Schistosoma japonicum cystatin attenuated CLP-induced sepsis in mice though inducing tolerogenic dendritic cells and regulatory T cells

Abstract

Sepsis is a life-threatening complication caused by the overwhelming immune response to bacterial infection leading to the fatal organ damage and even death. Helminth infections modulate host’s immune system through secreting functional proteins to reduce host immune attack as a survival strategy, therefore have been used for the therapy of some inflammatory or autoimmune diseases. Sj-Cys is a cysteine protease inhibitor secreted by Schistosoma japonicum exerting strong immunomodulatory function which has been used to treat sepsis, however, the mechanism underlying the therapeutic efficacy has not been fully elucidated. In this study, we expressed Sj-Cys as recombinant protein (rSj-Cys) in prokaryotic system and rSj-Cys was used to incubate with mouse bone marrow derived dendritic cells (BMDCs) in vitro. Our study revealed that rSj-Cys was able to induce differentiation of BMDCs to tolerant property (TolDCs). Adoptive transfer of rSj-Cys induced-TolDCs into mice with cecal ligation and puncture (CLP)-induced sepsis conferred a significant therapeutic effect on CLP-induced sepsis in mice with reduced mortality and vital organ damage. The therapeutic effect of Sj-Cys-induced TolDCs was associated with upregulation of CD3⁺CD4⁺CD25⁺Foxp3⁺ regulatory T cells (Tregs) and reduced inflammatory cytokines IL-6 and TNF-α and boosted level of regulatory cytokines IL-10 and TGF-β. The results identified in this study further suggest rSj-Cys has the potential to be developed into a drug substance for the treatment of inflammatory or autoimmune diseases due to its immunomodulatory effect on tolerant dendritic cells and regulatory T cells.