Protective effects of IRG1/itaconate on acute colitis through the inhibition of gasdermins-mediated pyroptosis and inflammation response

Wenchang Yang; Yaxin Wang; Tao Wang; Chengguo Li; Liang Shi; Peng Zhang; Yuping Yin; Kaixiong Tao; Ruidong Li

doi:10.1016/j.gendis.2022.05.039

Protective effects of IRG1/itaconate on acute colitis through the inhibition of gasdermins-mediated pyroptosis and inflammation response

Genes Dis. 2022 Jun 20;10(4):1552-1563. doi: 10.1016/j.gendis.2022.05.039. eCollection 2023 Jul.

Authors

Wenchang Yang¹, Yaxin Wang², Tao Wang¹, Chengguo Li¹, Liang Shi¹, Peng Zhang¹, Yuping Yin¹, Kaixiong Tao¹, Ruidong Li¹

Affiliations

¹ Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China.
² Department of Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China.

Abstract

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.

Keywords: Colitis; Gasdermin D; Gasdermin E; IRG1; Inflammation.