Defining novel physiological roles for cardiac-residen Macrophages

Abstract

Classically defined as defensive cells, macrophages are now known to be endowed with tissue-specific tasks unrelated to immunity (Davies et al., 2013). These pleiotropic functions are prominent in the heart, where tissue-resident macrophages have been shown to prevent fibrosis (Chakarov et al., 2019), facilitate electrical conduction in the atrioventricular node (Hulsmans et al., 2017), or to favour healing in injured areas (Dick et al., 2019; Nahrendorf and Swirski, 2013). Notwithstanding these observations, large numbers of macrophages of unknown functions populate other regions of the healthy heart, including the ventricular myocardium (Pinto et al., 2012), suggesting broader homeostatic functions for heart-resident macrophages.In this work, we have analysed macrophages lodged within the healthy murine myocardium, and find that they are broadly distributed and actively took cellular material derived from cardiomyocytes. Cardiomyocytes ejected mitochondria in dedicated membranous particles reminiscent of neural exophers, through a process driven by the cardiomyocyte’s autophagy machinery that was enhanced during cardiac stress. Mitochondria disposed through exophers were largely dysfunctional, and were efficiently eliminated by adjacent macrophages. Recognition of cardiac exophers by the phagocytic receptor Mertk prevented inflammasome activation, mitochondrial dysfunction and proteostatic defects, while elimination of macrophages with genetic tools results in a severe cardiomyopathy. Our findings identify an immune-parenchymal pair in the murine heart that allows material transfer to preserve metabolic stability and cell homeostasis.