The Cardiac Microenvironment Instructs Divergent Monocyte Fates and Functions in Myocarditis

Two types of monocytes, Ly6C^hi and Ly6C^lo, infiltrate the heart in murine experimental autoimmune myocarditis (EAM). We discovered a role for cardiac fibroblasts in facilitating monocyte-to-macrophage differentiation of both Ly6C^hi and Ly6C^lo cells, allowing these macrophages to perform divergent functions in myocarditis progression. During the acute phase of EAM, IL-17A is highly abundant. It signals through cardiac fibroblasts to attenuate efferocytosis of Ly6C^hi monocyte-derived macrophages (MDMs) and simultaneously prevents Ly6C^lo monocyte-to-macrophage differentiation. We demonstrated an inverse clinical correlation between heart IL-17A levels and efferocytic receptor expressions in humans with heart failure (HF). In the absence of IL-17A signaling, Ly6C^hi MDMs act as robust phagocytes and are less pro-inflammatory, whereas Ly6C^lo monocytes resume their differentiation into MHCII⁺ macrophages. We propose that MHCII⁺Ly6C^lo MDMs are associated with the reduction of cardiac fibrosis and prevention of the myocarditis sequalae. Hou et al. show that cardiac fibroblasts facilitate infiltrating Ly6C^hi and Ly6C^lo monocytes to become macrophages. IL-17A trans-signaling through cardiac fibroblasts increases MerTK shedding and promotes a pro-inflammatory and pro-tissue remodeling gene expression profile in Ly6C^hi monocyte-derived macrophages. Paradoxically, IL-17A signaling through cardiac fibroblasts can substantially inhibit Ly6C^lo monocyte-to-macrophage differentiation.