Indole-3-carbinol ameliorates necroptosis and inflammation of intestinal epithelial cells in mice with ulcerative colitis by activating aryl hydrocarbon receptor

Ulcerative colitis (UC) is a disease characterized by inflammation and disruption of the intestinal epithelial barrier. Necroptosis plays a critical role in disease progression. Indole-3-carbinol (I3C), a natural dietary agonist of Aryl Hydrocarbon Receptor (AHR), has shown alleviating effects on UC. However, its mechanisms of action have not been comprehensively elucidated. Therefore, we aimed at investigating the protective role of I3C in DSS-induced colitis mice models. I3C significantly ameliorated body weight loss, colon length shortening and colonic pathological damage in colitis mice, reduced disease activity index (DAI) and histological (HI) scores, as well as alleviated colonic Necroptosis and inflammation. In vitro, I3C attenuated Necroptosis and inflammation of colonoids and NCM460 cells. AHR, activated by I3C, inhibits activation of receptor-interacting protein kinase 1 (RIPK1) and the subsequent assembly of necrosome in a time-dependent manner, as well as suppressing NF-κB activation and decreasing TNF-α, IL-1β, IL-6 and IL-8 expression. Silencing of AHR aggravated Necroptosis and inflammation of NCM460 cells, and did not be ameliorated by I3C. Furthermore, AHR activation induces the expression of inhibitor of Apoptosis proteins (IAPs) and the ubiquitination of RIPK1. In conclusion, I3C exerts a protective effect in DSS-induced colitis mice models by alleviating the Necroptosis and inflammation of IECs through activating AHR.