Role of tissue resident VSIG4+ macrophages in cardiac remodeling after acute myocardial infarction in mice

Abstract

Adaptive and innate immune cells have been shown to govern cardiac injury and remodeling following acute myocardial infarction (AMI). A detailed understanding of the interactions between inflammation and the structural and functional alterations of the infarcted heart could pave the way for the development of innovative therapeutic strategies. In the infarcted heart, macrophages constitute a heterogeneous population including monocyte-derived macrophages (MDM) emerging from splenic and medullary reservoirs and tissue-resident macrophages (TRM). MDM rather exert pro-inflammatory deleterious effects whereas TRM are more likely to perform anti-inflammatory protective functions in the infarcted heart. Using single cell RNA sequencing, we revealed that VSIG4 (B7 family-related protein V-set and Ig domain-containing 4) characterized a specific subset of TRM in the cardiac tissue. In the present work, we therefore aim to evaluate the role of VSIG4 + TRM after AMI. 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. Vsig4 depletion impaired cardiac function and promoted adverse cardiac remodeling after experimental AMI in mice. WT mice, transplanted with bone marrow (BM) derived cells isolated from Vsig4-deficient mice (Vsig4-/-) or WT mice, exhibited comparable cardiac function and remodeling after AMI. Conversely, Vsig4 deficient mice transplanted with WT BM-derived cells, displayed worse cardiac function and adverse ventricular remodeling after AMI, when compared to WT mice re-supplemented with WT BM-derived cells. Moreover, FACS-sorted Vsig4+ macrophages injected into infarcted hearts 2 weeks post-AMI, improved cardiac function in both WT and Vsig4-/- mice, supporting the beneficial role of VSIG4+ TRM in the context of AMI. We have also demonstrated that IL4 and IL13, through IL4 receptor alpha and IL13 receptor alpha1, fostered Vsig4 expression in peritoneal macrophages (PEM), a prototypical example of TRM. Meanwhile, IL4 and IL13 elicited the release of CCL3, CCL4 and CCL5, chemokine ligands of CCR5, in cultured WT PEM but not in Vsig4-deficient PEM. Moreover, induction of AMI in Vsig4-/- mice hampered the number of CCR5+ regulatory T lymphocytes in infarcted hearts. VSIG4+ TRM are key regulators of cardiac healing after AMI likely through their ability to foster the infiltration of anti-inflammatory regulatory T cells in the infarcted heart.