Yang Wenchang, Wang Yaxin, Wang Tao, Li Chengguo, Shi Liang, Zhang Peng, Yin Yuping, Tao Kaixiong, Li Ruidong
Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China.
Department of Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China.
Genes Dis. 2022 Jun 20;10(4):1552-1563. doi: 10.1016/j.gendis.2022.05.039. eCollection 2023 Jul.
Inflammatory bowel disease (IBD) is a chronic relapsing gastrointestinal disorder, while the treatment effect is not satisfactory. Immune responsive gene 1 () 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 and . 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. 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 . Meanwhile, our study revealed that 4-OI inhibited caspase3/GSDME-mediated pyroptosis induced by TNF-α . 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.
炎症性肠病（IBD）是一种慢性复发性胃肠道疾病，而其治疗效果并不理想。免疫反应基因1（IRG1）是巨噬细胞中一种在炎症反应时高表达的基因，可催化衣康酸的产生。研究报道IRG1/衣康酸具有显著的抗氧化作用。本研究旨在探讨IRG1/衣康酸对葡聚糖硫酸钠（DSS）诱导的结肠炎的作用及机制。在实验中，我们发现IRG1/衣康酸通过增加小鼠体重、结肠长度、降低疾病活动指数和结肠炎症，对急性结肠炎发挥保护作用。同时，IRG1缺失加剧了巨噬细胞/CD4/CD8 T细胞的积聚，并增加了白细胞介素（IL）-1β、肿瘤坏死因子-α（TNF-α）、IL-6的释放，核因子-κB（NF-κB）/丝裂原活化蛋白激酶（MAPK）信号通路的激活以及gasdermin D（GSDMD）介导的细胞焦亡。衣康酸衍生物4-辛基衣康酸（4-OI）减轻了这些变化，从而缓解了DSS诱导的结肠炎。在实验中，我们发现4-OI抑制活性氧的产生，从而抑制RAW264.7和小鼠骨髓来源巨噬细胞中MAPK/NF-κB信号通路的激活。同时，我们发现4-OI抑制caspase1/GSDMD介导的细胞焦亡以减少细胞因子的释放。最后，我们发现抗TNF-α药物降低了DSS诱导的结肠炎的严重程度并抑制了gasdermin E（GSDME）介导的细胞焦亡。同时，我们的研究表明4-OI抑制了TNF-α诱导的caspase3/GSDME介导的细胞焦亡。综上所述，IRG1/衣康酸通过抑制炎症反应和GSDMD/GSDME介导的细胞焦亡在DSS诱导的结肠炎中发挥保护作用，这可能是IBD治疗的一个有前景的候选药物。
