Inflammatory bowel disease (IBD) is a chronic relapsing
gastrointestinal disorder, while the treatment effect is not satisfactory. Immune responsive gene 1 (IRG1) is a highly expressed gene in macrophage in response to inflammatory response and catalyzes the production of
itaconate. Studies have reported that IRG1/
itaconate has a significant
antioxidant effect. This study aimed to investigate the effect and mechanism of IRG1/
itaconate on
dextran sulfate sodium (DSS)-induced
colitis in vivo and in vitro. In vivo experiments, we found IRG1/
itaconate exerted protective effects against acute
colitis by increasing mice weight, the length of colon, reducing disease activity index and colonic
inflammation. Meanwhile, IRG1 deletion aggravated the macrophages/CD4+/CD8+ T-cell accumulation, and increased the release of
interleukin (IL)-1β,
tumor necrosis factor-α (TNF-α),
IL-6, the activation of nuclear factor-κB (NF-κB)/
mitogen-activated protein kinase (MAPK) signaling pathway, and gasdermin D (GSDMD) mediated pyroptosis. Four-octyl
itaconate (4-OI), a derivative of
itaconate, attenuated these changes, therefore relieved DSS-induced
colitis. In vitro experiment, we found 4-OI inhibited the
reactive oxygen species production, thereby inhibiting the activation of MAPK/NF-κB signaling pathway in RAW264.7 and murine bone-marrow-derived macrophages. Simultaneously, we found 4-OI inhibited caspase1/GSDMD-mediated pyroptosis to reduce the release of
cytokines. Finally, we found anti-TNF-α agent reduced the severity of DSS-induced
colitis and inhibited gasdermin E (GSDME)-mediated pyroptosis in vivo. Meanwhile, our study revealed that 4-OI inhibited caspase3/GSDME-mediated pyroptosis induced by TNF-α in vitro. Taken together, IRG1/
itaconate exerted a protective role in DSS-induced
colitis by inhibiting inflammatory response and GSDMD/GSDME-mediated pyroptosis, which could be a promising candidate for IBD
therapy.