Intestine epithelial cell-derived extracellular vesicles alleviate inflammation induced by TcdB through the activity of TGF-β1.

BACKGROUND

infection (CDI) has been primarily associated with the toxin B (TcdB), one of the three known protein toxins secreted by , 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 effect of I-Evs against 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 confirmed containing the Ev-associated specific 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 TcdB, but to increase both the gene expression and protein levels of TGF-β1. I-Evs treatment via intraperitoneal administration alleviates TcdB-induced local colon inflammation in mice and increased their survival rate from 50% up to 80%. Furthermore, I-Evs induced an increase in the proportion of CD4Foxp3Tregs 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 first time, our study demonstrated that I-Evs originated from intestine epithelial cells can alleviate inflammation induced by TcdB both in vitro and in vivo. Therefore, I-Evs might be potentially a novel endogenous candidate for effective treatment of CDI.