MIF deficiency enhances the efficacy of glucocorticoid treatment and ameliorates the progression of autoimmune myocarditis to dilated cardiomyopathy

Myocarditis, an inflammatory condition of the heart, often leads to dilated cardiomyopathy (DCM) and ultimately heart failure. The damage to the myocardium is mainly mediated by autoreactive T lymphocytes and proinflammatory cytokines. The autoimmune inflammation can be suppressed by glucocorticoids (GCs) during the early stage of myocarditis. However, GC treatment is symptomatic and cannot stop the progression of myocarditis to DCM. Macrophage migration inhibitory factor (MIF) is the only known proinflammatory cytokine induced by GCs and has the unique property to counter-regulate GC-mediated immunosuppression. It remains unknown whether the counter-regulation of GC-mediated immunosuppression by MIF promotes the progression of myocarditis to DCM. Therefore, we investigated dexamethasone (Dex) treatment in experimental autoimmune myocarditis (EAM) and the progression to DCM in MIF knockout (MIF-/-) Balb/c mice as compared with wild-type (Wt) mice. EAM and DCM severity were determined by histopathological analysis of murine heart tissue by H&E staining and Masson’s Trichrome collagen deposition staining. We found that Wt mice treated with Dex recovered from EAM after peak of disease but then progressed to chronic DCM with substantial myocardial fibrosis, whereas MIF-/- mice treated with Dex were resistant to both EAM and DCM. Our results indicate that MIF antagonizes the efficacy of GCs in EAM and DCM and suggests MIF blockade as a potential therapeutic strategy in combination with GC treatment for myocarditis as well as prevention of progression to DCM.