident microglia without affecting circulating and infiltrating monocytes or macrophages in an excitotoxic lesion model in rat striatum. The microRNA-9-regulated vectors described here are a straightforward and powerful tool that facilitates functional studies of resident microglia.

  9. The Many Alternative Faces of Macrophage Activation.

    PubMed

    Hume, David A

    2015-01-01

    Monocytes and macrophages provide the first line of defense against pathogens. They also initiate acquired immunity by processing and presenting antigens and provide the downstream effector functions. Analysis of large gene expression datasets from multiple cells and tissues reveals sets of genes that are co-regulated with the transcription factors that regulate them. In macrophages, the gene clusters include lineage-specific genes, interferon-responsive genes, early inflammatory genes, and genes required for endocytosis and lysosome function. Macrophages enter tissues and alter their function to deal with a wide range of challenges related to development and organogenesis, tissue injury, malignancy, sterile, or pathogenic inflammatory stimuli. These stimuli alter the gene expression to produce "activated macrophages" that are better equipped to eliminate the cause of their influx and to restore homeostasis. Activation or polarization states of macrophages have been classified as "classical" and "alternative" or M1 and M2. These proposed states of cells are not supported by large-scale transcriptomic data, including macrophage-associated signatures from large cancer tissue datasets, where the supposed markers do not correlate with other. Individual macrophage cells differ markedly from each other, and change their functions in response to doses and combinations of agonists and time. The most studied macrophage activation response is the transcriptional cascade initiated by the TLR4 agonist lipopolysaccharide. This response is reviewed herein. The network topology is conserved across species, but genes within the transcriptional network evolve rapidly and differ between mouse and human. There is also considerable divergence in the sets of target genes between mouse strains, between individuals, and in other species such as pigs. The deluge of complex information related to macrophage activation can be accessed with new analytical tools and new databases that provide

  10. Interactions between muscle and the immune system during modified musculoskeletal loading

    NASA Technical Reports Server (NTRS)

    Tidball, James G.

    2002-01-01

    Interactions between the immune system and skeletal muscle may play a significant role in modulating the course of muscle injury and repair after modified musculoskeletal loading. Current evidence indicates that activation of the complement system is an early event during modified loading, which then leads to inflammatory cell invasion. However, the functions of those inflammatory cells are complex and they seem to be capable of promoting additional injury and repair. Recent findings implicate an early invading neutrophil population in increasing muscle damage that is detected by the presence of muscle membrane lesions. Macrophages that invade subsequently serve to remove cellular debris, and seem to promote repair. However, macrophages also have the ability to increase damage in muscle in which there is an impaired capacity to generate nitric oxide. In vivo and in vitro evidence indicates that muscle-derived nitric oxide can serve an important role in protecting muscle from membrane damage by invading inflammatory cells. Collectively, these findings indicate that the dynamic balance between inflammatory cells, the complement system, and muscle-derived free radicals can play important roles in the secondary damage of muscle during modified musculoskeletal loading.

  11. Redesigning journal club in residency

    PubMed Central

    Al Achkar, Morhaf

    2016-01-01

    The gap between production and implementation of knowledge is the main reason for the suboptimal quality of health care. To eliminate this gap and improve the quality of patient care, journal club (JC) in graduate medical education provides an opportunity for learning the skills of evidence-based medicine. JC, however, continues to face many challenges mainly due to poorly defined goals, inadequate preparation, and lack of interest. This article presents an innovative model to prepare and present JC based on three pillars: dialogical learning through group discussion, mentored residents as peer teachers, and including JC as part of a structured curriculum to learn evidence-based medicine. This engaging model has the potential to transform JC from a moribund session that is daunting for residents into a lively discussion to redefine clinical practice using the most current evidence. PMID:27313486

  12. Reconceptualizing Benchmarks for Residency Training

    PubMed Central

    2017-01-01

    Postgraduate medical education (PGME) is currently transitioning to a competency-based framework. This model clarifies the desired outcome of residency training - competence. However, since the popularization of Ericsson's work on the effect of time and deliberate practice on performance level, his findings have been applied in some areas of residency training. Though this may be grounded in a noble effort to maximize patient well-being, it imposes unrealistic expectations on trainees. This work aims to demonstrate the fundamental flaws of this application and therefore the lack of validity in using Ericsson's work to develop training benchmarks at the postgraduate level as well as expose potential harms in doing so.

  13. Muscle shape consistency and muscle volume prediction of thigh muscles.

    PubMed

    Mersmann, F; Bohm, S; Schroll, A; Boeth, H; Duda, G; Arampatzis, A

    2015-04-01

    The present study investigated the applicability of a muscle volume prediction method using only the muscle length (L(M)), the maximum anatomical cross-sectional area (ACSA(max)), and a muscle-specific shape factor (p) on the quadriceps vastii. L(M), ACSA(max), muscle volume, and p were obtained from magnetic resonance images of the vastus intermedius (VI), lateralis (VL), and medialis (VM) of female (n = 20) and male (n = 17) volleyball athletes. The average p was used to predict muscle volumes (V(p)) using the equation V(p)  = p × ACSA(max)  × L(M). Although there were significant differences in the muscle dimensions between male and female athletes, p was similar and on average 0.582, 0.658, 0.543 for the VI, VL, and VM, respectively. The position of ACSA(max) showed low variability and was at 57%, 60%, and 81% of the thigh length for VI, VL, and VM. Further, there were no significant differences between measured and predicted muscle volumes with root mean square differences of 5-8%. These results suggest that the muscle shape of the quadriceps vastii is independent of muscle dimensions or sex and that the prediction method could be sensitive enough to detect changes in muscle volume related to degeneration, atrophy, or hypertrophy.

  14. The Role of Macrophages in Immunology

    PubMed Central

    Elhelu, Mohamed A.

    1983-01-01

    Macrophages play a significant part in immunity and immune responses. They assume a defensive role exhibited by their ability to carry on phagocytosis of parasites and microbes. They regulate lymphocyte activation and proliferation and they are essential in the activation process of T- and B-lymphocytes by antigens and allogenic cells. Enhanced bactericidal activity of “activated macrophages” is based on immunologically linked mechanisms involving lymphocytes. Macrophages kill ingested microbes but the mechanism by which this is accomplished is not completely understood. This paper discusses the role of macrophages in relation to immunity. PMID:6343621

  15. The killing of macrophages by Corynebacterium ulcerans.

    PubMed

    Hacker, Elena; Ott, Lisa; Schulze-Luehrmann, Jan; Lührmann, Anja; Wiesmann, Veit; Wittenberg, Thomas; Burkovski, Andreas

    2016-01-01

    Corynebacterium ulcerans is an emerging pathogen transmitted by a zoonotic pathway with a very broad host spectrum to humans. Despite rising numbers of infections and potentially fatal outcomes, data on the molecular basis of pathogenicity are scarce. In this study, the interaction of 2 C. ulcerans isolates - one from an asymptomatic dog, one from a fatal case of human infection - with human macrophages was investigated. C. ulcerans strains were able to survive in macrophages for at least 20 hours. Uptake led to delay of phagolysosome maturation and detrimental effects on the macrophages as deduced from cytotoxicity measurements and FACS analyses. The data presented here indicate a high infectious potential of this emerging pathogen.

  16. Macrophages and therapeutic resistance in cancer

    PubMed Central

    Ruffell, Brian; Coussens, Lisa M.

    2015-01-01

    How neoplastic cells respond to therapy is not solely dependent on the complexity of genomic aberrations they harbor, but is also regulated by numerous dynamic properties of the tumor microenvironment. Identifying and targeting critical pathways that improve therapeutic efficacy by bolstering anti-tumor immune responses holds great potential for improving outcomes and impacting long-term patient survival. Macrophages are key regulators of homeostatic tissue and tumor microenvironments; thus therapeutics impacting macrophage presence and/or bioactivity have shown promise in preclinical models, and are now being evaluated in the clinic. This review discusses the molecular/cellular pathways thus far identified whereby macrophages mediate therapeutic responses. PMID:25858805

  17. Migration Inhibitory Factor and Macrophage Bactericidal Function

    PubMed Central

    Simon, Harvey B.; Sheagren, John N.

    1972-01-01

    A homogeneous population of immunologically active lymphocytes was obtained from peritoneal exudates of guinea pigs with delayed hypersensitivity to bovine gamma globulin (BGG). The lymphocytes were cultured with and without BGG for 24 hr, and cell-free supernatant fluids were then assayed simultaneously for their ability to influence two in vitro parameters of macrophage function: migration from capillary tubes and bactericidal capacity. In four consecutive experiments, supernatants from antigenically stimulated lymphocytes exhibited substantial migration-inhibitory-factor activity without enhancing the ability of macrophages to kill Listeria monocytogenes. Lymphocyte lysates were inactive in both assays. Possible mechanisms of lymphocyte-macrophage interactions are discussed. PMID:4120244

  18. Direct measurement of oxidative and nitrosative stress dynamics in Salmonella inside macrophages

    PubMed Central

    van der Heijden, Joris; Bosman, Else S.; Reynolds, Lisa A.; Finlay, B. Brett

    2015-01-01

    Many significant bacterial pathogens have evolved virulence mechanisms to evade degradation and exposure to reactive oxygen (ROS) and reactive nitrogen species (RNS), allowing them to survive and replicate inside their hosts. Due to the highly reactive and short-lived nature of ROS and RNS, combined with limitations of conventional detection agents, the mechanisms underlying these evasion strategies remain poorly understood. In this study, we describe a system that uses redox-sensitive GFP to nondisruptively measure real-time fluctuations in the intrabacterial redox environment. Using this system coupled with high-throughput microscopy, we report the intrabacterial redox dynamics of Salmonella enterica Typhimurium (S. Typhimurium) residing inside macrophages. We found that the bacterial SPI-2 type III secretion system is required for ROS evasion strategies and this evasion relies on an intact Salmonella-containing vacuole (SCV) within which the bacteria reside during infection. Additionally, we found that cytosolic bacteria that escape the SCV experience increased redox stress in human and murine macrophages. These results highlight the existence of specialized evasion strategies used by intracellular pathogens that either reside inside a vacuole or “escape” into the cytosol. Taken together, the use of redox-sensitive GFP inside Salmonella significantly advances our understanding of ROS and RNS evasion strategies during infection. This technology can also be applied to measuring bacterial oxidative and nitrosative stress dynamics under different conditions in a wide variety of bacteria. PMID:25548165

  19. [Medical ethics in residency training].

    PubMed

    Civaner, Murat; Sarikaya, Ozlem; Balcioğlu, Harun

    2009-04-01

    Medical ethics education in residency training is one of the hot topics of continuous medical education debates. Its importance and necessity is constantly stressed in declarations and statements on national and international level. Parallel to the major structural changes in the organization and the finance model of health care system, patient-physician relationship, identity of physicianship, social perception and status of profession are changing. Besides, scientific developments and technological advancements create possibilities that never exists before, and bring new ethical dilemmas along with. To be able to transplant human organs has created two major problems for instance; procurement of organs in sufficient numbers, and allocating them to the patients in need by using some prioritizing criteria. All those new and challenging questions force the health care workers to find authentic and justifiable solutions while keeping the basic professional values. In that sense, proper medical ethics education in undergraduate and postgraduate term that would make physician-to-be's and student-physicians acquire the core professional values and skill to notice, analyze and develop justifiable solutions to ethical problems is paramount. This article aims to express the importance of medical ethics education in residency training, and to propose major topics and educational methods to be implemented into. To this aim, first, undergraduate medical education, physician's working conditions, the exam of selection for residency training, and educational environment were revised, and then, some topics and educational methods, which are oriented to educate physicians regarding the professional values that they should have, were proposed.

  20. Guardians of the Gut – Murine Intestinal Macrophages and Dendritic Cells

    PubMed Central

    Gross, Mor; Salame, Tomer-Meir; Jung, Steffen

    2015-01-01

    Intestinal mononuclear phagocytes find themselves in a unique environment, most prominently characterized by its constant exposure to commensal microbiota and food antigens. This anatomic setting has resulted in a number of specializations of the intestinal mononuclear phagocyte compartment that collectively contribute the unique steady state immune landscape of the healthy gut, including homeostatic innate lymphoid cells, B, and T cell compartments. As in other organs, macrophages and dendritic cells (DCs) orchestrate in addition the immune defense against pathogens, both in lymph nodes and mucosa-associated lymphoid tissue. Here, we will discuss origins and functions of intestinal DCs and macrophages and their respective subsets, focusing largely on the mouse and cells residing in the lamina propria. PMID:26082775

  1. Cryotherapy Reduces Inflammatory Response Without Altering Muscle Regeneration Process and Extracellular Matrix Remodeling of Rat Muscle

    PubMed Central

    Vieira Ramos, Gracielle; Pinheiro, Clara Maria; Messa, Sabrina Peviani; Delfino, Gabriel Borges; Marqueti, Rita de Cássia; Salvini, Tania de Fátima; Durigan, Joao Luiz Quagliotti

    2016-01-01

    The application of cryotherapy is widely used in sports medicine today. Cooling could minimize secondary hypoxic injury through the reduction of cellular metabolism and injury area. Conflicting results have also suggested cryotherapy could delay and impair the regeneration process. There are no definitive findings about the effects of cryotherapy on the process of muscle regeneration. The aim of the present study was to evaluate the effects of a clinical-like cryotherapy on inflammation, regeneration and extracellular matrix (ECM) remodeling on the Tibialis anterior (TA) muscle of rats 3, 7 and 14 days post-injury. It was observed that the intermittent application of cryotherapy (three 30-minute sessions, every 2 h) in the first 48 h post-injury decreased inflammatory processes (mRNA levels of TNF-α, NF-κB, TGF-β and MMP-9 and macrophage percentage). Cryotherapy did not alter regeneration markers such as injury area, desmin and Myod expression. Despite regulating Collagen I and III and their growth factors, cryotherapy did not alter collagen deposition. In summary, clinical-like cryotherapy reduces the inflammatory process through the decrease of macrophage infiltration and the accumulation of the inflammatory key markers without influencing muscle injury area and ECM remodeling. PMID:26725948

  2. Cryotherapy Reduces Inflammatory Response Without Altering Muscle Regeneration Process and Extracellular Matrix Remodeling of Rat Muscle.

    PubMed

    Vieira Ramos, Gracielle; Pinheiro, Clara Maria; Messa, Sabrina Peviani; Delfino, Gabriel Borges; Marqueti, Rita de Cássia; Salvini, Tania de Fátima; Durigan, Joao Luiz Quagliotti

    2016-01-04

    The application of cryotherapy is widely used in sports medicine today. Cooling could minimize secondary hypoxic injury through the reduction of cellular metabolism and injury area. Conflicting results have also suggested cryotherapy could delay and impair the regeneration process. There are no definitive findings about the effects of cryotherapy on the process of muscle regeneration. The aim of the present study was to evaluate the effects of a clinical-like cryotherapy on inflammation, regeneration and extracellular matrix (ECM) remodeling on the Tibialis anterior (TA) muscle of rats 3, 7 and 14 days post-injury. It was observed that the intermittent application of cryotherapy (three 30-minute sessions, every 2 h) in the first 48 h post-injury decreased inflammatory processes (mRNA levels of TNF-α, NF-κB, TGF-β and MMP-9 and macrophage percentage). Cryotherapy did not alter regeneration markers such as injury area, desmin and Myod expression. Despite regulating Collagen I and III and their growth factors, cryotherapy did not alter collagen deposition. In summary, clinical-like cryotherapy reduces the inflammatory process through the decrease of macrophage infiltration and the accumulation of the inflammatory key markers without influencing muscle injury area and ECM remodeling.

  3. Involvement of Cbl-b-mediated macrophage inactivation in insulin resistance

    PubMed Central

    Abe, Tomoki; Hirasaka, Katsuya; Nikawa, Takeshi

    2017-01-01

    Aging and overnutrition cause obesity in rodents and humans. It is well-known that obesity causes various diseases by producing insulin resistance (IR). Macrophages infiltrate the adipose tissue (AT) of obese individuals and cause chronic low-level inflammation associated with IR. Macrophage infiltration is regulated by the chemokines that are released from hypertrophied adipocytes and the immune cells in AT. Saturated fatty acids are recognized by toll-like receptor 4 (TLR4) and induce inflammatory responses in AT macrophages (ATMs). The inflammatory cytokines that are released from activated ATMs promote IR in peripheral organs, such as the liver, skeletal muscle and AT. Therefore, ATM activation is a therapeutic target for IR in obesity. The ubiquitin ligase Casitas b-lineage lymphoma-b (Cbl-b) appears to potently suppress macrophage migration and activation. Cbl-b is highly expressed in leukocytes and negatively regulates signals associated with migration and activation. Cbl-b deficiency enhances ATM accumulation and IR in aging- and diet-induced obese mice. Cbl-b inhibits migration-related signals and SFA-induced TLR4 signaling in ATMs. Thus, targeting Cbl-b may be a potential therapeutic strategy to reduce the IR induced by ATM activation. In this review, we summarize the regulatory functions of Cbl-b in ATMs. PMID:28344752

  4. Lipotoxicity in macrophages: evidence from diseases associated with the metabolic syndrome.

    PubMed

    Prieur, Xavier; Roszer, Tamás; Ricote, Mercedes

    2010-03-01

    Accumulation of lipid metabolites within non-adipose tissues can induce chronic inflammation by promoting macrophage infiltration and activation. Oxidized and glycated lipoproteins, free fatty acids, free cholesterol, triacylglycerols, diacylglycerols and ceramides have long been known to induce cellular dysfunction through their pro-inflammatory and pro-apoptotic properties. Emerging evidence suggests that macrophage activation by lipid metabolites and further modulation by lipid signaling represents a common pathogenic mechanism underlying lipotoxicity in atherosclerosis, obesity-associated insulin resistance and inflammatory diseases related to metabolic syndrome such as liver steatosis and chronic kidney disease. In this review, we discuss the latest discoveries that support the role of lipids in modulating the macrophage phenotype in different metabolic diseases. We describe the common mechanisms by which lipid derivatives, through modulation of macrophage function, promote plaque instability in the arterial wall, impair insulin responsiveness and contribute to inflammatory liver, muscle and kidney disease. We discuss the molecular mechanism of lipid activation of pro-inflammatory pathways (JNK, NFkappaB) and the key roles played by the PPAR and LXR nuclear receptors-lipid sensors that link lipid metabolism and inflammation.

  5. The Metabolic Prospective and Redox Regulation of Macrophage Polarization

    PubMed Central

    He, Chao; Carter, A Brent

    2016-01-01

    Macrophage plasticity is an important feature of these innate immune cells. Macrophage phenotypes are divided into two categories, the classically activated macrophages (CAM, M1 phenotype) and the alternatively activated macrophages (AAM, M2 phenotype). M1 macrophages are commonly associated with the generation of proinflammatory cytokines, whereas M2 macrophages are anti-inflammatory and often associated with tumor progression and fibrosis development. Macrophages produce high levels of reactive oxygen species (ROS). Recent evidence suggests ROS can potentially regulate macrophage phenotype. In addition, macrophages phenotypes are closely related to their metabolic patterns, particularly fatty acid/cholesterol metabolism. In this review, we briefly summarize recent advances in macrophage polarization with special attention to their relevance to specific disease conditions and metabolic regulation of polarization. Understanding these metabolic switches can facilitate the development of targeted therapies for various diseases. PMID:26962470

  6. Pneumolysin activates macrophage lysosomal membrane permeabilization and executes apoptosis by distinct mechanisms without membrane pore formation.

    PubMed

    Bewley, Martin A; Naughton, Michael; Preston, Julie; Mitchell, Andrea; Holmes, Ashleigh; Marriott, Helen M; Read, Robert C; Mitchell, Timothy J; Whyte, Moira K B; Dockrell, David H

    2014-10-07

    pneumoniae, the commonest cause of bacterial pneumonia, expresses the toxin pneumolysin, which can make holes in cell surfaces, causing tissue damage. Macrophages, resident immune cells essential for responses to bacteria in tissues, activate a program of cell suicide called apoptosis, maximizing bacterial clearance and limiting harmful inflammation. We examined pneumolysin's role in activating this response. We demonstrate that pneumolysin did not directly form holes in cells to trigger apoptosis and show that pneumolysin has two distinct roles which require only part of the molecule. Pneumolysin and other bacterial factors released by bacteria that have not been eaten by macrophages activate macrophages to release inflammatory factors but also make the cell compartment containing ingested bacteria leaky. Once inside the cell, pneumolysin ensures that the bacteria activate macrophage apoptosis, rather than necrosis, enhancing bacterial killing and limiting inflammation. This dual response to pneumolysin is critical for an effective immune response to S. pneumoniae.

  7. Green tea extract decreases muscle pathology and NF-κB immunostaining in regenerating muscle fibers of mdx mice

    PubMed Central

    Evans, Nicholas P.; Call, Jarrod A.; Bassaganya-Riera, Josep; Robertson, John L.; Grange, Robert W.

    2009-01-01

    BACKGROUND & AIMS Duchenne muscular dystrophy is a debilitating genetic disorder characterized by severe muscle wasting and early death in afflicted boys. The primary cause of this disease is mutations in the dystrophin gene resulting in massive muscle degeneration and inflammation. The purpose of this study was to determine if dystrophic muscle pathology and inflammation were decreased by pre-natal and early dietary intervention with green tea extract. METHODS Mdx breeder mice and pups were fed diets containing 0.25% or 0.5% green tea extract and compared to untreated mdx and C57BL/6J mice. Serum creatine kinase was assessed as a systemic indicator of muscle damage. Quantitative histopathological and immunohistochemical techniques were used to determine muscle pathology, macrophage infiltration, and NF-κB localization. RESULTS Early treatment of mdx mice with green tea extract significantly decreased serum creatine kinase by ~85% at age 42 days (P≤0.05). In these mice, the area of normal fiber morphology was increased by as much as ~32% (P≤0.05). The primary histopathological change was a ~21% decrease in the area of regenerating fibers (P≤0.05). NF-κB staining in regenerating muscle fibers was also significantly decreased in green tea extract-treated mdx mice when compared to untreated mdx mice. CONCLUSION Early treatment with green tea extract decreases dystrophic muscle pathology potentially by regulating NF-κB activity in regenerating muscle fibers. PMID:19897286

  8. Muscle-specific microRNA-206 targets multiple components in dystrophic skeletal muscle representing beneficial adaptations.

    PubMed

    Amirouche, Adel; Jahnke, Vanessa E; Lunde, John A; Koulmann, Nathalie; Freyssenet, Damien G; Jasmin, Bernard J

    2017-03-01

    Over the last several years, converging lines of evidence have indicated that miR-206 plays a pivotal role in promoting muscle differentiation and regeneration, thereby potentially impacting positively on the progression of neuromuscular disorders, including Duchenne muscular dystrophy (DMD). Despite several studies showing the regulatory function of miR-206 on target mRNAs in skeletal muscle cells, the effects of overexpression of miR-206 in dystrophic muscles remain to be established. Here, we found that miR-206 overexpression in mdx mouse muscles simultaneously targets multiple mRNAs and proteins implicated in satellite cell differentiation, muscle regeneration, and at the neuromuscular junction. Overexpression of miR-206 also increased the levels of several muscle-specific mRNAs/proteins, while enhancing utrophin A expression at the sarcolemma. Finally, we also observed that the increased expression of miR-206 in dystrophin-deficient mouse muscle decreased the production of proinflammatory cytokines and infiltration of macrophages. Taken together, our results show that miR-206 acts as a pleiotropic regulator that targets multiple key mRNAs and proteins expected to provide beneficial adaptations in dystrophic muscle, thus highlighting its therapeutic potential for DMD.

  9. Clinical Evaluation in a Family Medicine Residency.

    ERIC Educational Resources Information Center

    Herman, James M.; And Others

    1985-01-01

    A study assessed (1) the validity of the Bowman Gray School of Medicine evaluation instrument regarding the occurrence of halo effects and (2) possible relationships between the faculty's evaluations of the residents and the residents' cognitive knowledge and productivity. (MLW)

  10. 38 CFR 51.110 - Resident assessment.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ...) PER DIEM FOR NURSING HOME CARE OF VETERANS IN STATE HOMES Standards § 51.110 Resident assessment. The...) Review of assessments. The nursing facility management must examine each resident no less than once...

  11. 38 CFR 51.110 - Resident assessment.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ...) PER DIEM FOR NURSING HOME CARE OF VETERANS IN STATE HOMES Standards § 51.110 Resident assessment. The...) Review of assessments. The nursing facility management must examine each resident no less than once...

  12. 38 CFR 51.110 - Resident assessment.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ...) PER DIEM FOR NURSING HOME CARE OF VETERANS IN STATE HOMES Standards § 51.110 Resident assessment. The...) Review of assessments. The nursing facility management must examine each resident no less than once...

  13. 38 CFR 51.110 - Resident assessment.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ...) PER DIEM FOR NURSING HOME CARE OF VETERANS IN STATE HOMES Standards § 51.110 Resident assessment. The...) Review of assessments. The nursing facility management must examine each resident no less than once...

  14. Macrophage differentiation and function in atherosclerosis; opportunities for therapeutic intervention?

    PubMed Central

    Williams, Howell J.; Fisher, Edward A.; Greaves, David R.

    2013-01-01

    The macrophage is exquisitely sensitive to its microenvironment, as demonstrated primarily through in vitro study. Changes in macrophage phenotype and function within the atherosclerotic plaque have profound consequences for plaque biology, including rupture and arterial thrombosis leading to clinical events such as myocardial infarction. We review the evidence for dynamic changes in macrophage numbers and macrophage differentiation within the atherosclerotic plaque microenvironment and discuss potential approaches to target macrophage differentiation for therapeutic benefit in cardiovascular disease. PMID:22572544

  15. Microglia and monocyte-derived macrophages: functionally distinct populations that act in concert in CNS plasticity and repair

    PubMed Central

    London, Anat; Cohen, Merav; Schwartz, Michal

    2013-01-01

    Functional macrophage heterogeneity is recognized outside the central nervous system (CNS), where alternatively activated macrophages can perform immune-resolving functions. Such functional heterogeneity was largely ignored in the CNS, with respect to the resident microglia and the myeloid-derived cells recruited from the blood following injury or disease, previously defined as blood-derived microglia; both were indistinguishably perceived detrimental. Our studies have led us to view the myeloid-derived infiltrating cells as functionally distinct from the resident microglia, and accordingly, to name them monocyte-derived macrophages (mo-MΦ). Although microglia perform various maintenance and protective roles, under certain conditions when they can no longer provide protection, mo-MΦ are recruited to the damaged CNS; there, they act not as microglial replacements but rather assistant cells, providing activities that cannot be timely performed by the resident cells. Here, we focus on the functional heterogeneity of microglia/mo-MΦ, emphasizing that, as opposed to the mo-MΦ, microglia often fail to timely acquire the phenotype essential for CNS repair. PMID:23596391

  16. Treatment with selectin blocking antibodies after lengthening contractions of mouse muscle blunts neutrophil accumulation but does not reduce damage.

    PubMed

    Sloboda, Darcée D; Brooks, Susan V

    2016-01-01

    P- and E-selectins are expressed on the surface of endothelial cells and may contribute to neutrophil recruitment following injurious lengthening contractions of skeletal muscle. Blunting neutrophil, but not macrophage, accumulation after lengthening contractions may provide a therapeutic benefit as neutrophils exacerbate damage to muscle fibers, while macrophages promote repair. In this study, we tested the hypothesis that P- and E-selectins contribute to neutrophil, but not macrophage, accumulation in muscles after contraction-induced injury, and that reducing neutrophil accumulation by blocking the selectins would be sufficient to reduce damage to muscle fibers. To test our hypothesis, we treated mice with antibodies to block P- and E-selectin function and assessed leukocyte accumulation and damage in muscles 2 days after lengthening contractions. Treatment with P/E-selectin blocking antibodies reduced neutrophil content by about half in muscles subjected to lengthening contractions. In spite of the reduction in neutrophil accumulation, we did not detect a decrease in damage 2 days after lengthening contractions. We conclude that P- and/or E-selectin contribute to the neutrophil accumulation associated with contraction-induced muscle damage and that only a portion of the neutrophils that typically accumulate following injurious lengthening contractions is sufficient to induce muscle fiber damage and force deficits. Thus, therapeutic interventions based on blocking the selectins or other adhesion proteins will have to reduce neutrophil numbers by more than 50% in order to provide a benefit.

  17. The role of satellite cells in muscle hypertrophy.

    PubMed

    Blaauw, Bert; Reggiani, Carlo

    2014-02-01

    The role of satellite cells in muscle hypertrophy has long been a debated issue. In the late 1980s it was shown that proteins remain close to the myonucleus responsible for its synthesis, giving rise to the idea of a nuclear domain. This, together with the observation that during various models of muscle hypertrophy there is an activation of the muscle stem cells, i.e. satellite cells, lead to the idea that satellite cell activation is required for muscle hypertrophy. Thus, satellite cells are not only responsible for muscle repair and regeneration, but also for hypertrophic growth. Further support for this line of thinking was obtained after studies showing that irradiation of skeletal muscle, and therefore elimination of all satellite cells, completely prevented overload-induced hypertrophy. Recently however, using different transgenic approaches, it has become clear that muscle hypertrophy can occur without a contribution of satellite cells, even though in most situations of muscle hypertrophy satellite cells are activated. In this review we will discuss the contribution of satellite cells, and other muscle-resident stem cells, to muscle hypertrophy both in mice as well as in humans.

  18. Functional heterogeneity of side population cells in skeletal muscle

    SciTech Connect

    Uezumi, Akiyoshi; Ojima, Koichi; Fukada, So-ichiro; Ikemoto, Madoka; Masuda, Satoru; Miyagoe-Suzuki, Yuko; Takeda, Shin'ichi . E-mail: takeda@ncnp.go.jp

    2006-03-17

    Skeletal muscle regeneration has been exclusively attributed to myogenic precursors, satellite cells. A stem cell-rich fraction referred to as side population (SP) cells also resides in skeletal muscle, but its roles in muscle regeneration remain unclear. We found that muscle SP cells could be subdivided into three sub-fractions using CD31 and CD45 markers. The majority of SP cells in normal non-regenerating muscle expressed CD31 and had endothelial characteristics. However, CD31{sup -}CD45{sup -} SP cells, which are a minor subpopulation in normal muscle, actively proliferated upon muscle injury and expressed not only several regulatory genes for muscle regeneration but also some mesenchymal lineage markers. CD31{sup -}CD45{sup -} SP cells showed the greatest myogenic potential among three SP sub-fractions, but indeed revealed mesenchymal potentials in vitro. These SP cells preferentially differentiated into myofibers after intramuscular transplantation in vivo. Our results revealed the heterogeneity of muscle SP cells and suggest that CD31{sup -}CD45{sup -} SP cells participate in muscle regeneration.

  19. Amphibian macrophage development and antiviral defenses.

    PubMed

    Grayfer, Leon; Robert, Jacques

    2016-05-01

    Macrophage lineage cells represent the cornerstone of vertebrate physiology and immune defenses. In turn, comparative studies using non-mammalian animal models have revealed that evolutionarily distinct species have adopted diverse molecular and physiological strategies for controlling macrophage development and functions. Notably, amphibian species present a rich array of physiological and environmental adaptations, not to mention the peculiarity of metamorphosis from larval to adult stages of development, involving drastic transformation and differentiation of multiple new tissues. Thus it is not surprising that different amphibian species and their respective tadpole and adult stages have adopted unique hematopoietic strategies. Accordingly and in order to establish a more comprehensive view of these processes, here we review the hematopoietic and monopoietic strategies observed across amphibians, describe the present understanding of the molecular mechanisms driving amphibian, an in particular Xenopus laevis macrophage development and functional polarization, and discuss the roles of macrophage-lineage cells during ranavirus infections.

  20. L-arginine independent macrophage tumor cytotoxicity

    SciTech Connect

    Klostergaard, J.; Leroux, M.E. )

    1989-12-29

    We have investigated the role of L-arginine in macrophage tumor cytotoxicity in coculture. L929, EMT-6, MCA-26, and P815 targets were all susceptible to cytolysis by activated macrophages when cocultured in medium containing L-arginine. When cocultured in arginine-free medium, these targets displayed comparable or even higher levels of lysis. L1210 targets were lytically resistant under either condition. However, 59Fe release from this target did reflect strong dependence on the presence of arginine. The structural analogue, NG-monomethyl-L-arginine, was an effective inhibitor of iron-release from L1210 targets cocultured with activated macrophages, whereas it had minimal inhibitory effects on release of 51Cr from cocultured L929 cells. These results suggest that the L-arginine requiring cytotoxic pathway of activated macrophage is independent of major effector mechanisms involved in tumor cell lysis.

  1. Generation and Characterization of Mouse Regulatory Macrophages.

    PubMed

    Carretero-Iglesia, Laura; Hill, Marcelo; Cuturi, Maria Cristina

    2016-01-01

    In the last years, cell therapy has become a promising approach to therapeutically manipulate immune responses in autoimmunity, cancer, and transplantation. Several types of lymphoid and myeloid cells origin have been generated in vitro and tested in animal models. Their efficacy to decrease pharmacological treatment has successfully been established. Macrophages play an important role in physiological and pathological processes. They represent an interesting cell population due to their high plasticity in vivo and in vitro. Here, we describe a protocol to differentiate murine regulatory macrophages in vitro from bone marrow precursors. We also describe several methods to assess macrophage classical functions, as their bacterial killing capacity and antigen endocytosis and degradation. Importantly, regulatory macrophages also display suppressive characteristics, which are addressed by the study of their hypostimulatory T lymphocyte capacity and polyclonal T lymphocyte activation suppression.

  2. Muscle Weakness

    PubMed Central

    Al Kaissi, Ali; Ryabykh, Sergey; Ochirova, Polina; Kenis, Vladimir; Hofstätter, Jochen G.; Grill, Franz; Ganger, Rudolf; Kircher, Susanne Gerit

    2017-01-01

    Marked ligamentous hyperlaxity and muscle weakness/wasting associated with awkward gait are the main deficits confused with the diagnosis of myopathy. Seven children (6 boys and 1 girl with an average age of 8 years) were referred to our department because of diverse forms of skeletal abnormalities. No definitive diagnosis was made, and all underwent a series of sophisticated investigations in other institutes in favor of myopathy. We applied our methodology through the clinical and radiographic phenotypes followed by targeted genotypic confirmation. Three children (2 boys and 1 girl) were compatible with the diagnosis of progressive pseudorheumatoid chondrodysplasia. The genetic mutation was correlated with the WISP 3 gene actively expressed by articular chondrocytes and located on chromosome 6. Klinefelter syndrome was the diagnosis in 2 boys. Karyotyping confirmed 47,XXY (aneuploidy of Klinefelter syndrome). And 2 boys were finally diagnosed with Morquio syndrome (MPS type IV A) as both showed missense mutations in the N-acetylgalactosamine-sulfate sulfatase gene. Misdiagnosis can lead to the initiation of a long list of sophisticated investigations. PMID:28210640

  3. Redox Control of Inflammation in Macrophages

    PubMed Central

    Dehne, Nathalie; Grossmann, Nina; Jung, Michaela; Namgaladze, Dmitry; Schmid, Tobias; von Knethen, Andreas; Weigert, Andreas

    2013-01-01

    Abstract Macrophages are present throughout the human body, constitute important immune effector cells, and have variable roles in a great number of pathological, but also physiological, settings. It is apparent that macrophages need to adjust their activation profile toward a steadily changing environment that requires altering their phenotype, a process known as macrophage polarization. Formation of reactive oxygen species (ROS), derived from NADPH-oxidases, mitochondria, or NO-producing enzymes, are not necessarily toxic, but rather compose a network signaling system, known as redox regulation. Formation of redox signals in classically versus alternatively activated macrophages, their action and interaction at the level of key targets, and the resulting physiology still are insufficiently understood. We review the identity, source, and biological activities of ROS produced during macrophage activation, and discuss how they shape the key transcriptional responses evoked by hypoxia-inducible transcription factors, nuclear-erythroid 2-p45-related factor 2 (Nrf2), and peroxisome proliferator-activated receptor-γ. We summarize the mechanisms how redox signals add to the process of macrophage polarization and reprogramming, how this is controlled by the interaction of macrophages with their environment, and addresses the outcome of the polarization process in health and disease. Future studies need to tackle the option whether we can use the knowledge of redox biology in macrophages to shape their mediator profile in pathophysiology, to accelerate healing in injured tissue, to fight the invading pathogens, or to eliminate settings of altered self in tumors. Antioxid. Redox Signal. 19, 595–637. PMID:23311665

  4. The Many Alternative Faces of Macrophage Activation

    PubMed Central

    Hume, David A.

    2015-01-01

    Monocytes and macrophages provide the first line of defense against pathogens. They also initiate acquired immunity by processing and presenting antigens and provide the downstream effector functions. Analysis of large gene expression datasets from multiple cells and tissues reveals sets of genes that are co-regulated with the transcription factors that regulate them. In macrophages, the gene clusters include lineage-specific genes, interferon-responsive genes, early inflammatory genes, and genes required for endocytosis and lysosome function. Macrophages enter tissues and alter their function to deal with a wide range of challenges related to development and organogenesis, tissue injury, malignancy, sterile, or pathogenic inflammatory stimuli. These stimuli alter the gene expression to produce “activated macrophages” that are better equipped to eliminate the cause of their influx and to restore homeostasis. Activation or polarization states of macrophages have been classified as “classical” and “alternative” or M1 and M2. These proposed states of cells are not supported by large-scale transcriptomic data, including macrophage-associated signatures from large cancer tissue datasets, where the supposed markers do not correlate with other. Individual macrophage cells differ markedly from each other, and change their functions in response to doses and combinations of agonists and time. The most studied macrophage activation response is the transcriptional cascade initiated by the TLR4 agonist lipopolysaccharide. This response is reviewed herein. The network topology is conserved across species, but genes within the transcriptional network evolve rapidly and differ between mouse and human. There is also considerable divergence in the sets of target genes between mouse strains, between individuals, and in other species such as pigs. The deluge of complex information related to macrophage activation can be accessed with new analytical tools and new databases

  5. Dakin Solution Alters Macrophage Viability and Function

    DTIC Science & Technology

    2014-07-18

    significantly reduced at all tested concentrations by macrophages pretreated with DS. H2O2 production was reduced by 8% 38% following treatment with 0.00025... product information for all four di lutions are similar: once daily for lightly to moderately exudative wounds, and twice daily for heavily exudative...was evaluated by measuring the extracellular production of H2O2 following lipopolysaccharide (LPS) stimu lation in macrophages using the Amplex Red

  6. Lack of RNase L Attenuates Macrophage Functions

    PubMed Central

    Yi, Xin; Zeng, Chun; Liu, Hongli; Chen, Xiaoli; Zhang, Ping; Yun, Boo Seok; Jin, Ge; Zhou, Aimin

    2013-01-01

    Background Macrophages are one of the major cell types in innate immunity against microbial infection. It is believed that the expression of proinflammatory genes such as tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL–6, and cyclooxygenase-2 (Cox-2) by macrophages is also crucial for activation of both innate and adaptive immunities. RNase L is an interferon (IFN) inducible enzyme which is highly expressed in macrophages. It has been demonstrated that RNase L regulates the expression of certain inflammatory genes. However, its role in macrophage function is largely unknown. Methodology Bone marrow-derived macrophages (BMMs) were generated from RNase L+/+and −/− mice. The migration of BMMs was analyzed by using Transwell migration assays. Endocytosis and phagocytosis of macrophages were assessed by using fluorescein isothiocyanate (FITC)-Dextran 40,000 and FITC-E. coli bacteria, respectively. The expression of inflammatory genes was determined by Western Blot and ELISA. The promoter activity of Cox-2 was measured by luciferase reporter assays. Conclusions/Findings Lack of RNase L significantly decreased the migration of BMMs induced by M-CSF, but at a less extent by GM-CSF and chemokine C-C motif ligand-2 (CCL2). Interestingly, RNase L deficient BMMs showed a significant reduction of endocytic activity to FITC-Dextran 40,000, but no any obvious effect on their phagocytic activity to FITC-bacteria under the same condition. RNase L impacts the expression of certain genes related to cell migration and inflammation such as transforming growth factor (TGF)-β, IL-1β, IL-10, CCL2 and Cox-2. Furthermore, the functional analysis of the Cox-2 promoter revealed that RNase L regulated the expression of Cox-2 in macrophages at its transcriptional level. Taken together, our findings provide direct evidence showing that RNase L contributes to innate immunity through regulating macrophage functions. PMID:24324683

  7. Reconditioning aging muscles.

    PubMed

    Kraus, H

    1978-06-01

    Weakness or stiffness of key posture muscles can cause much of the disability seen in elderly patients. Too much tension and too little exercise greatly increase the natural loss of muscular fitness with age. A systematic program of exercise, stressing relaxation and stretching of tight muscles and strenghthening of weak muscles, can improve physical fitness. The program must be tailored to the patient, starting with relaxation and gentle limbering exercises and proceeding ultimately to vigorous muscle-stretching exercises. Muscle aches and pain from tension and muscle imbalance are to be expected. Relaxation relieves tension pain, and strengthening weak muscles and stretching tight muscles will correct muscle imbalance. To prevent acute muscle spasm, the patient should avoid excessive exertion and increase exercise intensity gradually.