Pathogenesis of Myocarditis and Inflammatory Dilated Cardiomyopathy: the Sign of Four
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Myocarditis and inflammatory dilated cardiomyopathy (DCMi) are major causes of heart failure in individuals below the age of 40. In the work presented in this dissertation, using a model of mouse experimental autoimmune myocarditis (EAM) and DCMi, the roles of four pathogenic factors: CD4+ T lymphocytes, interleukin 23 (IL-23), interleukin 17A (IL-17A), and granulocyte macrophage colony-stimulating factor (GM-CSF), are investigated. With transgenic IL-23a-/- and IL-17ra-/- mice, we demonstrate that IL-23 drives the pathogenicity of CD4+ T cells and maintains their IL-17A production. IL-17A induces chemokine production by cardiac fibroblasts, resulting in an infiltrate rich in neutrophils and Ly6Chi MO/MΦs in the heart, which aggravate disease and lead to worse prognosis. Furthermore, IL-17A directs monocytic infiltrates into an even more inflammatory phenotype by inducing GM-CSF production from cardiac fibroblasts. Taken together, this IL-23 – CD4+ T lymphocytes – IL-17A – GM-CSF axis provides a novel target for the treatment of DCMi and related inflammatory cardiac diseases. Adviser: Noel R. Rose, M.D., Ph. D. Readers: Daniela Čiháková, M.D., Ph.D., Fengyi Wan, Ph.D., Alan Scott, Ph.D., Patrizio Caturegli, M.D., Pierre A. Couloumbe, Ph.D., Jay H. Bream, Ph.D.