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Sample records for muscle resident macrophages

  1. Tissue-resident macrophages: then and now.

    PubMed

    Davies, Luke C; Taylor, Philip R

    2015-04-01

    Macrophages have been at the heart of immune research for over a century and are an integral component of innate immunity. Macrophages are often viewed as terminally differentiated monocytic phagocytes. They infiltrate tissues during inflammation, and form polarized populations that perform pro-inflammatory or anti-inflammatory functions. Tissue-resident macrophages were regarded as differentiated monocytes, which seed the tissues to perform immune sentinel and homeostatic functions. However, tissue-resident macrophages are not a homogeneous population, but are in fact a grouping of cells with similar functions and phenotypes. In the last decade, it has been revealed that many of these cells are not terminally differentiated and, in most cases, are not derived from haematopoiesis in the adult. Recent research has highlighted that tissue-resident macrophages cannot be grouped into simple polarized categories, especially in vivo, when they are exposed to complex signalling events. It has now been demonstrated that the tissue environment itself is a major controller of macrophage phenotype, and can influence the expression of many genes regardless of origin. This is consistent with the concept that cells within different tissues have diverse responses in inflammation. There is still a mountain to climb in the field, as it evolves to encompass not only tissue-resident macrophage diversity, but also categorization of specific tissue environments and the plasticity of macrophages themselves. This knowledge provides a new perspective on therapeutic strategies, as macrophage subsets can potentially be manipulated to control the inflammatory environment in a tissue-specific manner. PMID:25684236

  2. Tissue-resident macrophages: then and now

    PubMed Central

    Davies, Luke C; Taylor, Philip R

    2015-01-01

    Macrophages have been at the heart of immune research for over a century and are an integral component of innate immunity. Macrophages are often viewed as terminally differentiated monocytic phagocytes. They infiltrate tissues during inflammation, and form polarized populations that perform pro-inflammatory or anti-inflammatory functions. Tissue-resident macrophages were regarded as differentiated monocytes, which seed the tissues to perform immune sentinel and homeostatic functions. However, tissue-resident macrophages are not a homogeneous population, but are in fact a grouping of cells with similar functions and phenotypes. In the last decade, it has been revealed that many of these cells are not terminally differentiated and, in most cases, are not derived from haematopoiesis in the adult. Recent research has highlighted that tissue-resident macrophages cannot be grouped into simple polarized categories, especially in vivo, when they are exposed to complex signalling events. It has now been demonstrated that the tissue environment itself is a major controller of macrophage phenotype, and can influence the expression of many genes regardless of origin. This is consistent with the concept that cells within different tissues have diverse responses in inflammation. There is still a mountain to climb in the field, as it evolves to encompass not only tissue-resident macrophage diversity, but also categorization of specific tissue environments and the plasticity of macrophages themselves. This knowledge provides a new perspective on therapeutic strategies, as macrophage subsets can potentially be manipulated to control the inflammatory environment in a tissue-specific manner. PMID:25684236

  3. Ontogeny of Tissue-Resident Macrophages

    PubMed Central

    Hoeffel, Guillaume; Ginhoux, Florent

    2015-01-01

    The origin of tissue-resident macrophages, crucial for homeostasis and immunity, has remained controversial until recently. Originally described as part of the mononuclear phagocyte system, macrophages were long thought to derive solely from adult blood circulating monocytes. However, accumulating evidence now shows that certain macrophage populations are in fact independent from monocyte and even from adult bone marrow hematopoiesis. These tissue-resident macrophages derive from sequential seeding of tissues by two precursors during embryonic development. Primitive macrophages generated in the yolk sac (YS) from early erythro-myeloid progenitors (EMPs), independently of the transcription factor c-Myb and bypassing monocytic intermediates, first give rise to microglia. Later, fetal monocytes, generated from c-Myb+ EMPs that initially seed the fetal liver (FL), then give rise to the majority of other adult macrophages. Thus, hematopoietic stem cell-independent embryonic precursors transiently present in the YS and the FL give rise to long-lasting self-renewing macrophage populations. PMID:26441990

  4. Macrophage Plasticity in Skeletal Muscle Repair

    PubMed Central

    Rigamonti, Elena; Sciorati, Clara; Rovere-Querini, Patrizia

    2014-01-01

    Macrophages are one of the first barriers of host defence against pathogens. Beyond their role in innate immunity, macrophages play increasingly defined roles in orchestrating the healing of various injured tissues. Perturbations of macrophage function and/or activation may result in impaired regeneration and fibrosis deposition as described in several chronic pathological diseases. Heterogeneity and plasticity have been demonstrated to be hallmarks of macrophages. In response to environmental cues they display a proinflammatory (M1) or an alternative anti-inflammatory (M2) phenotype. A lot of evidence demonstrated that after acute injury M1 macrophages infiltrate early to promote the clearance of necrotic debris, whereas M2 macrophages appear later to sustain tissue healing. Whether the sequential presence of two different macrophage populations results from a dynamic shift in macrophage polarization or from the recruitment of new circulating monocytes is a subject of ongoing debate. In this paper, we discuss the current available information about the role that different phenotypes of macrophages plays after injury and during the remodelling phase in different tissue types, with particular attention to the skeletal muscle. PMID:24860823

  5. Macrophage Plasticity and the Role of Inflammation in Skeletal Muscle Repair

    PubMed Central

    Kharraz, Yacine; Guerra, Joana; Mann, Christopher J.; Serrano, Antonio L.; Muñoz-Cánoves, Pura

    2013-01-01

    Effective repair of damaged tissues and organs requires the coordinated action of several cell types, including infiltrating inflammatory cells and resident cells. Recent findings have uncovered a central role for macrophages in the repair of skeletal muscle after acute damage. If damage persists, as in skeletal muscle pathologies such as Duchenne muscular dystrophy (DMD), macrophage infiltration perpetuates and leads to progressive fibrosis, thus exacerbating disease severity. Here we discuss how dynamic changes in macrophage populations and activation states in the damaged muscle tissue contribute to its efficient regeneration. We describe how ordered changes in macrophage polarization, from M1 to M2 subtypes, can differently affect muscle stem cell (satellite cell) functions. Finally, we also highlight some of the new mechanisms underlying macrophage plasticity and briefly discuss the emerging implications of lymphocytes and other inflammatory cell types in normal versus pathological muscle repair. PMID:23509419

  6. 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

  7. Development and maintainance of resident macrophages

    PubMed Central

    Perdiguero, Elisa Gomez; Geissmann, Frederic

    2016-01-01

    The molecular and cellular mechanisms that underlie the many roles of macrophages in health and disease states in vivo remain poorly understood. The purpose of this Review is to present and discuss current knowledge on the developmental biology of macrophages, as it underlies the concept of a layered myeloid system composed of ‘resident’ macrophages that mostly originate from yolk sac progenitors and of ‘passenger’ or ‘transitory’ myeloid cells that originate and renew from bone marrow hematopoietic stem cells, and to provide a framework to investigate the functions of macrophages in vivo. PMID:26681456

  8. 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.

  9. Sphingosylphosphorylcholine inhibits macrophage adhesion to vascular smooth muscle cells.

    PubMed

    Wirrig, Christiane; McKean, Jenny S; Wilson, Heather M; Nixon, Graeme F

    2016-09-01

    Inflammation in de-endothelialised arteries contributes to the development of cardiovascular diseases. The process that initiates this inflammatory response is the adhesion of monocytes/macrophages to exposed vascular smooth muscle cells, typically stimulated by cytokines such as tumour necrosis factor-α (TNF). The aim of this study was to determine the effect of the sphingolipid sphingosylphosphorylcholine (SPC) on the interaction of monocytes/macrophages with vascular smooth muscle cells. Rat aortic smooth muscle cells and rat bone marrow-derived macrophages were co-cultured using an in vitro assay following incubation with sphingolipids to assess inter-cellular adhesion. We reveal that SPC inhibits the TNF-induced adhesion of macrophages to smooth muscle cells. This anti-adhesive effect was the result of SPC-induced changes to the smooth muscle cells (but not the macrophages) and was mediated, at least partly, via the sphingosine 1-phosphate receptor subtype 2. Lipid raft domains were also required. Although SPC did not alter expression or membrane distribution of the adhesion proteins intercellular adhesion molecule-1 and vascular cellular adhesion protein-1 in smooth muscle cells, SPC preincubation inhibited the TNF-induced increase in inducible nitric oxide synthase (NOS2) resulting in a subsequent decrease in nitric oxide production. Inhibiting NOS2 activation in smooth muscle cells led to a decrease in the adhesion of macrophages to smooth muscle cells. This study has therefore delineated a novel pathway which can inhibit the interaction between macrophages and vascular smooth muscle cells via SPC-induced repression of NOS2 expression. This mechanism could represent a potential drug target in vascular disease. PMID:27402344

  10. Altered macrophage phenotype transition impairs skeletal muscle regeneration.

    PubMed

    Wang, Hanzhou; Melton, David W; Porter, Laurel; Sarwar, Zaheer U; McManus, Linda M; Shireman, Paula K

    2014-04-01

    Monocyte/macrophage polarization in skeletal muscle regeneration is ill defined. We used CD11b-diphtheria toxin receptor transgenic mice to transiently deplete monocytes/macrophages at multiple stages before and after muscle injury induced by cardiotoxin. Fat accumulation within regenerated muscle was maximal when ablation occurred at the same time as cardiotoxin-induced injury. Early ablation (day 1 after cardiotoxin) resulted in the smallest regenerated myofiber size together with increased residual necrotic myofibers and fat accumulation. However, muscle regeneration after late (day 4) ablation was similar to controls. Levels of inflammatory cells in injured muscle following early ablation and associated with impaired muscle regeneration were determined by flow cytometry. Delayed, but exaggerated, monocyte [CD11b(+)(CD90/B220/CD49b/NK1.1/Ly6G)(-)(F4/80/I-Ab/CD11c)(-)Ly6C(+/-)] accumulation occurred; interestingly, Ly6C(+) and Ly6C(-) monocytes were present concurrently in ablated animals and control mice. In addition to monocytes, proinflammatory, Ly6C(+) macrophage accumulation following early ablation was delayed compared to controls. In both groups, CD11b(+)F4/80(+) cells exhibited minimal expression of the M2 markers CD206 and CD301. Nevertheless, early ablation delayed and decreased the transient accumulation of CD11b(+)F4/80(+)Ly6C(-)CD301(-) macrophages; in control animals, the later tissue accumulation of these cells appeared to correspond to that of anti-inflammatory macrophages, determined by cytokine production and arginase activity. In summary, impairments in muscle regeneration were associated with exaggerated monocyte recruitment and reduced Ly6C(-) macrophages; the switch of macrophage/monocyte subsets is critical to muscle regeneration. PMID:24525152

  11. Altered Macrophage Phenotype Transition Impairs Skeletal Muscle Regeneration

    PubMed Central

    Wang, Hanzhou; Melton, David W.; Porter, Laurel; Sarwar, Zaheer U.; McManus, Linda M.; Shireman, Paula K.

    2015-01-01

    Monocyte/macrophage polarization in skeletal muscle regeneration is ill defined. We used CD11b-diphtheria toxin receptor transgenic mice to transiently deplete monocytes/macrophages at multiple stages before and after muscle injury induced by cardiotoxin. Fat accumulation within regenerated muscle was maximal when ablation occurred at the same time as cardiotoxin-induced injury. Early ablation (day 1 after cardiotoxin) resulted in the smallest regenerated myofiber size together with increased residual necrotic myofibers and fat accumulation. However, muscle regeneration after late (day 4) ablation was similar to controls. Levels of inflammatory cells in injured muscle following early ablation and associated with impaired muscle regeneration were determined by flow cytometry. Delayed, but exaggerated, monocyte [CD11b+(CD90/B220/CD49b/NK1.1/Ly6G)−(F4/80/I-Ab/CD11c)−Ly6C+/−] accumulation occurred; interestingly, Ly6C+ and Ly6C− monocytes were present concurrently in ablated animals and control mice. In addition to monocytes, proinflammatory, Ly6C+ macrophage accumulation following early ablation was delayed compared to controls. In both groups, CD11b+F4/80+ cells exhibited minimal expression of the M2 markers CD206 and CD301. Nevertheless, early ablation delayed and decreased the transient accumulation of CD11b+F4/80+Ly6C−CD301− macrophages; in control animals, the later tissue accumulation of these cells appeared to correspond to that of anti-inflammatory macrophages, determined by cytokine production and arginase activity. In summary, impairments in muscle regeneration were associated with exaggerated monocyte recruitment and reduced Ly6C− macrophages; the switch of macrophage/monocyte subsets is critical to muscle regeneration. PMID:24525152

  12. Resident Macrophages and Lymphocytes in the Canine Endometrium.

    PubMed

    Pires, M A; Payan-Carreira, R

    2015-10-01

    Resident immune cells play a major role in endometrial immunity and in tissue homoeostasis. This study aimed to analyse the distribution of macrophages, B and T lymphocytes (respectively, Mø, B-Lym and T-Lym) in the canine endometrium throughout the oestrous cycle and in late involution (at the proestrus stage post-parturition). An immunohistochemistry technique was used on samples from 50 post-pubertal healthy female dogs, of which five in late post-partum. The distribution of resident immune cells was analysed in three endometrial layers (superficial, intermediate and basal areas). Mø, B-Lym and T-Lym were demonstrated to reside in the endometrium in all the stages of the canine cycle; their numbers being considerably higher during late involution. T-Lym were scattered in the stroma or amidst the glandular epithelium, constituting the predominant immune cell population in anestrus and proestrus, but decreased in number at all other stages. Endometrial B-Lym remained fairly constant during the canine cycle, although its numbers were higher in late involution. Mø counts were higher during anestrus compared to the other stages, the cells being displaced into the superficial endometrial layer. Mø demonstrated the highest level in late involution samples, forming small aggregates below the surface epithelium. The number of immune cells was not normally distributed, suggesting the influence of individual factors, such as age or parity, not explored herein due to limited sample availability. Still, this study provides important information for the interpretation of endometrial biopsies in dogs and for the understanding of the increased susceptibility to uterine infection during dioestrus found in the bitch. PMID:26234683

  13. Intracellular replication of Leishmania tropica in mouse peritoneal macrophages: amastigote infection of resident cells and inflammatory exudate macrophages.

    PubMed Central

    Fortier, A H; Hoover, D L; Nacy, C A

    1982-01-01

    C3HeB/FeJ peritoneal exudate cells elicited by a variety of sterile inflammatory agents were exposed to Leishmania tropica amastigotes in vitro. Cytochemical characterization of cells that contained intracellular parasites suggested that young, peroxidase-positive macrophages were more susceptible to infection by amastigotes than more mature cells. Replication of the parasite in these younger cells, however, was similar to that observed in resident peritoneal macrophages. PMID:7152674

  14. Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment.

    PubMed

    Lavin, Yonit; Winter, Deborah; Blecher-Gonen, Ronnie; David, Eyal; Keren-Shaul, Hadas; Merad, Miriam; Jung, Steffen; Amit, Ido

    2014-12-01

    Macrophages are critical for innate immune defense and also control organ homeostasis in a tissue-specific manner. They provide a fitting model to study the impact of ontogeny and microenvironment on chromatin state and whether chromatin modifications contribute to macrophage identity. Here, we profile the dynamics of four histone modifications across seven tissue-resident macrophage populations. We identify 12,743 macrophage-specific enhancers and establish that tissue-resident macrophages have distinct enhancer landscapes beyond what can be explained by developmental origin. Combining our enhancer catalog with gene expression profiles and open chromatin regions, we show that a combination of tissue- and lineage-specific transcription factors form the regulatory networks controlling chromatin specification in tissue-resident macrophages. The environment is capable of shaping the chromatin landscape of transplanted bone marrow precursors, and even differentiated macrophages can be reprogrammed when transferred into a new microenvironment. These results provide a comprehensive view of macrophage regulatory landscape and highlight the importance of the microenvironment, along with pioneer factors in orchestrating identity and plasticity. PMID:25480296

  15. Embryonic and adult-derived resident cardiac macrophages are maintained through distinct mechanisms at steady state and during inflammation.

    PubMed

    Epelman, Slava; Lavine, Kory J; Beaudin, Anna E; Sojka, Dorothy K; Carrero, Javier A; Calderon, Boris; Brija, Thaddeus; Gautier, Emmanuel L; Ivanov, Stoyan; Satpathy, Ansuman T; Schilling, Joel D; Schwendener, Reto; Sergin, Ismail; Razani, Babak; Forsberg, E Camilla; Yokoyama, Wayne M; Unanue, Emil R; Colonna, Marco; Randolph, Gwendalyn J; Mann, Douglas L

    2014-01-16

    Cardiac macrophages are crucial for tissue repair after cardiac injury but are not well characterized. Here we identify four populations of cardiac macrophages. At steady state, resident macrophages were primarily maintained through local proliferation. However, after macrophage depletion or during cardiac inflammation, Ly6c(hi) monocytes contributed to all four macrophage populations, whereas resident macrophages also expanded numerically through proliferation. Genetic fate mapping revealed that yolk-sac and fetal monocyte progenitors gave rise to the majority of cardiac macrophages, and the heart was among a minority of organs in which substantial numbers of yolk-sac macrophages persisted in adulthood. CCR2 expression and dependence distinguished cardiac macrophages of adult monocyte versus embryonic origin. Transcriptional and functional data revealed that monocyte-derived macrophages coordinate cardiac inflammation, while playing redundant but lesser roles in antigen sampling and efferocytosis. These data highlight the presence of multiple cardiac macrophage subsets, with different functions, origins, and strategies to regulate compartment size. PMID:24439267

  16. 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.

  17. Osteogenic potential of alpha smooth muscle actin expressing muscle resident progenitor cells.

    PubMed

    Matthews, Brya G; Torreggiani, Elena; Roeder, Emilie; Matic, Igor; Grcevic, Danka; Kalajzic, Ivo

    2016-03-01

    Heterotopic ossification (HO) is a pathological process where bone forms in connective tissues such as skeletal muscle. Previous studies have suggested that muscle-resident non-myogenic mesenchymal progenitors are the likely source of osteoblasts and chondrocytes in HO. However, the previously identified markers of muscle-resident osteoprogenitors label up to half the osteoblasts within heterotopic lesions, suggesting other cell populations are involved. We have identified alpha smooth muscle actin (αSMA) as a marker of osteoprogenitor cells in bone and periodontium, and of osteo-chondro progenitors in the periosteum during fracture healing. We therefore utilized a lineage tracing approach to evaluate whether αSMACreERT2 identifies osteoprogenitors in the muscle. We show that in the muscle, αSMACreERT2 labels both perivascular cells, and satellite cells. αSMACre-labeled cells undergo osteogenic differentiation in vitro and form osteoblasts and chondrocytes in BMP2-induced HO in vivo. In contrast, Pax7CreERT2-labeled muscle satellite cells were restricted to myogenic differentiation in vitro, and rarely contributed to HO in vivo. Our data indicate that αSMACreERT2 labels a large proportion of osteoprogenitors in skeletal muscle, and therefore represents another marker of muscle-resident cells with osteogenic potential under HO-inducing stimulus. In contrast, muscle satellite cells make minimal contribution to bone formation in vivo. PMID:26721734

  18. Chemokine CXCL16 Regulates Neutrophil and Macrophage Infiltration into Injured Muscle, Promoting Muscle Regeneration

    PubMed Central

    Zhang, Liping; Ran, Limei; Garcia, Gabriela E.; Wang, Xiaonan H.; Han, Shuhua; Du, Jie; Mitch, William E.

    2009-01-01

    Only a few specific chemokines that mediate interactions between inflammatory and satellite cells in muscle regeneration have been identified. The chemokine CXCL16 differs from other chemokines because it has both a transmembrane region and active, soluble chemokine forms. Indeed, we found increased expression of CXCL16 and its receptor, CXCR6, in regenerating myofibers. Muscle regeneration in CXCL16-deficient (CXCL16KO) mice was severely impaired compared with regeneration in wild-type mice. In addition, there was decreased MyoD and myogenin expression in regenerating muscle in CXCL16KO mice, indicating impaired satellite cell proliferation and differentiation. After 1 month, new myofibers in CXCL16KO mice remained significantly smaller than those in muscle of wild-type mice. To understand how CXCL16 regulates muscle regeneration, we examined cells infiltrating injured muscle. There were more infiltrating neutrophils and fewer macrophages in injured muscle of CXCL16KO mice compared with events in wild-type mice. Moreover, absence of CXCL16 led to different expression of cytokines/chemokines in injured muscles: mRNAs of macrophage-inflammatory protein (MIP)-1α, MIP-1β, and MIP-2 were increased, whereas regulated on activation normal T cell expressed and secreted, T-cell activation-3, and monocyte chemoattractant protein-1 mRNAs were lower compared with results in muscles of wild-type mice. Impaired muscle regeneration in CXCL16KO mice also resulted in fibrosis, which was linked to transforming growth factor-β1 expression. Thus, CXCL16 expression is a critical mediator of muscle regeneration, and it suppresses the development of fibrosis. PMID:19893053

  19. Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors.

    PubMed

    Gomez Perdiguero, Elisa; Klapproth, Kay; Schulz, Christian; Busch, Katrin; Azzoni, Emanuele; Crozet, Lucile; Garner, Hannah; Trouillet, Celine; de Bruijn, Marella F; Geissmann, Frederic; Rodewald, Hans-Reimer

    2015-02-26

    Most haematopoietic cells renew from adult haematopoietic stem cells (HSCs), however, macrophages in adult tissues can self-maintain independently of HSCs. Progenitors with macrophage potential in vitro have been described in the yolk sac before emergence of HSCs, and fetal macrophages can develop independently of Myb, a transcription factor required for HSC, and can persist in adult tissues. Nevertheless, the origin of adult macrophages and the qualitative and quantitative contributions of HSC and putative non-HSC-derived progenitors are still unclear. Here we show in mice that the vast majority of adult tissue-resident macrophages in liver (Kupffer cells), brain (microglia), epidermis (Langerhans cells) and lung (alveolar macrophages) originate from a Tie2(+) (also known as Tek) cellular pathway generating Csf1r(+) erythro-myeloid progenitors (EMPs) distinct from HSCs. EMPs develop in the yolk sac at embryonic day (E) 8.5, migrate and colonize the nascent fetal liver before E10.5, and give rise to fetal erythrocytes, macrophages, granulocytes and monocytes until at least E16.5. Subsequently, HSC-derived cells replace erythrocytes, granulocytes and monocytes. Kupffer cells, microglia and Langerhans cells are only marginally replaced in one-year-old mice, whereas alveolar macrophages may be progressively replaced in ageing mice. Our fate-mapping experiments identify, in the fetal liver, a sequence of yolk sac EMP-derived and HSC-derived haematopoiesis, and identify yolk sac EMPs as a common origin for tissue macrophages. PMID:25470051

  20. 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

  1. The Repair of Skeletal Muscle Requires Iron Recycling through Macrophage Ferroportin.

    PubMed

    Corna, Gianfranca; Caserta, Imma; Monno, Antonella; Apostoli, Pietro; Manfredi, Angelo A; Camaschella, Clara; Rovere-Querini, Patrizia

    2016-09-01

    Macrophages recruited at the site of sterile muscle damage play an essential role in the regeneration of the tissue. In this article, we report that the selective disruption of macrophage ferroportin (Fpn) results in iron accumulation within muscle-infiltrating macrophages and jeopardizes muscle healing, prompting fat accumulation. Macrophages isolated from the tissue at early time points after injury express ferritin H, CD163, and hemeoxygenase-1, indicating that they can uptake heme and store iron. At later time points they upregulate Fpn expression, thus acquiring the ability to release the metal. Transferrin-mediated iron uptake by regenerating myofibers occurs independently of systemic iron homeostasis. The inhibition of macrophage iron export via the silencing of Fpn results in regenerating muscles with smaller myofibers and fat accumulation. These results highlight the existence of a local pathway of iron recycling that plays a nonredundant role in the myogenic differentiation of muscle precursors, limiting the adipose degeneration of the tissue. PMID:27465531

  2. Monocyte/Macrophage-derived IGF-1 Orchestrates Murine Skeletal Muscle Regeneration and Modulates Autocrine Polarization.

    PubMed

    Tonkin, Joanne; Temmerman, Lieve; Sampson, Robert D; Gallego-Colon, Enrique; Barberi, Laura; Bilbao, Daniel; Schneider, Michael D; Musarò, Antonio; Rosenthal, Nadia

    2015-07-01

    Insulin-like growth factor 1 (IGF-1) is a potent enhancer of tissue regeneration, and its overexpression in muscle injury leads to hastened resolution of the inflammatory phase. Here, we show that monocytes/macrophages constitute an important initial source of IGF-1 in muscle injury, as conditional deletion of the IGF-1 gene specifically in mouse myeloid cells (ϕIGF-1 CKO) blocked the normal surge of local IGF-1 in damaged muscle and significantly compromised regeneration. In injured muscle, Ly6C+ monocytes/macrophages and CD206+ macrophages expressed equivalent IGF-1 levels, which were transiently upregulated during transition from the inflammation to repair. In injured ϕIGF-1 CKO mouse muscle, accumulation of CD206+ macrophages was impaired, while an increase in Ly6C+ monocytes/macrophages was favored. Transcriptional profiling uncovered inflammatory skewing in ϕIGF-1 CKO macrophages, which failed to fully induce a reparative gene program in vitro or in vivo, revealing a novel autocrine role for IGF-1 in modulating murine macrophage phenotypes. These data establish local macrophage-derived IGF-1 as a key factor in inflammation resolution and macrophage polarization during muscle regeneration. PMID:25896247

  3. Microparticles from apoptotic platelets promote resident macrophage differentiation

    PubMed Central

    Vasina, E M; Cauwenberghs, S; Feijge, M A H; Heemskerk, J W M; Weber, C; Koenen, R R

    2011-01-01

    Platelets shed microparticles not only upon activation, but also upon ageing by an apoptosis-like process (apoptosis-induced platelet microparticles, PMap). While the activation-induced microparticles have widely been studied, not much is known about the (patho)physiological consequences of PMap formation. Flow cytometry and scanning electron microscopy demonstrated that PMap display activated integrins and interact to form microparticle aggregates. PMap were chemotactic for monocytic cells, bound to these cells, an furthermore stimulated cell adhesion and spreading on a fibronectin surface. After prolonged incubation, PMap promoted cell differentiation, but inhibited proliferation. Monocyte membrane receptor analysis revealed increased expression levels of CD11b (integrin αMβ2), CD14 and CD31 (platelet endothelial cell adhesion molecule-1), and the chemokine receptors CCR5 and CXCR4, but not of CCR2. This indicated that PMap polarized the cells into resident M2 monocytes. Cells treated with PMap actively consumed oxidized low-density lipoprotein (oxLDL), and released matrix metalloproteinases and hydrogen peroxide. Further confirmation for the differentiation towards resident professional phagocytes came from the finding that PMap stimulated the expression of the (ox)LDL receptors, CD36 and CD68, and the production of proinflammatory and immunomodulating cytokines by monocytes. In conclusion, interaction of PMap with monocytic cells has an immunomodulating potential. The apoptotic microparticles polarize the cells into a resident M2 subset, and induce differentiation to resident professional phagocytes. PMID:21956548

  4. Most Tissue-Resident Macrophages Except Microglia Are Derived from Fetal Hematopoietic Stem Cells.

    PubMed

    Sheng, Jianpeng; Ruedl, Christiane; Karjalainen, Klaus

    2015-08-18

    Macrophages are one of the most diverse cell populations in terms of their anatomical location and functional specialization during both homeostasis and disease. Although it has been shown in different fate mapping models that some macrophages present in adult tissues are already established during fetal development, their exact origins are still under debate. In the current study, we developed a fate mapping strain, based on the Kit locus, which allowed us to readdress "the origins" question. Different types of macrophages from various adult tissues were traced to their fetal or adult sources by inducing labeling in precursors at several time points either during fetal development or in adult mice. We show that all adult macrophages, resident or infiltrating, are progenies of classical hematopoietic stem cells (HSC) with the exception of microglia and, partially epidermal Langerhans cells, which are yolk sac (YS)-derived. PMID:26287683

  5. 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.

  6. Immune Monitoring of Trans-endothelial Transport by Kidney-Resident Macrophages.

    PubMed

    Stamatiades, Efstathios G; Tremblay, Marie-Eve; Bohm, Mathieu; Crozet, Lucile; Bisht, Kanchan; Kao, Daniela; Coelho, Carolina; Fan, Xiying; Yewdell, William T; Davidson, Anne; Heeger, Peter S; Diebold, Sandra; Nimmerjahn, Falk; Geissmann, Frederic

    2016-08-11

    Small immune complexes cause type III hypersensitivity reactions that frequently result in tissue injury. The responsible mechanisms, however, remain unclear and differ depending on target organs. Here, we identify a kidney-specific anatomical and functional unit, formed by resident macrophages and peritubular capillary endothelial cells, which monitors the transport of proteins and particles ranging from 20 to 700 kDa or 10 to 200 nm into the kidney interstitium. Kidney-resident macrophages detect and scavenge circulating immune complexes "pumped" into the interstitium via trans-endothelial transport and trigger a FcγRIV-dependent inflammatory response and the recruitment of monocytes and neutrophils. In addition, FcγRIV and TLR pathways synergistically "super-activate" kidney macrophages when immune complexes contain a nucleic acid. These data identify a physiological function of tissue-resident kidney macrophages and a basic mechanism by which they initiate the inflammatory response to small immune complexes in the kidney. PMID:27477514

  7. Endurance interval training in obese mice reduces muscle inflammation and macrophage content independently of weight loss

    PubMed Central

    Samaan, M. Constantine; Marcinko, Katarina; Sikkema, Sarah; Fullerton, Morgan D.; Ziafazeli, Tahereh; Khan, Mohammad I.; Steinberg, Gregory R.

    2014-01-01

    Abstract Obesity is associated with chronic low‐grade inflammation that involves infiltration of macrophages into metabolic organs such as skeletal muscle. Exercise enhances skeletal muscle insulin sensitivity independently of weight loss; but its role in regulating muscle inflammation is not fully understood. We hypothesized that exercise training would inhibit skeletal muscle inflammation and alter macrophage infiltration into muscle independently of weight loss. Wild type C57BL/6 male mice were fed a chow diet or a high‐fat diet (HFD, 45% calories fat) for 6 weeks. Then, mice maintained on the HFD either remained sedentary (HFD Sed) or exercised (HFD Ex) on a treadmill for another 6 weeks. The exercise training protocol involved conducting intervals of 2 min in duration followed by 2 min of rest for 60 min thrice weekly. Chow‐fed control mice remained sedentary for the entire 12 weeks. Muscle cytokine and macrophage gene expression analysis were conducted using qRT‐PCR, and muscle macrophage content was also measured using immunohistochemistry. Muscle cytokine protein content was quantified using a cytokine array. The HFD increased adiposity and weight gain compared to chow‐fed controls. HFD Sed and HFD Ex mice had similar body mass as well as total and visceral adiposity. However, despite similar adiposity, exercise reduced inflammation and muscle macrophage infiltration. We conclude that Endurance exercise training modulates the immune‐metabolic crosstalk in obesity independently of weight loss, and may have potential benefits in reducing obesity‐related muscle inflammation. PMID:24843075

  8. 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. PMID:26642357

  9. Tissue-Resident CD169(+) Macrophages Form a Crucial Front Line against Plasmodium Infection.

    PubMed

    Gupta, Pravesh; Lai, Si Min; Sheng, Jianpeng; Tetlak, Piotr; Balachander, Akhila; Claser, Carla; Renia, Laurent; Karjalainen, Klaus; Ruedl, Christiane

    2016-08-01

    Tissue macrophages exhibit diverse functions, ranging from the maintenance of tissue homeostasis, including clearance of senescent erythrocytes and cell debris, to modulation of inflammation and immunity. Their contribution to the control of blood-stage malaria remains unclear. Here, we show that in the absence of tissue-resident CD169(+) macrophages, Plasmodium berghei ANKA (PbA) infection results in significantly increased parasite sequestration, leading to vascular occlusion and leakage and augmented tissue deposition of the malarial pigment hemozoin. This leads to widespread tissue damage culminating in multiple organ inflammation. Thus, the capacity of CD169(+) macrophages to contain the parasite burden and its sequestration into different tissues and to limit infection-induced inflammation is crucial to mitigating Plasmodium infection and pathogenesis. PMID:27477286

  10. Contrasting Roles of Islet Resident Immunoregulatory Macrophages and Dendritic Cells in Experimental Autoimmune Type 1 Diabetes

    PubMed Central

    Thornley, Thomas B.; Ma, Lingzhi; Chipashvili, Vaja; Aker, Jonathan E.; Korniotis, Sarantis; Csizmadia, Eva; Strom, Terry B.; Koulmanda, Maria

    2016-01-01

    The innate immune system critically shapes diabetogenic adaptive immunity during type 1 diabetes (T1D) pathogenesis. While the role of tissue-infiltrating monocyte-derived macrophages in T1D is well established, the role of their tissue-resident counterparts remains undefined. We now demonstrate that islet resident macrophages (IRMs) from non-autoimmune mice have an immunoregulatory phenotype and powerfully induce FoxP3+ Tregs in vitro. The immunoregulatory phenotype and function of IRMs is compromised by TLR4 activation in vitro. Moreover, as T1D approaches in NOD mice, the immunoregulatory phenotype of IRMs is diminished as is their relative abundance compared to immunostimulatory DCs. Our findings suggest that maintenance of IRM abundance and their immunoregulatory phenotype may constitute a novel therapeutic strategy to prevent and/or cure T1D. PMID:26943809

  11. Prostacyclin mediates neuropathic pain through interleukin 1β-expressing resident macrophages.

    PubMed

    Schuh, Claus Dieter; Pierre, Sandra; Weigert, Andreas; Weichand, Benjamin; Altenrath, Kai; Schreiber, Yannick; Ferreiros, Nerea; Zhang, Dong Dong; Suo, Jing; Treutlein, Elsa-Marie; Henke, Marina; Kunkel, Hana; Grez, Manuel; Nüsing, Rolf; Brüne, Bernhard; Geisslinger, Gerd; Scholich, Klaus

    2014-03-01

    Prostacyclin is an important mediator of peripheral pain sensation. Here, we investigated its potential participation in mediating neuropathic pain and found that prostacyclin receptor (IP) knockout mice exhibited markedly decreased pain behavior. Application of an IP antagonist to the injury site or selective IP deficiency in myeloid cells mimicked the antinociceptive effect observed in IP knockout mice. At the site of nerve injury, IP was expressed in interleukin (IL) 1β-containing resident macrophages, which were less common in IP knockout mice. Local administration of the IP agonist cicaprost inhibited macrophage migration in vitro and promoted accumulation of IP- and IL1β-expressing cells as well as an increase of IL1β concentrations at the application site in vivo. Fittingly, the IL1-receptor antagonist anakinra (IL-1ra) decreased neuropathic pain behavior in wild-type mice but not in IP knockout mice. Finally, continuous, but not single administration, of the cyclooxygenase inhibitor meloxicam early after nerve injury decreased pain behavior and the number of resident macrophages. Thus, early synthesis of prostacyclin at the site of injury causes accumulation of IL1β-expressing macrophages as a key step in neuropathic pain after traumatic injury. PMID:24333781

  12. Depletion of resident alveolar macrophages does not prevent Fas-mediated lung injury in mice.

    PubMed

    Bem, R A; Farnand, A W; Wong, V; Koski, A; Rosenfeld, M E; van Rooijen, N; Frevert, C W; Martin, T R; Matute-Bello, G

    2008-08-01

    Activation of the Fas/Fas ligand (FasL) system in the lungs results in a form of injury characterized by alveolar epithelial apoptosis and neutrophilic inflammation. Studies in vitro show that Fas activation induces apoptosis in alveolar epithelial cells and cytokine production in alveolar macrophages. The main goal of this study was to determine the contribution of alveolar macrophages to Fas-induced lung inflammation in mice, by depleting alveolar macrophages using clodronate-containing liposomes. Liposomes containing clodronate or PBS were instilled by intratracheal instillation. After 24 h, the mice received intratracheal instillations of the Fas-activating monoclonal antibody Jo2 or an isotype control antibody and were studied 18 h later. The Jo2 MAb induced increases in bronchoalveolar lavage fluid (BALF) total neutrophils, lung caspase-3 activity, and BALF total protein and worsened histological lung injury in the macrophage-depleted mice. Studies in vitro showed that Fas activation induced the release of the cytokine KC in a mouse lung epithelial cell line, MLE-12. These results suggest that the lung inflammatory response to Fas activation is not primarily dependent on resident alveolar macrophages and may instead depend on cytokine release by alveolar epithelial cells. PMID:18556802

  13. 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

  14. Regulation of skeletal muscle regeneration by CCR2-activating chemokines is directly related to macrophage recruitment

    PubMed Central

    Martinez, Carlo O.; McHale, Matthew J.; Wells, Jason T.; Ochoa, Oscar; Michalek, Joel E.; McManus, Linda M.

    2010-01-01

    Muscle regeneration requires CC chemokine receptor 2 (CCR2) expression on bone marrow-derived cells; macrophages are a prominent CCR2-expressing cell in this process. CCR2−/− mice have severe impairments in angiogenesis, macrophage recruitment, and skeletal muscle regeneration following cardiotoxin (CTX)-induced injury. However, multiple chemokines activate CCR2, including monocyte chemotactic proteins (MCP)-1, -3, and -5. We hypothesized that MCP-1 is the chemokine ligand that mediates the impairments present in CCR2−/− mice. We examined muscle regeneration, capillary density, and cellular recruitment in MCP-1−/− and CCR2−/− mice following injury. Muscle regeneration and adipocyte accumulation, but not capillary density, were significantly impaired in MCP-1−/− compared with wild-type (WT) mice; however, muscle regeneration and adipocyte accumulation impairments were not as severe as observed in CCR2−/− mice. Although tissue levels of MCP-5 were elevated in MCP-1−/− mice compared with WT, the administration of MCP-5 neutralizing antibody did not alter muscle regeneration in MCP-1−/− mice. While neutrophil accumulation after injury was similar in all three mouse strains, macrophage recruitment was highest in WT mice, intermediate in MCP-1−/− mice, and severely impaired in CCR2−/− mice. In conclusion, while the absence of MCP-1 resulted in impaired macrophage recruitment and muscle regeneration, MCP-1−/− mice exhibit an intermediate phenotype compared with CCR2−/− mice. Intermediate macrophage recruitment in MCP-1−/− mice was associated with similar capillary density to WT, suggesting that fewer macrophages may be needed to restore angiogenesis vs. muscle regeneration. Finally, other chemokines, in addition to MCP-1 and MCP-5, may activate CCR2-dependent regenerative processes resulting in an intermediate phenotype in MCP-1−/− mice. PMID:20631294

  15. Regulation of skeletal muscle regeneration by CCR2-activating chemokines is directly related to macrophage recruitment.

    PubMed

    Martinez, Carlo O; McHale, Matthew J; Wells, Jason T; Ochoa, Oscar; Michalek, Joel E; McManus, Linda M; Shireman, Paula K

    2010-09-01

    Muscle regeneration requires CC chemokine receptor 2 (CCR2) expression on bone marrow-derived cells; macrophages are a prominent CCR2-expressing cell in this process. CCR2-/- mice have severe impairments in angiogenesis, macrophage recruitment, and skeletal muscle regeneration following cardiotoxin (CTX)-induced injury. However, multiple chemokines activate CCR2, including monocyte chemotactic proteins (MCP)-1, -3, and -5. We hypothesized that MCP-1 is the chemokine ligand that mediates the impairments present in CCR2-/- mice. We examined muscle regeneration, capillary density, and cellular recruitment in MCP-1-/- and CCR2-/- mice following injury. Muscle regeneration and adipocyte accumulation, but not capillary density, were significantly impaired in MCP-1-/- compared with wild-type (WT) mice; however, muscle regeneration and adipocyte accumulation impairments were not as severe as observed in CCR2-/- mice. Although tissue levels of MCP-5 were elevated in MCP-1-/- mice compared with WT, the administration of MCP-5 neutralizing antibody did not alter muscle regeneration in MCP-1-/- mice. While neutrophil accumulation after injury was similar in all three mouse strains, macrophage recruitment was highest in WT mice, intermediate in MCP-1-/- mice, and severely impaired in CCR2-/- mice. In conclusion, while the absence of MCP-1 resulted in impaired macrophage recruitment and muscle regeneration, MCP-1-/- mice exhibit an intermediate phenotype compared with CCR2-/- mice. Intermediate macrophage recruitment in MCP-1-/- mice was associated with similar capillary density to WT, suggesting that fewer macrophages may be needed to restore angiogenesis vs. muscle regeneration. Finally, other chemokines, in addition to MCP-1 and MCP-5, may activate CCR2-dependent regenerative processes resulting in an intermediate phenotype in MCP-1-/- mice. PMID:20631294

  16. Piperine metabolically regulates peritoneal resident macrophages to potentiate their functions against bacterial infection.

    PubMed

    Pan, Hao; Xu, Li-Hui; Huang, Mei-Yun; Zha, Qing-Bing; Zhao, Gao-Xiang; Hou, Xiao-Feng; Shi, Zi-Jian; Lin, Qiu-Ru; Ouyang, Dong-Yun; He, Xian-Hui

    2015-10-20

    Pepper, a daily-used seasoning for promoting appetite, is widely used in folk medicine for treating gastrointestinal diseases. Piperine is the major alkaloid in pepper and possesses a wide range of pharmacological activities. However, the mechanism for linking metabolic and medicinal activities of piperine remains unknown. Here we report that piperine robustly boosts mTORC1 activity by recruiting more system L1 amino acid transporter (SLC7A5/SLC3A2) to the cell membrane, thus promoting amino acid metabolism. Piperine-induced increase of mTORC1 activity in resident peritoneal macrophages (pMΦs) is correlated with enhanced production of IL-6 and TNF-α upon LPS stimulation. Such an enhancement of cytokine production could be abrogated by inhibitors of the mTOR signaling pathway, indicating mTOR's action in this process. Moreover, piperine treatment protected resident pMΦs from bacterium-induced apoptosis and disappearance, and increased their bacterial phagocytic ability. Consequently, piperine administration conferred mice resistance against bacterial infection and even sepsis. Our data highlight that piperine has the capacity to metabolically reprogram peritoneal resident macrophages to fortify their innate functions against bacterial infection. PMID:26439699

  17. 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. PMID:23876342

  18. Yolk Sac Macrophages, Fetal Liver, and Adult Monocytes Can Colonize an Empty Niche and Develop into Functional Tissue-Resident Macrophages.

    PubMed

    van de Laar, Lianne; Saelens, Wouter; De Prijck, Sofie; Martens, Liesbet; Scott, Charlotte L; Van Isterdael, Gert; Hoffmann, Eik; Beyaert, Rudi; Saeys, Yvan; Lambrecht, Bart N; Guilliams, Martin

    2016-04-19

    Tissue-resident macrophages can derive from yolk sac macrophages (YS-Macs), fetal liver monocytes (FL-MOs), or adult bone-marrow monocytes (BM-MOs). The relative capacity of these precursors to colonize a niche, self-maintain, and perform tissue-specific functions is unknown. We simultaneously transferred traceable YS-Macs, FL-MOs, and BM-MOs into the empty alveolar macrophage (AM) niche of neonatal Csf2rb(-/-) mice. All subsets produced AMs, but in competition preferential outgrowth of FL-MOs was observed, correlating with their superior granulocyte macrophage-colony stimulating factor (GM-CSF) reactivity and proliferation capacity. When transferred separately, however, all precursors efficiently colonized the alveolar niche and generated AMs that were transcriptionally almost identical, self-maintained, and durably prevented alveolar proteinosis. Mature liver, peritoneal, or colon macrophages could not efficiently colonize the empty AM niche, whereas mature AMs could. Thus, precursor origin does not affect the development of functional self-maintaining tissue-resident macrophages and the plasticity of the mononuclear phagocyte system is largest at the precursor stage. PMID:26992565

  19. Data on macrophage mediated muscle transfection upon delivery of naked plasmid DNA with block copolymers.

    PubMed

    Mahajan, Vivek; Gaymalov, Zagit; Alakhova, Daria; Gupta, Richa; Zucker, Irving H; Kabanov, Alexander V

    2016-06-01

    The data contains 14 figures supporting the research article "Horizontal gene transfer from macrophages to ischemic muscles upon delivery of naked DNA with Pluronic block copolymers" [1]. The data explains the surgical procedure and histological characterization of Murine Hind Limb Ischemia. The data also shows the kinetics of luciferase gene expression, spread of GFP expression through muscle and the colocalization of GFP with cellular markers in ischemic muscles injected with pDNA alone or pDNA/Pluronic. Finally the data shows the effect of Pluronic Block Copolymer to enhance total gene expression (cmv-promoter driven luciferase gene) in coculture of DNA transfected MØs with muscle cells. PMID:27222845

  20. Identification and characterization of a non-satellite cell muscle resident progenitor during postnatal development.

    PubMed

    Mitchell, Kathryn J; Pannérec, Alice; Cadot, Bruno; Parlakian, Ara; Besson, Vanessa; Gomes, Edgar R; Marazzi, Giovanna; Sassoon, David A

    2010-03-01

    Satellite cells are resident myogenic progenitors in postnatal skeletal muscle involved in muscle postnatal growth and adult regenerative capacity. Here, we identify and describe a population of muscle-resident stem cells, which are located in the interstitium, that express the cell stress mediator PW1 but do not express other markers of muscle stem cells such as Pax7. PW1(+)/Pax7(-) interstitial cells (PICs) are myogenic in vitro and efficiently contribute to skeletal muscle regeneration in vivo as well as generating satellite cells and PICs. Whereas Pax7 mutant satellite cells show robust myogenic potential, Pax7 mutant PICs are unable to participate in myogenesis and accumulate during postnatal growth. Furthermore, we found that PICs are not derived from a satellite cell lineage. Taken together, our findings uncover a new and anatomically identifiable population of muscle progenitors and define a key role for Pax7 in a non-satellite cell population during postnatal muscle growth. PMID:20118923

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

    PubMed

    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

  2. RNA from LPS-stirnulated macrophages induces the release of tumour necrosis factor-α and interleukin-1 by resident macrophages

    PubMed Central

    Ribeiro, R. A.; Flores, C. A.; Cunha, F. Q.; Ferreira, S. H.

    1993-01-01

    The effect of exogenous RNA on many cellular functions has been studied in a variety of eukaryotic cells but there are few reports on macrophages. In the present study, it is demonstrated that cytoplasmatic RNA extracted from rat macrophages stimulated with Escherichia coli lipopolysaccharide (LPS), referred to as L-RNA, induced the release of TNF-α and IL-1 from monolayers of peritoneal resident macrophages. The activity of L-RNA was not altered by polymyxin B but was abolished by ribonuclease (RNase) pretreatment, indicating the absence of LPS contamination and that the integrity of the polynucleotide chain is essential for this activity. Both the poly A(−) and poly A(+) fractions obtained from L-RNA applied to oligo(dT)–cellulose chromatography induced TNF-α and IL-1 release. The L-RNA-induced cytokine release was inhibited by dexamethasone and seemed to be dependent on protein synthesis since this effect was abolished by cycloheximide or actinomycin-D. The LPS-stimulated macrophages, when pre-incubated with [5-3H]-uridine, secreted a trichloroacetic acid (TCA) precipitable material which was sensitive to RNase and KOH hydrolysis, suggesting that the material is RNA. This substance was also released from macrophage monolayers stimulated with IL-1β but not with TNF-α, IL-6 or IL-8. The substance secreted (3H-RNA) sediments in the 4–5S region of a 5–20% sucrose gradient. These results show that L-RNA induces cytokine secretion by macrophage monolayers and support the idea that, during inflammation, stimulated macrophages could release RNA which may further induce the release of cytokines by the resident cell population. PMID:18475560

  3. 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

  4. Activated macrophages as a feeder layer for growth of resident cardiac progenitor cells.

    PubMed

    Sepúlveda, Diana E; Cabeza Meckert, Patricia; Locatelli, Paola; Olea, Fernanda D; Pérez, Néstor G; Pinilla, Oscar A; Díaz, Romina G; Crottogini, Alberto; Laguens, Rubén P

    2016-08-01

    The adult heart contains a population of cardiac progenitor cells (CPCs). Growing and collecting an adequate number of CPCs demands complex culture media containing growth factors. Since activated macrophages secrete many growth factors, we investigated if activated isolated heart cells seeded on a feeder layer of activated peritoneal macrophages (PM) could result in CPCs and if these, in turn, could exert cardioprotection in rats with myocardial infarction (MI). Heart cells of inbred Wistar rats were isolated by collagenase digestion and cultured on PM obtained 72 h after intraperitoneal injection of 12 ml thioglycollate. Cells (1 × 10(6)) exhibiting CPC phenotype (immunohistochemistry) were injected in the periphery of rat MI 10 min after coronary artery occlusion. Control rats received vehicle. Three weeks later, left ventricular (LV) function (echocardiogram) was assessed, animals were euthanized and the hearts removed for histological studies. Five to six days after seeding heart cells on PM, spherical clusters composed of small bright and spherical cells expressing mostly c-Kit and Sca-1 antigens were apparent. After explant, those clusters developed cobblestone-like monolayers that expressed smooth muscle actin and sarcomeric actin and were successfully transferred for more than ten passages. When injected in the MI periphery, many of them survived at 21 days after coronary ligature, improved LV ejection fraction and decreased scar size as compared with control rats. CPC-derived cells with cardiocyte and smooth muscle phenotypes can be successfully grown on a feeder layer of activated syngeneic PM. These cells decreased scar size and improved heart function in rats with MI. PMID:25432330

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

    PubMed Central

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

    2014-01-01

    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. PMID:24973296

  6. 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. PMID:24973296

  7. Development of the smooth muscle foam cell: uptake of macrophage lipid inclusions.

    PubMed

    Wolfbauer, G; Glick, J M; Minor, L K; Rothblat, G H

    1986-10-01

    A possible mechanism for the formation of smooth muscle foam cells in the atherosclerotic lesion was explored. Cultured macrophages (J774 cell line) were induced to form cytoplasmic cholesteryl ester inclusions by exposure to acetylated low density lipoprotein in the presence of cholesterol-rich phospholipid dispersions. The macrophages were disrupted by brief sonication, and the inclusions were isolated by flotation. When these inclusions were placed in direct contact with cultured smooth muscle cells, cellular uptake of the inclusions in a time- and dose-dependent manner was observed. Light and electron microscopy indicated the presence of lipid inclusions throughout the cytoplasm of the cells. Uptake of inclusion lipid by the smooth muscle cells was inhibited by several metabolic inhibitors, indicating that the process is dependent on metabolic activity. A modest but significant hydrolysis of the cholesteryl ester was observed, showing that the stored cholesteryl esters are metabolically available. PMID:3020555

  8. Increased expression of fatty acid binding protein 4 and leptin in resident macrophages characterises atherosclerotic plaque rupture

    PubMed Central

    Lee, K.; Santibanez-Koref, M.; Polvikoski, T.; Birchall, D.; Mendelow, A.D.; Keavney, B.

    2013-01-01

    Objective Resident macrophages play an important role in atheromatous plaque rupture. The macrophage gene expression signature associated with plaque rupture is incompletely defined due to the complex cellular heterogeneity in the plaque. We aimed to characterise differential gene expression in resident plaque macrophages from ruptured and stable human atheromatous lesions. Methods and results We performed genome-wide expression analyses of isolated macrophage-rich regions of stable and ruptured human atherosclerotic plaques. Plaques present in carotid endarterectomy specimens were designated as stable or ruptured using clinical, radiological and histopathological criteria. Macrophage-rich regions were excised from 5 ruptured and 6 stable plaques by laser micro-dissection. Transcriptional profiling was performed using Affymetrix microarrays. The profiles were characteristic of activated macrophages. At a false discovery rate of 10%, 914 genes were differentially expressed between stable and ruptured plaques. The findings were confirmed in fourteen further stable and ruptured samples for a subset of eleven genes with the highest expression differences (p < 0.05). Pathway analysis revealed that components of the PPAR/Adipocytokine signaling pathway were the most significantly upregulated in ruptured compared to stable plaques (p = 5.4 × 10−7). Two key components of the pathway, fatty-acid binding-protein 4 (FABP4) and leptin, showed nine-fold (p = 0.0086) and five-fold (p = 0.0012) greater expression respectively in macrophages from ruptured plaques. Conclusions We found differences in gene expression signatures between macrophages isolated from stable and ruptured human atheromatous plaques. Our findings indicate the involvement of FABP4 and leptin in the progression of atherosclerosis and plaque rupture, and suggest that down-regulation of PPAR/adipocytokine signaling within plaques may have therapeutic potential. PMID:23122912

  9. 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

    2015-01-01

    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

  10. 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

  11. Data on macrophage mediated muscle transfection upon delivery of naked plasmid DNA with block copolymers

    PubMed Central

    Mahajan, Vivek; Gaymalov, Zagit; Alakhova, Daria; Gupta, Richa; Zucker, Irving H.; Kabanov, Alexander V.

    2016-01-01

    The data contains 14 figures supporting the research article “Horizontal gene transfer from macrophages to ischemic muscles upon delivery of naked DNA with Pluronic block copolymers” [1]. The data explains the surgical procedure and histological characterization of Murine Hind Limb Ischemia. The data also shows the kinetics of luciferase gene expression, spread of GFP expression through muscle and the colocalization of GFP with cellular markers in ischemic muscles injected with pDNA alone or pDNA/Pluronic. Finally the data shows the effect of Pluronic Block Copolymer to enhance total gene expression (cmv-promoter driven luciferase gene) in coculture of DNA transfected MØs with muscle cells. PMID:27222845

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

    PubMed

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

    2013-04-01

    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

  13. Activation of Cytosolic Phospholipase A2α in Resident Peritoneal Macrophages by Listeria monocytogenes Involves Listeriolysin O and TLR2*

    PubMed Central

    Noor, Shahid; Goldfine, Howard; Tucker, Dawn E.; Suram, Saritha; Lenz, Laurel L.; Akira, Shizuo; Uematsu, Satoshi; Girotti, Milena; Bonventre, Joseph V.; Breuel, Kevin; Williams, David L.; Leslie, Christina C.

    2016-01-01

    Eicosanoid production by macrophages is an early response to microbial infection that promotes acute inflammation. The intracellular pathogen Listeria monocytogenes stimulates arachidonic acid release and eicosanoid production from resident mouse peritoneal macrophages through activation of group IVA cytosolic phospholipase A2 (cPLA2α). The ability of wild type L. monocytogenes (WTLM) to stimulate arachidonic acid release is partially dependent on the virulence factor listeriolysin O; however, WTLM and L. monocytogenes lacking listeriolysin O (ΔhlyLM) induce similar levels of cyclooxygenase 2. Arachidonic acid release requires activation of MAPKs by WTLM and ΔhlyLM. The attenuated release of arachidonic acid that is observed in TLR2−/− and MyD88−/− macrophages infected with WTLM and ΔhlyLM correlates with diminished MAPK activation. WTLM but not ΔhlyLM increases intracellular calcium, which is implicated in regulation of cPLA2α. Prostaglandin E2, prostaglandin I2, and leukotriene C4 are produced by cPLA2α+/+ but not cPLA2α−/− macrophages in response to WTLM and ΔhlyLM. Tumor necrosis factor (TNF)-α production is significantly lower in cPLA2α+/+ than in cPLA2α−/− macrophages infected with WTLM and ΔhlyLM. Treatment of infected cPLA2α+/+ macrophages with the cyclooxygenase inhibitor indomethacin increases TNFα production to the level produced by cPLA2α−/− macrophages implicating prostaglandins in TNFα down-regulation. Therefore activation of cPLA2α in macrophages may impact immune responses to L. monocytogenes. PMID:18083708

  14. Resident alveolar macrophages suppress while recruited monocytes promote allergic lung inflammation in murine models of asthma

    PubMed Central

    Zasłona, Zbigniew; Przybranowski, Sally; Wilke, Carol; van Rooijen, Nico; Teitz-Tennenbaum, Seagal; Osterholzer, John J.; Wilkinson, John E.; Moore, Bethany B.; Peters-Golden, Marc

    2014-01-01

    The role and origin of alveolar macrophages (AMs) in asthma are incompletely defined. We sought to clarify these issues in the context of acute allergic lung inflammation utilizing house dust mite and ovalbumin murine models. Use of liposomal clodronate to deplete resident AMs (rAMs) resulted in increased levels of inflammatory cytokines and eosinophil numbers in lavage fluid and augmented histopathologic evidence of lung inflammation, suggesting a suppressive role of rAMs. Lung digests of asthmatic mice revealed an increased percentage of Ly6Chigh/CD11bpos inflammatory monocytes. Clodronate depletion of circulating monocytes, by contrast, resulted in an attenuation of allergic inflammation. A CD45.1/CD45.2 chimera model demonstrated that recruitment at least partially contributes to the AM pool in irradiated non-asthmatic mice, but its contribution was no greater in asthma. Ki-67 staining of AMs supported a role for local proliferation, which was increased in asthma. Our data demonstrate that rAMs dampen, while circulating monocytes promote, early events in allergic lung inflammation. Moreover, maintenance of the AM pool in the early stages of asthmatic inflammation depends on local proliferation but not recruitment. PMID:25225663

  15. Tissue-resident mesenchymal stem/progenitor cells in skeletal muscle: collaborators or saboteurs?

    PubMed Central

    Judson, Robert N.; Zhang, Regan-Heng; Rossi, Fabio M. A.

    2016-01-01

    Although the regenerative potential of adult skeletal muscle is maintained by satellite cells, other stem/progenitor cell populations also reside in skeletal muscle. These heterogeneous cellular pools with mesenchymal lineage potentially play important roles in tissue homeostasis, with reciprocal collaborations between these cells and satellite cells appearing critical for effective regeneration. However, in disease settings, these mesenchymal stem/progenitors adopt a more sinister role – likely providing a major source of fibrosis, fatty tissue and extracellular matrix protein deposition in dystrophic tissue. Development of therapies for muscle degeneration therefore requires complete understanding of the multiple cell types involved and their complex interactions. PMID:23763717

  16. 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

  17. Macrophagic myofasciitis lesions assess long-term persistence of vaccine-derived aluminium hydroxide in muscle.

    PubMed

    Gherardi, R K; Coquet, M; Cherin, P; Belec, L; Moretto, P; Dreyfus, P A; Pellissier, J F; Chariot, P; Authier, F J

    2001-09-01

    Macrophagic myofasciitis (MMF) is an emerging condition of unknown cause, detected in patients with diffuse arthromyalgias and fatigue, and characterized by muscle infiltration by granular periodic acid-Schiff's reagent-positive macrophages and lymphocytes. Intracytoplasmic inclusions have been observed in macrophages of some patients. To assess their significance, electron microscopy was performed in 40 consecutive cases and chemical analysis was done by microanalysis and atomic absorption spectrometry. Inclusions were constantly detected and corresponded to aluminium hydroxide, an immunostimulatory compound frequently used as a vaccine adjuvant. A lymphocytic component was constantly observed in MMF lesions. Serological tests were compatible with exposure to aluminium hydroxide-containing vaccines. History analysis revealed that 50 out of 50 patients had received vaccines against hepatitis B virus (86%), hepatitis A virus (19%) or tetanus toxoid (58%), 3-96 months (median 36 months) before biopsy. Diffuse myalgias were more frequent in patients with than without an MMF lesion at deltoid muscle biopsy (P < 0.0001). Myalgia onset was subsequent to the vaccination (median 11 months) in 94% of patients. MMF lesion was experimentally reproduced in rats. We conclude that the MMF lesion is secondary to intramuscular injection of aluminium hydroxide-containing vaccines, shows both long-term persistence of aluminium hydroxide and an ongoing local immune reaction, and is detected in patients with systemic symptoms which appeared subsequently to vaccination. PMID:11522584

  18. The pancreas anatomy conditions the origin and properties of resident macrophages

    PubMed Central

    Calderon, Boris; Carrero, Javier A.; Ferris, Stephen T.; Sojka, Dorothy K.; Moore, Lindsay; Epelman, Slava; Murphy, Kenneth M.; Yokoyama, Wayne M.; Randolph, Gwendalyn J.

    2015-01-01

    We examine the features, origin, turnover, and gene expression of pancreatic macrophages under steady state. The data distinguish macrophages within distinct intrapancreatic microenvironments and suggest how macrophage phenotype is imprinted by the local milieu. Macrophages in islets of Langerhans and in the interacinar stroma are distinct in origin and phenotypic properties. In islets, macrophages are the only myeloid cells: they derive from definitive hematopoiesis, exchange to a minimum with blood cells, have a low level of self-replication, and depend on CSF-1. They express Il1b and Tnfa transcripts, indicating classical activation, M1, under steady state. The interacinar stroma contains two macrophage subsets. One is derived from primitive hematopoiesis, with no interchange by blood cells and alternative, M2, activation profile, whereas the second is derived from definitive hematopoiesis and exchanges with circulating myeloid cells but also shows an alternative activation profile. Complete replacement of islet and stromal macrophages by donor stem cells occurred after lethal irradiation with identical profiles as observed under steady state. The extraordinary plasticity of macrophages within the pancreatic organ and the distinct features imprinted by their anatomical localization sets the base for examining these cells in pathological conditions. PMID:26347472

  19. Apoptosis of resident and inflammatory macrophages before and during the inflammatory response of the virgin bovine mammary gland

    PubMed Central

    2010-01-01

    Background Macrophages may play a prominent role in defense of the bovine mammary gland, and their functionality is necessary for successful eradication of bacterial pathogens. In contrast to necrosis, however, apoptosis has not yet been studied in macrophages from bovine mammary glands. Therefore, the aim of this study was to confirm the occurrence of apoptosis in macrophages from resting heifer mammary glands and during the inflammatory response. Methods Inflammatory response was induced by phosphate buffered saline (PBS) and by lipopolysaccharide (LPS). Resident macrophages (RESMAC) were obtained before and inflammatory macrophages (INFMAC) 24, 48, 72 and 168 hours after inducing inflammatory response in mammary glands of unbred heifers. Cell samples were analyzed for differential counts, apoptosis and necrosis using flow cytometry. Results Populations of RESMAC and INFMAC contained monocyte-like cells and vacuolized cells. Apoptosis was detected differentially in both morphologically different types of RESMAC and INFMAC and also during initiation and resolution of the inflammatory response. In the RESMAC population, approximately one-tenth of monocyte-like cells and one-third of vacuolized cells were apoptotic. In the INFMAC population obtained 24 h after PBS treatment, approximately one-tenth of monocyte-like cells and almost one-quarter of vacuolized cells were apoptotic. At the same time following LPS, however, we observed a significantly lower percentage of apoptotic cells in the population of monocyte-like INFMAC and vacuolized INFMAC. Moreover, a higher percentage of apoptotic cells in INFMAC was detected during all time points after PBS in contrast to LPS. Comparing RESMAC and INFMAC, we observed that vacuolized cells from populations of RESMAC and INFMAC underwent apoptosis more intensively than did monocyte-like cells. Conclusions We conclude that apoptosis of virgin mammary gland macrophages is involved in regulating their lifespan, and it is involved

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

    PubMed Central

    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

    2016-01-01

    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

  1. Macrophages in Injured Skeletal Muscle: A Perpetuum Mobile Causing and Limiting Fibrosis, Prompting or Restricting Resolution and Regeneration

    PubMed Central

    Bosurgi, Lidia; Manfredi, Angelo A.; Rovere-Querini, Patrizia

    2011-01-01

    Macrophages are present in regenerating skeletal muscles and participate in the repair process. This is due to a unique feature of macrophages, i.e., their ability to perceive signals heralding ongoing tissue injury and to broadcast the news to cells suited at regenerating the tissue such as stem and progenitor cells. Macrophages play a complex role in the skeletal muscle, probably conveying information on the pattern of healing which is appropriate to ensure an effective healing of the tissue, yielding novel functional fibers. Conversely, they are likely to be involved in limiting the efficacy of regeneration, with formation of fibrotic scars and fat replacement of the tissue when the original insult persists. In this review we consider the beneficial versus the detrimental actions of macrophages during the response to muscle injury, with attention to the available information on the molecular code macrophages rely on to guide, throughout the various phases of muscle healing, the function of conventional and unconventional stem cells. Decrypting this code would represent a major step forward toward the establishment of novel targeted therapies for muscle diseases. PMID:22566851

  2. 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

  3. Kinetics of tumour necrosis factor and prostaglandin production by murine resident peritoneal macrophages as affected by dietary n-3 polyunsaturated fatty acids.

    PubMed Central

    Hardard'ottir, I; Whelan, J; Kinsella, J E

    1992-01-01

    Cell-associated and secreted tumour necrosis factor (TNF), prostaglandin (PG) E2, and 6-keto PGF1 alpha were monitored at various times following in vitro stimulation of resident peritoneal macrophages with lipopolysaccharide (LPS). Macrophages were obtained from mice maintained on diets containing 1.5 wt% n-3 polyunsaturated fatty acids (PUFA)+ 1.5 wt% n-6 fatty acids; 1.5 wt% n-6 fatty acids; or 3 wt% n-6 fatty acids, for 4 weeks. Cell-associated TNF increased transiently in the resident peritoneal macrophages from mice consuming all diets and decreased after TNF secretion had reached maximum and plateaued. Macrophages from mice consuming the n-3 PUFA contained more cell-associated TNF and secreted more TNF than macrophages from mice consuming diets containing n-6 fatty acids only, at all time-points studied. Macrophages from mice consuming the n-3 PUFA showed an earlier increase in cell-associated and secreted TNF compared with macrophages from mice consuming n-6 fatty acids only. Kinetics of maximum TNF production was not affected by the diets and dietary n-3 PUFA did not cause a prolonged increase in TNF secretion. Macrophages from mice consuming the n-3 PUFA produced less PG than macrophages from mice consuming the n-6 fatty acids only. PG secretion increased following appearance of cell-associated TNF but when PG had accumulated in the medium there was no further increase in TNF production. PMID:1398747

  4. 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, andN-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

  5. 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.

  6. Decreased eccentric exercise-induced macrophage infiltration in skeletal muscle after supplementation with a class of ginseng-derived steroids.

    PubMed

    Yu, Szu-Hsien; Huang, Chih-Yang; Lee, Shin-Da; Hsu, Ming-Fen; Wang, Ray-Yau; Kao, Chung-Lan; Kuo, Chia-Hua

    2014-01-01

    Dammarane steroids (DS) are a class of chemical compounds present in Panax ginseng. Here, we evaluated the effect of 10 weeks of DS supplementation on inflammatory modulation in the soleus muscle following eccentric exercise (EE)-induced muscle damage (downhill running). Eighty rats were randomized into 4 groups of DS supplementation (saline, 20, 60, 120 mg/kg body weight). Inflammatory markers were measured at rest and again 1 h after EE. At rest, NFκB signaling, TNF-alpha and IL-6 mRNAs, 3-nitrotyrosine, glutathione peroxidase, and GCS (glutamylcysteine synthetase) levels were significantly elevated in the skeletal muscle of DS-treated rats in a dose-dependent manner. Additionally, there were no detectable increases in the number of necrotic muscle fibers or CD68+ M1 macrophages. However, muscle strength, centronucleation, IL-10 mRNA expression, and the number of CD163+ M2 macrophages increased significantly over controls with DS treatment in rat soleus muscle. Under EE-challenged conditions, significant increases in muscle fiber necrosis, CD68+ M1 macrophage distribution, and 3-nitrotyrosine were absent in rats that received low and medium doses (20 and 60 mg/kg) of DS treatment, suggesting that DS possess anti-inflammatory action protecting against a muscle-damaging challenge. However, this protective activity was diminished when a high dose of DS (120 mg/kg) was administered, suggesting that DS possess hormetic properties. In conclusion, our study provides new evidence suggesting that DS is an ergogenic component of ginseng that potentiate inflammation at baseline but that produce anti-inflammatory effects on skeletal muscle following muscle-damaging exercise. Furthermore, high doses should be avoided in formulating ginseng-based products. PMID:25500579

  7. Horizontal gene transfer from macrophages to ischemic muscles upon delivery of naked DNA with Pluronic block copolymers.

    PubMed

    Mahajan, Vivek; Gaymalov, Zagit; Alakhova, Daria; Gupta, Richa; Zucker, Irving H; Kabanov, Alexander V

    2016-01-01

    Intramuscular administration of plasmid DNA (pDNA) with non-ionic Pluronic block copolymers increases gene expression in injected muscles and lymphoid organs. We studied the role of immune cells in muscle transfection upon inflammation. Local inflammation in murine hind limb ischemia model (MHLIM) drastically increased DNA, RNA and expressed protein levels in ischemic muscles injected with pDNA/Pluronic. The systemic inflammation (MHLIM or peritonitis) also increased expression of pDNA/Pluronic in the muscles. When pDNA/Pluronic was injected in ischemic muscles the reporter gene, Green Fluorescent Protein (GFP) co-localized with desmin(+) muscle fibers and CD11b(+) macrophages (MØs), suggesting transfection of MØs along with the muscle cells. P85 enhanced (∼ 4 orders) transfection of MØs with pDNA in vitro. Moreover, adoptively transferred MØs were shown to pass the transgene to inflamed muscle cells in MHLIM. Using a co-culture of myotubes (MTs) and transfected MØs expressing a reporter gene under constitutive (cmv-luciferase) or muscle specific (desmin-luciferase) promoter we demonstrated that P85 enhances horizontal gene transfer from MØ to MTs. Therefore, MØs can play an important role in muscle transfection with pDNA/Pluronic during inflammation, with both inflammation and Pluronic contributing to the increased gene expression. pDNA/Pluronic has potential for therapeutic gene delivery in muscle pathologies that involve inflammation. PMID:26480472

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

    PubMed

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

    2013-10-21

    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

  9. Insulin Resistance is Associated with MCP1-Mediated Macrophage Accumulation in Skeletal Muscle in Mice and Humans

    PubMed Central

    Patsouris, David; Cao, Jingwei-Ji; Vial, Guillaume; Bravard, Amelie; Lefai, Etienne; Durand, Annie; Durand, Christine; Chauvin, Marie-Agnés; Laugerette, Fabienne; Debard, Cyrille; Michalski, Marie-Caroline; Laville, Martine; Vidal, Hubert; Rieusset, Jennifer

    2014-01-01

    Inflammation is now recognized as a major factor contributing to type 2 diabetes (T2D). However, while the mechanisms and consequences associated with white adipose tissue inflammation are well described, very little is known concerning the situation in skeletal muscle. The aim of this study was to investigate, in vitro and in vivo, how skeletal muscle inflammation develops and how in turn it modulates local and systemic insulin sensitivity in different mice models of T2D and in humans, focusing on the role of the chemokine MCP1. Here, we found that skeletal muscle inflammation and macrophage markers are increased and associated with insulin resistance in mice models and humans. In addition, we demonstrated that intra-muscular TNFα expression is exclusively restricted to the population of intramuscular leukocytes and that the chemokine MCP1 was associated with skeletal muscle inflammatory markers in these models. Furthermore, we demonstrated that exposure of C2C12 myotubes to palmitate elevated the production of the chemokine MCP1 and that the muscle-specific overexpression of MCP1 in transgenic mice induced the local recruitment of macrophages and altered local insulin sensitivity. Overall our study demonstrates that skeletal muscle inflammation is clearly increased in the context of T2D in each one of the models we investigated, which is likely consecutive to the lipotoxic environment generated by peripheral insulin resistance, further increasing MCP1 expression in muscle. Consequently, our results suggest that MCP1-mediated skeletal muscle macrophages recruitment plays a role in the etiology of T2D. PMID:25337938

  10. Resident bone marrow macrophages produce type 1 interferons that can selectively inhibit interleukin-7-driven growth of B lineage cells.

    PubMed

    Wang, J; Lin, Q; Langston, H; Cooper, M D

    1995-10-01

    Type 1 interferons alpha and beta are found to be potent inhibitors of IL-7-induced growth of early B lineage cells, while having no effect on cell growth induced by IL-2, IL-3, IL-4, or autogenous factors. The combination of IL-7 and interferons alpha/beta induces bcl-2 down-regulation and cell death by apoptosis. These conclusions were derived initially from experiments employing exogenous cytokines, but functional type 1 interferons are also shown to be produced by resident bone marrow macrophages. As physiological modulators of IL-7-driven proliferation and cell survival, interferons alpha/beta may cooperate with other homeostatic factors to maintain the balanced production of normal B lineage cells. PMID:7584138

  11. 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

  12. 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.

  13. C-Myb(+) erythro-myeloid progenitor-derived fetal monocytes give rise to adult tissue-resident macrophages.

    PubMed

    Hoeffel, Guillaume; Chen, Jinmiao; Lavin, Yonit; Low, Donovan; Almeida, Francisca F; See, Peter; Beaudin, Anna E; Lum, Josephine; Low, Ivy; Forsberg, E Camilla; Poidinger, Michael; Zolezzi, Francesca; Larbi, Anis; Ng, Lai Guan; Chan, Jerry K Y; Greter, Melanie; Becher, Burkhard; Samokhvalov, Igor M; Merad, Miriam; Ginhoux, Florent

    2015-04-21

    Although classified as hematopoietic cells, tissue-resident macrophages (MFs) arise from embryonic precursors that seed the tissues prior to birth to generate a self-renewing population, which is maintained independently of adult hematopoiesis. Here we reveal the identity of these embryonic precursors using an in utero MF-depletion strategy and fate-mapping of yolk sac (YS) and fetal liver (FL) hematopoiesis. We show that YS MFs are the main precursors of microglia, while most other MFs derive from fetal monocytes (MOs). Both YS MFs and fetal MOs arise from erythro-myeloid progenitors (EMPs) generated in the YS. In the YS, EMPs gave rise to MFs without monocytic intermediates, while EMP seeding the FL upon the establishment of blood circulation acquired c-Myb expression and gave rise to fetal MOs that then seeded embryonic tissues and differentiated into MFs. Thus, adult tissue-resident MFs established from hematopoietic stem cell-independent embryonic precursors arise from two distinct developmental programs. PMID:25902481

  14. 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. PMID:24361424

  15. 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

  16. Difference in LDL receptor feedback regulation in macrophages and vascular smooth muscle cells: foam cell transformation under inflammatory stress.

    PubMed

    Ye, Qiang; Lei, Han; Fan, Zhongcai; Zheng, Wenwu; Zheng, Shuzhan

    2014-04-01

    Macrophages and vascular smooth muscle cells (VSMCs) are the major cell types involved in foam cell formation associated with atherosclerosis. The aim of this experiment was to clarify cell-specific regulation of LDL receptor in THP-1 macrophages and human VSMCs under physiological and inflammatory conditions and its potential mechanisms. Inflammatory stress was induced by adding lipopolysaccharide (LPS) to human THP-1 macrophages and human VSMCs. Intracellular total cholesterol, free cholesterol, and cholesterol ester were measured by an enzymic assay. Oil Red O staining was used to visualize lipid droplet accumulation in cells. Total cellular RNA was isolated from cells for detecting LDL receptor, sterol regulatory element binding protein (SREBP)-2 and SREBP cleavage-activating protein (SCAP) mRNA levels using real-time quantitative polymerase chain reaction. LDL receptor, SREBP-2 and SCAP protein expression were examined by Western blotting. The translocation of SCAP from ER to Golgi was detected by confocal microscopy. LDL loading increased intracellular cholesterol level, reducing LDL receptor mRNA level in both THP-1 macrophages and VSMCs under physiological conditions. The IC50 in VSMCs was 11.25 μg/ml, which is much lower than 18.125 μg/ml in THP-1 macrophages. With the increase in concentration of LPS (0-400 ng/ml), the LDL receptor mRNA levels were upregulated in both cells, but the curve of LDL receptor mRNA in VSMCs exhibited a flatter profile than that of THP-1 macrophages. Under the treatment of 200 ng/ml of LPS, the upregulation fold of the LDL receptor mRNA in THP-1 macrophages was much higher than that of VSMCs (0.33 vs 0.04). LDL receptor blocking agent heparin decreased lipid droplets induced by LPS significantly in THP-1 macrophages and VSMCs. LDL loading reduced the SREBP2 and SCAP protein expression under physiological conditions. Exposure to LPS caused overexpression of SREBP2 and SCAP despite a high concentration of LDL in the culture

  17. Macrophages commit postnatal endothelium-derived progenitors to angiogenesis and restrict endothelial to mesenchymal transition during muscle regeneration

    PubMed Central

    Zordan, P; Rigamonti, E; Freudenberg, K; Conti, V; Azzoni, E; Rovere-Querini, P; Brunelli, S

    2014-01-01

    The damage of the skeletal muscle prompts a complex and coordinated response that involves the interactions of many different cell populations and promotes inflammation, vascular remodeling and finally muscle regeneration. Muscle disorders exist in which the irreversible loss of tissue integrity and function is linked to defective neo-angiogenesis with persistence of tissue necrosis and inflammation. Here we show that macrophages (MPs) are necessary for efficient vascular remodeling in the injured muscle. In particular, MPs sustain the differentiation of endothelial-derived progenitors to contribute to neo-capillary formation, by secreting pro-angiogenic growth factors. When phagocyte infiltration is compromised endothelial-derived progenitors undergo a significant endothelial to mesenchymal transition (EndoMT), possibly triggered by the activation of transforming growth factor-β/bone morphogenetic protein signaling, collagen accumulates and the muscle is replaced by fibrotic tissue. Our findings provide new insights in EndoMT in the adult skeletal muscle, and suggest that endothelial cells in the skeletal muscle may represent a new target for therapeutic intervention in fibrotic diseases. PMID:24481445

  18. Colony-Stimulating Factor-1-Responsive Macrophage Precursors Reside in the Amphibian (Xenopus laevis) Bone Marrow Rather than the Hematopoietic Sub-Capsular Liver

    PubMed Central

    Grayfer, Leon; Robert, Jacques

    2013-01-01

    Macrophage precursors originate from, and undergo lineage commitment within designated sites of hematopoiesis, such as the mammalian bone marrow. These cells subsequently differentiate in response to stimulation with macrophage colony-stimulating factor (CSF-1). The amphibian bone marrow, unlike that of mammals, has been overlooked as a source of leukocyte precursors in favor of the liver sub-capsular region, where hematopoiesis occurs in anurans. Here we report that the bone marrow rather than the liver periphery provides macrophage progenitors to the amphibian Xenopus laevis. We identified the amphibian CSF-1, examined its gene expression in developing and virally infected X. laevis and produce it in recombinant form (rXlCSF-1). This rXlCSF-1 did not bind or elicit proliferation/differentiation of sub-cortical liver cells. Surprisingly, a sub-population of bone marrow cells engaged this growth factor and formed rXlCSF-1-concentration-dependant colonies in semi-solid medium. Furthermore, rXlCSF-1-treated bone marrow (but not liver) cultures comprised of cells with characteristic macrophage morphology and high gene expression of the macrophage marker, colony stimulating factor-1 receptor (CSF-1R). Together, our findings indicate that in contrast to all other vertebrates studied to date, Xenopus committed macrophage precursors populations are not present in the central site of hematopoiesis, but reside in the bone marrow. PMID:23485675

  19. Relationship between Isometric Strength of Six Lower Limb Muscle Groups and Motor Skills among Nursing Home Residents.

    PubMed

    Buckinx, F; Croisier, J L; Reginster, J Y; Petermans, J; Goffart, E; Bruyère, O

    2015-01-01

    This research aimed to assess the correlation between isometric muscle strength of the lower limb and motor skills. This is a cross sectional study performed among volunteer nursing home residents included in the SENIOR (Sample of Elderly Nursing home Individuals: an Observational Research) cohort. The present analysis focused on isometric muscle strength of 6 lower limb muscle groups (i.e. knee extensors, knee flexors, hip abductors, hip extensors, ankle flexors and ankle extensors), assessed using a validated hand-held dynamometer (i.e. the MicroFET2 device), and motor skills evaluated using the Tinetti test, the Timed Up and Go test, the Short Physical Performance Battery test (SPPB) and the walking speed. The relationship between all these parameters was tested by means of a multiple correlation, adjusted on age, sex and body mass index. 450 nursing home residents (69.8% of women) with a mean age of 83.1±9.4 years were included in this study. Our results showed a significant inverse correlation between lower limb muscle strength and the time required to perform the TUG test or gait speed, except for ankle flexors and ankle extensors. The relationship between the Tinetti test or the SPPB score, and lower limb muscle strength was significant, except for ankle flexors and ankle extensors. In conclusion, a positive association between lower limb muscle strength of the four main muscle groups and motor skills of the elderly nursing residents was found in this research. Therefore, special attention should be given to these muscle groups during rehabilitation programs. PMID:27031016

  20. Soluble β-glucan from Grifola frondosa induces proliferation and Dectin-1/Syk signaling in resident macrophages via the GM-CSF autocrine pathway.

    PubMed

    Masuda, Yuki; Togo, Takuya; Mizuno, Shigeto; Konishi, Morichika; Nanba, Hiroaki

    2012-04-01

    MD-Fraction, a highly purified, soluble β-(1,3) (1,6)-glucan obtained from Grifola frondosa (an oriental edible mushroom), has been reported to inhibit tumor growth by modulating host immunity. β-Glucan, a major component of the fungal cell wall, is generally recognized by PRRs expressed on macrophages and DCs, such as Dectin-1, and the ability of β-glucans to modulate host immunity is influenced by their structure and purity. Most cellular studies have used particulate β-glucans, such as yeast zymosan (crude β-glucan) and curdlan (purified β-glucan). However, little is known about the cellular mechanism of soluble β-glucans, including MD-Fraction, despite significant therapeutic implications. In this study, we investigated the cellular mechanism of MD-Fraction in murine resident macrophages and compared it with two well-known β-glucan particles. MD-Fraction induced GM-CSF production rapidly through Dectin-1-independent ERK and p38 MAPK activation. Subsequently, MD-Fraction-induced GM-CSF enhanced proliferation and Dectin-1 expression, which permitted Dectin-1-mediated TNF-α induction through the Syk pathway. Curdlan induced not only the proliferation and activation of Dectin-1/Syk signaling in a manner similar to MD-Fraction but also the uncontrolled, proinflammatory cytokine response. Contrastingly, zymosan reduced proliferation and Dectin-1 expression significantly, indicating that the mechanism of macrophage activation by MD-Fraction differs from that of zymosan. This is the first study to demonstrate that purified β-glucans, such as MD-Fraction and curdlan, induce GM-CSF production directly, resulting in Dectin-1/Syk activation in resident macrophages. In conclusion, we demonstrated that MD-Fraction induces cell proliferation and cytokine production without excessive inflammation in resident macrophages, supporting its immunotherapeutic potential. PMID:22028332

  1. Interplay of IKK/NF-κB signaling in macrophages and myofibers promotes muscle degeneration in Duchenne muscular dystrophy

    PubMed Central

    Acharyya, Swarnali; Villalta, S. Armando; Bakkar, Nadine; Bupha-Intr, Tepmanas; Janssen, Paul M.L.; Carathers, Micheal; Li, Zhi-Wei; Beg, Amer A.; Ghosh, Sankar; Sahenk, Zarife; Weinstein, Michael; Gardner, Katherine L.; Rafael-Fortney, Jill A.; Karin, Michael; Tidball, James G.; Baldwin, Albert S.; Guttridge, Denis C.

    2007-01-01

    Duchenne muscular dystrophy (DMD) is a lethal X-linked disorder associated with dystrophin deficiency that results in chronic inflammation and severe skeletal muscle degeneration. In DMD mouse models and patients, we find that IκB kinase/NF-κB (IKK/NF-κB) signaling is persistently elevated in immune cells and regenerative muscle fibers. Ablation of 1 allele of the p65 subunit of NF-κB was sufficient to improve pathology in mdx mice, a model of DMD. In addition, conditional deletion of IKKβ in mdx mice elucidated that NF-κB functions in activated macrophages to promote inflammation and muscle necrosis and in skeletal muscle fibers to limit regeneration through the inhibition of muscle progenitor cells. Furthermore, specific pharmacological inhibition of IKK resulted in improved pathology and muscle function in mdx mice. Collectively, these results underscore the critical role of NF-κB in the progression of muscular dystrophy and suggest the IKK/NF-κB signaling pathway as a potential therapeutic target for DMD. PMID:17380205

  2. Balance between fatty acid degradation and lipid accumulation in cultured smooth muscle cells and IC-21 macrophages exposed to oleic acid.

    PubMed

    Moinat, M; Kossovsky, M; Chevey, J M; Giacobino, J P

    1991-01-01

    1. The effect of changes in fatty acid beta-oxidation activity on triglyceride and cholesteryl ester synthesis were studied in cultured smooth muscle cells (SMC) and in a macrophage cell line IC-21 in the presence of oleic acid (100 microM). 2. Etomoxir, an inhibitor of carnitine palmitoyltransferase I, stimulated the incorporation of [2-3H]glycerol into triglycerides in SMC and in macrophages 6.2- and 8.2-fold, respectively, and the incorporation of [4-14C]cholesterol into cholesteryl esters in macrophages 3.5-fold. 3. L-Carnitine, a cofactor of fatty acid beta-oxidation, decreased the incorporation of [2-3H]glycerol into triglycerides in smooth muscle cells by 69% and the incorporation of [4-14C]cholesterol into cholesteryl esters by 52%. L-Carnitine had no effect on the macrophages. PMID:2060277

  3. CD163L1 and CLEC5A discriminate subsets of human resident and inflammatory macrophages in vivo.

    PubMed

    González-Domínguez, Érika; Samaniego, Rafael; Flores-Sevilla, José Luis; Campos-Campos, Salvador F; Gómez-Campos, Guillermo; Salas, Azucena; Campos-Peña, Victoria; Corbí, Ángel L; Sánchez-Mateos, Paloma; Sánchez-Torres, Carmen

    2015-10-01

    Macrophages (Mϕ) can be differentiated and polarized in vitro from human CD14(+) monocytes under the influence of GM-CSF (GM-Mϕ) and M-CSF (M-Mϕ). GM-Mϕs are proinflammatory and M-Mϕs have an anti-inflammatory phenotype. We found selective expression of the lectin C-type lectin domain family 5 member A (CLEC5A) transcripts in GM-Mϕs and the scavenger receptor CD163 molecule-like 1 (CD163L1) in M-Mϕs by microarray assay. In vitro, CD163L1 expression was induced by IL-10 and M-CSF and CLEC5A by inflammatory cytokines and cell adherence. In secondary lymphoid organs, their respective expression was restricted to CD68(+)/CD163(+) Mϕs that preferentially produced either TNF (CLEC5A(+)) or IL-10 (CD163L1(+)). Mϕs from healthy liver and colon tissue were mostly CD163L1(+), and CLEC5A(+) cells were scarce. In contrast, CLEC5A(+) Mϕs were abundant in the intestinal lamina propria from patients with inflammatory bowel disease (IBD), with higher numbers of CLEC5A(+)CD163L1(+) found compared with those in secondary lymphoid organs. CLEC5A(+) cells were CD14(+)CD209(-)CD11b(+)CD11c(+)TNF(+)IL-10(+), and single positive CD163L1(+) cells were CD14(-)CD209(+)CD11b(-)CD11c(-)TNF(-)IL-10(+) in healthy donors and had lost the ability to produce IL-10 and to express CD209 in those with IBD. In melanomas, CLEC5A(+) tumor-associated Mϕs (TAMs) were not detected in 42% of the cases evaluated, but CD163L1(+) TAMs were found in 100%. Similar to IBD, CD163L1(+) TAMs expressed high levels of CD209 and produced significant amounts of IL-10, and CLEC5A(+) TAMs were CD14(hi) and produced enhanced levels of TNF in metastases. Overall, these results suggest that CD163L1 expression is associated with tissue-resident Mϕs with an anti-inflammatory or anergic phenotype and that CLEC5A(+) Mϕs exhibit TNF-producing ability and might display a proinflammatory effect. PMID:25877931

  4. High-resolution intravital imaging reveals that blood derived macrophages but not resident microglia facilitate secondary axonal dieback in traumatic spinal cord injury

    PubMed Central

    Evans, Teresa A.; Barkauskas, Deborah S.; Myers, Jay; Hare, Elisabeth G.; You, Jingquang; Ransohoff, Richard M.; Huang, Alex Y.; Silver, Jerry

    2014-01-01

    After traumatic spinal cord injury, functional deficits increase as axons die back from the center of the lesion and the glial scar forms. Axonal die back occurs in two phases: an initial axon intrinsic stage that occurs over the first several hours and a secondary phase which takes place over the first few weeks after injury. Here, we examine the secondary phase, which is marked by infiltration of macrophages. Using powerful time lapse multi-photon imaging, we captured images of interactions between Cx3cr1+/GFP macrophages and microglia and Thy-1YFP axons in a mouse dorsal column crush spinal cord injury model. Over the first few weeks after injury, axonal retraction bulbs within the lesion are static except when axonal fragments are lost by a blebbing mechanism in response to physical contact followed by phagocytosis by mobile Cx3Cr1+/GFP cells. Utilizing a radiation chimera model to distinguish marrow-derived cells from radio-resistant CNS resident microglia, we determined that the vast majority of accumulated cells in the lesion are derived from the blood and only these are associated with axonal damage. Interestingly, CNS-resident Cx3Cr1+/GFP microglia did not increasingly accumulate nor participate in neuronal destruction in the lesion during this time period. Additionally, we found that the blood-derived cells consisted mainly of singly labeled Ccr2+/RFP macrophages, singly labeled Cx3Cr1+/GFP macrophages and a small population of double-labeled cells. Since all axon destructive events were seen in contact with a Cx3Cr1+/GFP cell, we infer that the CCR2 single positive subset is likely not robustly involved in axonal dieback. Finally, in our model, deletion of CCR2, a chemokine receptor, did not alter the position of axons after dieback. Understanding the in vivo cellular interactions involved in secondary axonal injury may lead to clinical treatment candidates involving modulation of destructive infiltrating blood monocytes. PMID:24468477

  5. Amendment of the cytokine profile in macrophages subsequent to their interaction with smooth muscle cells: Differential modulation by fractalkine and resistin.

    PubMed

    Tucureanu, Monica Madalina; Butoi, Elena; Gan, Ana-Maria; Stan, Daniela; Constantinescu, Cristina Ana; Calin, Manuela; Simionescu, Maya; Manduteanu, Ileana

    2016-07-01

    In atherosclerotic plaques, macrophages (MAC) and smooth muscle cells (SMC) frequently reside in close proximity and resistin (Rs) and fractalkine (Fk) are present at increased levels, resistin being associated with CD68 macrophages and fractalkine predominantly associated with intimal SMC; however, their role in this location is not clear, yet. The objective of this study was to determine whether the cross-talk between MAC-SMC induces changes in MAC cytokine phenotype and if Fk and Rs have a role in the process. To this purpose, macrophages (THP-1 monocytes differentiated with phorbol myristate acetate) were interacted with SMC cultured on the membrane inserts in the presence or absence of Rs or Fk. After 24h, MAC were removed from the co-culture and the gene and protein expression of 57 cytokines was assessed by QPCR and Proteome Profiler™ Array. Fk secreted in the culture medium following MAC-SMC interaction was determined (ELISA assay) and the role of Fk in MAC cytokine gene expression was assessed by silencing the Fk receptor in both cell types. The results showed that subsequent to the interaction with SMC, MAC exhibit: (1) a general increased expression of chemokines (the highest fold increase: VCC-1 and GRO-α) and of some interleukins, such as interleukins IL-5 (∼8-fold) and IL-6; (2) an increased Fk expression that in turn induces expression of: CXCL17, CCL19, CCL2, CXCL10, CXCL12, CXCL4, CXCL7, CCL4, CCL18, CXCL16, CXCL1 and IL-27; (3) in the presence of Rs, a predominant increased expression of interleukins (the highest fold increase: IL-6, IL-27, IL-23 and IL-5) and an augmented expression of some chemokines such as MIP-1β, GRO-α and CCL1. In addition, the secretome collected from the SMC-MAC co-culture increased human monocytes chemotaxis. DAVID analysis of the data revealed that the switch of MAC to a pro-inflammatory phenotype, prime the cells to intervene in the immune response, chemotaxis and inflammatory response. In conclusion, MAC

  6. 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...

  7. Intermuscular and perimuscular fat expansion in obesity correlates with skeletal muscle T cell and macrophage infiltration and insulin resistance

    PubMed Central

    Khan, Ilvira M.; Dai Perrard, Xiao-Yuan; Brunner, Gerd; Lui, Hua; Sparks, Lauren M.; Smith, Steven R.; Wang, Xukui; Shi, Zheng-Zheng; Lewis, Dorothy E.; Wu, Huaizhu; Ballantyne, Christie M.

    2015-01-01

    Background/Objectives Limited numbers of studies demonstrated obesity-induced macrophage infiltration in skeletal muscle (SM), but dynamics of immune cell accumulation and contribution of T cells to SM insulin resistance are understudied. Subjects/Methods T cells and macrophage markers were examined in SM of obese humans by RT-PCR. Mice were fed high-fat diet (HFD) for 2–24 weeks, and time course of macrophage and T cell accumulation was assessed by flow cytometry and quantitative RT-PCR. Extramyocellular adipose tissue (EMAT) was quantified by high-resolution micro-CT, and correlation to T cell number in SM was examined. CD11a−/− mice and C57BL/6 mice were treated with CD11a-neutralizing antibody to determine the role of CD11a in T cell accumulation in SM. To investigate the involvement JAK/STAT, the major pathway for T helper I (TH1) cytokine IFNγ? in SM and adipose tissue inflammation and insulin resistance, mice were treated with a JAK1/JAK2 inhibitor, baricitinib. Results Macrophage and T cells markers were upregulated in SM of obese compared with lean humans. SM of obese mice had higher expression of inflammatory cytokines, with macrophages increasing by 2 weeks on HFD and T cells increasing by 8 weeks. The immune cells were localized in EMAT. Micro-CT revealed that EMAT expansion in obese mice correlated with T cell infiltration and insulin resistance. Deficiency or neutralization of CD11a reduced T cell accumulation in SM of obese mice. T cells polarized into a proinflammatory TH1 phenotype, with increased STAT1 phosphorylation in SM of obese mice. In vivo inhibition of JAK/STAT pathway with baricitinib reduced T cell numbers and activation markers in SM and adipose tissue and improved insulin resistance in obese mice. Conclusions Obesity-induced expansion of EMAT in SM was associated with accumulation and proinflammatory polarization of T cells, which may regulate SM metabolic functions through paracrine mechanisms. Obesity-associated SM

  8. Suppression of viability and acetyl-LDL metabolism in RAW 264 macrophage-like and smooth muscle cells by bisphosphonates in vitro.

    PubMed

    Tuominen, O M; Hollmén, M; Jaakkola, O; Mönkkönen, J; Ylitalo, R

    2002-10-01

    Etidronate and clodronate are bisphosphonates that inhibit the development of experimental atherosclerosis. Etidronate decreases the intimamedia thickness of carotid artery even in man. Liposome-encapsulated bisphosphonates inhibit the cellular metabolism of atherogenic, modified low-density lipoprotein (acetyl-LDL) by cultured macrophages. In the present study, the effects of new bisphosphonate tiludronate and nitrogen-containing bisphosphonate alendronate on cell viability and cellular uptake and degradation of acetyl-LDL were investigated in vitro with macrophages and arterial smooth muscle cells, which have a significant role in atherogenesis. Tiludronate and alendronate decreased the viability of RAW 264 macrophages at high concentration (1,000 microM; p < 0.05), while liposome-encapsulated drugs suppressed the viability at concentrations of 30-300 microM. At concentrations greater than or equal to 10 microM, tiludronate and alendronate inhibited the uptake and degradation of acetyl-LDL by RAW 264 cells in a concentration-dependent manner (p < 0.001). None of the bisphosphonates affected the viability of smooth muscle cells, and none but alendronate at a high concentration (1,000 microM) inhibited the uptake and degradation of acetyl-LDL by smooth muscle cells. The results show that tiludronate and alendronate inhibit the atherogenic activity of macrophages in vitro, as shown previously with etidronate and clodronate, providing further evidence for the antiatherogenic effects of bisphosphonates. PMID:12500427

  9. Masseter muscle tension, chewing ability, and selected parameters of physical fitness in elderly care home residents in Lodz, Poland

    PubMed Central

    Gaszynska, Ewelina; Godala, Malgorzata; Szatko, Franciszek; Gaszynski, Tomasz

    2014-01-01

    Background Maintaining good physical fitness and oral function in old age is an important element of good quality of life. Disability-related impairment of oral function contributes to a deterioration of the diet of older people and to the reduction of their social activity. Objectives Investigate the association between masseter muscle tension, dental status, and physical fitness parameters. Materials and methods Two hundred fifty-nine elderly care home residents (97 men, 162 women; mean age, 75.3±8.9 years) were involved in this cross-sectional study. Their chewing ability was evaluated by masseter muscle tension palpation, differences of masseter muscle thickness, self-reported chewing ability, number of present and functional teeth, and number of posterior tooth pairs. Masseter muscle thickness was measured by ultrasonography. To assess physical fitness, hand grip strength and the timed up-and-go test were performed. Nutritional status was assessed using body mass index and body cell mass index (BCMI), calculated on the basis of electrical bioimpedance measurements. Medical records were used to collect information on systemic diseases and the number of prescribed medications. Subjects were also evaluated for their ability to perform ten activities of daily living. Results Ninety-seven percent of the subjects suffered from systemic diseases. The three most prevalent illnesses were cardiac/circulatory 64.5%, musculoskeletal 37.3%, and endocrine/metabolic/nutritional 29.3%. Of the participants, 1.5% were underweight and more than one third (34.4%) were overweight. Malnutrition (BCMI below normal) was found in almost half (45.2%) of the subjects. Only 5.8% had a sufficient number of functional natural teeth. Statistically significant correlations were found between palpation of masseter muscle tension and perceived chewing ability, number of present teeth, number of functional teeth, number of posterior tooth pairs, timed up-and-go, hand grip strength, body mass

  10. 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

  11. 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

  12. MicroRNAs Control Macrophage Formation and Activation: The Inflammatory Link between Obesity and Cardiovascular Diseases

    PubMed Central

    Chang, Richard Cheng-An; Ying, Wei; Bazer, Fuller W.; Zhou, Beiyan

    2014-01-01

    Activation and recruitment of resident macrophages in tissues in response to physiological stress are crucial regulatory processes in promoting the development of obesity-associated metabolic disorders and cardiovascular diseases. Recent studies have provided compelling evidence that microRNAs play important roles in modulating monocyte formation, macrophage maturation, infiltration into tissues and activation. Macrophage-dependent systemic physiological and tissue-specific responses also involve cell-cell interactions between macrophages and host tissue niche cell components, including other tissue-resident immune cell lineages, adipocytes, vascular smooth muscle and others. In this review, we highlight the roles of microRNAs in regulating the development and function of macrophages in the context of obesity, which could provide insights into the pathogenesis of obesity-related metabolic syndrome and cardiovascular diseases. PMID:25014161

  13. Liver-resident macrophage necroptosis orchestrates type 1 microbicidal inflammation and type-2-mediated tissue repair during bacterial infection.

    PubMed

    Blériot, Camille; Dupuis, Théo; Jouvion, Grégory; Eberl, Gérard; Disson, Olivier; Lecuit, Marc

    2015-01-20

    Kupffer cells, the phagocytes of fetal origin that line the liver sinusoids, are key contributors of host defense against enteroinvasive bacteria. Here, we found that infection by Listeria monocytogenes induced the early necroptotic death of Kupffer cells, which was followed by monocyte recruitment and an anti-bacterial type 1 inflammatory response. Kupffer cell death also triggered a type 2 response that involved the hepatocyte-derived alarmin interleukin-33 (IL-33) and basophil-derived interleukin-4 (IL-4). This led to the alternative activation of the monocyte-derived macrophages recruited to the liver, which thereby replaced ablated Kupffer cells and restored liver homeostasis. Kupffer cell death is therefore a key signal orchestrating type 1 microbicidal inflammation and type-2-mediated liver repair upon infection. This indicates that beyond the classical dichotomy of type 1 and type 2 responses, these responses can develop sequentially in the context of a bacterial infection and act interdependently, orchestrating liver immune responses and return to homeostasis, respectively. PMID:25577440

  14. Ang-2/VEGF bispecific antibody reprograms macrophages and resident microglia to anti-tumor phenotype and prolongs glioblastoma survival

    PubMed Central

    Kloepper, Jonas; Riedemann, Lars; Amoozgar, Zohreh; Seano, Giorgio; Susek, Katharina; Yu, Veronica; Dalvie, Nisha; Amelung, Robin L.; Datta, Meenal; Song, Jonathan W.; Askoxylakis, Vasileios; Taylor, Jennie W.; Lu-Emerson, Christine; Batista, Ana; Kirkpatrick, Nathaniel D.; Jung, Keehoon; Snuderl, Matija; Muzikansky, Alona; Stubenrauch, Kay G.; Krieter, Oliver; Wakimoto, Hiroaki; Xu, Lei; Munn, Lance L.; Duda, Dan G.; Fukumura, Dai; Batchelor, Tracy T.; Jain, Rakesh K.

    2016-01-01

    Inhibition of the vascular endothelial growth factor (VEGF) pathway has failed to improve overall survival of patients with glioblastoma (GBM). We previously showed that angiopoietin-2 (Ang-2) overexpression compromised the benefit from anti-VEGF therapy in a preclinical GBM model. Here we investigated whether dual Ang-2/VEGF inhibition could overcome resistance to anti-VEGF treatment. We treated mice bearing orthotopic syngeneic (Gl261) GBMs or human (MGG8) GBM xenografts with antibodies inhibiting VEGF (B20), or Ang-2/VEGF (CrossMab, A2V). We examined the effects of treatment on the tumor vasculature, immune cell populations, tumor growth, and survival in both the Gl261 and MGG8 tumor models. We found that in the Gl261 model, which displays a highly abnormal tumor vasculature, A2V decreased vessel density, delayed tumor growth, and prolonged survival compared with B20. In the MGG8 model, which displays a low degree of vessel abnormality, A2V induced no significant changes in the tumor vasculature but still prolonged survival. In both the Gl261 and MGG8 models A2V reprogrammed protumor M2 macrophages toward the antitumor M1 phenotype. Our findings indicate that A2V may prolong survival in mice with GBM by reprogramming the tumor immune microenvironment and delaying tumor growth. PMID:27044098

  15. Cross-talk between macrophages and smooth muscle cells impairs collagen and metalloprotease synthesis and promotes angiogenesis.

    PubMed

    Butoi, E; Gan, A M; Tucureanu, M M; Stan, D; Macarie, R D; Constantinescu, C; Calin, M; Simionescu, M; Manduteanu, I

    2016-07-01

    Coronary atherosclerosis complicated by plaque disruption and thrombosis is a critical event in myocardial infarction and stroke, the major causes of cardiovascular death. In atherogenesis, macrophages (MAC) and smooth muscle cells (SMC) are key actors; they synthesize matrix components and numerous factors involved in the process. Here, we design experiments to investigate whether SMC-MAC communication induces changes in ECM protein composition and/or neo-angiogenesis. Cell to cell communication was achieved using trans-well chambers, where SMCs were grown in the upper chamber and differentiated MAC in the bottom chamber for 24 or 72h. We found that cross-talk between MAC and SMC during co-culture: (i) significantly decreased the expression of ECM proteins (collagen I, III, elastin) in SMC; (ii) increased the expression and activity of metalloprotease MMP-9 and expression of collagenase MMP-1, in both MAC and SMC; (iii) augmented the secretion of soluble VEGF in the conditioned media of cell co-culture and VEGF gene expression in both cell types, compared with control cells. Moreover, the conditioned media collected from MAC-SMC co-culture promoted endothelial cell tube formation in Matrigel, signifying an increased angiogenic effect. In addition, the MAC-SMC communication led to an increase in inflammatory IL-1β and TLR-2, which could be responsible for cellular signaling. In conclusion, MAC-SMC communication affects factors and molecules that could alter ECM composition and neo-angiogenesis, features that could directly dictate the progression of atheroma towards the vulnerable plaque. Targeting the MAC-SMC cross-talk may represent a novel therapeutic strategy to slow-down or retard the plaque progression. PMID:27060293

  16. Effects of Hyperbaric Oxygen at 1.25 Atmospheres Absolute with Normal Air on Macrophage Number and Infiltration during Rat Skeletal Muscle Regeneration

    PubMed Central

    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. PMID:25531909

  17. Mitsugumin 56 (hedgehog acyltransferase-like) is a sarcoplasmic reticulum-resident protein essential for postnatal muscle maturation.

    PubMed

    Van, Bo; Nishi, Miyuki; Komazaki, Shinji; Ichimura, Atsuhiko; Kakizawa, Sho; Nakanaga, Keita; Aoki, Junken; Park, Ki-Ho; Ma, Jianjie; Ueyama, Tomomi; Ogata, Takehiro; Maruyama, Naoki; Takeshima, Hiroshi

    2015-04-28

    Mitsugumin 56 (MG56), also known as the membrane-bound O-acyl-transferase family member hedgehog acyltransferase-like, was identified as a new sarcoplasmic reticulum component in striated muscle. Mg56-knockout mice grew normally for a week after birth, but shortly thereafter exhibited a suckling defect and died under starvation conditions. In the knockout skeletal muscle, regular contractile features were largely preserved, but sarcoplasmic reticulum elements swelled and further developed enormous vacuoles. In parallel, the unfolded protein response was severely activated in the knockout muscle, and presumably disrupted muscle development leading to the suckling failure. Therefore, MG56 seems essential for postnatal skeletal muscle maturation. PMID:25841338

  18. Effects of phorbol 12-myristate 13-acetate on triglyceride and cholesteryl ester synthesis in cultured coronary smooth muscle cells and macrophages.

    PubMed

    Moinat, M; Chevey, J M; Muzzin, P; Giacobino, J P; Kossovsky, M

    1990-02-01

    In cultured pig coronary smooth muscle cells phorbol 12-myristate 13-acetate (PMA) stimulated the conversion of [4-14C]cholesterol into cholesteryl esters and the incorporation of [2-3H]glycerol into triglycerides 6.4- and 4.5-fold, respectively. The maximal effects occurred after 3 h of treatment and there was a return to basal values after 72 h. In the presence of 400 microM oleic acid, PMA stimulated the conversion of [4-14C]cholesterol into cholesteryl esters and that of [2-3H]glycerol into triglycerides 5.3- and 2.3-fold, respectively. The stimulatory effects were more sustained (still significant after 72 h) and their maxima were delayed (peaks after 24 h). PMA was also found to increase 2-fold the amount of triglyceride that accumulated in the cells in the presence of oleic acid after 24 h. In macrophages IC-21, the effects of PMA were observed only in the presence of oleic acid. They consisted of a 1.9-fold stimulation in the conversion of [4-14C]cholesterol into cholesteryl esters after 72 h and of a 1.7-fold stimulation in the incorporation of [2-3H]glycerol into triglycerides after 24 h. PMA also increased the amount of triglyceride that accumulated in the cells 1.9-fold after 72 h. It is concluded that PMA, and possibly growth factors, may promote lipid storage in smooth muscle cells and that fatty acids favor long lasting effects of PMA in smooth muscle cells and are necessary for any effect of PMA in macrophages. PMID:2324651

  19. A murine platelet-activating factor receptor gene: cloning, chromosomal localization and up-regulation of expression by lipopolysaccharide in peritoneal resident macrophages.

    PubMed Central

    Ishii, S; Matsuda, Y; Nakamura, M; Waga, I; Kume, K; Izumi, T; Shimizu, T

    1996-01-01

    A murine gene encoding a platelet-activating factor receptor (PAFR) was cloned. The gene was mapped to a region of the D2.2 band of chromosome 4 both by fluorescence in situ hybridization and by molecular linkage analysis. Northern blot analysis showed a high expression of the PAFR message in peritoneal macrophages. When C3H/HeN macrophages were treated with bacterial lipopolysaccharide (LPS) or synthetic lipid A, the PAFR gene expression was induced. Bacterial LPS, but not lipid A, induced the level of PAFR mRNA in LPS unresponsive C3H/HeJ macrophages. These induction patterns were parallel to those of tumor necrosis factor-alpha mRNA. Thus the PAFR in macrophages is important in LPS-induced pathologies. PMID:8670084

  20. Differences in Lsh gene control over systemic Leishmania major and Leishmania donovani or Leishmania mexicana mexicana infections are caused by differential targeting to infiltrating and resident liver macrophage populations.

    PubMed Central

    Davies, E V; Singleton, A M; Blackwell, J M

    1988-01-01

    Earlier studies had shown that the viscerotropic NIH 173 strain of cutaneous Leishmania major fails to come under Lsh gene control. Visceral Leishmania donovani LV9 and another viscerotropic cutaneous strain, Leishmania mexicana mexicana LV4, are controlled by Lsh. The results of double-infection experiments presented here show that expression of Lsh resistance against L. mexicana mexicana was enhanced in the presence of L. donovani, whereas L. major still failed to come under Lsh gene control, even in the presence of L. donovani. Prior irradiation (850 rads) of mice showed that in the absence of infiltrating monocytes, Lsh did exert some influence over L. major. The presence of a higher infiltrate of fresh monocytes after L. major infection was confirmed in liver macrophage populations isolated from mice after infection in vivo and in liver cryosections immunostained with monoclonal antibody M1/70 directed against the type 3 complement receptor CR3. The results support the hypothesis that Lsh is expressed maximally in the resident tissue macrophages and poorly in the immature macrophages preferentially infected by L. major amastigotes. Images PMID:3356462

  1. Early hematopoiesis and macrophage development.

    PubMed

    McGrath, Kathleen E; Frame, Jenna M; Palis, James

    2015-12-01

    The paradigm that all blood cells are derived from hematopoietic stem cells (HSCs) has been challenged by two findings. First, there are tissue-resident hematopoietic cells, including subsets of macrophages that are not replenished by adult HSCs, but instead are maintained by self-renewal of fetal-derived cells. Second, during embryogenesis, there is a conserved program of HSC-independent hematopoiesis that precedes HSC function and is required for embryonic survival. The presence of waves of HSC-independent hematopoiesis as well as fetal HSCs raises questions about the origin of fetal-derived adult tissue-resident macrophages. In the murine embryo, historical examination of embryonic macrophage and monocyte populations combined with recent reports utilizing genetic lineage-tracing approaches has led to a model of macrophage ontogeny that can be integrated with existing models of hematopoietic ontogeny. The first wave of hematopoiesis contains primitive erythroid, megakaryocyte and macrophage progenitors that arise in the yolk sac, and these macrophage progenitors are the source of early macrophages throughout the embryo, including the liver. A second wave of multipotential erythro-myeloid progenitors (EMPs) also arises in the yolk sac. EMPs colonize the fetal liver, initiating myelopoiesis and forming macrophages. Lineage tracing indicates that this second wave of macrophages are distributed in most fetal tissues, although not appreciably in the brain. Thus, fetal-derived adult tissue-resident macrophages, other than microglia, appear to predominately derive from EMPs. While HSCs emerge at midgestation and colonize the fetal liver, the relative contribution of fetal HSCs to tissue macrophages at later stages of development is unclear. The inclusion of macrophage potential in multiple waves of hematopoiesis is consistent with reports of their functional roles throughout development in innate immunity, phagocytosis, and tissue morphogenesis and remodeling

  2. 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. PMID:27337479

  3. 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. PMID:27039885

  4. A crosstalk triggered by hypoxia and maintained by MCP-1/miR-98/IL-6/p38 regulatory loop between human aortic smooth muscle cells and macrophages leads to aortic smooth muscle cells apoptosis via Stat1 activation.

    PubMed

    Wang, Qing; Shu, Chang; Su, Jing; Li, Xin

    2015-01-01

    Hypoxia and inflammation are central characteristics of the abdominal aortic aneurysm (AAA), but the mechanisms for their relationship and actual role remain far from full understood. Here, we showed MCP-1 (monocyte chemotactic protein-1) induced by hypoxia in primary human Aortic Smooth Muscle Cells (hASMCs) increased the chemotaxis of THP-1 macrophages and MCP-1 induced IL-6 expression in THP-1 cells via downregulating miR-98 which directly targets IL-6. In addition, IL-6 positively feedback regulated MCP-1 expression in hASMCs via p38 signal that is independent on hypoxia, and inhibition of p38 signal blocked the effect of IL-6 on MCP-1 expression regulation. Moreover, IL-6 exposure time-dependently induces phASMCs apoptosis via Stat1 activation. Collectively, our data provide compelling evidence on the association between hypoxia and inflammation triggered by hypoxia and then mediated by MCP-1/miR-98/IL-6/p38 regulatory loop, which leads to hASMCs apoptosis via Stat1 activation to contribute to AAA formation and progression. PMID:26045772

  5. The Elusive Antifibrotic Macrophage.

    PubMed

    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

  6. Pulmonary Macrophage Transplantation Therapy

    PubMed Central

    Suzuki, Takuji; Arumugam, Paritha; Sakagami, Takuro; Lachmann, Nico; Chalk, Claudia; Sallese, Anthony; Abe, Shuichi; Trapnell, Cole; Carey, Brenna; Moritz, Thomas; Malik, Punam; Lutzko, Carolyn; Wood, Robert E.; Trapnell, Bruce C.

    2014-01-01

    SUMMARY Bone marrow transplantation is an effective cell therapy but requires myeloablation, which increases infection-risk and mortality. Recent lineage-tracing studies documenting that resident macrophage populations self-maintain independent of hematologic progenitors prompted us to consider organ-targeted, cell-specific therapy. Here, using GM-CSF receptor-β deficient (Csf2rb−/−) mice that develop a myeloid cell disorder identical to hereditary pulmonary alveolar proteinosis (hPAP) in children with CSF2RA/CSF2RB mutations, we show that pulmonary macrophage transplantation (PMT) of either wild-type or Csf2rb-gene-corrected macrophages without myeloablation was safe, well-tolerated, and that one administration corrected the lung disease, secondary systemic manifestations, normalized disease-related biomarkers, and prevented disease-specific mortality. PMT-derived alveolar macrophages persisted for at least one year as did therapeutic effects. Results identify mechanisms regulating alveolar macrophage population size in health and disease, indicate that GM-CSF is required for phenotypic determination of alveolar macrophages, and support translation of PMT as the first specific therapy for children with hPAP. PMID:25274301

  7. 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

  8. Origin and Functions of Tissue Macrophages

    PubMed Central

    Epelman, Slava; Lavine, Kory J.; Randolph, Gwendalyn J.

    2015-01-01

    Macrophages are distributed in tissues throughout the body and contribute to both homeostasis and disease. Recently, it has become evident that most adult tissue macrophages originate during embryonic development and not from circulating monocytes. Each tissue has its own composition of embryonically derived and adult-derived macrophages, but it is unclear whether macrophages of distinct origins are functionally interchangeable or have unique roles at steady state. This new understanding also prompts reconsideration of the function of circulating monocytes. Classical Ly6chi monocytes patrol the extravascular space in resting organs, and Ly6clo nonclassical monocytes patrol the vasculature. Inflammation triggers monocytes to differentiate into macrophages, but whether resident and newly recruited macrophages possess similar functions during inflammation is unclear. Here, we define the tools used for identifying the complex origin of tissue macrophages and discuss the relative contributions of tissue niche versus ontological origin to the regulation of macrophage functions during steady state and inflammation. PMID:25035951

  9. 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

  10. Macrophage permissiveness for Legionella pneumophila growth modulated by iron.

    PubMed Central

    Gebran, S J; Newton, C; Yamamoto, Y; Widen, R; Klein, T W; Friedman, H

    1994-01-01

    We have investigated the modulation of iron in two populations of macrophages which differ in susceptibility to Legionella pneumophila intracellular proliferation. Previously, we reported that thioglycolate-elicited peritoneal macrophages obtained from the inbred A/J mouse strain readily support the intracellular growth of L. pneumophila, while resident macrophages from the same strain do not. In this study, we show that A/J elicited macrophages exhibit markedly higher expression of transferrin receptor and intracellular iron content than A/J resident macrophages. Furthermore, apotransferrin and desferrioxamine inhibited the intracellular proliferation of L. pneumophila in elicited macrophages, and this suppression was reversed by the additions of Fe-transferrin or ferric nitrilotriacetate. Fe-transferrin and ferric nitrilotriacetate did not further increase the intracellular proliferation of L. pneumophila in thioglycolate-elicited macrophages. However, ferric citrate and ferric nitrilotriacetate stimulated in a dose-dependent manner the growth of L. pneumophila in resident macrophages. Furthermore, equimolar concentrations of desferrioxamine reversed the stimulatory effect of iron in these resident cells. These data provide evidence supporting the hypothesis that differences in susceptibility to L. pneumophila growth between permissive elicited macrophages and nonpermissive resident macrophages from the A/J mouse strain are due to intracellular availability of iron. PMID:8300214

  11. Macrophages and cellular immunity in Drosophila melanogaster.

    PubMed

    Gold, Katrina S; Brückner, Katja

    2015-12-01

    The invertebrate Drosophila melanogaster has been a powerful model for understanding blood cell development and immunity. Drosophila is a holometabolous insect, which transitions through a series of life stages from embryo, larva and pupa to adulthood. In spite of this, remarkable parallels exist between Drosophila and vertebrate macrophages, both in terms of development and function. More than 90% of Drosophila blood cells (hemocytes) are macrophages (plasmatocytes), making this highly tractable genetic system attractive for studying a variety of questions in macrophage biology. In vertebrates, recent findings revealed that macrophages have two independent origins: self-renewing macrophages, which reside and proliferate in local microenvironments in a variety of tissues, and macrophages of the monocyte lineage, which derive from hematopoietic stem or progenitor cells. Like vertebrates, Drosophila possesses two macrophage lineages with a conserved dual ontogeny. These parallels allow us to take advantage of the Drosophila model when investigating macrophage lineage specification, maintenance and amplification, and the induction of macrophages and their progenitors by local microenvironments and systemic cues. Beyond macrophage development, Drosophila further serves as a paradigm for understanding the mechanisms underlying macrophage function and cellular immunity in infection, tissue homeostasis and cancer, throughout development and adult life. PMID:27117654

  12. 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

  13. MKP-1 coordinates ordered macrophage-phenotype transitions essential for stem cell-dependent tissue repair.

    PubMed

    Perdiguero, Eusebio; Kharraz, Yacine; Serrano, Antonio L; Muñoz-Cánoves, Pura

    2012-03-01

    Re-establishing tissue homoeostasis in response to injury requires infiltration of inflammatory cells and activation of resident stem cells. However, full tissue recovery also requires that the inflammation is resolved. While it is known that disturbing the interactions between inflammatory cells and tissue resident cells prevents successful healing, the molecular mechanisms underlying the paracrine interactions between these cell types are practically unknown. Here, and in a recent study, we provide mechanistic evidence that macrophages control stem cell-dependent tissue repair. In particular, we found that the temporal spacing of the pro- to anti-inflammatory macrophage polarization switch is controlled by the balance of p38 MAPK (termed here p38) and the MAPK phosphatase MKP-1 during the muscle healing process. Moreover, we demonstrate a new function for MKP-1-regulated p38 signaling in deactivating macrophages during inflammation resolution after injury. Specifically, at advanced stages of regeneration, MKP-1 loss caused an unscheduled "exhaustion-like" state in muscle macrophages, in which neither pro- nor anti-inflammatory cytokines are expressed despite persistent tissue damage, leading to dysregulated reparation by the tissue stem cells. Mechanistically, we demonstrate that p38 and MKP-1 control the AKT pathway through a miR-21-dependent PTEN regulation. Importantly, both genetic and pharmacological interference with the individual components of this pathway restored inflammation-dependent tissue homeostasis in MKP-1-deficient mice and delayed inflammation resolution and tissue repair dysregulation in wild-type mice. Because the process of tolerance to bacterial infection involves a progressive attenuation of pro-inflammatory gene expression, we discuss here the potential similarities between the mechanisms underlying inflammation resolution during tissue repair and those controlling endotoxin tolerance. PMID:22361726

  14. Resident recruitment.

    PubMed

    Longmaid, H Esterbrook

    2003-02-01

    This article has introduced the reader to the critical components of successful recruitment of radiology residents. With particular attention to the ACGME institutional and program requirements regarding resident recruitment, and an explanation of the support systems (ERAS and NRMP) currently available to those involved in applicant review and selection, the article has sought to delineate a sensible approach to recruitment. Successful recruiters have mastered the essentials of these programs and have learned to adapt the programs to their needs. As new program directors work with their departments' resident selection committees, they will identify the factors that faculty and current residents cite as most important in the successful selection of new residents. By structuring the application review process, exploiting the power of the ERAS, and crafting a purposeful and friendly interview process, radiology residency directors can find and recruit the residents who best match their programs. PMID:12585436

  15. Macrophages and Alcohol-Related Liver Inflammation

    PubMed Central

    Ju, Cynthia; Mandrekar, Pranoti

    2015-01-01

    Recent studies have suggested that macrophages have a critical role in the development of alcohol-induced inflammation in the liver. To define the precise pathogenic function of these cells during alcoholic liver disease (ALD), it is extremely important to conduct extensive studies in clinical settings that further elucidate the phenotypic diversity of macrophages in the context of ALD. Research to date already has identified several characteristics of macrophages that underlie the cells’ actions, including macrophage polarization and their phenotypic diversity. Other analyses have focused on the contributions of resident versus infiltrating macrophages/monocytes, as well as on the roles of macrophage mediators, in the development of ALD. Findings point to the potential of macrophages as a therapeutic target in alcoholic liver injury. Future studies directed toward understanding how alcohol affects macrophage phenotypic switch in the liver and other tissues, whether the liver microenvironment determines macrophage function in ALD, and if targeting of macrophages alleviates alcoholic liver injury, will provide promising strategies to manage patients with alcoholic hepatitis. PMID:26717583

  16. Macrophages: Their Emerging Roles in Bone.

    PubMed

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

    2015-12-01

    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

  17. 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

  18. Accelerated Vascular Disease in Systemic Lupus Erythematosus: Role of Macrophage

    PubMed Central

    Al Gadban, Mohammed M.; Alwan, Mohamed M.; Smith, Kent J.; Hammad, Samar M.

    2015-01-01

    Atherosclerosis is a chronic inflammatory condition that is considered a major cause of death worldwide. Striking phenomena of atherosclerosis associated with systemic lupus erythematosus (SLE) is its high incidence in young patients. Macrophages are heterogeneous cells that differentiate from hematopoietic progenitors and reside in different tissues to preserve tissue integrity. Macrophages scavenge modified lipids and play a major role in the development of atherosclerosis. When activated, macrophages secret inflammatory cytokines. This activation triggers apoptosis of cells in the vicinity of macrophages. As such, macrophages play a significant role in tissue remodeling including atherosclerotic plaque formation and rupture. In spite of studies carried on identifying the role of macrophages in atherosclerosis, this role has not been studied thoroughly in SLE-associated atherosclerosis. In this review, we address factors released by macrophages as well as extrinsic factors that may control macrophage behavior and their effect on accelerated development of atherosclerosis in SLE. PMID:25638414

  19. CD163 Identifies Perivascular Macrophages in Normal and Viral Encephalitic Brains and Potential Precursors to Perivascular Macrophages in Blood

    PubMed Central

    Kim, Woong-Ki; Alvarez, Xavier; Fisher, Jeanne; Bronfin, Benjamin; Westmoreland, Susan; McLaurin, JoAnne; Williams, Kenneth

    2006-01-01

    Perivascular macrophages are uniquely situated at the intersection between the nervous and immune systems. Although combined myeloid marker detection differentiates perivascular from resident brain macrophages (parenchymal microglia), no single marker distinguishes perivascular macrophages in humans and mice. Here, we present the macrophage scavenger receptor CD163 as a marker for perivascular macrophages in humans, monkeys, and mice. CD163 was primarily confined to perivascular macrophages and populations of meningeal and choroid plexus macrophages in normal brains and in brains of humans and monkeys with human immunodeficiency virus or simian immunodeficiency virus (SIV) encephalitis. Scattered microglia in SIV encephalitis lesions and multinucleated giant cells were also CD163 positive. Consistent with prior findings that perivascular macrophages are primary targets of human immunodeficiency virus and SIV, all SIV-infected cells in the brain were CD163 positive. Using fluorescent dyes that definitively and selectively label perivascular macrophages in vivo, we confirmed that dye-labeled simian perivascular macrophages were CD163 positive and able to repopulate the central nervous system within 24 hours. Flow cytometric studies demonstrated a subset of monocytes (CD163+CD14+CD16+) that were immunophenotypically similar to brain perivascular macrophages. These findings recognize CD163+ blood monocytes/macrophages as a source of brain perivascular macrophages and underscore the utility of this molecule in studying the biology of perivascular macrophages and their precursors in humans, monkeys, and mice. PMID:16507898

  20. SHP-1-dependent macrophage differentiation exacerbates virus-induced myositis

    PubMed Central

    Watson, Neva B.; Schneider, Karin M.; Massa, Paul T.

    2015-01-01

    Virus-induced myositis is an emerging global affliction that remains poorly characterized with few treatment options. Moreover, muscle-tropic viruses often spread to the central nervous system causing dramatically increased morbidity. Therefore, there is an urgent need to explore genetic factors involved in this class of human disease. This report investigates critical innate immune pathways affecting murine virus-induced myositis. Of particular importance, the key immune regulator SHP-1, which normally suppresses macrophage-mediated inflammation, is a major factor in promoting clinical disease in muscle. We show that Theiler’s murine encephalomyelitis virus infection of skeletal myofibers induces inflammation and subsequent dystrophic calcification with loss of ambulation in wild type mice. Surprisingly, although similar extensive myofiber infection and inflammation is observed in SHP-1-deficient (SHP-1−/−) mice, these mice neither accumulate dead calcified myofibers nor lose ambulation. Macrophages were the predominant effector cells infiltrating WT and SHP-1−/− muscle, and an increased infiltration of immature monocytes/macrophages correlated with absence of clinical disease in SHP-1−/− mice, while mature M1-like macrophages corresponded with increased myofiber degeneration in WT mice. Furthermore, blocking SHP-1 activation in WT macrophages blocked virus-induced myofiber degeneration, and pharmacologic ablation of macrophages inhibited muscle calcification in TMEV-infected WT animals. These data suggest that following TMEV infection of muscle, SHP-1 promotes M1 differentiation of infiltrating macrophages, and these inflammatory macrophages are likely involved in damaging muscle fibers. These findings reveal a pathological role for SHP-1 in promoting inflammatory macrophage differentiation and myofiber damage in virus-infected skeletal muscle, thus identifying SHP-1 and M1 macrophages as essential mediators of virus-induced myopathy. PMID:25681345

  1. 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

  2. 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

  3. Developmental origin of lung macrophage diversity.

    PubMed

    Tan, Serena Y S; Krasnow, Mark A

    2016-04-15

    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

  4. 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

  5. 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.

  6. Dissociation of skeletal muscle for flow cytometric characterization of immune cells in macaques.

    PubMed

    Liang, Frank; Ploquin, Aurélie; Hernández, José DelaO; Fausther-Bovendo, Hugues; Lindgren, Gustaf; Stanley, Daphne; Martinez, Aiala Salvador; Brenchley, Jason M; Koup, Richard A; Loré, Karin; Sullivan, Nancy J

    2015-10-01

    The majority of vaccines and several treatments are administered by intramuscular injection. The aim is to engage and activate immune cells, although they are rare in normal skeletal muscle. The phenotype and function of resident as well as infiltrating immune cells in the muscle after injection are largely unknown. While methods for obtaining and characterizing murine muscle cell suspensions have been reported, protocols for nonhuman primates (NHPs) have not been well defined. NHPs comprise important in vivo models for studies of immune cell function due to their high degree of resemblance with humans. In this study, we developed and systematically compared methods to collect vaccine-injected muscle tissue to be processed into single cell suspensions for flow cytometric characterization of immune cells. We found that muscle tissue processed by mechanical disruption alone resulted in significantly lower immune cell yields compared to enzymatic digestion using Liberase. Dendritic cell subsets, monocytes, macrophages, neutrophils, B cells, T cells and NK cells were readily detected in the muscle by the classic human markers. The methods for obtaining skeletal muscle cell suspension established here offer opportunities to increase the understanding of immune responses in the muscle, and provide a basis for defining immediate post-injection vaccine responses in primates. PMID:26099800

  7. Permanent resident

    PubMed Central

    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. PMID:27193992

  8. Macrophagic myofasciitis in childhood: a controversial entity.

    PubMed

    Rivas, Eloy; Gómez-Arnáiz, Mercedes; Ricoy, Jose R; Mateos, Fernando; Simón, Rogelio; García-Peñas, Juan J; Garcia-Silva, Maria T; Martín, Elena; Vázquez, María; Ferreiro, Ana; Cabello, Ana

    2005-11-01

    Macrophagic myofasciitis is an unusual inflammatory myopathy, which has been almost exclusively reported in French adults with diffuse arthromyalgias and asthenia. It is characterized by an infiltrate of densely packed macrophages, with granular periodic-acid-Schiff positive content, on muscle biopsies at the site of vaccination. The presence of aluminum inclusions in these macrophages points to an inappropriate reaction to aluminum used as an adjuvant in some vaccines. Although in adults this entity is well defined, less than 15 cases have been reported in children. This study describes seven children, younger than 3 years of age, with typical lesions of macrophagic myofasciitis on quadriceps muscle biopsy. In five cases, biopsies were performed to exclude mitochondrial pathology. All the children developed hypotonia and motor or psychomotor delay, associated with others symptoms. Abnormal neuroimaging was evident in six cases. Spectrometry studies detected elevated levels of aluminum in muscle in three of four cases tested. Despite the wide use of vaccines in childhood, macrophagic myofasciitis was rarely observed in children and its characteristic histologic pattern could not be correlated with a distinctive clinical syndrome. PMID:16243223

  9. 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

  10. Macrophagic myofasciitis: an infantile Italian case.

    PubMed

    Di Muzio, A; Capasso, M; Verrotti, A; Trotta, D; Lupo, S; Pappalepore, N; Manzoli, C; Chiarelli, F; Uncini, A

    2004-02-01

    Macrophagic myofasciitis is a recently identified inflammatory myopathy mostly described in adult French patients complaining of arthro-myalgias and fatigue. It is probably due to intramuscular injection of aluminium-containing vaccines and is characterized by a typical muscular infiltrate of large macrophages with aluminium inclusions. We report a 1-year-old Italian child presenting irritability, delayed motor development, hyperCKemia (up to 10 times the normal value), and typical features of macrophagic myofasciitis on muscle biopsy. The child recovered fully after steroid therapy. Macrophagic myofasciitis is a new treatable cause of motor retardation and hyperCKemia in children, and is probably more common than reported. Diagnosis requires a high index of suspicion and can be missed if biopsy is performed outside the vaccination site. PMID:14733966

  11. Your Muscles

    MedlinePlus

    ... Homework? Here's Help White House Lunch Recipes Your Muscles KidsHealth > For Kids > Your Muscles Print A A ... and skeletal (say: SKEL-uh-tul) muscle. Smooth Muscles Smooth muscles — sometimes also called involuntary muscles — are ...

  12. Inflammatory myopathy with abundant macrophages (IMAM): a condition sharing similarities with cytophagic histiocytic panniculitis and distinct from macrophagic myofasciitis.

    PubMed

    Bassez, Guillaume; Authier, Francois-Jérôme; Lechapt-Zalcman, Emmanuèle; Delfau-Larue, Marie Hélène; Plonquet, Anne; Coquet, Michelle; Illa, Isabel; Gherardi, Romain K

    2003-05-01

    We describe the unreported pattern of inflammatory myopathy with abundant macrophages (IMAM) as a main differential diagnosis of postimmunization aluminum hydroxide-induced macrophagic myofasciitis (MMF). IMAM was mainly detected among patients with a dermatomyositis (DM)-like disease. Among 113 muscle biopsies from DM patients collected from 1974 to 2000, intensity of macrophage infiltration was highly variable: 41.5% (-/+); 34.5% (+); 17% (++): and 7% (+++). The 27 patients from groups (++) and (+++) had a similar pattern of macrophagic infiltration and were considered to have IMAM. They were compared to 40 MMF patients. In IMAM, macrophage infiltrates were diffuse and correlated positively with both T cell infiltrates and acute muscle fiber damage, and showed pictures of hemophagocytosis (21/27). Connective tissue structures were infiltrated by noncohesive, ribbon-forming collections of large basophilic macrophages containing no crystalline inclusions. In MMF, macrophage infiltrates were focal and formed compact well-delineated aggregates of granular PAS+ cells, loaded with crystalline aluminum hydroxide particles, in the absence of either hemophagocytosis or conspicuous muscle damage. Review of the literature indicates similarities between IMAM and "cytophagic histiocytic panniculitis" (CHP), a condition characterized by T cell-triggered macrophage hyperactivation. Both IMAM and CHP, but not MMF, may be associated with a life-threatening hemophagocytic syndrome. PMID:12769186

  13. In vitro interactions between macrophages and aluminum-containing adjuvants.

    PubMed

    Rimaniol, Anne-Cécile; Gras, Gabriel; Clayette, Pascal

    2007-09-17

    Intramuscular administration of aluminum-adjuvanted vaccines induces an infiltration of aluminum-containing macrophages between muscle fibers. In vitro stimulation of human monocyte-derived macrophages with aluminum hydroxide (AlOOH) induces similar intracellular crystalline inclusions as well as phenotypical and functional modifications. We compared in this study the ability of other adjuvants to exert similar changes in macrophages in vitro. All mineral salts, i.e. aluminic (AlOOH, AlPO(4)) and non-aluminic mineral adjuvants (CaPO(4), FePO(4)) but not emulsion were able to increase macrophages capacity to potentiate autologous memory T lymphocyte proliferation, while only aluminic adjuvants induced CD83 expression and increased CD86 on macrophages. All together, this suggests that aluminic and non-aluminic adjuvants exerted their immunoactivities by distinct mechanisms on macrophages. PMID:17689842

  14. 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

  15. Macrophage heterogeneity in the context of rheumatoid arthritis.

    PubMed

    Udalova, Irina A; Mantovani, Alberto; Feldmann, Marc

    2016-08-01

    Macrophages are very important in the pathogenesis of rheumatoid arthritis (RA). The increase in the number of sublining macrophages in the synovium is an early hallmark of active rheumatic disease, and high numbers of macrophages are a prominent feature of inflammatory lesions. The degree of synovial macrophage infiltration correlates with the degree of joint erosion, and depletion of these macrophages from inflamed tissue has a profound therapeutic benefit. Research has now uncovered an unexpectedly high level of heterogeneity in macrophage origin and function, and has emphasized the role of environmental factors in their functional specialization. Although the heterogeneous populations of macrophages in RA have not been fully characterized, preliminary results in mouse models of arthritis have contributed to our understanding of the phenotype and ontogeny of synovial macrophages, and to deciphering the properties of monocyte-derived infiltrating and tissue-resident macrophages. Elucidating the molecular mechanisms that drive polarization of macrophages towards proinflammatory or anti-inflammatory phenotypes could lead to identification of signalling pathways that inform future therapeutic strategies. PMID:27383913

  16. 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. PMID:25319333

  17. Macrophage Phenotype and Function in Different Stages of Atherosclerosis.

    PubMed

    Tabas, Ira; Bornfeldt, Karin E

    2016-02-19

    The remarkable plasticity and plethora of biological functions performed by macrophages have enticed scientists to study these cells in relation to atherosclerosis for >50 years, and major discoveries continue to be made today. It is now understood that macrophages play important roles in all stages of atherosclerosis, from initiation of lesions and lesion expansion, to necrosis leading to rupture and the clinical manifestations of atherosclerosis, to resolution and regression of atherosclerotic lesions. Lesional macrophages are derived primarily from blood monocytes, although recent research has shown that lesional macrophage-like cells can also be derived from smooth muscle cells. Lesional macrophages take on different phenotypes depending on their environment and which intracellular signaling pathways are activated. Rather than a few distinct populations of macrophages, the phenotype of the lesional macrophage is more complex and likely changes during the different phases of atherosclerosis and with the extent of lipid and cholesterol loading, activation by a plethora of receptors, and metabolic state of the cells. These different phenotypes allow the macrophage to engulf lipids, dead cells, and other substances perceived as danger signals; efflux cholesterol to high-density lipoprotein; proliferate and migrate; undergo apoptosis and death; and secrete a large number of inflammatory and proresolving molecules. This review article, part of the Compendium on Atherosclerosis, discusses recent advances in our understanding of lesional macrophage phenotype and function in different stages of atherosclerosis. With the increasing understanding of the roles of lesional macrophages, new research areas and treatment strategies are beginning to emerge. PMID:26892964

  18. Macrophagic myofasciitis in children is a localized reaction to vaccination.

    PubMed

    Lach, Boleslaw; Cupler, Edward J

    2008-06-01

    Macrophagic myofasciitis is a novel, "inflammatory myopathy" described after a variety of vaccinations, almost exclusively in adults. We examined the relevance of histological findings of this myopathy to the clinical presentation in pediatric patients. Muscle biopsies from 8 children (7 months to 6 years old) with histological features of macrophagic myofasciitis were reviewed and correlated with the clinical manifestations. Patients underwent quadriceps muscle biopsy for suspected mitochondrial disease (4 patients), spinal muscular atrophy (2 patients), myoglobinuria (1 patient), and hypotonia with motor delay (1 patient). All biopsies showed identical granulomas composed of periodic acid-Schiff-positive and CD68-positive macrophages. Characteristic aluminum hydroxide crystals were identified by electron microscopy in 2 cases. The biopsy established diagnoses other than macrophagic myofasciitis in 5 patients: spinal muscular atrophy (2), Duchenne muscular dystrophy (1), phospho-glycerate kinase deficiency (1), and cytochrome c oxidase deficiency (1). Three children with manifestations and/or a family history of mitochondrial disease had otherwise morphologically normal muscle. All children had routine vaccinations between 2 months and 1 year before the biopsy, with up to 11 intramuscular injections, including the biopsy sites. There was no correlation between histological findings of macrophagic myofasciitis in biopsies and the clinical symptoms. We believe that macrophagic myofasciitis represents a localized histological hallmark of previous immunization with the aluminum hydroxide adjuvants contained in vaccines, rather than a primary or distinct inflammatory muscle disease. PMID:18281624

  19. Of macrophages and red blood cells; a complex love story.

    PubMed

    de Back, Djuna Z; Kostova, Elena B; van Kraaij, Marian; van den Berg, Timo K; van Bruggen, Robin

    2014-01-01

    Macrophages tightly control the production and clearance of red blood cells (RBC). During steady state hematopoiesis, approximately 10(10) RBC are produced per hour within erythroblastic islands in humans. In these erythroblastic islands, resident bone marrow macrophages provide erythroblasts with interactions that are essential for erythroid development. New evidence suggests that not only under homeostasis but also under stress conditions, macrophages play an important role in promoting erythropoiesis. Once RBC have matured, these cells remain in circulation for about 120 days. At the end of their life span, RBC are cleared by macrophages residing in the spleen and the liver. Current theories about the removal of senescent RBC and the essential role of macrophages will be discussed as well as the role of macrophages in facilitating the removal of damaged cellular content from the RBC. In this review we will provide an overview on the role of macrophages in the regulation of RBC production, maintenance and clearance. In addition, we will discuss the interactions between these two cell types during transfer of immune complexes and pathogens from RBC to macrophages. PMID:24523696

  20. Aging affects the responsiveness of rat peritoneal macrophages to GM-CSF and IL-4.

    PubMed

    Dimitrijević, Mirjana; Stanojević, Stanislava; Blagojević, Veljko; Ćuruvija, Ivana; Vujnović, Ivana; Petrović, Raisa; Arsenović-Ranin, Nevena; Vujić, Vesna; Leposavić, Gordana

    2016-04-01

    Macrophages undergo significant functional alterations during aging. The aim of the present study was to investigate changes of rat macrophage functions and response to M1/M2 polarization signals with age. Therefore, resident and thioglycollate-elicited peritoneal macrophages from young (3-month-old) and aged (18-19-month-old) rats were tested for phagocytic capacity and ability to secrete inflammatory mediators following in vitro stimulation with LPS and GM-CSF, and IL-4, prototypic stimulators for classically (M1) and alternatively activated (M2) macrophages, respectively. Aging increased the frequency of monocyte-derived (CCR7+ CD68+) and the most mature (CD163+ CD68+) macrophages within resident and thioglycollate-elicited peritoneal macrophages, respectively. The ability to phagocyte zymosan of none of these two cell subsets was affected by either LPS and GM-CSF or IL-4. The upregulated production of IL-1β, IL-6 and IL-10 and downregulated that of TGF-β was observed in response to LPS in resident and thioglycollate-elicited macrophages from rats of both ages. GM-CSF elevated production of IL-1β and IL-6 in resident macrophages from aged rats and in thioglycollate-elicited macrophages from young rats. Unexpectedly, IL-4 augmented production of proinflammatory mediators, IL-1β and IL-6, in resident macrophages from aged rats. In both resident and thioglycollate-elicited macrophages aging decreased NO/urea ratio, whereas LPS but not GM-SCF, shifted this ratio toward NO in the macrophages from animals of both ages. Conversely, IL-4 reduced NO/urea ratio in resident and thioglycollate-elicited macrophages from young rats only. In conclusion, our study showed that aging diminished GM-CSF-triggered polarization of elicited macrophages and caused paradoxical IL-4-driven polarization of resident macrophages toward proinflammatory M1 phenotype. This age-related deregulation of macrophage inflammatory mediator secretion and phagocytosis in response to M1/M2

  1. 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

  2. Macrophage heterogeneity in tissues: phenotypic diversity and functions

    PubMed Central

    Gordon, Siamon; Plüddemann, Annette; Martinez Estrada, Fernando

    2014-01-01

    During development and throughout adult life, macrophages derived from hematopoietic progenitors are seeded throughout the body, initially in the absence of inflammatory and infectious stimuli as tissue-resident cells, with enhanced recruitment, activation, and local proliferation following injury and pathologic insults. We have learned a great deal about macrophage properties ex vivo and in cell culture, but their phenotypic heterogeneity within different tissue microenvironments remains poorly characterized, although it contributes significantly to maintaining local and systemic homeostasis, pathogenesis, and possible treatment. In this review, we summarize the nature, functions, and interactions of tissue macrophage populations within their microenvironment and suggest questions for further investigation. PMID:25319326

  3. 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

  4. Tissue-Specific Signals Control Reversible Program of Localization and Functional Polarization of Macrophages

    PubMed Central

    Okabe, Yasutaka; Medzhitov, Ruslan

    2014-01-01

    SUMMARY Tissue-resident macrophages are highly heterogeneous in terms of their functions and phenotypes as a consequence of adaptation to different tissue environments. Local tissue-derived signals are thought to control functional polarization of resident macrophages; however, the identity of these signals remains largely unknown. It is also unknown whether functional heterogeneity is a result of irreversible lineage-specific differentiation or a consequence of continuous but reversible induction of diverse functional programs. Here, we identified retinoic acid as a signal that induces tissue-specific localization and functional polarization of peritoneal macrophages through the reversible induction of transcription factor GATA6. We further found that GATA6 in macrophages regulates gut IgA production through peritoneal B-1 cells. These results provide insight into the regulation of tissue-resident macrophage functional specialization by tissue-derived signals. PMID:24792964

  5. Stromelysin-2 (MMP10) Moderates Inflammation by Controlling Macrophage Activation.

    PubMed

    McMahan, Ryan S; Birkland, Timothy P; Smigiel, Kate S; Vandivort, Tyler C; Rohani, Maryam G; Manicone, Anne M; McGuire, John K; Gharib, Sina A; Parks, William C

    2016-08-01

    Several members of the matrix metalloproteinase (MMP) family control a range of immune processes, such as leukocyte influx and chemokine activity. Stromelysin-2 (MMP10) is expressed by macrophages in numerous tissues after injury; however, little is known of its function. In this study, we report that MMP10 is expressed by macrophages in human lungs from patients with cystic fibrosis and induced in mouse macrophages in response to Pseudomonas aeruginosa infection both in vivo and by isolated resident alveolar and bone marrow-derived macrophages (BMDM). Our data indicates that macrophage MMP10 serves a beneficial function in response to acute infection. Whereas wild-type mice survived infection with minimal morbidity, 50% of Mmp10(-/-) mice died and all showed sustained weight loss (morbidity). Although bacterial clearance and neutrophil influx did not differ between genotypes, macrophage numbers were ∼3-fold greater in infected Mmp10(-/-) lungs than in wild-types. Adoptive transfer of wild-type BMDM normalized infection-induced morbidity in Mmp10(-/-) recipients to wild-type levels, demonstrating that the protective effect of MMP10 was due to its production by macrophages. Both in vivo and in cultured alveolar macrophages and BMDM, expression of several M1 macrophage markers was elevated, whereas M2 markers were reduced in Mmp10(-/-) tissue and cells. Global gene expression analysis revealed that infection-mediated transcriptional changes persisted in Mmp10(-/-) BMDM long after they were downregulated in wild-type cells. These results indicate that MMP10 serves a beneficial role in response to acute infection by moderating the proinflammatory response of resident and infiltrating macrophages. PMID:27316687

  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. Muscle atrophy

    MedlinePlus

    Muscle wasting; Wasting; Atrophy of the muscles ... There are two types of muscle atrophy. Disuse atrophy occurs from a lack of physical activity. In most people, muscle atrophy is caused by not using the ...

  8. 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 ...

  9. Muscle atrophy

    MedlinePlus

    Muscle wasting; Wasting; Atrophy of the muscles ... There are two types of muscle atrophy: disuse and neurogenic. Disuse atrophy is caused by not using the muscles enough . This type of atrophy can often be ...

  10. 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 ...

  11. Influence of icing on muscle regeneration after crush injury to skeletal muscles in rats.

    PubMed

    Takagi, Ryo; Fujita, Naoto; Arakawa, Takamitsu; Kawada, Shigeo; Ishii, Naokata; Miki, Akinori

    2011-02-01

    The influence of icing on muscle regeneration after crush injury was examined in the rat extensor digitorum longus. After the injury, animals were randomly divided into nonicing and icing groups. In the latter, ice packs were applied for 20 min. Due to the icing, degeneration of the necrotic muscle fibers and differentiation of satellite cells at early stages of regeneration were retarded by ∼1 day. In the icing group, the ratio of regenerating fibers showing central nucleus at 14 days after the injury was higher, and cross-sectional area of the muscle fibers at 28 days was evidently smaller than in the nonicing group. Besides, the ratio of collagen fibers area at 14 and 28 days after the injury in the icing group was higher than in the nonicing group. These findings suggest that icing applied soon after the injury not only considerably retarded muscle regeneration but also induced impairment of muscle regeneration along with excessive collagen deposition. Macrophages were immunohistochemically demonstrated at the injury site during degeneration and early stages of regeneration. Due to icing, chronological changes in the number of macrophages and immunohistochemical expression of transforming growth factor (TGF)-β1 and IGF-I were also retarded by 1 to 2 days. Since it has been said that macrophages play important roles not only for degeneration, but also for muscle regeneration, the influence of icing on macrophage activities might be closely related to a delay in muscle regeneration, impairment of muscle regeneration, and redundant collagen synthesis. PMID:21164157

  12. Macrophages are critical effectors of antibody therapies for cancer

    PubMed Central

    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. PMID:25667985

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

    PubMed Central

    Rückerl, Dominik; Allen, Judith E

    2014-01-01

    Summary: 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. PMID:25319331

  14. 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. PMID:25667985

  15. Accumulation of M1-like macrophages in type 2 diabetic islets is followed by a systemic shift in macrophage polarization.

    PubMed

    Cucak, Helena; Grunnet, Lars Groth; Rosendahl, Alexander

    2014-01-01

    Human T2D is characterized by a low-grade systemic inflammation, loss of β-cells, and diminished insulin production. Local islet immunity is still poorly understood, and hence, we evaluated macrophage subpopulations in pancreatic islets in the well-established murine model of T2D, the db/db mouse. Already at 8 weeks of disease, on average, 12 macrophages were observed in the diabetic islets, whereas only two were recorded in the nondiabetic littermates. On a detailed level, the islet resident macrophages increased fourfold compared with nondiabetic littermates, whereas a pronounced recruitment (eightfold) of a novel subset of macrophages (CD68+F4/80-) was observed. The majority of the CD68+F4/80+ but only 40% of the CD68+F4/80- islet macrophages expressed CD11b. Both islet-derived macrophage subsets expressed moderate MHC-II, high galectin-3, and low CD80/CD86 levels, suggesting the cells to be macrophages rather than DCs. On a functional level, the vast majority of the macrophages in the diabetic islets was of the proinflammatory, M1-like phenotype. The systemic immunity in diabetic animals was characterized by a low-grade inflammation with elevated cytokine levels and increase of splenic cytokine, producing CD68+F4/80- macrophages. In late-stage diabetes, the cytokine signature changed toward a TGF-β-dominated profile, coinciding with a significant increase of galectin-3-positive macrophages in the spleen. In summary, our results show that proinflammatory M1-like galectin-3+ CD80/CD86(low) macrophages invade diabetic islets. Moreover, the innate immunity matures in a diabetes-dependent manner from an initial proinflammatory toward a profibrotic phenotype, supporting the concept that T2D is an inflammatory disease. PMID:24009176

  16. Local proliferation initiates macrophage accumulation in adipose tissue during obesity

    PubMed Central

    Zheng, C; Yang, Q; Cao, J; Xie, N; Liu, K; Shou, P; Qian, F; Wang, Y; Shi, Y

    2016-01-01

    Obesity-associated chronic inflammation is characterized by an accumulation of adipose tissue macrophages (ATMs). It is generally believed that those macrophages are derived from peripheral blood monocytes. However, recent studies suggest that local proliferation of macrophages is responsible for ATM accumulation. In the present study, we revealed that both migration and proliferation contribute to ATM accumulation during obesity development. We show that there is a significant increase in ATMs at the early stage of obesity, which is largely due to an enhanced in situ macrophage proliferation. This result was obtained by employing fat-shielded irradiation and bone marrow reconstitution. Additionally, the production of CCL2, a pivotal chemoattractant of monocytes, was not found to be increased at this stage, corroborating with a critical role of proliferation. Nonetheless, as obesity proceeds, the role of monocyte migration into adipose tissue becomes more significant and those new immigrants further proliferate locally. These proliferating ATMs mainly reside in crown-like structures formed by macrophages surrounding dead adipocytes. We further showed that IL-4/STAT6 is a driving force for ATM proliferation. Therefore, we demonstrated that local proliferation of resident macrophages contributes to ATM accumulation during obesity development and has a key role in obesity-associated inflammation. PMID:27031964

  17. Local proliferation initiates macrophage accumulation in adipose tissue during obesity.

    PubMed

    Zheng, C; Yang, Q; Cao, J; Xie, N; Liu, K; Shou, P; Qian, F; Wang, Y; Shi, Y

    2016-01-01

    Obesity-associated chronic inflammation is characterized by an accumulation of adipose tissue macrophages (ATMs). It is generally believed that those macrophages are derived from peripheral blood monocytes. However, recent studies suggest that local proliferation of macrophages is responsible for ATM accumulation. In the present study, we revealed that both migration and proliferation contribute to ATM accumulation during obesity development. We show that there is a significant increase in ATMs at the early stage of obesity, which is largely due to an enhanced in situ macrophage proliferation. This result was obtained by employing fat-shielded irradiation and bone marrow reconstitution. Additionally, the production of CCL2, a pivotal chemoattractant of monocytes, was not found to be increased at this stage, corroborating with a critical role of proliferation. Nonetheless, as obesity proceeds, the role of monocyte migration into adipose tissue becomes more significant and those new immigrants further proliferate locally. These proliferating ATMs mainly reside in crown-like structures formed by macrophages surrounding dead adipocytes. We further showed that IL-4/STAT6 is a driving force for ATM proliferation. Therefore, we demonstrated that local proliferation of resident macrophages contributes to ATM accumulation during obesity development and has a key role in obesity-associated inflammation. PMID:27031964

  18. 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.

  19. Macrophage Autophagy in Atherosclerosis

    PubMed Central

    Maiuri, Maria Chiara; Grassia, Gianluca; Platt, Andrew M.; Carnuccio, Rosa; Ialenti, Armando; Maffia, Pasquale

    2013-01-01

    Macrophages play crucial roles in atherosclerotic immune responses. Recent investigation into macrophage autophagy (AP) in atherosclerosis has demonstrated a novel pathway through which these cells contribute to vascular inflammation. AP is a cellular catabolic process involving the delivery of cytoplasmic contents to the lysosomal machinery for ultimate degradation and recycling. Basal levels of macrophage AP play an essential role in atheroprotection during early atherosclerosis. However, AP becomes dysfunctional in the more advanced stages of the pathology and its deficiency promotes vascular inflammation, oxidative stress, and plaque necrosis. In this paper, we will discuss the role of macrophages and AP in atherosclerosis and the emerging evidence demonstrating the contribution of macrophage AP to vascular pathology. Finally, we will discuss how AP could be targeted for therapeutic utility. PMID:23401644

  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. 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...

  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. PMID:26273949

  3. 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.

  4. Macrophage and microglial plasticity in the injured spinal cord.

    PubMed

    David, S; Greenhalgh, A D; Kroner, A

    2015-10-29

    Macrophages in the injured spinal cord arise from resident microglia and from infiltrating peripheral myeloid cells. Microglia respond within minutes after central nervous system (CNS) injury and along with other CNS cells signal the influx of their peripheral counterpart. Although some of the functions they carry out are similar, they appear to be specialized to perform particular roles after CNS injury. Microglia and macrophages are very plastic cells that can change their phenotype drastically in response to in vitro and in vivo conditions. They can change from pro-inflammatory, cytotoxic cells to anti-inflammatory, pro-repair phenotypes. The microenvironment of the injured CNS importantly influences macrophage plasticity. This review discusses the phagocytosis and cytokine-mediated effects on macrophage plasticity in the context of spinal cord injury. PMID:26342747

  5. 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.

  6. 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

  7. 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 ...

  8. 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 ...

  9. Muscle disorder

    MedlinePlus

    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 of a muscle disorder, tests such as an electromyogram , ...

  10. [Pregnancy during residency].

    PubMed

    Maas, S M; van 't Hoff, B W; Rings, E H; van der Waals, F W; Büller, H A

    1992-12-19

    The number of female residents in the Netherlands has steadily increased in recent years. Due to the increased time on waiting lists to enter residency programmes and to the increased duration of training, female residents will be older during their residencies. This will probably result in an increased number of pregnancies during residencies. A questionnaire regarding pregnancy during residency was sent to 191 residents in two university hospitals in the Netherlands. The response rate was 74.3%. Fifty percent of the male and only 19% of the female residents had children. No negative effects of a pregnancy on their training were experienced or anticipated by the residents. However, a negative effect on the functioning of the department was expected. No formal provisions, like replacements were available and many solutions to replace pregnant colleagues depended on the flexibility of the colleagues. The wish to have children was high and equally distributed among male and female residents, 92% and 96%, resp. Given the difficulty to seek a permanent position and to have children after residency, the choice of many female residents will be to have their children during residency. This increase in number of pregnancies requires anticipation of the residency programme directors. They should take the lead in proposing adequate regulations. PMID:1470257

  11. Exposure to p,p'-DDE Alters Macrophage Reactivity and Increases Macrophage Numbers in Adipose Stromal Vascular Fraction.

    PubMed

    Mangum, Lauren H; Crow, John Allen; Stokes, John V; Howell, George E; Ross, Matthew K; Pruett, Stephen B; Chambers, Janice E

    2016-03-01

    Exposure to p,p'-DDE (DDE), the main bioaccumulative metabolite of the organochlorine insecticide p,p'-DDT, is associated with a higher prevalence of obesity, dyslipidemia, insulin resistance, metabolic syndrome, and immunomodulation. The present study was carried out to determine whether DDE perturbs adipose tissue homeostasis through modulation of macrophage function. Treatment with DDE or a cyclooxygenase-2 inhibitor prior to lipopolysaccharide exposure significantly decreased production of prostaglandins (PG) from J774a.1 macrophages in vitro. Similarly, J774A.1 cell lysates incubated with DDE or a specific cyclooxygenase-2 inhibitor (NS-398) produced significantly less PGE2 and PGF2α. Macrophage polarization studies revealed a pattern of DDE effects that were not fully consistent with a purely pro- or purely anti- M1 or M2 effect. However, DDE suppressed expression of two M1 markers (induced by an M1 stimulus) and enhanced expression of an M2 marker (induced by an M2 stimulus). Further studies including assessment of macrophage function are needed to fully characterize the effects of DDE on macrophage polarization. Obesity is characterized by an increase in the number of resident adipose tissue macrophages. To assess monocyte/macrophage recruitment to the adipose tissue in vivo, male C57Bl/6H mice were treated with 2 mg/kg DDE or corn oil vehicle for 5 days by gavage. Epididymal fat pads were digested and macrophage populations were analyzed by flow cytometry. In DDE-treated animals, there was a significant increase (37%) in F4/80(+)CD11b(+) macrophages/g of epididymal adipose over vehicle (P < .05). Together, these results suggest a role for DDE in the enhancement of adipose tissue macrophage recruitment and/or proliferation, as well as modulation of immune cell function that may contribute to the etiology of metabolic diseases associated with organochlorine exposure. PMID:26748080

  12. Highly Dynamic Transcriptional Signature of Distinct Macrophage Subsets during Sterile Inflammation, Resolution, and Tissue Repair.

    PubMed

    Varga, Tamas; Mounier, Rémi; Horvath, Attila; Cuvellier, Sylvain; Dumont, Florent; Poliska, Szilard; Ardjoune, Hamida; Juban, Gaëtan; Nagy, Laszlo; Chazaud, Bénédicte

    2016-06-01

    Macrophage gene expression determines phagocyte responses and effector functions. Macrophage plasticity has been mainly addressed in in vitro models that do not account for the environmental complexity observed in vivo. In this study, we show that microarray gene expression profiling revealed a highly dynamic landscape of transcriptomic changes of Ly6C(pos)CX3CR1(lo) and Ly6C(neg)CX3CR1(hi) macrophage populations during skeletal muscle regeneration after a sterile damage. Systematic gene expression analysis revealed that the time elapsed, much more than Ly6C status, was correlated with the largest differential gene expression, indicating that the time course of inflammation was the predominant driving force of macrophage gene expression. Moreover, Ly6C(pos)/Ly6C(neg) subsets could not have been aligned to canonical M1/M2 profiles. Instead, a combination of analyses suggested the existence of four main features of muscle-derived macrophages specifying important steps of regeneration: 1) infiltrating Ly6C(pos) macrophages expressed acute-phase proteins and exhibited an inflammatory profile independent of IFN-γ, making them damage-associated macrophages; 2) metabolic changes of macrophages, characterized by a decreased glycolysis and an increased tricarboxylic acid cycle/oxidative pathway, preceded the switch to and sustained their anti-inflammatory profile; 3) Ly6C(neg) macrophages, originating from skewed Ly6C(pos) cells, actively proliferated; and 4) later on, restorative Ly6C(neg) macrophages were characterized by a novel profile, indicative of secretion of molecules involved in intercellular communications, notably matrix-related molecules. These results show the highly dynamic nature of the macrophage response at the molecular level after an acute tissue injury and subsequent repair, and associate a specific signature of macrophages to predictive specialized functions of macrophages at each step of tissue injury/repair. PMID:27183604

  13. The interaction between CD8+ cytotoxic T cells and Leishmania-infected macrophages

    PubMed Central

    1991-01-01

    Leishmania is resident within the macrophages of its vertebrate host. In any intramacrophage infection, where the pathogen is present in a form capable of mediating cell to cell transmission, the contribution of a cytotoxic T cell response to protective immunity is questionable. This study presents data from an in vitro model designed to elucidate the outcome of an interaction between CD8+, cytotoxic T cells and infected macrophages. Experiments were conducted with an H-2d- restricted, cytotoxic CD8+ T cell clone and Leishmania parasites present in mixed macrophage cultures, with the parasites confined to either histocompatible BALB/c macrophages, or incompatible CBA macrophages. Initial experiments indicated that the viability of Leishmania was unaffected by the lysis of its host macrophage by cytotoxic T cells. However, extended experiments showed that the parasites were killed between 24 and 72 h. The same results were obtained regardless of whether the parasites were resident in the target, BALB/c, macrophages or the bystander, CBA, macrophages. Addition of neutralizing, anti-IFN-g antibody to the cultures ablated most of the leishmanicidal behavior, indicating that parasite death was attributable to macrophage activation, resulting from cytokine secretion from the T cells following the initial recognition event. PMID:1908507

  14. The transcriptional coregulator GRIP1 controls macrophage polarization and metabolic homeostasis.

    PubMed

    Coppo, Maddalena; Chinenov, Yurii; Sacta, Maria A; Rogatsky, Inez

    2016-01-01

    Diet-induced obesity causes chronic macrophage-driven inflammation in white adipose tissue (WAT) leading to insulin resistance. WAT macrophages, however, differ in their origin, gene expression and activities: unlike infiltrating monocyte-derived inflammatory macrophages, WAT-resident macrophages counteract inflammation and insulin resistance, yet, the mechanisms underlying their transcriptional programming remain poorly understood. We recently reported that a nuclear receptor cofactor-glucocorticoid receptor (GR)-interacting protein (GRIP)1-cooperates with GR to repress inflammatory genes. Here, we show that GRIP1 facilitates macrophage programming in response to IL4 via a GR-independent pathway by serving as a coactivator for Kruppel-like factor (KLF)4-a driver of tissue-resident macrophage differentiation. Moreover, obese mice conditionally lacking GRIP1 in macrophages develop massive macrophage infiltration and inflammation in metabolic tissues, fatty livers, hyperglycaemia and insulin resistance recapitulating metabolic disease. Thus, GRIP1 is a critical regulator of immunometabolism, which engages distinct transcriptional mechanisms to coordinate the balance between macrophage populations and ultimately promote metabolic homeostasis. PMID:27464507

  15. The transcriptional coregulator GRIP1 controls macrophage polarization and metabolic homeostasis

    PubMed Central

    Coppo, Maddalena; Chinenov, Yurii; Sacta, Maria A.; Rogatsky, Inez

    2016-01-01

    Diet-induced obesity causes chronic macrophage-driven inflammation in white adipose tissue (WAT) leading to insulin resistance. WAT macrophages, however, differ in their origin, gene expression and activities: unlike infiltrating monocyte-derived inflammatory macrophages, WAT-resident macrophages counteract inflammation and insulin resistance, yet, the mechanisms underlying their transcriptional programming remain poorly understood. We recently reported that a nuclear receptor cofactor—glucocorticoid receptor (GR)-interacting protein (GRIP)1—cooperates with GR to repress inflammatory genes. Here, we show that GRIP1 facilitates macrophage programming in response to IL4 via a GR-independent pathway by serving as a coactivator for Kruppel-like factor (KLF)4—a driver of tissue-resident macrophage differentiation. Moreover, obese mice conditionally lacking GRIP1 in macrophages develop massive macrophage infiltration and inflammation in metabolic tissues, fatty livers, hyperglycaemia and insulin resistance recapitulating metabolic disease. Thus, GRIP1 is a critical regulator of immunometabolism, which engages distinct transcriptional mechanisms to coordinate the balance between macrophage populations and ultimately promote metabolic homeostasis. PMID:27464507

  16. Peroxidatic activity distinct from myeloperoxidase in human monocytes cultured in vitro and in alveolar macrophages.

    PubMed

    Breton-Gorius, J; Vildé, J L; Guichard, J; Vainchenker, W; Basset, F

    1982-01-01

    Human monocytes develop a peroxidatic activity (PA) in rough endoplasmic reticulum (RER) after adherence or after culture in semi-solid medium. This enzyme activity disappears after three days of culture in the majority of macrophages derived from adult monocytes but persists for one week in macrophages derived from neonatal monocytes. The PA is due to an enzyme distinct from myeloperoxidase (MPO), since monocytes from a patient with MPO deficiency develop the same PA as that of normal monocytes after adherence. By its localization and other characteristics, PA of adherent monocytes resembles that of rodent macrophages. We therefore investigated whether human alveolar macrophages exhibit PA, using a sensitive cytochemical method which prevents inhibition by aldehyde in adherent monocytes. In various pathological cases, four types of macrophages could be identified: the majority were peroxidase-negative, a small percentage was of exudate type exhibiting a PA in granules as blood monocytes, while few macrophages were intermediate, possessing only PA in RER i.e. of type resident and a smaller proportion had PA in RER and in granules i.e. exudate-resident macrophages. These findings demonstrate that human macrophages and adherent monocytes may exhibit PA in RER as has been reported for rodent macrophages. The true nature and function of the enzyme responsible for this PA, which is distinct from MPO, remains unknown, but some arguments seem to suggest its role in prostaglandin synthesis. PMID:6283838

  17. 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

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

  18. Delineation of Diverse Macrophage Activation Programs in Response to Intracellular Parasites and Cytokines

    PubMed Central

    Zhang, Shuyi; Kim, Charles C.; Batra, Sajeev; McKerrow, James H.; Loke, P'ng

    2010-01-01

    Background The ability to reside and proliferate in macrophages is characteristic of several infectious agents that are of major importance to public health, including the intracellular parasites Trypanosoma cruzi (the etiological agent of Chagas disease) and Leishmania species (etiological agents of Kala-Azar and cutaneous leishmaniasis). Although recent studies have elucidated some of the ways macrophages respond to these pathogens, the relationships between activation programs elicited by these pathogens and the macrophage activation programs elicited by bacterial pathogens and cytokines have not been delineated. Methodology/Principal Findings To provide a global perspective on the relationships between macrophage activation programs and to understand how certain pathogens circumvent them, we used transcriptional profiling by genome-wide microarray analysis to compare the responses of mouse macrophages following exposure to the intracellular parasites T. cruzi and Leishmania mexicana, the bacterial product lipopolysaccharide (LPS), and the cytokines IFNG, TNF, IFNB, IL-4, IL-10, and IL-17. We found that LPS induced a classical activation state that resembled macrophage stimulation by the Th1 cytokines IFNG and TNF. However, infection by the protozoan pathogen L. mexicana produced so few transcriptional changes that the infected macrophages were almost indistinguishable from uninfected cells. T. cruzi activated macrophages produced a transcriptional signature characterized by the induction of interferon-stimulated genes by 24 h post-infection. Despite this delayed IFN response by T. cruzi, the transcriptional response of macrophages infected by the kinetoplastid pathogens more closely resembled the transcriptional response of macrophages stimulated by the cytokines IL-4, IL-10, and IL-17 than macrophages stimulated by Th1 cytokines. Conclusions/Significance This study provides global gene expression data for a diverse set of biologically significant pathogens and

  19. Macrophage Inflammatory Assay

    PubMed Central

    Ylostalo, Joni H.

    2016-01-01

    Macrophages represent a widely distributed and functionally diverse population of innate myeloid cells involved in inflammatory response to pathogens, tissue homeostasis and tissue repair (Murray and Wynn, 2011). Macrophages can be broadly grouped into two subpopulations with opposing activites: M1 or pro-inflammatory macrophages that promote T-helper type 1 (Th1) cell immunity and tissue damage, and M2 or anti-inflammatory/alternatively activated macrophages implicated in Th2 response and resolution of inflammation. Here we describe a rapid assay we used previously to monitor changes in pro-inflammatory and anti-inflammatory cytokine production by lipopolysaccharide (LPS)-activated macrophages in response to therapeutic paracrine factors produced by adult stem cells (Bartosh et al., 2010; Ylostalo et al., 2012; Bartosh et al., 2013). The assay can be adapted appropriately to test macrophage response to other agents as well that will be referred to herein as ‘test reagents’ or ‘test compounds’. In this protocol, the mouse macrophage cell line J774A.1 is expanded as an adherent monolayer on petri dishes allowing for the cells to be harvested easily without enzymes or cell scrapers that can damage the cells. The macropahges are then stimulated in suspension with LPS and seeded into 12-well cell culture plates containing the test reagents. After 16–18 h, the medium conditioned by the macrophages is harvested and the cytokine profile in the medium determined with enzyme-linked immunosorbent assays (ELISA). We routinely measure levels of the pro-inflammtory cytokine TNF-alpha and the anti-inflammatory cytokine interleukin-10 (IL-10).

  20. 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. PMID:26210152

  1. Isolation of Mouse and Human Tumor-Associated Macrophages

    PubMed Central

    Cassetta, Luca; Noy, Roy; Swierczak, Agnieszka; Sugano, Gaël; Smith, Harriet; Wiechmann, Lisa; Pollard, Jeffrey W.

    2016-01-01

    The tumor microenvironment is a complex network of cells that support tumor progression and malignancy. It has been demonstrated that tumor cells can educate the immune system to promote a tumor-friendly environment. Among all these immune cells, tumor-associated macrophages (TAMs) are well represented and their presence in mouse models has been shown to promote tumor progression and metastasis. These effects are through the stimulation of angiogenesis, enhancement of tumor cell invasion and intravasation, immunosuppression, and at the metastatic site tumor cell extravasation and growth. However, the precise mechanisms are not fully understood. Furthermore there is limited information on TAMs derived from human cancers. For this reason it is important to be able to extract TAMs from tumors in order to compare their phenotypes, functions, and transcriptomes with normal resident tissue macrophages. Isolation of these cells is challenging due to the lack of markers and standardized protocols. Here we show an optimized protocol for the efficient isolation and extraction of resident macrophages and TAMs from human and mouse tissues by using multicolor flow cytometry. These protocols allow for the extraction of thousands of macrophages in less than 5 h from tissues as small as half a gram. The isolated macrophages can then be used for both “omics” and in vitro studies. PMID:27325269

  2. Isolation of Mouse and Human Tumor-Associated Macrophages.

    PubMed

    Cassetta, Luca; Noy, Roy; Swierczak, Agnieszka; Sugano, Gaël; Smith, Harriet; Wiechmann, Lisa; Pollard, Jeffrey W

    2016-01-01

    The tumor microenvironment is a complex network of cells that support tumor progression and malignancy. It has been demonstrated that tumor cells can educate the immune system to promote a tumor-friendly environment. Among all these immune cells, tumor-associated macrophages (TAMs) are well represented and their presence in mouse models has been shown to promote tumor progression and metastasis. These effects are through the stimulation of angiogenesis, enhancement of tumor cell invasion and intravasation, immunosuppression, and at the metastatic site tumor cell extravasation and growth. However, the precise mechanisms are not fully understood. Furthermore there is limited information on TAMs derived from human cancers. For this reason it is important to be able to extract TAMs from tumors in order to compare their phenotypes, functions, and transcriptomes with normal resident tissue macrophages. Isolation of these cells is challenging due to the lack of markers and standardized protocols. Here we show an optimized protocol for the efficient isolation and extraction of resident macrophages and TAMs from human and mouse tissues by using multicolor flow cytometry. These protocols allow for the extraction of thousands of macrophages in less than 5 h from tissues as small as half a gram. The isolated macrophages can then be used for both "omics" and in vitro studies. PMID:27325269

  3. Macrophage Polarization in Inflammatory Diseases

    PubMed Central

    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. PMID:24910531

  4. 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.

  5. Role of activation in alveolar macrophage-mediated suppression of the plaque-forming cell response.

    PubMed Central

    Mbawuike, I N; Herscowitz, H B

    1988-01-01

    Alveolar macrophages (AM) are highly suppressive of the in vitro plaque-forming cell (PFC) response of spleen cells obtained from mice primed with sheep erythrocytes. Comparison of macrophage populations obtained from disparate anatomical sites revealed that although in both cases there was a cell-concentration-dependent suppression of the PFC response, resident AM or AM activated as a result of intravenous injection of Mycobacterium bovis BCG were equally suppressive at the doses examined. Although there was a similar dose-dependent suppression with peritoneal macrophages, BCG-activated cells were more suppressive of the PFC response than were resident cells. In contrast, splenic macrophages at comparable concentrations were not at all suppressive. Resident AM exhibited significantly lower levels of 5'-nucleotidase activity than did resident peritoneal macrophages. Macrophage-mediated suppression of the in vitro PFC response could not be attributed to the release of toxic oxygen metabolites (H2O2, O2- ,and .OH) or prostaglandins, since the addition of catalase, superoxide dismutase, 2-mercaptoethanol, or indomethacin did not completely reverse suppression. These results suggest that the lung microenvironment may maintain AM in an activated state which contributes to their potential immunoregulatory functions. PMID:2830191

  6. Myelin and macrophages in the PNS: An intimate relationship in trauma and disease.

    PubMed

    Klein, Dennis; Martini, Rudolf

    2016-06-15

    Macrophages of the peripheral nervous system belong to the so-called tissue macrophages, with multiple functions during injury and disease. Their origin during ontogeny has not yet been completely resolved, but it is clear that upon injury and disease conditions, they are supplemented by hematopoietic derivatives. In the peripheral nervous system, the most abundantly investigated scenario in which resident and infiltrating macrophages are involved is the so-called "Wallerian degeneration", a complex degenerative process where macrophages exhibit mostly beneficial functions by phagocytosing myelin and axonal remnants. Of special interest is the implication of macrophages in inflammatory nerve diseases, like acute Guillain-Barré syndromes and its permanent variant, chronic inflammatory demyelinating polyneuropathy, where macrophages are supposed to be substantial (co-)mediators of the diseases. In inherited peripheral neuropathies nerve macrophages possess a clear disease-amplifying function. In the corresponding animal models, a coordinated interplay between mutant Schwann cells, macrophages, endoneurial fibroblasts and the target structure, myelin, emerged. Along this process, a newly discovered disease mechanism mediated by macrophages is the dedifferentiation of myelinating Schwann cells. As macrophages are amplifiers of the genetically-mediated, non-curable diseases, targeting the mechanisms of their activation might be a promising strategy to treat these disorders. This article is part of a Special Issue entitled SI: Myelin Evolution. PMID:26631844

  7. 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.

  8. Neuro-immune Interactions Drive Tissue Programming in Intestinal Macrophages.

    PubMed

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

    2016-01-28

    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

  9. 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. PMID:27091452

  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. 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

  12. Muscle biopsy

    MedlinePlus

    ... that affect the muscles (such as trichinosis or toxoplasmosis ) Muscle disorders such as muscular dystrophy or congenital ... nodosa Polymyalgia rheumatica Polymyositis - adult Thyrotoxic periodic paralysis Toxoplasmosis Trichinosis Update Date 9/8/2014 Updated by: ...

  13. Muscle Disorders

    MedlinePlus

    ... cause weakness, pain or even paralysis. Causes of muscle disorders include Injury or overuse, such as sprains or strains, cramps or tendinitis A genetic disorder, such as muscular dystrophy Some ... muscles Infections Certain medicines Sometimes the cause is not ...

  14. Two Unique Human Decidual Macrophage Populations

    PubMed Central

    Houser, Brandy L.; Tilburgs, Tamara; Hill, Jonathan; Nicotra, Matthew L.; Strominger, Jack L.

    2013-01-01

    Several important events occur at the maternal–fetal interface, including generation of maternal–fetal tolerance, remodeling of the uterine smooth muscle and its spiral arteries and glands, and placental construction. Fetal-derived extravillous trophoblasts come in direct contact with maternal decidual leukocytes. Macrophages represent ~20% of the leukocytes at this interface. In this study, two distinct subsets of CD14+ decidual macrophages (dMϕs) are found to be present in first-trimester decidual tissue, CD11cHI and CD11cLO. Gene expression analysis by RNA microarray revealed that 379 probes were differentially expressed between these two populations. Analysis of the two subsets revealed several clusters of coregulated genes that suggest distinct functions for these subsets in tissue remodeling, growth, and development. CD11cHI dMϕs express genes associated with lipid metabolism and inflammation, whereas CD11cLO dMϕs express genes associated with extracellular matrix formation, muscle regulation, and tissue growth. The CD11cHI dMϕs also differ from CD11cLO dMϕs in their ability to process protein Ag and are likely to be the major APCs in the decidua. Moreover, these populations each secrete both proinflammatory and anti-inflammatory cytokines that may contribute to the balance that establishes fetal–maternal tolerance. Thus, they do not fit the conventional M1/M2 categorization. PMID:21257965

  15. Cortisol regulates the paracrine action of macrophages by inducing vasoactive gene expression in endometrial cells.

    PubMed

    Thiruchelvam, Uma; Maybin, Jacqueline A; Armstrong, Gregory M; Greaves, Erin; Saunders, Philippa T K; Critchley, Hilary O D

    2016-06-01

    The human endometrium undergoes inflammation and tissue repair during menstruation. We hypothesized that the local availability of bioactive glucocorticoids plays an important role in immune cell-vascular cell interactions in endometrium during tissue repair at menstruation, acting either directly or indirectly via tissue resident macrophages. We sought to determine whether endometrial macrophages are direct targets for glucocorticoids; whether cortisol-treated macrophages have a paracrine effect on angiogenic gene expression by endometrial endothelial cells; and whether endometrial macrophages express angiogenic factors. Human endometrium (n = 41) was collected with ethical approval and subject consent. Donor peripheral blood monocyte-derived macrophages were treated with estradiol, progesterone, or cortisol. The effect of peripheral blood monocyte-derived macrophage secretory products on the expression of angiogenic RNAs by endothelial cells was examined. Immunofluorescence was used to examine localization in macrophages and other endometrial cell types across the menstrual cycle. Endometrial macrophages express the glucocorticoid receptor. In vitro culture with supernatants from cortisol-treated peripheral blood monocyte-derived macrophages resulted in altered endometrial endothelial cell expression of the angiogenic genes, CXCL2, CXCL8, CTGF, and VEGFC These data highlight the importance of local cortisol in regulating paracrine actions of macrophages in the endometrium. CXCL2 and CXCL8 were detected in endometrial macrophages in situ. The expression of these factors was highest in the endometrium during the menstrual phase, consistent with these factors having a role in endometrial repair. Our data have indicated that activation of macrophages with glucocorticoids might have paracrine effects by increasing angiogenic factor expression by endometrial endothelial cells. This might reflect possible roles for macrophages in endometrial repair of the vascular bed

  16. 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…

  17. Wormhole Travel for Macrophages.

    PubMed

    Okabe, Yasutaka; Medzhitov, Ruslan

    2016-04-21

    Leukocyte recruitment is generally achieved by rapid migration of inflammatory cells out of circulation, through modified blood vessels, and into affected tissues. Now, Wang and Kubes show that macrophages can be rapidly recruited from body cavities to the liver, via a non-vascular route, where they help to coordinate tissue repair. PMID:27104973

  18. 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. PMID:27049910

  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. Residency Decisions: Another Look.

    ERIC Educational Resources Information Center

    Davidson, Barry S.

    The process of determining student's residency status for fee payment at the University of Nevada-Reno is described and supplemental information forms that are used at the university are included. At the University of Nevada-Reno, residency decisions are the responsibility of admissions office professional staff. The university has a formal…

  1. 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

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

    PubMed

    DiNapoli, Sarah R; Hirsch, Vanessa M; Brenchley, Jason M

    2016-09-01

    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

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

    PubMed

    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

    2009-02-01

    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. PMID:18827026

  4. Decidual Macrophages and Their Roles at the Maternal-Fetal Interface

    PubMed Central

    Houser, Brandy L.

    2012-01-01

    The semi-allogeneic fetus, whose genome consists of maternally and paternally inherited alleles, must coexist with an active maternal immune system during its 9 months in utero. Macrophages are the second most abundant immune cell at the maternal-fetal interface, although populations and functions for these populations remain ill defined. We have previously reported two distinct subsets of CD14+ decidual macrophages found to be present in first trimester decidual tissue, 20 percent CD11cHI and 68 percent CD11cLO. Interestingly, CD11cHI decidual macrophages express genes associated with lipid metabolism, inflammation, and antigen presentation function and specifically upregulate CD1 molecules. Conversely, CD11cLO decidual macrophages express genes associated with extracellular matrix formation, muscle regulation, and tissue growth. The large abundance of CD11cHI decidual macrophages and their ability to process antigens more efficiently than CD11cLO macrophages suggests that CD11cHI macrophages may be important antigen processing and presenting cells at the maternal-fetal interface, while CD11cLO macrophages may perform necessary homeostatic functions during placental construction. Thus, macrophage heterogeneity may be an important and necessary division of labor that leads to both an induction of maternal immune cell tolerance to fetal antigens as well as basic homeostatic functions in human pregnancy. PMID:22461749

  5. CX3CR1-dependent renal macrophage survival promotes Candida control and host survival

    PubMed Central

    Lionakis, Michail S.; Swamydas, Muthulekha; Fischer, Brett G.; Plantinga, Theo S.; Johnson, Melissa D.; Jaeger, Martin; Green, Nathaniel M.; Masedunskas, Andrius; Weigert, Roberto; Mikelis, Constantinos; Wan, Wuzhou; Lee, Chyi-Chia Richard; Lim, Jean K.; Rivollier, Aymeric; Yang, John C.; Laird, Greg M.; Wheeler, Robert T.; Alexander, Barbara D.; Perfect, John R.; Gao, Ji-Liang; Kullberg, Bart-Jan; Netea, Mihai G.; Murphy, Philip M.

    2013-01-01

    Systemic Candida albicans infection causes high morbidity and mortality and is associated with neutropenia; however, the roles of other innate immune cells in pathogenesis are poorly defined. Here, using a mouse model of systemic candidiasis, we found that resident macrophages accumulated in the kidney, the main target organ of infection, and formed direct contacts with the fungus in vivo mainly within the first few hours after infection. Macrophage accumulation and contact with Candida were both markedly reduced in mice lacking chemokine receptor CX3CR1, which was found almost exclusively on resident macrophages in uninfected kidneys. Infected Cx3cr1–/– mice uniformly succumbed to Candida-induced renal failure, but exhibited clearance of the fungus in all other organs tested. Renal macrophage deficiency in infected Cx3cr1–/– mice was due to reduced macrophage survival, not impaired proliferation, trafficking, or differentiation. In humans, the dysfunctional CX3CR1 allele CX3CR1-M280 was associated with increased risk of systemic candidiasis. Together, these data indicate that CX3CR1-mediated renal resident macrophage survival is a critical innate mechanism of early fungal control that influences host survival in systemic candidiasis. PMID:24177428

  6. Macrophages contribute to the cyclic activation of adult hair follicle stem cells.

    PubMed

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

    2014-12-01

    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

  7. New Insights Into Tissue Macrophages: From Their Origin to the Development of Memory

    PubMed Central

    Italiani, Paola

    2015-01-01

    Macrophages are the main effector cells of innate immunity and are involved in inflammatory and anti-infective processes. They also have an essential role in maintaining tissue homeostasis, supporting tissue development, and repairing tissue damage. Until few years ago, it was believed that tissue macrophages derived from circulating blood monocytes, which terminally differentiated in the tissue and unable to proliferate. Recent evidence in the biology of tissue macrophages has uncovered a series of immune and ontogenic features that had been neglected for long, despite old observations. These include origin, heterogeneity, proliferative potential (or self-renewal), polarization, and memory. In recent years, the number of publications on tissue resident macrophages has grown rapidly, highlighting the renewed interest of the immunologists for these key players of innate immunity. This mini-review aims to summarizing the new current knowledge in macrophage immunobiology, in order to offer a clear and immediate overview of the field. PMID:26330802

  8. 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

  9. The Role of Macrophages in Promoting and Maintaining Homeostasis at the Fetal-Maternal Interface.

    PubMed

    Svensson-Arvelund, Judit; Ernerudh, Jan

    2015-08-01

    A successful pregnancy requires that the maternal immune system adapts properly to avoid rejection of the semi-allogeneic fetus without compromising the ability to protect the mother and the fetus against infections. In this review, we describe the role of decidual macrophages in creating a homeostatic environment at the fetal-maternal interface. We also discuss their role in pregnancy complications as well as future possibilities to modulate macrophage function therapeutically. Decidual macrophages are enriched at the fetal-maternal interface and play a major role in the regulation of inflammatory responses and the maintenance of a tolerant environment. Their function is, however, not restricted to immune tolerance, but extends to include functions such as the recognition and clearance of infections, the clearance of apoptotic debris, and tissue remodeling. Decidual macrophages seem to largely function as tissue-resident macrophages that are crucial for maintaining homeostasis and reproductive success. PMID:25582625

  10. 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. PMID:25779326

  11. Gene silencing in adipose tissue macrophages regulates whole-body metabolism in obese mice.

    PubMed

    Aouadi, Myriam; Tencerova, Michaela; Vangala, Pranitha; Yawe, Joseph C; Nicoloro, Sarah M; Amano, Shinya U; Cohen, Jessica L; Czech, Michael P

    2013-05-14

    Adipose tissue (AT) inflammation and infiltration by macrophages is associated with insulin resistance and type 2 diabetes in obese humans, offering a potential target for therapeutics. However, whether AT macrophages (ATMs) directly contribute to systemic glucose intolerance has not been determined. The reason is the lack of methods to ablate inflammatory genes expressed in macrophages specifically localized within AT depots, leaving macrophages in other tissues unaffected. Here we report that i.p. administration of siRNA encapsulated by glucan shells in obese mice selectively silences genes in epididymal ATMs, whereas macrophages within lung, spleen, kidney, heart, skeletal muscle, subcutaneous (SubQ) adipose, and liver are not targeted. Such administration of GeRPs to silence the inflammatory cytokines TNF-α or osteopontin in epididymal ATMs of obese mice caused significant improvement in glucose tolerance. These data are consistent with the hypothesis that cytokines produced by ATMs can exacerbate whole-body glucose intolerance. PMID:23630254

  12. Endogenous interferon production by endotoxin-responsive macrophages provides an autostimulatory differentiation signal.

    PubMed Central

    Vogel, S N; Fertsch, D

    1984-01-01

    Previous studies have demonstrated that peritoneal macrophages (resident or thioglycolate-induced) derived from mouse strains fully responsive to gram-negative endotoxins continue to differentiate in vitro, as evidenced by an increased capacity to phagocytose via the Fc receptor with time in culture. In contrast, macrophages derived from endotoxin-hyporesponsive mouse strains (e.g., C3H/HeJ or C57BL/10ScN) exhibit no such increase in phagocytic capacity, and, in fact, significantly lose the capacity to phagocytose particles opsonized with immunoglobulin G with time in culture. This defect was found to be fully correctable by the addition to the cultures of an exogenous source of alpha, beta, or gamma interferon. In this study, we compared C3H/HeN (endotoxin-responsive) and C3H/HeJ (endotoxin-responsive) and C3H/HeJ (endotoxin-hyporesponsive) macrophages in an attempt to elucidate the mechanism responsible for this difference in phagocytic (differentiative) potential. The following observations support the hypothesis that endotoxin-responsive macrophages, in contrast to endotoxin-hyporesponsive macrophages, produce significantly higher levels of an autostimulatory differentiation signal that appears to be macrophage-derived interferon. (i) Anti-alpha/beta-interferon antibody greatly reduces the ability of C3H/HeN macrophages to phagocytose opsonized erythrocytes: (ii) C3H/HeJ macrophages can be made more phagocytic by coculture with C3H/HeN macrophages or by treatment with supernatants derived from C3H/HeN macrophage cultures; and (iii) C3H/HeN macrophages spontaneously lose Mac-1 antigen with time in culture. C3H/HeJ macrophages must be interferon-treated to be equivalently down-regulated. PMID:6378797

  13. Alpha-D-galactosylation of surface fucoglycoconjugate(s) upon stimulation/activation of murine peritoneal macrophages.

    PubMed

    Petryniak, J

    1992-04-01

    Murine resident macrophages express, on their surface, carbohydrate epitopes which undergo changes during their stimulation/activation as monitored by binding of 125I labelled Evonymus europaea and Griffonia simplicifolia I-B4 lectins. Treatment of the stimulated macrophages with coffee bean alpha-galactosidase abolished binding of the GS I-B4 isolectin and changed the binding pattern of the Evonymus lectin. The affinity (Ka) of Evonymus lectin for alpha-galactosidase-treated macrophages decreased approximately 23-fold, from 1.25 x 10(8) M-1 to 5.5 x 10(6) M-1. Subsequent digestion of alpha-galactosidase-treated macrophages with alpha-L-fucosidase from Trichomonas foetus, further reduced binding of Evonymus lectin. Resident macrophages showed the same pattern of Evonymus lectin binding, with the same affinity, as alpha-galactosidase-treated, stimulated macrophages. These results, together with a consideration of the carbohydrate binding specificity of the Evonymus lectin which, in the absence of alpha-D-galactosyl groups, requires alpha-L-fucosyl groups for binding, indicate the presence, on resident macrophages, of glycoconjugates with terminal alpha-L-fucosyl residues. It is also concluded that during macrophage stimulation/activation alpha-D-galactosyl residues are added to this glycoconjugate and that they form part of the receptor for Evonymus lectin. The same glycoconjugate(s) is/are also expressed on the activated macrophage IC-21 cell line which exhibits the same characteristics as that of stimulated peritoneal macrophages, i.e., it contains alpha-D-galactosyl end groups and is resistant to the action of trypsin. Both lectins were also specifically bound to Corynaebacterium parvum activated macrophages. PMID:1344714

  14. The heterogeneity of lung macrophages in the susceptibility to disease.

    PubMed

    Morales-Nebreda, Luisa; Misharin, Alexander V; Perlman, Harris; Budinger, G R Scott

    2015-09-01

    Alveolar macrophages are specialised resident phagocytes in the alveolus, constituting the first line of immune cellular defence in the lung. As the lung microenvironment is challenged and remodelled by inhaled pathogens and air particles, so is the alveolar macrophage pool altered by signals that maintain and/or replace its composition. The signals that induce the recruitment of circulating monocytes to the injured lung, as well as their distinct gene expression profile and susceptibility to epigenetic reprogramming by the local environment remain unclear. In this review, we summarise the unique characteristics of the alveolar macrophage pool ontogeny, phenotypic heterogeneity and plasticity during homeostasis, tissue injury and normal ageing. We also discuss new evidence arising from recent studies where investigators described how the epigenetic landscape drives the specific gene expression profile of alveolar macrophages. Altogether, new analysis of macrophages by means of "omic" technologies will allow us to identify key pathways by which these cells contribute to the development and resolution of lung disease in both mice and humans. PMID:26324812

  15. Mobilization of stored triglycerides from macrophages as free fatty acids.

    PubMed

    von Hodenberg, E; Khoo, J C; Jensen, D; Witztum, J L; Steinberg, D

    1984-01-01

    Because many or most lipid-laden foam cells in atheromas and in xanthomas derive from macrophages, it is important to understand how they accumulate lipids and how they can divest themselves of lipids. The mobilization of stored triglycerides from macrophages was studied in cell cultures. Mouse resident peritoneal macrophages and J774 macrophages increased their triglyceride content six- to tenfold during a 24-hour incubation with free fatty acids complexed to albumin. Subsequent incubation in fresh medium containing free fatty acid-poor albumin was accompanied by a fall in cell triglyceride content (50% in 20 hours) and a corresponding increase in medium-free fatty acid. Release of free fatty acid was linear as a function of time, provided fresh medium was added hourly. When medium was not changed, release rates fell off rapidly, probably due to re-uptake of released free fatty acid. Chloroquine did not affect the rate of free fatty acid release. The results suggest that macrophages-foam cells can reduce their triglyceride stores via the action of a nonlysosomal (presumably cytoplasmic) neutral triglyceride lipase. PMID:6508637

  16. Macrophage Apoptosis Triggered by IpaD from Shigella flexneri.

    PubMed

    Arizmendi, Olivia; Picking, William D; Picking, Wendy L

    2016-06-01

    Shigellosis, a potentially severe bacillary dysentery, is an infectious gastrointestinal disease caused by Shigella spp. Shigella invades the human colonic epithelium and avoids clearance by promoting apoptosis of resident immune cells in the gut. This process is dependent on the Shigella type III secretion system (T3SS), which injects effector proteins into target cells to alter their normal cellular functions. Invasion plasmid antigen D (IpaD) is a structural component that forms a complex at the tip of the T3SS apparatus needle. Recently, IpaD has also been shown to indirectly induce apoptosis in B lymphocytes. In this study, we explored the cytotoxicity profile during macrophage infection by Shigella and discovered that the pathogen induces macrophage cell death independent of caspase-1. Our results demonstrate that IpaD triggers apoptosis in macrophages through activation of host caspases accompanied by mitochondrial disruption. Additionally, we found that the IpaD N-terminal domain is necessary for macrophage killing and SipD, a structural homologue from Salmonella, was found to promote similar cytotoxicity. Together, these findings indicate that IpaD is a contributing factor to macrophage cell death during Shigella infection. PMID:27068089

  17. Microglia: unique and common features with other tissue macrophages.

    PubMed

    Prinz, Marco; Tay, Tuan Leng; Wolf, Yochai; Jung, Steffen

    2014-09-01

    Microglia are highly specialized tissue macrophages of the brain with dedicated functions in neuronal development, homeostasis and recovery from pathology Despite their unique localization in the central nervous system (CNS), microglia are ontogenetically and functionally related to their peripheral counterparts of the mononuclear phagocytic system in the body, namely tissue macrophages and circulating myeloid cells. Recent developments provided new insights into the myeloid system in the body with microglia emerging as intriguing unique archetypes. Similar to other tissue macrophages, microglia develop early during embryogenesis from immature yolk sac progenitors. But in contrast to most of their tissue relatives microglia persist throughout the entire life of the organism without any significant input from circulating blood cells due to their longevity and their capacity of self-renewal. Notably, microglia share some features with short-lived blood monocytes to limit CNS tissue damage in pathologies, but only bone marrow-derived cells display the ability to become permanently integrated in the parenchyma. This emphasizes the therapeutic potential of bone marrow-derived microglia-like cells. Further understanding of both fate and function of microglia during CNS pathologies and considering their uniqueness among other tissue macrophages will be pivotal for potential manipulation of immune cell function in the CNS, thereby reducing disease burden. Here, we discuss new aspects of myeloid cell biology in general with special emphasis on the brain-resident macrophages and microglia. PMID:24652058

  18. 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.

  19. 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

  20. 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)

  1. Technology in Residence.

    ERIC Educational Resources Information Center

    Fox, Jordan

    1999-01-01

    Discusses the necessity for incorporating current technology in today's college residence halls to meet the more diverse and continued activities of its students. Technology addressed covers data networking and telecommunications, heating and cooling systems, and fire-safety systems. (GR)

  2. Activation of mouse macrophages causes no change in expression and function of phorbol diesters' receptors, but is accompanied by alterations in the activity and kinetic parameters of NADPH oxidase.

    PubMed Central

    Berton, G; Cassatella, M; Cabrini, G; Rossi, F

    1985-01-01

    Mouse peritoneal macrophages activated in vivo by the injection of Corynebacterium parvum release larger amounts of superoxide anion (O2-) than macrophages from control mice when stimulated with phorbol myristate acetate (PMA). The biochemical bases for this enhanced response of activated macrophages have been investigated by studying the expression and function of receptors for the stimulant, and the activity of the enzyme NADPH oxidase which is responsible for the production of O2- in leucocytes. Studies of binding of phorbol dibutyrate, an agent closely related to PMA, showed that the affinity constants (Kds) and the number of binding sites were the same in resident and activated peritoneal macrophages. The activity of the NADPH oxidase was, however, different in the two macrophage populations which differ in their capacity to release O2-. NADPH oxidase activity was studied in macrophage monolayers after lysis with deoxycholate. The main features of this activity were as follows: stimulation of macrophages with PMA or zymosan caused an increase in NADPH-dependent O2- production; NADPH oxidase activity in the lysates followed the same dose-response curve for different concentrations of PMA as O2- release by intact macrophages; O2- release by intact macrophages could be fully accounted for by NADPH-dependent O2- production by macrophage lysates; activity was strictly substrate-specific, in that NADH could not substitute for NADPH; after stimulation with PMA or zymosan, NADPH oxidase activity was higher in lysates of C. parvum-activated macrophages than in lysates of resident macrophages; NADPH oxidase activities of activated and resident macrophages differed markedly in their kinetic parameters. The NADPH oxidase of macrophages activated by C. parvum or trehalose dimycolate of mycobacterial origin displayed a five to seven times lower Km compared to the enzyme in resident macrophages. PMID:2981767

  3. 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

  4. Macrophage immunoregulatory pathways in tuberculosis

    PubMed Central

    Rajaram, Murugesan V.S.; Ni, Bin; Dodd, Claire E.; Schlesinger, Larry S.

    2014-01-01

    Macrophages, the major host cells harboring Mycobacterium tuberculosis (M.tb), are a heterogeneous cell type depending on their tissue of origin and host they are derived from. Significant discord in macrophage responses to M.tb exists due to differences in M.tb strains and the various types of macrophages used to study tuberculosis (TB). This review will summarize current concepts regarding macrophage responses to M.tb infection, while pointing out relevant differences in experimental outcomes due to the use of divergent model systems. A brief description of the lung environment is included since there is increasing evidence that the alveolar macrophage (AM) has immunoregulatory properties that can delay optimal protective host immune responses. In this context, this review focuses on selected macrophage immunoregulatory pattern recognition receptors (PRRs), cytokines, negative regulators of inflammation, lipid mediators and microRNAs (miRNAs). PMID:25453226

  5. The identification of markers of macrophage differentiation in PMA-stimulated THP-1 cells and monocyte-derived macrophages.

    PubMed

    Daigneault, Marc; Preston, Julie A; Marriott, Helen M; Whyte, Moira K B; Dockrell, David H

    2010-01-01

    Differentiated macrophages are the resident tissue phagocytes and sentinel cells of the innate immune response. The phenotype of mature tissue macrophages represents the composite of environmental and differentiation-dependent imprinting. Phorbol-12-myristate-13-acetate (PMA) and 1,25-dihydroxyvitamin D3 (VD(3)) are stimuli commonly used to induce macrophage differentiation in monocytic cell lines but the extent of differentiation in comparison to primary tissue macrophages is unclear. We have compared the phenotype of the promonocytic THP-1 cell line after various protocols of differentiation utilising VD(3) and PMA in comparison to primary human monocytes or monocyte-derived macrophages (MDM). Both stimuli induced changes in cell morphology indicative of differentiation but neither showed differentiation comparable to MDM. In contrast, PMA treatment followed by 5 days resting in culture without PMA (PMAr) increased cytoplasmic to nuclear ratio, increased mitochondrial and lysosomal numbers and altered differentiation-dependent cell surface markers in a pattern similar to MDM. Moreover, PMAr cells showed relative resistance to apoptotic stimuli and maintained levels of the differentiation-dependent anti-apoptotic protein Mcl-1 similar to MDM. PMAr cells retained a high phagocytic capacity for latex beads, and expressed a cytokine profile that resembled MDM in response to TLR ligands, in particular with marked TLR2 responses. Moreover, both MDM and PMAr retained marked plasticity to stimulus-directed polarization. These findings suggest a modified PMA differentiation protocol can enhance macrophage differentiation of THP-1 cells and identify increased numbers of mitochondria and lysosomes, resistance to apoptosis and the potency of TLR2 responses as important discriminators of the level of macrophage differentiation for transformed cells. PMID:20084270

  6. Macrophages in homeostatic immune function.

    PubMed

    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

  7. 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.

  8. Bioelectric modulation of macrophage polarization

    PubMed Central

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

    2016-01-01

    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. PMID:26869018

  9. Bioelectric modulation of macrophage polarization.

    PubMed

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

    2016-01-01

    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. PMID:26869018

  10. 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

  11. Divergent impact of Toll-like receptor 2 deficiency on repair mechanisms in healthy muscle versus Duchenne muscular dystrophy.

    PubMed

    Mojumdar, Kamalika; Giordano, Christian; Lemaire, Christian; Liang, Feng; Divangahi, Maziar; Qureshi, Salman T; Petrof, Basil J

    2016-05-01

    Injury to skeletal muscle, whether acute or chronic, triggers macrophage-mediated innate immunity in a manner which can be either beneficial or harmful for subsequent repair. Endogenous ligands for Toll-like receptor 2 (TLR2) are released by damaged tissues and might play an important role in activating the innate immune system following muscle injury. To test this hypothesis, we compared macrophage behaviour and muscle repair mechanisms in mice lacking TLR2 under conditions of either acute (cardiotoxin-induced) or chronic (mdx mouse genetic model of Duchenne muscular dystrophy; DMD) muscle damage. In previously healthy muscle subjected to acute damage, TLR2 deficiency reduced macrophage numbers in the muscle post-injury but did not alter the expression pattern of the prototypical macrophage polarization markers iNOS and CD206. In addition, there was abnormal persistence of necrotic fibres and impaired regeneration in TLR2-/- muscles after acute injury. In contrast, TLR2 ablation in chronically diseased muscles of mdx mice not only resulted in significantly reduced macrophage numbers but additionally modified their phenotype by shifting from inflammatory (iNOS(pos) CD206(neg) ) to more anti-inflammatory (iNOS(neg) CD206(pos) ) characteristics. This decrease in macrophage-mediated inflammation was associated with ameliorated muscle histopathology and improved force-generating capacity of the dystrophic muscle. Our results suggest that the role of TLR2 in macrophage function and skeletal muscle repair depends greatly upon the muscle injury context, and raise the possibility that inhibition of TLR2 could serve as a useful therapeutic measure in DMD. PMID:26800321

  12. 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.

  13. 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. PMID:15908457

  14. 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. PMID:25421226

  15. Muscle cramps.

    PubMed

    Miller, Timothy M; Layzer, Robert B

    2005-10-01

    Muscle cramps are a common problem characterized by a sudden, painful, involuntary contraction of muscle. These true cramps, which originate from peripheral nerves, may be distinguished from other muscle pain or spasm. Medical history, physical examination, and a limited laboratory screen help to determine the various causes of muscle cramps. Despite the "benign" nature of cramps, many patients find the symptom very uncomfortable. Treatment options are guided both by experience and by a limited number of therapeutic trials. Quinine sulfate is an effective medication, but the side-effect profile is worrisome, and other membrane-stabilizing drugs are probably just as effective. Patients will benefit from further studies to better define the pathophysiology of muscle cramps and to find more effective medications with fewer side-effects. PMID:15902691

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

    PubMed

    Gensel, John C; Zhang, Bei

    2015-09-01

    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. PMID:25578260

  17. Ultrastructural studies of the killing of schistosomula of Schistosoma mansoni by activated macrophages in vitro.

    PubMed

    McLaren, D J; James, S L

    1985-05-01

    Immunologically activated murine macrophages have been shown elsewhere to kill skin stage schistosomula of Schistosoma mansoni in vitro, in a manner analogous to the extracellular killing of tumour cell targets. In this study, the kinetics of the interaction between activated macrophages and larval targets and the resultant ultrastructural changes in parasite morphology that culminated in death have been analysed in detail. Unlike granulocyte-mediated schistosomular killing, macrophage-mediated cytotoxicity did not appear to be directed against the surface tissues of the parasite. Macrophages adhered only transiently following initiation of the cultures, yet changes in the subtegumental mitochondria and muscle cells of the larva were detected within the first hour of incubation. Progressive internal disorganisation followed rapidly, but the tegument and tegumental outer membrane remained intact, to form a 'shell' that maintained the general shape of the parasite. Such changes were recognised irrespective of whether the effector cell population comprised peritoneal macrophages activated by lymphokine treatment in vitro, or by infection with Mycobacterium bovis (strain BCG), or S. mansoni in vivo. That macrophages rather than contaminating granulocytes or lymphocytes, had mediated the observed damage was demonstrated by the use of a lymphokine treated macrophage cell line, IC-21. The observation that macrophage cytotoxicity is directed against internal organelles rather than the tegumental outer membrane of this multicellular target, may help to elucidate the general mechanism of extracellular killing by these cells. PMID:3892433

  18. Aluminum hydroxide adjuvant induces macrophage differentiation towards a specialized antigen-presenting cell type.

    PubMed

    Rimaniol, Anne-Cécile; Gras, Gabriel; Verdier, François; Capel, Francis; Grigoriev, Vladimir B; Porcheray, Fabrice; Sauzeat, Elisabeth; Fournier, Jean-Guy; Clayette, Pascal; Siegrist, Claire-Anne; Dormont, Dominique

    2004-08-13

    Aluminum hydroxide (AlOOH) has been used for many years as a vaccine adjuvant, but little is known about its mechanism of action. We investigated in this study the in vitro effect of aluminum hydroxide adjuvant on isolated macrophages. We showed that AlOOH-stimulated macrophages contain large and persistent intracellular crystalline inclusions, a characteristic property of muscle infiltrated macrophages described in animal models of vaccine injection, as well as in the recently described macrophagic myofasciitis (MMF) histological reaction in humans. AlOOH-loaded macrophages exhibited phenotypical and functional modifications, as they expressed the classical markers of myeloid dendritic cells (HLA-DR(high)/CD86(high)/CD83(+)/CD1a(-)/CD14(-)) and displayed potent ability to induce MHC-II-restricted antigen specific memory responses, but kept a macrophage morphology. This suggests a key role of macrophages, in the reaction to AlOOH-adjuvanted vaccines and these mature antigen-presenting macrophages may therefore be of particular importance in the establishment of memory responses and in vaccination mechanisms leading to long-lasting protection. PMID:15297065

  19. Foam Cell Formation In Vivo Converts Macrophages to a Pro-Fibrotic Phenotype

    PubMed Central

    Thomas, Anita C.; Eijgelaar, Wouter J.; Daemen, Mat J. A. P.; Newby, Andrew C.

    2015-01-01

    Formation of foam cell macrophages, which sequester extracellular modified lipids, is a key event in atherosclerosis. How lipid loading affects macrophage phenotype is controversial, with evidence suggesting either pro- or anti-inflammatory consequences. To investigate this further, we compared the transcriptomes of foamy and non-foamy macrophages that accumulate in the subcutaneous granulomas of fed-fat ApoE null mice and normal chow fed wild-type mice in vivo. Consistent with previous studies, LXR/RXR pathway genes were significantly over-represented among the genes up-regulated in foam cell macrophages. Unexpectedly, the hepatic fibrosis pathway, associated with platelet derived growth factor and transforming growth factor-β action, was also over-represented. Several collagen polypeptides and proteoglycan core proteins as well as connective tissue growth factor and fibrosis-related FOS and JUN transcription factors were up-regulated in foam cell macrophages. Increased expression of several of these genes was confirmed at the protein level in foam cell macrophages from subcutaneous granulomas and in atherosclerotic plaques. Moreover, phosphorylation and nuclear translocation of SMAD2, which is downstream of several transforming growth factor-β family members, was also detected in foam cell macrophages. We conclude that foam cell formation in vivo leads to a pro-fibrotic macrophage phenotype, which could contribute to plaque stability, especially in early lesions that have few vascular smooth muscle cells. PMID:26197235

  20. Effects of Nanosized Lithium Carbonate Particles on the Functional Activity of Macrophages During Development of Hepatocarcinoma 29.

    PubMed

    Konenkov, V I; Borodin, Yu I; Makarova, O P; Bgatova, N P; Rachkovskaya, L N

    2015-08-01

    The functional activity of macrophages in response to injection of nanosized lithium carbonate particles after initiation of hepatocarcinoma 29 in male CBA mice was evaluated by the production of NO, arginase activity, and absorption of zymosan granules. In intact animals, NO production by peritoneal macrophages increased by 4 times and arginase activity 3.1 times in response to a single injection of nanosized particles into the hip muscle. The level of NO production by macrophages remained high after 4 and 5 injections, while arginase activity returned to normal. The level of phagocytic peritoneal macrophages increased by 1.4 times after 5 injections of the particles. The level of NO production by macrophages gradually increased in animals with hepatocarcinoma developing in the hip muscle: by 1.6 times on day 3, 3.2 times on day 7, and by 2.6 times on day 13 in comparison with the corresponding parameters in intact animals. The increase of NO production by peritoneal macrophages after tumor process initiation was not paralleled by changes in arginase activity and absorption of zymosan granules. The results indicated that injection of nanosized lithium carbonate particles after inoculation of hepatocarcinoma 29 cells in the right hip muscle tissue was inessential for the function of peritoneal macrophages by the studied parameters. PMID:26388569

  1. Neuron-macrophage crosstalk in the intestine: a “microglia” perspective

    PubMed Central

    Verheijden, Simon; Schepper, Sebastiaan De; Boeckxstaens, Guy E.

    2015-01-01

    Intestinal macrophages are strategically located in different layers of the intestine, including the mucosa, submucosa and muscularis externa, where they perform complex tasks to maintain intestinal homeostasis. As the gastrointestinal tract is continuously challenged by foreign antigens, macrophage activation should be tightly controlled to prevent chronic inflammation and tissue damage. Unraveling the precise cellular and molecular mechanisms underlying the tissue-specific control of macrophage activation is crucial to get more insight into intestinal immune regulation. Two recent reports provide unanticipated evidence that the enteric nervous system (ENS) acts as a critical regulator of macrophage function in the myenteric plexus. Both studies clearly illustrate that enteric neurons reciprocally interact with intestinal macrophages and are actively involved in shaping their phenotype. This concept has striking parallels with the central nervous system (CNS), where neuronal signals maintain microglia, the resident macrophages of the CNS, in a quiescent, anti-inflammatory state. This inevitably evokes the perception that the ENS and CNS share mechanisms of neuroimmune interaction. In line, intestinal macrophages, both in the muscularis externa and (sub)mucosa, express high levels of CX3CR1, a feature that was once believed to be unique for microglia. CX3CR1 is the sole receptor of fractalkine (CX3CL1), a factor mainly produced by neurons in the CNS to facilitate neuron-microglia communication. The striking parallels between resident macrophages of the brain and intestine might provide a promising new line of thought to get more insight into cellular and molecular mechanisms controlling macrophage activation in the gut. PMID:26528133

  2. Macrophages in Collateral Arteriogenesis

    PubMed Central

    Fung, Erik; Helisch, Armin

    2012-01-01

    Arteriosclerotic vascular disease is the most common cause of death and a major cause of disability in the developed world. Adverse outcomes of arteriosclerotic vascular disease are related to consequences of tissue ischemia and necrosis affecting the heart, brain, limbs, and other organs. Collateral artery growth or arteriogenesis occurs naturally and can help restore perfusion to ischemic tissues. Understanding the mechanisms of collateral artery growth may provide therapeutic options for patients with ischemic vascular disease. In this review, we examine the evidence for a role of monocytes and macrophages in collateral arteriogenesis. PMID:23055975

  3. Hedgehog and Resident Vascular Stem Cell Fate

    PubMed Central

    Mooney, Ciaran J.; Hakimjavadi, Roya; Fitzpatrick, Emma; Kennedy, Eimear; Walls, Dermot; Morrow, David; Redmond, Eileen M.; Cahill, Paul A.

    2015-01-01

    The Hedgehog pathway is a pivotal morphogenic driver during embryonic development and a key regulator of adult stem cell self-renewal. The discovery of resident multipotent vascular stem cells and adventitial progenitors within the vessel wall has transformed our understanding of the origin of medial and neointimal vascular smooth muscle cells (SMCs) during vessel repair in response to injury, lesion formation, and overall disease progression. This review highlights the importance of components of the Hh and Notch signalling pathways within the medial and adventitial regions of adult vessels, their recapitulation following vascular injury and disease progression, and their putative role in the maintenance and differentiation of resident vascular stem cells to vascular lineages from discrete niches within the vessel wall. PMID:26064136

  4. Teaching professionalism to residents.

    PubMed

    Klein, Eileen J; Jackson, J Craig; Kratz, Lyn; Marcuse, Edgar K; McPhillips, Heather A; Shugerman, Richard P; Watkins, Sandra; Stapleton, F Bruder

    2003-01-01

    The need to teach professionalism during residency has been affirmed by the Accreditation Council for Graduate Medical Education, which will require documentation of education and evaluation of professionalism by 2007. Recently the American Academy of Pediatrics has proposed the following components of professionalism be taught and measured: honesty/integrity, reliability/responsibility, respect for others, compassion/empathy, self-improvement, self-awareness/knowledge of limits, communication/collaboration, and altruism/advocacy. The authors describe a curriculum for introducing the above principles of professionalism into a pediatrics residency that could serve as a model for other programs. The curriculum is taught at an annual five-day retreat for interns, with 11 mandatory sessions devoted to addressing key professionalism issues. The authors also explain how the retreat is evaluated and how the retreat's topics are revisited during the residency, and discuss general issues of teaching and evaluating professionalism. PMID:12525406

  5. The Ron Receptor Tyrosine Kinase Regulates Macrophage Heterogeneity and Plays a Protective Role in Diet-Induced Obesity, Atherosclerosis, and Hepatosteatosis.

    PubMed

    Yu, Shan; Allen, Joselyn N; Dey, Adwitia; Zhang, Limin; Balandaram, Gayathri; Kennett, Mary J; Xia, Mingcan; Xiong, Na; Peters, Jeffrey M; Patterson, Andrew; Hankey-Giblin, Pamela A

    2016-07-01

    Obesity is a chronic inflammatory disease mediated in large part by the activation of inflammatory macrophages. This chronic inflammation underlies a whole host of diseases including atherosclerosis, hepatic steatosis, insulin resistance, type 2 diabetes, and cancer, among others. Macrophages are generally classified as either inflammatory or alternatively activated. Some tissue-resident macrophages are derived from yolk sac erythromyeloid progenitors and fetal liver progenitors that seed tissues during embryogenesis and have the ability to repopulate through local proliferation. These macrophages tend to be anti-inflammatory in nature and are generally involved in tissue remodeling, repair, and homeostasis. Alternatively, during chronic inflammation induced by obesity, bone marrow monocyte-derived macrophages are recruited to inflamed tissues, where they produce proinflammatory cytokines and exacerbate inflammation. The extent to which these two populations of macrophages are plastic in their phenotype remains controversial. We have demonstrated previously that the Ron receptor tyrosine kinase is expressed on tissue-resident macrophages, where it limits inflammatory macrophage activation and promotes a repair phenotype. In this study, we demonstrate that Ron is expressed in a subpopulation of macrophages during chronic inflammation induced by obesity that exhibit a repair phenotype as determined by the expression of arginase 1. In addition, we demonstrate that the Ron receptor plays a protective role in the progression of diet-induced obesity, hepatosteatosis, and atherosclerosis. These results suggest that altering macrophage heterogeneity in vivo could have the potential to alleviate obesity-associated diseases. PMID:27233965

  6. Phosphatase regulation of macrophage activation.

    PubMed

    Kozicky, Lisa K; Sly, Laura M

    2015-08-01

    Macrophages are innate immune cells that play critical roles in tissue homeostasis and the immune response to invading pathogens or tumor cells. A hallmark of macrophages is their "plasticity," that is, their ability to respond to cues in their local microenvironment and adapt their activation state or phenotype to mount an appropriate response. During the inflammatory response, macrophages may be required to mount a profound anti-bacterial or anti-tumor response, an anti-inflammatory response, an anti-parasitic response, or a wound healing response. To do so, macrophages express cell surface receptors for growth factors, chemokines and cytokines, as well pathogen and danger associated molecular patterns. Downstream of these cell surface receptors, cell signalling cascades are activated and deactivated by reversible and competing activities of lipid and protein kinases and phosphatases. While kinases drive the activation of cell signalling pathways critical for macrophage activation, the strength and duration of the signalling is regulated by phosphatases. Hence, gene knockout mouse models have revealed critical roles for lipid and protein phosphatases in macrophage activation. Herein, we describe our current understanding and the key roles of specific cellular phosphatases in the regulation of the quality of macrophage polarization as well as the quantity of cytokines produced by activated macrophages. PMID:26216598

  7. 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

  8. 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.

  9. 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…

  10. Role of cellular prion proteins in the function of macrophages and dendritic cells.

    PubMed

    Nitta, Kayako; Sakudo, Akikazu; Masuyama, Jun; Xue, Guangai; Sugiura, Katsuaki; Onodera, Takashi

    2009-01-01

    The cellular isoform of prion proteins (PrPC) is expressed in hematopoietic stem cells, granulocytes, T and B lymphocyte natural killer cells, platelets, monocytes, dendritic cells, and follicular dendritic cells, which may act as carrier cells for the spread of its abnormal isoform (PrPSc) before manifesting transmissible spongiform encephalopathies (TSEs). In particular, macrophages and dendritic cells seem to be involved in the replication of PrPSc after ingestion. In addition, information on the role of PrPC during phagocytotic activity in these cells has been obtained. A recent study showed that resident macrophages from ZrchI PrP gene (Prnp)-deficient (Prnp-/-) mice show augmented phagocytotic activity compared to Prnp+/+ counterparts. In contrast, our study suggests that Rikn Prnp-/- peritoneal macrophages show pseudopodium extension arrest and up-regulation of phagocytotic activity compared to Prnp+/+ cells. Although reports regarding phagocytotic activity in resident and peritoneal macrophages are inconsistent between ZrchI and Rikn Prnp-/- mice, it seems plausible that PrPC in macrophages could contribute to maintain the immunological environment. This review will introduce the recent progress in understanding the functions of PrPC in macrophages and dendritic cells under physiological conditions and its involvement in the pathogenesis of prion diseases. PMID:19275736