The Cardiac Microenvironment Instructs Divergent Monocyte Fates and Functions in Myocarditis.

Two types of monocytes, Ly6C and Ly6C, 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 and Ly6C 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 monocyte-derived macrophages (MDMs) and simultaneously prevents Ly6C 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 MDMs act as robust phagocytes and are less pro-inflammatory, whereas Ly6C monocytes resume their differentiation into MHCII macrophages. We propose that MHCIILy6C MDMs are associated with the reduction of cardiac fibrosis and prevention of the myocarditis sequalae.