The cardiac microenvironment uses non‐canonical WNT signaling to activate monocytes after myocardial infarction

A disturbed inflammatory response following myocardial infarction (MI) is associated with poor prognosis and increased tissue damage. Monocytes are key players in healing after MI, but little is known about the role of the cardiac niche in monocyte activation. This study investigated microenvironment‐dependent changes in inflammatory monocytes after MI. RNA sequencing analysis of murine Ly6C(high) monocytes on day 3 after MI revealed differential regulation depending on location. Notably, the local environment strongly impacted components of the WNT signaling cascade. Analysis of WNT modulators revealed a strong upregulation of WNT Inhibitory Factor 1 (WIF1) in cardiomyocytes—but not fibroblasts or endothelial cells—upon hypoxia. Compared to wild‐type (WT) littermates, WIF1 knockout mice showed severe adverse remodeling marked by increased scar size and reduced ejection fraction 4 weeks after MI. While FACS analysis on day 1 after MI revealed no differences in neutrophil numbers, the hearts of WIF1 knockouts contained significantly more inflammatory monocytes than hearts from WT animals. Next, we induced AAV‐mediated cardiomyocyte‐specific WIF1 overexpression, which attenuated the monocyte response and improved cardiac function after MI, as compared to control‐AAV‐treated animals. Finally, WIF1 overexpression in isolated cardiomyocytes limited the activation of non‐canonical WNT signaling and led to reduced IL‐1β and IL‐6 expression in monocytes/macrophages. Taken together, we investigated the cardiac microenvironment's interaction with recruited monocytes after MI and identified a novel mechanism of monocyte activation. The local initiation of non‐canonical WNT signaling shifts the accumulating myeloid cells toward a pro‐inflammatory state and impacts healing after myocardial infarction.