PMID- 33718268 OWN - NLM STAT- MEDLINE DCOM- 20210702 LR - 20210702 IS - 2235-2988 (Electronic) IS - 2235-2988 (Linking) VI - 11 DP - 2021 TI - Schistosoma japonicum Cystatin Alleviates Sepsis Through Activating Regulatory Macrophages. PG - 617461 LID - 10.3389/fcimb.2021.617461 [doi] LID - 617461 AB - Multi-organ failure caused by the inflammatory cytokine storm induced by severe infection is the major cause of death for sepsis. Sj-Cys is a cysteine protease inhibitor secreted by Schistosoma japonicum with strong immunomodulatory functions on host immune system. Our previous studies have shown that treatment with Sj-Cys recombinant protein (rSj-Cys) attenuated inflammation caused by sepsis. However, the immunological mechanism underlying the immunomodulation of Sj-Cys for regulating inflammatory diseases is not yet known. In this study, we investigated the effect of Sj-Cys on the macrophage M2 polarization and subsequent therapeutic effect on sepsis. The rSj-Cys was expressed in yeast Pichia pastoris. Incubation of mouse bone marrow-derived macrophages (BMDMs) with yeast-expressed rSj-Cys significantly activated the polarization of macrophages to M2 subtype characterized by the expression of F4/80(+) CD206(+) with the elated secretion of IL-10 and TGF-beta. Adoptive transfer of rSj-Cys treated BMDMs to mice with sepsis induced by cecal ligation and puncture (CLP) significantly improved their survival rates and the systemic clinical manifestations of sepsis compared with mice receiving non-treated normal BMDMs. The therapeutic effect of Sj-Cys-induced M2 macrophages on sepsis was also reflected by the reduced pathological damages in organs of heart, lung, liver and kidney and reduced serological levels of tissue damage-related ALT, AST, BUN and Cr, associated with downregulated pro-inflammatory cytokines (IFN-gamma and IL-6) and upregulated regulatory anti-inflammatory cytokines (IL-10 and TGF-beta). Our results demonstrated that Sj-Cys is a strong immunomodulatory protein with anti-inflammatory features through activating M2 macrophage polarization. The findings of this study suggested that Sj-Cys itself or Sj-Cys-induced M2 macrophages could be used as therapeutic agents in the treatment of sepsis or other inflammatory diseases. CI - Copyright (c) 2021 Xie, Wu, Chen, Gao, Li, Yuan, Liang, Wang, Wang, Xu, Chu, Zhan, Zhou and Yang. FAU - Xie, Hong AU - Xie H AD - Anhui Key Laboratory of Infection and Immunity of Bengbu Medical College, Bengbu, China. AD - Department of Basic Medical College, Bengbu Medical College, Bengbu, China. FAU - Wu, Lingqin AU - Wu L AD - Anhui Key Laboratory of Infection and Immunity of Bengbu Medical College, Bengbu, China. AD - Department of Pediatric, First Affiliated Hospital of Bengbu Medical College, Bengbu, China. FAU - Chen, Xingzhi AU - Chen X AD - Anhui Key Laboratory of Infection and Immunity of Bengbu Medical College, Bengbu, China. AD - Department of Basic Medical College, Bengbu Medical College, Bengbu, China. FAU - Gao, Shifang AU - Gao S AD - Anhui Key Laboratory of Infection and Immunity of Bengbu Medical College, Bengbu, China. FAU - Li, Huihui AU - Li H AD - Anhui Key Laboratory of Infection and Immunity of Bengbu Medical College, Bengbu, China. AD - Department of Basic Medical College, Bengbu Medical College, Bengbu, China. FAU - Yuan, Yuan AU - Yuan Y AD - Anhui Key Laboratory of Infection and Immunity of Bengbu Medical College, Bengbu, China. AD - Department of Basic Medical College, Bengbu Medical College, Bengbu, China. FAU - Liang, Jinbao AU - Liang J AD - Anhui Key Laboratory of Infection and Immunity of Bengbu Medical College, Bengbu, China. FAU - Wang, Xiaoli AU - Wang X AD - Anhui Key Laboratory of Infection and Immunity of Bengbu Medical College, Bengbu, China. AD - Department of Basic Medical College, Bengbu Medical College, Bengbu, China. FAU - Wang, Shuying AU - Wang S AD - Anhui Key Laboratory of Infection and Immunity of Bengbu Medical College, Bengbu, China. AD - Department of Pediatric, First Affiliated Hospital of Bengbu Medical College, Bengbu, China. FAU - Xu, Changyan AU - Xu C AD - Anhui Key Laboratory of Infection and Immunity of Bengbu Medical College, Bengbu, China. AD - Department of Basic Medical College, Bengbu Medical College, Bengbu, China. FAU - Chu, Liang AU - Chu L AD - Department of General Surgery, Second Affiliated Hospital of Bengbu Medical College, Bengbu, China. FAU - Zhan, Bin AU - Zhan B AD - National School of Tropical Medicine, Baylor College of Medicine, Houston, TX, United States. FAU - Zhou, Rui AU - Zhou R AD - Department of Pediatric, First Affiliated Hospital of Bengbu Medical College, Bengbu, China. AD - Anhui Province Key Laboratory of Immunology in Chronic Diseases of Bengbu Medical College, Bengbu, China. FAU - Yang, Xiaodi AU - Yang X AD - Anhui Key Laboratory of Infection and Immunity of Bengbu Medical College, Bengbu, China. AD - Department of Basic Medical College, Bengbu Medical College, Bengbu, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20210224 PL - Switzerland TA - Front Cell Infect Microbiol JT - Frontiers in cellular and infection microbiology JID - 101585359 RN - 0 (Cystatins) RN - Komagataella pastoris SB - IM MH - Animals MH - *Cystatins MH - Macrophages MH - Mice MH - Saccharomycetales MH - *Schistosoma japonicum MH - *Sepsis PMC - PMC7943722 OTO - NOTNLM OT - Schistosoma japonicum OT - adoptive transfer OT - cysteine protease inhibitor OT - immunomodulation OT - macrophage OT - sepsis COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2021/03/16 06:00 MHDA- 2021/07/03 06:00 PMCR- 2021/01/01 CRDT- 2021/03/15 07:08 PHST- 2020/10/14 00:00 [received] PHST- 2021/01/14 00:00 [accepted] PHST- 2021/03/15 07:08 [entrez] PHST- 2021/03/16 06:00 [pubmed] PHST- 2021/07/03 06:00 [medline] PHST- 2021/01/01 00:00 [pmc-release] AID - 10.3389/fcimb.2021.617461 [doi] PST - epublish SO - Front Cell Infect Microbiol. 2021 Feb 24;11:617461. doi: 10.3389/fcimb.2021.617461. eCollection 2021.