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. Macrophages (Mps) play an essential role in both inflammatory and reparative phases within the ischemic myocardium and the balance between the two controls disease outcome. Cardiac macrophages populations are heterogenous and encompass embryonically-derived resident cardiac macrophages (RCM) and monocyte-derived macrophages (MDM). RCM possess strong immunomodulatory and reparative functions, largely due to their efferocytosis ability—phagocytosing dead cells to control inflammation and tissue remodeling. RCM are distinguished by high expression of efferocytosis receptors like VSIG4 (V-Set And Immunoglobulin Domain Containing 4) and TIMD4 (T-cell immunoglobulin and mucin domain containing 4). However, the molecular mechanisms linking efferocytosis, macrophage plasticity, and tissue repair remain unclear.

My project aims to investigate the role of VSIG4 and TIMD4 efferocytosis receptors in macrophage-dependent efferocytosis during cardiac repair.

Acute MI was induced by permanent ligation of the left anterior descending coronary artery in mice. Cardiac function and remodeling were assessed using echocardiography and immunohistochemistry. Macrophage efferocytosis and impact of efferocytosis on macrophage signaling pathways, secretion and reprogramming is investigated in primary macrophages.

Using single cell RNA sequencing, we revealed that VSIG4 characterized a specific subset of RCM in the cardiac tissue (Fig. 1). VSIG4 deficiency worsen post-ischemic cardiac function and remodeling, which is rescued when VSIG4+ RCM are reintroduced by intramyocardial injection (Fig. 2). In vitro, VSIG4 and TIMD4 receptors not only seem to confer Mps with increased dead cell binding capacity but also evoke the AKT and AMPK pathways and trigger the secretion of soluble factors (Fig. 3).

In conclusion, our data suggest that TIMD4+ VSIG4+ RMCs are key regulators of post-ischemic cardiac healing, probably through their enhanced efferocytosis capacity but also the contribution of their regulated efferocytosis-stimulated cytokine secretion.