MTOR-Mediated Autophagy Regulates Fumonisin B1-Induced Intestinal Inflammation via Pyroptosis In Vivo and In Vitro.

Abstract

Fumonisin B1 (FB1) is a fungal metabolite, which has an incremental detection rate in grains and feed worldwide. The nucleotide-binding oligomerization domain-like pyrin domain containing protein 3 (NLRP3) inflammasome is a critical element in pyroptosis activation, which participates in regulating enteritis. Meanwhile, autophagy is also engaged in intestinal inflammation. However, the function of pyroptosis and autophagy in FB1-mediated enterotoxicity remains unclear. In this study, we explored the effects of FB1 on enteritis and the underlying mechanism in vivo and in vitro. Our data showed that FB1 exposure damaged the intestinal epithelium and promoted the secretion of inflammatory cytokines. Meanwhile, FB1 exposure significantly upregulated the expression of pyroptosis-related genes. Then, MCC950, an inhibitor of NLRP3, significantly blocked FB1-induced pyroptosis in IPEC-J2 cells. In addition, FB1 treatment elevated the levels of autophagy. Moreover, the phosphorylation of the mammalian target of rapamycin (mTOR), an upstream protein of the autophagy pathway, was inhibited by FB1 exposure. Notably, rapamycin, an inhibitor of mTOR, instead of MHY1485, an agonist of mTOR, could ameliorate FB1-induced intestinal inflammatory injury and inhibit the upregulation of pyroptosis-related genes. In summary, we demonstrated that autophagy exhibited a protective effect against NLRP3 inflammasome-dependent pyroptosis on FB1-induced enteritis. Our data clarify a favorable protective role for the activation of autophagy in FB1 poisoning.