Macrophage MERTK mediates pressure overload-induced heart failure via type I interferon response

Macrophages play a critical role in the pathogenesis and progression of heart failure, wherein sustained cardiomyocyte apoptosis is a key feature. The MER proto-oncogene tyrosine kinase (MERTK) is a critical receptor that mediates the efferocytosis of apoptotic cells by macrophages. However, the role and mechanism of action of MERTK in pressure overload-induced heart failure remains unclear. Here, we demonstrate that MERTK expression was upregulated in cardiac tissue macrophages of mice with pressure overload-induced heart failure. Deletion of MERTK ameliorated transverse aortic constriction (TAC)- and Ang II-induced cardiac hypertrophy and heart failure. This protective effect was associated with reduced type I interferon signaling and was reversed by interferon receptor activation. Efferocytosis assays were performed to demonstrate that mitochondrial double-stranded RNA from apoptotic cardiomyocytes activated Toll-like receptor 3 in macrophages, promoting Interferon beta (IFNb) expression. In vitro experiment identified that IFNb sensitized cardiomyocytes to Ang II stimulation by augmenting the P53 pathway, suppressing Ang II-induced protective mitophagy and promoting cardiomyocyte apoptosis. In conclusion, macrophage MERTK receptor exacerbated post-TAC heart failure and cardiac hypertrophy by mediating the phagocytosis of apoptotic cardiomyocytes and promoting IFNb expression. This study provides novel insights into the role of macrophage MERTK-mediated efferocytosis and type I interferon response in the pathogenesis of heart failure. These findings highlight an unrecognized function of MERTK in pressure overload-induced cardiac remodeling and identify IFNb as a key downstream effector of MERTK in this pathological process