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.