Abstract
Ethyl pyruvate (EP) has profound anti-inflammatory and immunomodulatory properties. Here, its effects were determined on experimental autoimmune myocarditis (EAM) induced in mice by heart-specific myosin-alpha heavy chain peptide immunization. EP was applied intraperitoneally, daily, starting with the immunization. Severity of EAM was determined by histological assessment of immune cell infiltrates into the heart. Cells were phenotypically characterized by flow cytometry. Concentration of cytokines in cell culture supernatants and sera was determined by ELISA. EP reduced the infiltration of immune cells into the heart and lessened heart inflammation. Smaller number of total immune cells, as well as of CD11b+ and CD11c+ cells were isolated from the hearts of EP-treated mice. A reduced number of antigen-presenting cells, detected by anti-CD11c, MHC class II and CD86 antibodies, as well as of T helper (Th)1 and Th17 cells, detected by anti-CD4, IFN-γ and IL-17 antibodies, was determined in mediastinal lymph nodes draining the heart, in parallel. In the spleen, only the number of CD11c+ cells were reduced, but not of the other examined populations, thus implying limited systemic effect of EP. Reduced production of IFN-γ and IL-17 by myosin-alpha heavy chain peptide-restimulated cells of the lymph nodes draining the site of immunization was observed in EP-treated mice. Our results clearly imply that EP restrains autoimmunity in EAM. Therapeutic application of EP in the treatment of myocarditis in humans should be addressed in the forthcoming studies.
Highlights
Myocarditis is the inflammation of the heart muscular tissue
Experimental autoimmune myocarditis (EAM) severity grades clearly showed that Ethyl pyruvate (EP) efficiently reduced heart inflammation, infiltration (Figure 2E), fibrosis (Figure 2F), and cardiomyocyte necrosis (Figure 2G), and the cumulative severity score (Figure 2H) was reduced in EP-treated mice
While there were no differences in heart weights between the groups (Figure 2I), absolute numbers of heart CD11c+ and CD11b+ cells were reduced in EP-treated mice (Figure 2J,K)
Summary
Acute inflammation of the myocardium may advance to a chronic stage and cause heart tissue remodeling, fibrosis and loss of function, i.e., to the development of dilated cardiomyopathy [1]. This is a life-threatening condition, as the dilatation of heart chambers leads to systolic function impairment and heart failure, for which the only definitive treatment is organ transplantation [1]. It is assumed that up to 50% of dilated cardiomyopathy cases develop as a consequence of chronic inflammation associated with a persistent autoimmune response against the heart [1]. The pathogenesis of EAM and myocarditis involves multiple arms of the innate and adaptive immune response, with CD4+ T cells, i.e.,
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