The Role Of Myeloid-derived Suppressed Cells In Experimental Autoimmune Myocarditis

Background and ObjectiveMyeloid-derived suppressor cells(MDSCs)are a heterogeneous population that is comprised of immature granulocytes,macrophages and dendritic cells.MDSCs were observed in cancer,inflammation and infection with a remarkable ability to suppress T-cell responses.So far,the effect of MDSCs on autoimmune myocarditis is still unknown.This study aims to explore the role and mechanism of MDSCs in autoimmune myocarditisMethods and Results1.MDSCs were accumulated in autoimmune myocarditisThe murine model of experimental autoimmune myocarditis was induced after subcutaneously injection with 250ug a-My HC peptide emulsified complete Freund’s adjuvant on day 0 and day 7.MDSCs were obviously increased in bone marrow,peripheral blood,spleen and heart in mice with autoimmune myocarditis.MDSCs purified from spleen of autoimmune myocarditis mice could inhibit na?ve T-cell proliferation in vitro study.2.Eliminating MDSCs alleviated autoimmune myocarditisTo know the effect of MDSCs on autoimmune myocarditis,gemcitabine was used to eliminate endogenous MDSCs.Data showed that the administration of gemcitabine could significantly alleviate cardiac dysfunction and inflammatory response in mice with autoimmune myocarditis,which manifested as enhanced ejection fraction(EF)and short axis shortening rate(FS),decreased left ventricular systolic end internal diameter(LVID;s)and diastole end internal diameter(LVID;d),reduced cardiac inflammation infiltration,lower levels of pro-inflammatory cytokines in the heart tissue and plasma,decreased Th17cells in the spleen.3.Adoptive transfer of MDSCs exacerbated autoimmune myocarditisConversely,adoptive transfer of MDSCs from autoimmune myocarditis mice to autoimmune myocarditis mice further aggravated cardiac dysfunction and inflammatory response,which manifested as decreased EF and FS,increased LVID;s.increased inflammatory infiltration,higher levels of pro-inflammatory cytokines in the heart tissue and plasma,accumulated Th17 cells in the spleen.4.MDSCs promoted Th17 differentiationMDSCs were isolated from the spleen of mice with autoimmune myocarditis and co-cultured with na?ve CD4~+T cells.Results showed that MDSCs could promote the differentiation of na?ve CD4~+T cells into Th17 cells and promote the secretion of IL-17A.ConclusionIn summary,MDSCs were accumulated in autoimmune myocarditis mice and displayed a harmful effect by pro-inflammation through promoting Th17 differentiation.Eliminating MDSCs could alleviate cardiac dysfunction and inflammation,which provide a new insight for development of new therapeutic strategy for autoimmune myocarditis.