Alterations of CCR2 and CX3CR1 on Three Monocyte Subsets During HIV-1/Treponema pallidum Coinfection
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HIV-1/Treponema pallidum (T. pallidum) coinfection has become a global challenge, and three monocyte subsets express varying levels of the chemokine receptors CCR2 and CX3CR1. We recently evaluated the association between monocyte subsets and regulatory T cells in HIV-infected individuals with syphilis. Currently, the dynamic changes of CCR2 and CX3CR1 on monocyte subsets during HIV-1 and syphilis coinfection have not been fully investigated. In this study, cell surface staining was used to explore CCR2 and CX3CR1 expression on three monocyte subsets during HIV-1/T. pallidum coinfection. We found that CCR2 densities on the classical monocyte subsets decreased in acute HIV-1 infected (AHI) patients, chronic HIV-1-infected individuals without antiviral therapy (ART) (CHI+ART-), chronic HIV-1-infected individuals receiving ART (CHI+ART+), rapid plasma reagin-positive (RPR+) individuals, CHI+ART- plus RPR+ (CHI+RPR+ART-) individuals, and CHI+ART+ plus RPR+ (CHI+RPR+ART+) individuals. CX3CR1 density increased on the three monocyte subsets during HIV-1 and/or T. pallidum infection. CX3CR1 density on the intermediate and nonclassical monocyte subsets in CHI+ART- individuals was lower than that in CHI+ART+ individuals, and CX3CR1 density on the three monocyte subsets in CHI+ART+ individuals was higher than that in CHI+RPR+ART+ individuals. Our data provide new insight into the roles of CCR2 and CX3CR1 on three monocyte subsets in HIV-1 and T. pallidum pathogenesis.Keywords:
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Monocytes are central mediators in the advance of atherosclerotic plaque, making them a natural therapeutic target for reducing disease burden. Here, we highlight recent advances in our current understanding of monocyte heterogeneity and its relevance to regulation of monocyte accumulation and function within atherosclerotic plaques. Differences that distinguish monocyte subsets include differential expression of chemokine receptors, especially CCR2 and CX3CR1. Ablation of expression of these 2 receptors (or their ligands) in mice has an additive inhibition on monocyte recruitment to atherosclerotic plaques. Moreover, simultaneously interfering with 3 key pathways—CCR2, CX3CR1, and CCR5—essentially abolishes atherosclerosis in mice. Here, we discuss how these chemokine receptors act at multiple points on at least 1 monocyte subset, regulating their mobilization from bone marrow, survival, or recruitment to plaques. Finally, we discuss how this knowledge may be useful clinically, emphasizing that CX3CR1 may in particular be a viable target for therapeutic manipulation of monocyte-derived cell fate in cardiovascular disease.
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Abstract Background Brain white matter (WM) malfunction is deeply involved in many neurological and psychiatric disorders, and may lead to problems with cognition. Neuroinflammation occurs in the majority of WM injuries regardless of pathogenesis. Adverse effects of neuroinflammation on neurophysiological properties of the WM tracts has been observed before. The fractalkine (CX3CL1) and monocyte chemoattractant protein-1 (CCL2) and their respective receptors, CX3CR1 and CCR2, play important roles in immune cell infiltration and microglia activation. Whether the CX3CL1 or CCL2 and their receptors associated neuroinflammation would change neurophysiological property of the WM tract remains unknown. Methods In this work, we used a common leukocyte marker CD45 to explore the extent to which the circulating immune cells were recruited into the corpus callosum (CC) WM, and the CC microglia were activated, reflected by proportional area, in the CCR2 +/+ CX3CR1 −/− or CX3CR1 +/+ CCR2 −/− mouse following systemic lipopolysaccharide (LPS). Then, electrophysiological recording of WM tract compound action potentials (CAP) was performed in normal and LPS treated CCR2 +/+ CX3CR1 −/− or CX3CR1 +/+ CCR2 −/− mouse. Results 1) Nearly significant more infiltrated circulating immune cells were found in the CC of CX3CR1 +/+ CCR2 −/− mouse following systemic LPS. 2) Significant larger microglial proportional area was identified, after endotoxemia, in the CC of CX3CR1 +/+ CCR2 −/− mouse, comparing to that in the CCR2 +/+ CX3CR1 −/− mouse. 3) Absence of either CX3CR1 or CCR2 reduced the density of microglia in the normal CC WM. 4) Endotoxemia induced a nearly significant downshift of N1 (myelinated axon) input-output curve, and a slight downshift of N2 (unmyelinated axon) input-output curve recorded from the CC of CX3CR1 +/+ CCR2 −/− mouse, which was not detected in the CCR2 +/+ CX3CR1 −/− mouse. Conclusions CX3CR1 plays more significant roles in guiding infiltration of circulating immune cells into the CC WM, and in activation of CC microglia following systemic LPS. Consequently, CX3CR1 mediated inflammation evidently declines the WM tract conductivity during endotoxemia. A possibility that endotoxin-mediated microglial pseudopodia distortion may impact WM tract signal transmission was discussed, as we had demonstrated microglial pseudopodia directly contact with Ranvier’s node and paranodal segment. We thought inflammation-mediated declination of WM tract conductivity may interrupt brain network connectivity and lead to cognitive problems.
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Monocytes participate critically in atherosclerosis. There are 2 major subsets expressing different chemokine receptor patterns: CCR2+CX3CR1+Ly-6Chi and CCR2–CX3CR1++Ly-6Clo monocytes. Both C-C motif chemokine receptor 2 (CCR2) and C-X3-C motif chemokine receptor 1 (CX3CR1) are linked to progression of atherosclerotic plaques. Here, we analyzed mouse monocyte subsets in apoE-deficient mice and traced their differentiation and chemokine receptor usage as they accumulated within atherosclerotic plaques. Blood monocyte counts were elevated in apoE–/– mice and skewed toward an increased frequency of CCR2+Ly-6Chi monocytes in apoE–/– mice fed a high-fat diet. CCR2+Ly-6Chi monocytes efficiently accumulated in plaques, whereas CCR2–Ly-6Clo monocytes entered less frequently but were more prone to developing into plaque cells expressing the dendritic cell–associated marker CD11c, indicating that phagocyte heterogeneity in plaques is linked to distinct types of entering monocytes. CCR2– monocytes did not rely on CX3CR1 to enter plaques. Instead, they were partially dependent upon CCR5, which they selectively upregulated in apoE–/– mice. By comparison, CCR2+Ly-6Chi monocytes unexpectedly required CX3CR1 in addition to CCR2 and CCR5 to accumulate within plaques. In many other inflammatory settings, these monocytes utilize CCR2, but not CX3CR1, for trafficking. Thus, antagonizing CX3CR1 may be effective therapeutically in ameliorating CCR2+ monocyte recruitment to plaques without impairing their CCR2-dependent responses to inflammation overall.
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Abstract Background We investigated the expression of chemokine receptors CCR2 (C‐C chemokine receptor) 2 and CX3CR1 (C‐X3‐C receptor 1) on circulating monocyte subsets in patients with neovascular age‐related macular degeneration (AMD) and patients with polypoidal choroidal vasculopathy (PCV). Methods We recruited patients with neovascular AMD, patients with PCV and age‐matched healthy controls for this prospective case–control study. All participants underwent comprehensive clinical examination and imaging. Freshly sampled venous blood was prepared for flow cytometry, where we determined the proportion of CCR2 + ‐ and CX3CR1 + ‐positive cells in monocyte subsets identified using monocyte identification and subgrouping surface markers CD14, CD16 and HLA‐DR. Results Patients with neovascular AMD had significantly increased proportion of CCR2 + and CX3CR1 + non‐classical monocytes. PCV type 1 was associated with significantly increased CCR2 + and CX3CR1 + in all monocyte subsets when compared to PCV type 2. Conclusions Neovascular AMD is associated with increased expression of angiogenesis‐associated chemokine receptors in the pro‐inflammatory non‐classical monocytes. PCV differs from neovascular AMD immunologically and show immunological heterogeneity across angiographic subtypes.
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Monocyte subpopulations distinguished by differential expression of chemokine receptors CCR2 and CX3CR1 are difficult to track in vivo, partly due to lack of CCR2 reagents.We created CCR2-red fluorescent protein (RFP) knock-in mice and crossed them with CX3CR1-GFP mice to investigate monocyte subset trafficking. In mice with experimental autoimmune encephalomyelitis, CCR2 was critical for efficient intrathecal accumulation and localization of Ly6C(hi)/CCR2(hi) monocytes. Surprisingly, neutrophils, not Ly6C(lo) monocytes, largely replaced Ly6C(hi) cells in the central nervous system of these mice. CCR2-RFP expression allowed the first unequivocal distinction between infiltrating monocytes/macrophages from resident microglia.These results refine the concept of monocyte subsets, provide mechanistic insight about monocyte entry into the central nervous system, and present a novel model for imaging and quantifying inflammatory myeloid populations.
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The chemokine receptors CCR2 and CX3CR1 are important in the development of coronary artery disease. The purpose of this study is to analyze the effect of a novel CCR2 inhibitor in conjunction with CX3CR1 deletion on vascular inflammation.The novel CCR2 antagonist MRL-677 was characterized using an in vivo model of monocyte migration. To determine the relative roles of CCR2 and CX3CR1 in vascular remodeling, normal or CX3CR1 deficient mice were treated with MRL-677. After 14 days, the level of intimal hyperplasia in the artery was visualized by paraffin sectioning and histology of the hind limbs.MRL-677 is a CCR2 antagonist that is effective in blocking macrophage trafficking in a peritoneal thioglycollate model. Intimal hyperplasia resulting from vascular injury was also assessed in mice. Based on the whole-blood potency of MRL-677, sufficient drug levels were maintained for the entire 14 day experimental period to afford good coverage of mCCR2 with MRL-677. Blocking CCR2 with MRL-677 resulted in a 56% decrease in the vascular injury response (n = 9, p < 0.05) in normal animals. Mice in which both CCR2 and CX3CR1 pathways were targeted (CX3CR1 KO mice given MRL-677) had an 88% decrease in the injury response (n = 6, p = 0.009).In this study we have shown that blocking CCR2 with a low molecular weight antagonist ameliorates the inflammatory response to vascular injury. The protective effect of CCR2 blockade is increased in the presence of CX3CR1 deficiency suggesting that CX3CR1 and CCR2 have non-redundant functions in the progression of vascular inflammation.
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Abstract Chemokine receptor/ligand interactions orchestrate the migration of cells to peripheral tissues such as the skin. We analysed chemokine receptor expression by acute myeloid leukaemic (AML) cells present in peripheral blood (n = 7), bone marrow (n = 6), or skin (n = 11) obtained from 15 paediatric AML patients with skin involvement and in 10 AML patients without skin involvement. High percentages of circulating CCR2 pos AML cells were only detected in patients with extramedullary disease. Skin‐residing AML cells displayed a different set of receptors in situ, namely: CCR5, CXCR4, CXCR7 and CX3CR1. These results suggest the involvement of different chemokine/chemokine receptor interactions in homing and retention of AML blasts in the skin. Pediatr Blood Cancer. 2010;55:344–348. © 2010 Wiley–Liss, Inc.
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Abstract Chemokines and their receptors play an essential role within the immune system by dictating cellular migration. In vivo , receptor–ligand interactions rarely occur in isolation as cellular recruitment and migration are complex and highly coordinated processes often involving networks of multiple chemokines and multiple receptors. Simultaneous detection of multiple chemokine receptors on the single cell level is necessary to allow immunophenotyping studies that will help understand the intricacies of these networks. Chemokine receptors undergo a basal level of ongoing internalization, intracellular trafficking, and recycling back to the cell surface, even in the absence of the ligand. In the presence of ligand, receptor–ligand interactions enhance receptor internalization, reducing the cell surface receptor concentration, making precise determination of intrinsic levels challenging. Using multicolor flow cytometry, we sought to evaluate and optimize the simultaneous detection of cell surface expression levels of CCR2, CX3CR1, and CCR5 in primary human monocytes using a single antibody panel. We observed that staining for CCR2 alone or for CX3CR1 alone showed greater expression levels than when the cells were stained with the full panel of antibodies. Fluorescent‐minus‐one (FMO) controls revealed that ligation of the CCR5 monoclonal antibody to the receptor interfered with detection of CX3CR1 and CCR2. Sequential addition of antibodies during the staining procedure was sufficient to restore the detection levels, suggesting close proximity and possible functional interactions between CCR2/CCR5 and CX3CR1/CCR5 in monocytes. This study highlights the importance of optimizing staining procedures and using proper controls when simultaneously evaluating expression levels of multiple chemokine receptors by flow cytometry. Concurrent assessment of multiple receptors will provide insight and greater understanding of the complex interactions involved in cellular migration. © 2013 International Society for Advancement of Cytometry
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