Abstract 581: Divergent Roles for Mertk and Axl in Resident Vs Recruited Phagocytes After Reperfusion of Ischemic Hearts

Abstract

Objective: Following myocardial infarction (MI), recruited and resident phagocytes are mobilized at the heart to promote clearance of dying myocardial cells by efferocytosis. This occurs in part through the actions of the macrophage receptor tyrosine kinases, Tyro 3, Axl, and Mertk (TAM), although potential differential contributions of TAMs on recruited vs resident phagocytes, as well as the contribution to clinically-relevant reperfusion, are unknown. We set out to test the significance of recruited vs resident Mertk + phagocytes during ischemia/reperfusion (I/R) and in comparison to Axl + phagocytes. Methods and Results: In contrast to MI, I/R resulted in elevated inflammation and early loss of Mertk on phagocytes in the infarcted tissue with a concomitant increase in serum levels of soluble Mertk in both mice and humans. In mice, Mertk-deficiency during I/R led to decreased cardiac efferocytosis, increased infarct size, and depressed cardiac contractility, newly revealing the importance of efferocytosis during clinically-relevant reperfusion. These endpoints were similarly affected after blocking blood-borne recruited monocytes with CCR2 antagonists, thereby specifically implicating resident Mertk + phagocytes to cardiac repair. We observed the highest expression of Mertk on Ly6C lo MHCII lo cardiac resident macrophages, which resulted in increased efferocytosis-efficiency by these cells compared to other cardiac phagocytes. Shedding of Mertk from Ly6C lo MHCII lo cardiac resident macrophages was observed after I/R and specific inhibition of Mertk cleavage using mice that express a cleavage-resistant Mertk reduced infarct size after I/R, identifying Mertk cleavage as a new therapeutic target after reperfusion injury. Interestingly, Axl was selectively expressed on Ly6C lo MHCII hi cardiac resident macrophages and surprisingly, Axl-deficiency during I/R led to reduced infarct size and improved cardiac contractility, suggesting differential roles between TAMs during cardiac repair. Conclusions: These data newly support the importance of efferocytosis pathways post-I/R and reveal both Axl and specifically Mertk on resident macrophages as key molecular mediators of inflammation resolution during atherothrombosis.