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Wan Shuangshuang,Song Guangzhong,Hu Hui,Xu Yaqing,Zeng Peng,Lin Shan,Yang Jun,Jiang Jinqin,Song Xiaojun,Luo Yongneng,Jin Dazhi 대한독성 유전단백체 학회 2023 Molecular & cellular toxicology Vol.19 No.3
Background Clostridioides diffi cile infection (CDI) has been primarily associated with the toxin B (TcdB), one of the three known protein toxins secreted by C. diffi cile , which can activate the intestinal immune system and lead to pathological damage. Even though the biological functions of intestine epithelial cell-derived extracellular vesicles (I-Evs) have been well documented, the role of I-Evs in the process of CDI is still unknown. Objectives The protective eff ect of I-Evs against C. diffi cile TcdB was investigated both in cultured murine colon carcinoma MC38 cells and a mouse model used in this study. Results Mouse I-Evs with mean diameter ranging from 100 to 200 nm and a density of 1.09–1.17 g/mL were obtained and confi rmed containing the Ev-associated specifi c surface markers CD63 and TSG101 as well as high level of TGF-β1. In MC38 cells, I-Evs were able to decrease the gene expression of IL-6, TNF-α, IL-1β, and IL-22 induced by C. diffi cile TcdB, but to increase both the gene expression and protein levels of TGF-β1. I-Evs treatment via intraperitoneal administration alleviates C. diffi cile TcdB-induced local colon infl ammation in mice and increased their survival rate from 50% up to 80%. Furthermore, I-Evs induced an increase in the proportion of CD4 + Foxp3 + Tregs in vitro and in vivo through a TGF-β1-dependent mechanism by activating the TGF-β1 pathway and prompting phosphorylation of the downstream proteins Smad 2/3. Conclusion For the fi rst time, our study demonstrated that I-Evs originated from intestine epithelial cells can alleviate infl ammation induced by C. diffi cile TcdB both in vitro and in vivo. Therefore, I-Evs might be potentially a novel endogenous candidate for eff ective treatment of CDI.
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