VSIG4+ resident tissue macrophages govern cardiac remodeling and function after acute myocardial infarction in mice

Abstract Background/Introduction After acute myocardial infarction (AMI), the massive loss of cardiomyocytes triggers an intense inflammatory response and a progressive adverse remodeling eventually leading to heart failure. Although inflammation is a major determinant of cardiac repair and function in the infarcted heart, it directly fuels pathological remodeling when unchecked. Resident tissue macrophages (RTM) are essential cellular hubs regulating cardiac homeostasis beyond their classical immune surveillance functions. Their beneficial function relies notably on efferocytosis, i.e, the phagocytosis of apoptotic cells, an essential mechanism for RTM to control inflammation and tissue remodeling. Purpose Using Single Cell RNA Sequencing, we identified a new subpopulation of cardiac RTM characterized by the expression of VSIG4 (B7 family-related protein V-set and Ig domain-containing 4), a complement receptor involved in phagocytosis of pathogens and dead cells. In this work, we hypothesized that VSIG4+ RTM display protective function in the infarcted heart and aimed to investigate the molecular mechanisms, potentially mediated by efferocytosis, in the context of cardiac repair. Methods Using a model of experimental myocardial infarction by the permanent ligation of the left descending coronary artery in mice genetically invalidated for VSIG4, we investigated the role of this receptor on post-ischemic cardiac remodeling and function. Cardiac function was assessed by echocardiography while remodeling was evaluated by immunohistochemistry for infarct size, interstitial fibrosis and capillary density. Macrophage efferocytosis and impact of efferocytosis on macrophage signaling pathways, secretion and reprogramming was investigated in primary macrophages. Results VSIG4 deficiency worsen post-ischemic cardiac function and remodeling at day 14 and 28 after the onset of ischemia when compared to their wild-type littermates. Echocardiography-based transthoracic injection of FACS-sorted VSIG4+ macrophages into infarcted hearts 2 weeks post-AMI, improved cardiac function in Vsig4-/- mice underlying the protective role of VSIG4+ RTM in this pathological setting. Conversely, injection of Vsig4-/- macrophages impaired cardiac function in WT animals. VSIG4 deficiency is associated with higher number of neutrophils, inflammatory monocytes and macrophages. In cultured peritoneal macrophages, a prototypical example of RTM, VSIG4 receptor not only seems to confer macrophage with increased dead cell binding capacity but also evoke the AKT pathway and trigger the secretion of soluble factors in response to efferocytosis. Conclusions Our data suggest that VSIG4+ RTMs are key regulators of post-ischemic cardiac healing, likely through their ability to hamper inflammation through their enhanced efferocytosis capacity but also the contribution of their regulated efferocytosis-stimulated cytokine secretion.