Hypoxia Sensing in Resident Cardiac Macrophages Regulates Monocyte-Derived Macrophage Fate Specification following Myocardial Infarction

Abstract

AbstractCardiac macrophages orchestrate inflammatory responses following myocardial injury and represent powerful determinants of cardiac tissue remodeling and outcomes. Following myocardial infarction, large numbers of monocytes are recruited to the heart, infiltrate into the myocardium, and differentiate into diverse populations of macrophages and dendritic cells with divergent inflammatory and reparative transcriptional signatures. The molecular mechanisms that drive monocyte fate decisions in the injured heart remained to be defined. Here, we tested the hypothesis that macrophage hypoxia sensing regulates monocyte differentiation and cardiac remodeling following myocardial infarction. Using a mouse model of ischemia reperfusion injury, we uncovered that deletion of the hypoxia sensor, Hif1a, in macrophages resulted in increased infarct size and accelerated adverse remodeling without impacting coronary angiogenesis. Single cell RNA sequencing revealed that loss of macrophage hypoxia sensing led to an overrepresentation of a subpopulation of monocyte-derived macrophages marked by Arginase 1 (Arg1) mRNA and protein expression. Trajectory and pathway enrichment analysis predicted that Arg1+ macrophages were derived from Ly6Chi monocytes and represented an early stage of macrophage differentiation and expressed genes associated with metabolism and inflammation. Conditional deletion of Hif1a in cardiac resident macrophages and not monocyte-derived macrophages resulted in increased Arg1+ macrophage abundance and was sufficient to increase infarct size and accelerate adverse remodeling. Collectively, these findings identify hypoxia sensing in resident cardiac macrophages as a non-cell autonomous mediator of monocyte fate specification and outcomes in the context of myocardial infarction.