PMID- 35691271 OWN - NLM STAT- MEDLINE DCOM- 20220621 LR - 20220621 IS - 1878-1705 (Electronic) IS - 1567-5769 (Linking) VI - 109 DP - 2022 Aug TI - Trichinella spiralis cystatin alleviates polymicrobial sepsis through activating regulatory macrophages. PG - 108907 LID - S1567-5769(22)00391-5 [pii] LID - 10.1016/j.intimp.2022.108907 [doi] AB - BACKGROUND: Sepsis is a life-threateningorgandysfunction caused by the cytokine storm induced by the severe bacterial infection. Excessive inflammatory responses are responsible for the lethal organ damage during the early stage of sepsis. Helminth infection and helminth-derived proteins have been identified to have the ability to immunomodulate the host immune system by reducing inflammation against inflammatory diseases. Trichinella spiralis cystatin (Ts-Cys) is a cysteine protease inhibitor with strong immunomodulatory functions on host immune system. Our previous studies have shown that excretory-secretory proteins of T. spiralis reduced sepsis-induced inflammation and Ts-Cys was able to inhibit macrophages to produce inflammatory cytokines. Whether Ts-Cys has a therapeutic effect on polymicrobial sepsis and related immunological mechanism are not yet known. METHODS: Sepsis was induced in BALB/c mice using cecal ligation and puncture (CLP), followed by intraperitoneal injection of 15 microg recombinant Ts-Cys (rTs-Cys). The therapeutic effect of rTs-Cys on sepsis was evaluated by observing the 72-hour survival rates of CLP-induced septic mice and the acute injury of lung and kidney through measuring the wet/dry weight ratio of lung, the levels of blood urea nitrogen (BUN) and creatinine (Cr) in sera and the tissue section pathology. The potential underlying mechanism was investigated using mouse bone marrow-derived macrophages (BMDMs) by observing the effect of rTs-Cys on LPS-stimulated macrophage polarization. The expression of genes associated with macrophage polarization in BMDMs and tissues of septic mice was measured by Western Blotting and qPCR. RESULTS: In this study, we demonstrated the treatment with rTs-Cys alleviated CLP-induced sepsis in mice with significantly reduced pathological injury in vital organs of lung and kidney and reduced mortality of septic mice. The further study identified that treatment with rTs-Cys promoted macrophage polarization from classically activated macrophage (M1) to alternatively activated macrophage (M2) phenotype via inhibiting TLR2/MyD88 signal pathway and increasing expression of mannose receptor (MR), inhibited pro-inflammatory cytokines (TNF-alpha, IL-6 and IL-1beta) and increased regulatory anti-inflammatory cytokines (IL-10 and TGF-beta) in sera and tissues (lung and kidney) of mice with polymicrobial sepsis. CONCLUSIONS: Our results demonstrated that rTs-Cys had a therapeutic effect on sepsis through activating regulatory macrophages possibly via suppressing TLR2/MyD88 signal pathway. We also identified that rTs-Cys-induced M2 macrophage differentiation was associated with increased expression of MR on the surface of macrophages. Our results underscored the importance of MR in regulating macrophages during the treatment with rTs-Cys, providing another immunological mechanism in which helminths and their derived proteins modulate the host immune system. The findings in this study suggest that rTs-Cys is a potential therapeutic agent for the prevention and treatment of sepsis and other inflammatory diseases. CI - Copyright (c) 2022 The Authors. Published by Elsevier B.V. All rights reserved. FAU - Li, Huihui AU - Li H AD - Department of Basic Medical College, Bengbu Medical College, Bengbu, China; Anhui Key Laboratory of Infection and Immunity of Bengbu Medical College, Bengbu, China. FAU - Qiu, Dapeng AU - Qiu D AD - Department of Orthopedics, Second Affiliated Hospital of Bengbu Medical College, Bengbu, China. FAU - Yuan, Yuan AU - Yuan Y AD - Department of Basic Medical College, Bengbu Medical College, Bengbu, China; Anhui Key Laboratory of Infection and Immunity of Bengbu Medical College, Bengbu, China. FAU - Wang, Xiaoli AU - Wang X AD - Department of Basic Medical College, Bengbu Medical College, Bengbu, China; Anhui Key Laboratory of Infection and Immunity of Bengbu Medical College, Bengbu, China. FAU - Wu, Fengjiao AU - Wu F AD - Department of Basic Medical College, Bengbu Medical College, Bengbu, China; Anhui Key Laboratory of Infection and Immunity of Bengbu Medical College, Bengbu, China. FAU - Yang, Huijuan AU - Yang H AD - Department of Nephrology, First Affiliated Hospital of Bengbu Medical College, Bengbu, China. FAU - Wang, Shuying AU - Wang S AD - Department of Basic Medical College, Bengbu Medical College, Bengbu, China; Anhui Key Laboratory of Infection and Immunity of Bengbu Medical College, Bengbu, China. FAU - Ma, Mengxi AU - Ma M AD - Department of Basic Medical College, Bengbu Medical College, Bengbu, China; Anhui Key Laboratory of Infection and Immunity of Bengbu Medical College, Bengbu, China. FAU - Qian, Yayun AU - Qian Y AD - Department of Basic Medical College, Bengbu Medical College, Bengbu, China; Anhui Key Laboratory of Infection and Immunity of Bengbu Medical College, Bengbu, China. FAU - Zhan, Bin AU - Zhan B AD - National School of Tropical Medicine, Baylor College of Medicine, Houston, TX, USA. FAU - Yang, Xiaodi AU - Yang X AD - Department of Basic Medical College, Bengbu Medical College, Bengbu, China; Anhui Key Laboratory of Infection and Immunity of Bengbu Medical College, Bengbu, China. Electronic address: yxd_qf@163.com. LA - eng PT - Journal Article DEP - 20220609 PL - Netherlands TA - Int Immunopharmacol JT - International immunopharmacology JID - 100965259 RN - 0 (Cystatins) RN - 0 (Cytokines) RN - 0 (Helminth Proteins) RN - 0 (Myeloid Differentiation Factor 88) RN - 0 (Toll-Like Receptor 2) SB - IM MH - Animals MH - *Cystatins/genetics/metabolism/therapeutic use MH - Cytokines/metabolism MH - Helminth Proteins MH - Inflammation MH - Macrophages MH - Mice MH - Myeloid Differentiation Factor 88/metabolism MH - *Sepsis/drug therapy/microbiology MH - Toll-Like Receptor 2/metabolism MH - *Trichinella spiralis OTO - NOTNLM OT - Cystatin OT - Immunoregulation OT - Mannose receptor OT - Sepsis OT - Trichinella spiralis EDAT- 2022/06/13 06:00 MHDA- 2022/06/22 06:00 CRDT- 2022/06/12 18:19 PHST- 2022/03/17 00:00 [received] PHST- 2022/05/19 00:00 [revised] PHST- 2022/05/25 00:00 [accepted] PHST- 2022/06/13 06:00 [pubmed] PHST- 2022/06/22 06:00 [medline] PHST- 2022/06/12 18:19 [entrez] AID - S1567-5769(22)00391-5 [pii] AID - 10.1016/j.intimp.2022.108907 [doi] PST - ppublish SO - Int Immunopharmacol. 2022 Aug;109:108907. doi: 10.1016/j.intimp.2022.108907. Epub 2022 Jun 9.