Role of CCR2-Positive Macrophages in Pathological Ventricular Remodelling

Abstract

Even with recent advances in care, heart failure remains a major cause of morbidity and mortality, which urgently needs new treatments. One of the major antecedents of heart failure is pathological ventricular remodelling, the abnormal change in the size, shape, function or composition of the cardiac ventricles in response to load or injury. Accumulating immune cell subpopulations contribute to the change in cardiac cellular composition that occurs during ventricular remodelling, and these immune cells can facilitate heart failure development. Among cardiac immune cell subpopulations, macrophages that are recognized by their transcriptional or cell-surface expression of the chemokine receptor C-C chemokine receptor type 2 (CCR2), have emerged as playing an especially important role in adverse remodelling. Here, we assimilate the literature that has been generated over the past two decades describing the pathological roles that CCR2⁺ macrophages play in ventricular remodelling. The goal is to facilitate research and innovation efforts in heart failure therapeutics by drawing attention to the importance of studying the manner by which CCR2⁺ macrophages mediate their deleterious effects.

Keywords: CCR2; heart failure; inflammation; macrophage; monocyte; myocardial infarction; pressure overload; single-cell RNA sequencing; ventricular remodelling.

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. The TIMD4 cluster and MHC-II cluster resident macrophages exert reparative functions to heal cardiac damage and help in tissue regeneration. The ISG cluster is also expanded after injury and its function and contribution to adverse cardiac remodelling is uncertain. The change in the number of cells from each cluster in the disease state indicates their increase or decrease with respect to the steady state. Abbreviations: TIMD4 = T cell immunoglobulin and mucin domain containing 4, CCR2 = C-C chemokine receptor type 2, MHC-II = major histocompatibility complex class II, ISG = interferon stimulated gene, Ly6C = lymphocyte antigen 6 complex, locus C1, Mφ = macrophage, CCL2 = C-C motif chemokine ligand 2, CC7 = C-C motif chemokine ligand 7.

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 proteins promoting arrhythmias and impairing contractility. Abbreviations: CCR2 = C-C chemokine receptor type 2, TGF-β = transforming growth factor beta, MMP14 = matrix metallopeptidase 14, PDGFR = platelet-derived growth factor receptor, TNF-α = tumour necrosis factor alpha, SERCA2a = sarco/endoplasmic reticulum Ca²⁺ adenosine triphosphatase-2a.