Role of CCR2-Positive Macrophages in Pathological Ventricular Remodelling

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  Figure 1. Illustrating the contemporary perspective on cardiac macrophage heterogeneity under steady state and disease condition, based on findings published and discussed in [43,46]. By single-cell RNA sequencing, under steady-state conditions, the healthy adult mouse heart contains four clusters of cardiac macrophages (TIMD4, MHC-II, CCR2 and ISG clusters). Both TIMD4 and MHC-II clusters are maintained by in situ, proliferation-based self-renewal. The CCR2 cluster is derived from circulating monocytes. The ISG cluster is derived and maintained by the CCR2 cluster rather than directly from monocytes. Some Ly6Chi monocytes that enter the tissue remain as “tissue monocytes” without converting to macrophages or dendritic cells. Under disease conditions, large numbers of circulating monocytes infiltrate the myocardium under the influence of chemokines secreted from tissue resident CCR2+ macrophages and other cells. CCR2+ infiltrating macrophages derived from circulating monocytes acquire different transcriptional active states and contribute to adverse cardiac remodelling changes. Some recruited macrophages may acquire states that help in the resolution of inflammation and repair of tissue.…

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  Figure 2. Summarizing some of the reported effects of CCR2+ macrophages on other cardiac cell-types. CCR2+ macrophages can activate T-cell-mediated immune responses through cardiac antigen presentation. The multiple cytokines secreted by CCR2+ cells can also cause cardiac inflammation. CCR2+ macrophages can also induce cardiac fibrosis and myofibroblast activation through the secretion of TGF-β and osteopontin. They can also induce fibroblast-mediated IL-6 secretion and autocrine activation of fibroblast proliferation. Other reports have suggested that proinflammatory macrophages can have opposing effects on fibroblasts, for instance, through oncostatin-M-mediated inhibition of myofibroblast activation or through the inhibition of fibroblast proliferation by miR-155-containing exosomes. CCR2+ macrophages inhibit endothelial tube formation. They have also been reported to promote endothelial mesenchymal transition through MMP14-mediated release of TGF-β from latent complex. Exosomes released by macrophages containing miR-155 can promote hypertrophy and pyroptosis of cardiomyocytes. Proinflammatory cytokines released by macrophages can also inhibit Ca2+ dynamics and affect contractile…