CD200 Limits Monopoiesis and Monocyte Recruitment in Atherosclerosis (original) (raw)
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CD100 Effects in Macrophages and Its Roles in Atherosclerosis
Frontiers in Cardiovascular Medicine
CD100 or Sema4D is a protein from the semaphorin family with important roles in the vascular, nervous and immune systems. It may be found as a membrane bound dimer or as a soluble molecule originated by proteolytic cleavage. Produced by the majority of hematopoietic cells including B and T lymphocytes, natural killer and myeloid cells, as well as endothelial cells, CD100 exerts its actions by binding to different receptors depending on the cell type and on the organism. Cell-to-cell adhesion, angiogenesis, phagocytosis, T cell priming, and antibody production are examples of the many functions of this molecule. Of note, high CD100 serum levels has been found in inflammatory as well as in infectious diseases, but the roles of the protein in the pathogenesis of these diseases has still to be clarified. Macrophages are highly heterogeneous cells present in almost all tissues, which may change their functions in response to microenvironmental conditions. They are key players in the innate and adaptive immune responses and have decisive roles in sterile conditions but also in several diseases such as atherosclerosis, autoimmunity, tumorigenesis, and antitumor responses, among others. Although it is known that macrophages express CD100 and its receptors, few studies have focused on the role of this semaphorin in this cell type or in macrophage-associated diseases. The aim of this review is to critically revise the available data about CD100 and atherosclerosis, with special emphasis on its roles in macrophages and monocytes. We will also describe the few available data on treatments with anti-CD100 antibodies in different diseases. We hope that this review stimulates future studies on the effects of such an important molecule in a cell type with decisive roles in inflammatory diseases such as atherosclerosis.
Vascular smooth muscle cells (VSMCs) play a central role in the development of atherosclerosis due in part to their capability to phenotypically transition into either a protective or harmful state. However, the ability to identify and trace VSMCs and their progeny in vivo is limited due to the lack of well-defined VSMC cell surface markers. Therefore, investigations into VSMC fate must utilize lineage-tracing mouse models, which are time-consuming and challenging to generate and not feasible in humans. Here, we employed CITE-seq to characterize the phenotypic expression of 119 cell surface proteins in mouse atherosclerosis. We found that CD200 is a highly expressed and specific marker of VSMCs, which persists even with phenotypic modulation. We validated our findings using a combination of flow cytometry, qPCR, and immunohistochemistry, all confirming that CD200 can identify and mark VSMCs and their derived cells in early to advanced mouse atherosclerotic lesions. Additionally, we ...
Transplantation, 2007
Background. CD200:CD200R interactions deliver immunoregulatory signals. A family of CD200Rs (CD200R1-5) has been described, and engagement of CD200R1 by its ligand CD200 suppresses LPS-induced macrophage cytokine production, decreases alloimmune responses in vivo and in vitro, and suppresses collagen-induced arthritis. Methods. We generated C57BL/6 mice lacking the genomic exons encoding the extracellular domains of the CD200R1 molecule using transformation of ES cells and explored cell subtypes and immune responses in these mice. Results. Myeloid cells/splenocytes from CD200R1 Ϫ/Ϫ mice were not stained in FACS by anti-CD200R1 mAb. Stimulation of splenic tumor necrosis factor-␣ production by lipopolysaccharide was enhanced relative to control (ϩ/ϩ) mice and was not suppressed by addition of exogenous CD200Fc. Modulation of alloreactivity in mixed leukocyte cultures by CD200Fc depended upon CD200R1 ϩ stimulatory cells, although maximal immunoregulation by CD200Fc occurred only when CD200R1 ϩ T responder cells also were used. CD200Fc failed to suppress graft rejection in CD200R1 Ϫ/Ϫ mice. Conclusion. CD200:CD200R1 plays an immunoregulatory role in vivo.
American Society for Investigative Pathology, 2020
Macrophage-derived foam cells in developing athero-sclerotic lesions may potentially originate either from recruitment of circulating monocytes or from migration of resident tissue macrophages. In this study , we have determined the source of intimal macrophages in the apoE-knockout mouse flow-cessation/hyper-cholesterolemia model of atherosclerosis using a bone marrow transplantation approach. We also examined the time course and spatial distribution of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 expression to assess whether endothelial adhesion molecules were involved in recruitment of either circulating monocytes or resident macrophages. We used allelic variants of the mouse common leukocyte antigen (CD45) to distinguish host-derived and donor-derived white blood cells (WBCs) both in blood and in macrophage-rich carotid lesions. We found that the distribution of CD45 iso-forms in lesions is similar to that of circulating WBCs , whereas the host-type CD45 isoform is more prevalent in resident adventitial macrophages. These data indicate that macrophage-derived foam cells in the lesion derive mainly from circulating precursors rather than from resident macrophages. The corresponding time course of intercellular adhesion molecule -1 and vascular cell adhesion molecule-1 expression suggests that recruitment of circulating WBCs by endothelial adhesion molecules is likely to be more important during lesion initiation than during the later phase of rapid lesion growth. (Am J Pathol 2002, 160:2145-2155) Both in experimental models of atherosclerosis and in human disease, infiltration of macrophages into the arterial intima constitutes one of the earliest cellular events in the development of atherosclerotic lesions. 1-3 Macro-phages in the lesion may be derived either from cells already resident in the arterial wall 4 or from circulating monocytes that have undergone diapedesis. Because the mechanisms of cellular recruitment and/or activation are likely to differ depending on the source of the inflam-matory cells, determining the relative contribution to le-sion growth of cells from these two sources may have important implications in devising successful strategies to slow the growth of lesions. Although much convincing evidence demonstrates the importance of blood-borne monocytes in early lesion development , 1,5,6 the potential contribution of resident mac-rophages has been more difficult to assess. Experiments involving injection of labeled tracer monocytes can provide estimates for the rate of recruitment of circulating inflammatory cells but do not directly address the issue of mobilization of macrophages already present in arterial tissue. Moreover, alterations in adhesion molecule expression that can occur during monocyte isolation and labeling may modify the interaction between circulating monocytes and the vascular wall. The recent development of a polymerase chain reaction-based method of quantifying monocyte recruitment has shown promise of improved sensitivity and ease of quantitation compared to more traditional approaches such as labeling injected cells with radioisotopes or with fluorescent dyes, 6 but this method has not yet been adapted to the purpose of measuring resident macrophage recruitment. A recent study in which adventitial macrophages were fluorescently labeled in vivo by direct application of a dye solution provided evidence of a possible role for adventitial macrophage recruitment in the development of porcine coronary lesions. 4 In the present work, we have developed a novel approach to assess the relative contribution of resident versus circulating inflammatory cells to the development of macrophage-rich arterial lesions in the apoE knockout (KO) mouse using bone marrow transplantation (BMT). We have taken advantage of naturally occurring allelic variants of the mouse common leukocyte antigen (CD45 or Ptprc) to distinguish between host-and donor-derived
The CD200-CD200 Receptor Inhibitory Axis Controls Arteriogenesis and Local T Lymphocyte Influx
PLoS ONE, 2014
The role of the CD200 ligand-CD200 receptor (CD200-CD200R) inhibitory axis is highly important in controlling myeloid cell function. Since the activation of myeloid cells is crucial in arteriogenesis, we hypothesized that disruption of the CD200-CD200R axis promotes arteriogenesis in a murine hindlimb ischemia model. Female Cd200 2/2 and wildtype (C57Bl/6J) mice underwent unilateral femoral artery ligation. Perfusion recovery was monitored over 7 days using Laser-Doppler analysis and was increased in Cd200 2/2 mice at day 3 and 7 after femoral artery ligation, compared to wildtype. Histology was performed on hindlimb muscles at baseline, day 3 and 7 to assess vessel geometry and number and inflammatory cell influx. Vessel geometry in non-ischemic muscles was larger, and vessel numbers in ischemic muscles were increased in Cd200 2/2 mice compared to wildtype. Furthermore, T lymphocyte influx was increased in Cd200 2/2 compared to wildtype. CD200R agonist treatment was performed in male C57Bl/6J mice to validate the role of the CD200-CD200R axis in arteriogenesis. CD200R agonist treatment after unilateral femoral artery ligation resulted in a significant decrease in vessel geometry, perfusion recovery and T lymphocyte influx at day 7 compared to isotype treatment. In this study, we show a causal role for the CD200-CD200R inhibitory axis in arteriogenesis in a murine hindlimb ischemia model. Lack of CD200R signaling is accompanied by increased T lymphocyte recruitment to the collateral vasculature and results in enlargement of preexisting collateral arteries.
CD36 and macrophages in atherosclerosis
Cardiovascular Research, 2007
CD36 is a multi-ligand scavenger receptor present on the surface of a number of cells such as platelets, monocytes/macrophages, endothelial and smooth muscle cells. Monocyte/macrophage CD36 has been shown to play a critical role in the development of atherosclerotic lesions by its capacity to bind and endocytose oxidized low density lipoproteins (OxLDL), and it is implicated in the formation of foam cells. However, the significance of CD36 in atherosclerosis has recently been called into question by different studies, and therefore its exact role still needs to be clarified. The aim of this article is to carefully review the importance of CD36 as an essential component in the pathogenesis of atherosclerosis.
Arteriosclerosis, thrombosis, and vascular biology, 2016
To create a model of atherosclerosis using green fluorescent protein (GFP)-targeted monocytes/macrophages, allowing analysis of both endogenous GFP(+) and adoptively transferred GFP(+) myeloid cells in arterial inflammation. APPROACH AND RESULTS: hCD68GFP reporter mice were crossed with ApoE(-/-) mice. Expression of GFP was localized to macrophages in atherosclerotic plaques and in angiotensin II-induced aortic aneurysms and correlated with galectin 3 and mCD68 expression. Flow cytometry confirmed GFP(+) expression in CD11b(+)/CD64(+), CD11c(+)/MHC-II(HI), and CD11b(+)/F4/80(+) myeloid cells. Adoptive transfer of GFP(+) monocytes demonstrated monocyte recruitment to both adventitia and atherosclerotic plaque, throughout the aortic root, within 72 hours. We demonstrated the biological utility of hCD68GFP monocytes by comparing the recruitment of wild-type and CCR2(-/-) monocytes to sites of inflammation. hCD68GFP/ApoE(-/-) mice provide a new approach to study macrophage accumulation ...
European Journal of Immunology, 2011
Accumulating evidence supports the notion that defective phagocytic clearance of dying cells, or defective "efferocytosis," is causally linked to the progression of advanced atherosclerosis. In advanced atherosclerotic lesions, defective efferocytosis leads to post-apoptotic necrosis, expansion of plaque necrotic cores, and susceptibility to atherothrombosis. Both macrophages and DC-like efferocytes are juxtaposed near expanding necrotic cores, where they engage apoptotic cells. In this Viewpoint, we discuss how reduced efferocytosis by macrophages and CD11c HI DClike cells may combine to reduce overall plaque stability and therefore promote susceptibility to acute atherothrombosis.
R Innate immunity and monocyte-macrophage activation in atherosclerosis
Innate inflammation is a hallmark of both experimental and human atherosclerosis. The predominant innate immune cell in the atherosclerotic plaque is the monocyte-macrophage. The behaviour of this cell type within the plaque is heterogeneous and depends on the recruitment of diverse monocyte subsets. Furthermore, the plaque microenvironment offers polarisation and activation signals which impact on phenotype. Microenvironmental signals are sensed through pattern recognition receptors, including toll-like and NOD-like receptors thus dictating macrophage behaviour and outcome in atherosclerosis. Recently cholesterol crystals and modified lipoproteins have been recognised as able to directly engage these pattern recognition receptors. The convergent role of such pathways in terms of macrophage activation is discussed in this review.