PMID- 37470905 OWN - NLM STAT- MEDLINE DCOM- 20240304 LR - 20240304 IS - 1568-5608 (Electronic) IS - 0925-4692 (Linking) VI - 32 IP - 1 DP - 2024 Feb TI - Immune Response Gene-1 [IRG1]/itaconate protect against multi-organ injury via inhibiting gasdermin D-mediated pyroptosis and inflammatory response. PG - 419-432 LID - 10.1007/s10787-023-01278-x [doi] AB - Sepsis is a multiple organ dysfunction syndrome due to a dysregulated response to infection with unacceptably high mortality. Currently, no effective treatment exists for sepsis. IRG1/itaconate has been considered to play a protective role for various inflammatory diseases. In the present study, we explored the protective role and mechanisms of IRG1/itaconate on lipopolysaccharide (LPS)-induced multi-organ injury. The LPS-induced sepsis model was used. IRG1(-/-) and wild type mice were used to explore the protective role of IRG1/itaconate on multi-organ injury. GSDMD(-/-) mice were used to explore the effect of GSDMD-mediated pyroptosis on LPS-induced model. RAW264.7 cells and bone-marrow-derived macrophages (BMDMs) were used for in vitro studies. In vivo experiments, we found IRG1 deficiency aggravated LPS-induced multi-organ injury especially lung injury. 4-Octyl itaconate (4-OI), a derivative of itaconate, significantly ameliorated LPS-induced acute lung, liver, and kidney injury. Furthermore, IRG1/4-OI decreased serum interleukin-1beta (IL-1beta), IL-6, tumor necrosis factor-alpha (TNF-alpha) level, macrophage infiltration, and TUNEL-positive cells in lung and liver tissue. Western blot showed IRG1/itaconate decreased the expressions of p-ERK, p-P38, p-JNK, and p-P65 and increased the expression of Nrf2/HO-1 in lung tissue. Meanwhile, 4-OI inhibited the expression of GSDMD-N. In vitro experiments, 4-OI inhibited ROS production and promoted apoptosis under LPS stimulation in RAW264.7 cells. Furthermore, 4-OI inhibited nuclear factor-kappaB/mitogen-activated protein kinase pathways and GSDMD-medicated pyroptosis in BMDMs. Finally, we used GSDMD(-/-) mice to explore the effect of pyroptosis on LPS-induced multi-organ injury. The results showed that GSDMD deficiency significantly ameliorated lung injury. In conclusion, our data demonstrated that IRG1/itaconate protect against multi-organ injury via inhibiting inflammation response and GSDMD-indicated pyroptosis, which may be a promising agent for protecting against sepsis. CI - (c) 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG. FAU - Yang, Wenchang AU - Yang W AD - Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan, 430022, Hubei Province, China. FAU - Wang, Yaxin AU - Wang Y AD - Department of Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. FAU - Huang, Yongzhou AU - Huang Y AD - Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan, 430022, Hubei Province, China. AD - Department of General Surgery, First Affiliated Hospital, School of Medicine, Shihezi University, Shihezi, 832000, Xinjiang, People's Republic of China. FAU - Wang, Tao AU - Wang T AD - Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan, 430022, Hubei Province, China. FAU - Li, Chengguo AU - Li C AD - Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan, 430022, Hubei Province, China. FAU - Zhang, Peng AU - Zhang P AD - Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan, 430022, Hubei Province, China. FAU - Liu, Weizhen AU - Liu W AD - Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan, 430022, Hubei Province, China. FAU - Yin, Yuping AU - Yin Y AD - Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan, 430022, Hubei Province, China. FAU - Li, Ruidong AU - Li R AUID- ORCID: 0000-0003-1356-2427 AD - Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan, 430022, Hubei Province, China. liruidong@hust.edu.cn. FAU - Tao, Kaixiong AU - Tao K AD - Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan, 430022, Hubei Province, China. kaixiongtao@hust.edu.cn. LA - eng GR - 81701883/National Natural Science Foundation of China/ GR - 82072736/National Natural Science Foundation of China/ GR - 82172171/National Natural Science Foundation of China/ PT - Journal Article DEP - 20230720 PL - Switzerland TA - Inflammopharmacology JT - Inflammopharmacology JID - 9112626 RN - Q4516562YH (itaconic acid) RN - 0 (Gasdermins) RN - 0 (Lipopolysaccharides) RN - 0 (Succinates) SB - IM MH - Animals MH - Mice MH - Pyroptosis MH - Gasdermins MH - Lipopolysaccharides/pharmacology MH - *Lung Injury MH - *Sepsis/drug therapy MH - Immunity MH - *Succinates OTO - NOTNLM OT - Inflammation OT - LPS OT - Multi-organ injury OT - Pyroptosis OT - Sepsis EDAT- 2023/07/20 13:07 MHDA- 2024/03/04 06:46 CRDT- 2023/07/20 11:11 PHST- 2023/01/29 00:00 [received] PHST- 2023/06/09 00:00 [accepted] PHST- 2024/03/04 06:46 [medline] PHST- 2023/07/20 13:07 [pubmed] PHST- 2023/07/20 11:11 [entrez] AID - 10.1007/s10787-023-01278-x [pii] AID - 10.1007/s10787-023-01278-x [doi] PST - ppublish SO - Inflammopharmacology. 2024 Feb;32(1):419-432. doi: 10.1007/s10787-023-01278-x. Epub 2023 Jul 20.