Molecular mechanisms promoting progression of autoimmune myocarditis to dilated cardiomyopathy.

Abstract Myocarditis is an inflammatory disease of the myocardium, described by infiltration of immune cells and cardiomyocyte necrosis. It is a major cause of sudden death in young adults. Patients often progress to a more severe form of the disease termed dilated cardiomyopathy (DCM). It is characterized by extensive fibrosis leading to impaired cardiac function. Immunosuppressive treatments with corticosteroids (CSs) have not been effective in preventing the disease. We hypothesized that macrophage migration inhibitory factor (MIF), being the only known pro-inflammatory cytokine induced by CSs may play a role in resistance to CSs. Also, 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, from a translational approach, treatment using small molecule inhibitors of MIF combined with Dex recapitulated this phenotype in wild type mice. We observed that treated mice showed decreased expression of key chemokines and extracellular matrix molecules compared with controls, implicating these molecules in disease progression. Currently, we are investigating these molecules by selectively inhibiting them in order to understand their contribution to disease pathogenesis. We observed that inhibition of CCL2 after, although not prior to establishment of EAM attenuated progression to DCM. Thereby, suggesting that CCL2 is predominantly involved during the fibrotic phase aiding in progression as opposed to the induction phase of the disease. Besides a novel approach to prevent DCM, our studies may provide new insights into the mechanisms driving DCM.