Dehydroepiandrosterone alleviates intestinal inflammatory damage via GPR30-mediated Nrf2 activation and NLRP3 inflammasome inhibition in colitis mice

Abstract

Dehydroepiandrosterone (DHEA) is a popular dietary supplement that has anti-inflammatory, anti-oxidant and immune-regulating role; meanwhile, it also can effective in the protection of inflammation diseases such as inflammatory bowel disease (IBD), but the underlying mechanisms remain elusive. Here, we demonstrated that DHEA inhibits excessive inflammation response and enhances gut barrier function via activating the G protein-coupled receptor 30 (GPR30). GPR30-induced the ERK phosphorylation and p62 accumulation led to the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway, which subsequently inhibited the reactive oxygen species (ROS) overproduction and finally alleviated the intestinal barrier dysfunction. Furthermore, DHEA blocked the p38-induced NLRP3 inflammasome activation in both LPS-stimulated colon epithelial cells and macrophages. In addition, in vivo results showed that DHEA and GPR30 agonist G1 attenuated inflammatory responses and gut barrier dysfunction in colitis mice, while the GPR30 specific inhibitor G15 abrogated these beneficial effects of DHEA. Cumulatively, our study unveiled that DHEA is an effective anti-inflammatory agent and suggested that GPR30 could as a potential target for the treatment of IBD.

Keywords: Colitis; Dehydroepiandrosterone; GPR30; NLRP3 inflammasome; Nrf2.