The role of monocytes and macrophages in the pathogenesis of autoimmune myocarditis and dilated cardiomyopathy

Approximately 30% of myocarditis patients progress to develop dilated cardiomyopathy, which is a major cause of sudden death in children and young adults. Ly6Chi inflammatory monocytes are thought to play a detrimental role in a mouse model of experimental autoimmune myocarditis (EAM). Their recruitment in large numbers to the heart has been linked to cardiac fibrosis and ventricular dysfunction. However, the mechanism underlying the pathogenic role of Ly6Chi monocytes has been overlooked, and the protective role of Ly6Clo monocytes was largely presumed based on extrapolation from other disease models. We therefore studied the fates and functions of these two types of monocytes to better understand their roles in the injured myocardium. We demonstrated in vitro that cardiac fibroblasts mediate monocyte-to-macrophage differentiation through direct contact with Ly6Chi and Ly6Clo monocytes. IL-17A is significantly elevated during acute myocarditis. It signals through cardiac fibroblasts to abolish Ly6Clo monocyte-to-macrophage differentiation as well as to hamper phagocytic function in Ly6Chi monocyte-derived macrophages. Phagocytosis of apoptotic/necrotic myocardial cells by macrophages plays a crucial role in minimizing myocardial damage and subsequent dysfunction. Strikingly, cardiac IL-17A in heart failure patients is inversely correlated with phagocytic receptor expression in the myeloid compartment. This highlights the clinical relevance of our finding and can lead to the development of diagnostic biomarkers or novel treatment approaches. IL-17A signaling wanes during inflammation resolution, allowing Ly6Clo monocyte-to-macrophage differentiation to resume. These macrophages display antigen presentation properties which coincide with cardiac protection in IL-17Ra–/– mice in vivo. In conclusion, we described how the inflammatory environment modulates the phenotype and functions of infiltrating monocytes with potential implications for other autoimmune and inflammatory diseases

Sca-1+ cardiac fibroblasts promote development of heart failure

The causative effect of GM-CSF produced by cardiac fibroblasts to development of heart failure has not been shown. We identified the pathological GM-CSF-producing cardiac fibroblast subset and the specific deletion of IL-17A signaling to these cells attenuated cardiac inflammation and heart failure. We describe here the CD45−CD31−CD29+mEFSK4+PDGFRα+Sca-1+periostin+ (Sca-1+) cardiac fibroblast subset as the main GM-CSF producer in both experimental autoimmune myocarditis and myocardial infarction mouse models. Specific ablation of IL-17A signaling to Sca-1+periostin+ cardiac fibroblasts (PostnCreIl17rafl/fl) protected mice from post-infarct heart failure and death. Moreover, PostnCreIl17rafl/fl mice had significantly fewer GM-CSF-producing Sca-1+ cardiac fibrob-lasts and inflammatory Ly6Chi monocytes in the heart. Sca-1+ cardiac fibroblasts were not only potent GM-CSF producers, but also exhibited plasticity and switched their cytokine production profiles depending on local microenvironments. Moreover, we also found GMCSF-positive cardiac fibroblasts in cardiac biopsy samples from heart failure patients of myocarditis or ischemic origin. Thus, this is the first identification of a pathological GMCSF-producing cardiac fibroblast subset in human and mice hearts with myocarditis and ischemic cardiomyopathy. Sca-1+ cardiac fibroblasts direct the type of immune cells infiltrating the heart during cardiac inflammation and drive the development of heart failure

Non-cytotoxic Cardiac Innate Lymphoid Cells Are a Resident and Quiescent Type 2-Commited Population

Innate lymphoid cells (ILC) are a subset of leukocytes with lymphoid properties that lack antigen specific receptors. They can be stimulated by and exert their effect via specific cytokine axes, whereas Natural Killers (NK) cells are the only known cytotoxic member of this family. ILCs are considered key in linking the innate and adaptive response in physiologic and pathologic environments. In this study, we investigated the properties of non-cytotoxic cardiac ILCs in physiologic, inflammatory, and ischemic conditions. We found that in healthy humans and mice, non-cytotoxic cardiac ILCs are predominantly a type 2-committed population with progenitor-like features, such as an absence of type-specific immunophenotype, intermediate GATA3 expression, and capacity to transiently express Pro-myelocytic Leukemia Zinc Finger protein (PLZF) upon activation. During myocarditis and ischemia, in both human and mice, cardiac ILCs differentiated into conventional ILC2s. We found that cardiac ILCs lack IL-25 receptor and cannot become inflammatory ILC2s. We found a strong correlation between IL-33 production in the heart and the ability of cardiac ILCs to become conventional ILC2s. The main producer of IL-33 was a subset of CD29+Sca-1+ cardiac fibroblasts. ILC2 expansion and fibroblast-derived IL-33 production were significantly increased in the heart in mouse models of infarction and myocarditis. Despite its progenitor-like status in healthy hearts, cardiac ILCs were unable to become ILC1 or ILC3 in vivo and in vitro. Using adoptive transfer and parabiosis, we demonstrated that the heart, unlike other organs such as lung, cannot be infiltrated by circulating ILCs in adulthood even during cardiac inflammation or ischemia. Thus, the ILC2s present during inflammatory conditions are derived from the heart-resident and quiescent steady-state population. Non-cytotoxic cardiac ILCs are a resident population of ILC2-commited cells, with undifferentiated progenitor-like features in steady-state conditions and an ability to expand and develop pro-inflammatory type 2 features during inflammation or ischemia