Protective effects of IRG1/itaconate on acute colitis through the inhibition of gasdermins-mediated pyroptosis and inflammation response
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 rep...
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| Format: | Article |
| Language: | English |
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KeAi Communications Co., Ltd.
2023-07-01
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| Series: | Genes and Diseases |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S235230422200174X |
| _version_ | 1797802197221638144 |
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| author | Wenchang Yang Yaxin Wang Tao Wang Chengguo Li Liang Shi Peng Zhang Yuping Yin Kaixiong Tao Ruidong Li |
| author_facet | Wenchang Yang Yaxin Wang Tao Wang Chengguo Li Liang Shi Peng Zhang Yuping Yin Kaixiong Tao Ruidong Li |
| author_sort | Wenchang Yang |
| collection | DOAJ |
| description | 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. |
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| format | Article |
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| institution | Directory Open Access Journal |
| issn | 2352-3042 |
| language | English |
| last_indexed | 2024-03-13T05:02:40Z |
| publishDate | 2023-07-01 |
| publisher | KeAi Communications Co., Ltd. |
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| series | Genes and Diseases |
| spelling | doaj.art-c5932bb50d16407fbda024c53adbcd2f2023-06-17T05:18:58ZengKeAi Communications Co., Ltd.Genes and Diseases2352-30422023-07-0110415521563Protective effects of IRG1/itaconate on acute colitis through the inhibition of gasdermins-mediated pyroptosis and inflammation responseWenchang Yang0Yaxin Wang1Tao Wang2Chengguo Li3Liang Shi4Peng Zhang5Yuping Yin6Kaixiong Tao7Ruidong Li8Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, ChinaDepartment of Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, ChinaDepartment of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, ChinaDepartment of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, ChinaDepartment of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, ChinaDepartment of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, ChinaDepartment of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, ChinaDepartment of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China; Corresponding author. Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology No. 1277 Jiefang Avenue, Wuhan, Hubei 430022, China.Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China; Corresponding author. Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology No. 1277 Jiefang Avenue, Wuhan, Hubei 430022, China.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.http://www.sciencedirect.com/science/article/pii/S235230422200174XColitisGasdermin DGasdermin EInflammationIRG1 |
| spellingShingle | Wenchang Yang Yaxin Wang Tao Wang Chengguo Li Liang Shi Peng Zhang Yuping Yin Kaixiong Tao Ruidong Li Protective effects of IRG1/itaconate on acute colitis through the inhibition of gasdermins-mediated pyroptosis and inflammation response Genes and Diseases Colitis Gasdermin D Gasdermin E Inflammation IRG1 |
| title | Protective effects of IRG1/itaconate on acute colitis through the inhibition of gasdermins-mediated pyroptosis and inflammation response |
| title_full | Protective effects of IRG1/itaconate on acute colitis through the inhibition of gasdermins-mediated pyroptosis and inflammation response |
| title_fullStr | Protective effects of IRG1/itaconate on acute colitis through the inhibition of gasdermins-mediated pyroptosis and inflammation response |
| title_full_unstemmed | Protective effects of IRG1/itaconate on acute colitis through the inhibition of gasdermins-mediated pyroptosis and inflammation response |
| title_short | Protective effects of IRG1/itaconate on acute colitis through the inhibition of gasdermins-mediated pyroptosis and inflammation response |
| title_sort | protective effects of irg1 itaconate on acute colitis through the inhibition of gasdermins mediated pyroptosis and inflammation response |
| topic | Colitis Gasdermin D Gasdermin E Inflammation IRG1 |
| url | http://www.sciencedirect.com/science/article/pii/S235230422200174X |
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