The clinical picture of myocarditis varies from asymptomatic to cardiogenic shock. Current therapy for myocarditis is supportive, aimed at management of clinical symptoms of both myocarditis and cardiomyopathy. At the time of diagnosis, it is difficult to assert definitively an aberrant immune reaction to infection or a precise pathogenetic mechanism of myocarditis. The routine use of immunosuppressive agents in patients with myocarditis and cardiomyopathy is not indicated since it is not clear in which cases immunosuppression is likely to be beneficial. Although there is a high rate of spontaneous improvement in acute myocarditis and cardiomyopathy, patients who develop chronic DCM have an abysmal 5-year survival rate of below 50%. In the present study, we used a well established murine model to gain fresh insights into the pathogenesis of myocarditis that can be exploited for novel Carfilzomib 868540-17-4 therapeutic strategies. Experimental autoimmune myocarditis is a TH17 mediated disease whose induction depends on dendritic cells that encounter autoantigen and present it in an immunogenic fashion in conjunction with MHC II molecules. In in vitro models, TLRs, and specifically TLR4, have a crucial role in this process. Histopathologically, EAM is characterized by an inflammatory infiltrate that consists mostly of lymphocytes and macrophages. Heart macrophages are thought to exert both protective and detrimental effects in the course of EAM. The environmental clues that determine the function of effector T cells and inflammatory macrophages in EAM remain poorly understood. In particular, the role of the molecular pattern recognition receptor TLR4 in induction, maintenance and resolution of EAM is controversial. Therefore, in the present study, we examined the effect of TLR4 signaling on prevalence and severity of EAM. We found that TLR4 signaling significantly ameliorated histopathological disease severity, accelerated its resolution, and that TLR4 is required for the induction of CXCL1/KC expression. Based on this endogenous induction of circulatory CXCL1/KC in the course of EAM, we hypothesized that treatment with exogenous recombinant CXCL1/KC would abrogate inflammation in EAM. The results presented here have uncovered an essential function of TLR4 in the induction of the chemokine CXCL1/KC in an organ-specific autoimmune disease. CXCL1/KC exerts an effective anti-inflammatory effect in a heart-specific autoimmune disease. The “hygiene hypothesis” entails that prior exposure to infectious agents can prevent inflammatory responses, e.g., in atopic disease or inflammatory bowel disease and multiple sclerosis. Interestingly, mild gastroeneritis in patients caused by E. coli is associated with reduced risk for cardiovascular disease. Our data provide a mechanism by which LPS, a defined component of E. coli, can significantly ameliorate autoimmune inflammatory heart disease.