Inhibition of MIF as a novel treatment for autoimmune myocarditis and dilated cardiomyopathy.

Abstract

Abstract Myocarditis is an inflammatory disease of the myocardium and a major cause of sudden death in young adults. It is characterized by the presence of immune infiltrates and necrotic myocytes in the myocardium. Importantly, patients often progress to a more severe form of the disease termed dilated cardiomyopathy (DCM), which leads to ventricular dilation and impaired cardiac function. Despite the inflammatory and autoimmune nature of this disease condition, immunosuppressive treatments such as corticosteroids (CSs) have not been very effective in preventing myocarditis and its progression to DCM. We hypothesized that macrophage migration inhibitory factor (MIF) may play a role in resistance to CSs, as it is the only known pro-inflammatory cytokine to be induced by CSs. Importantly, MIF counter-regulates CS-mediated immunosuppression. Using the experimental autoimmune myocarditis (EAM) animal model, we observed that MIF−/− mice treated with Dexamethasone (Dex) were highly resistant to EAM and progression to DCM. Furthermore, using small molecule inhibitors of MIF combined with Dex treatment recapitulated this phenotype in wild type mice. Investigating the mechanism we found that treatment with MIF inhibitors and Dex decreased the expression of key chemokines and adhesion molecules and implicated these molecules in the progression of EAM to DCM. Our results suggest that MIF promotes the recruitment of inflammatory cells to the myocardium to promote DCM. Moreover, the results suggest therapeutic inhibition of MIF in combination with CSs as a novel treatment approach to prevent DCM. Last, our studies may provide new insights into the mechanisms driving DCM.