UCP2 knockout exacerbates sepsis-induced intestinal injury by promoting NLRP3-mediated pyroptosis

• Published in: International immunopharmacology 2024-11, Vol.141, p.112935, Article 112935
• Main Authors: Huang, Bolun, Lin, Gangxi, Chen, Feiyan, Yang, Wenmin, Zhang, Chunmin, Yao, Yu, Zeng, Qiyi, Yang, Yiyu, Huang, Jinda
• Format: Article
• Language: English
• Subjects: Animals; Disease Models, Animal; Furans - pharmacology; Indenes; Inflammasomes - metabolism; Intestinal Mucosa - immunology; Intestinal Mucosa - metabolism; Intestinal Mucosa - pathology; Intestines - immunology; Intestines - pathology; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; NLR Family, Pyrin Domain-Containing 3 Protein - genetics; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; NLRP3; Oxidative Stress; Pyroptosis; Sepsis - complications; Sepsis - immunology; Sepsis - metabolism; Sepsis-induced intestinal injury; Sulfonamides - pharmacology; Sulfones - pharmacology; UCP2; Uncoupling Protein 2 - genetics; Uncoupling Protein 2 - metabolism
• ISSN: 1567-5769; 1878-1705; 1878-1705
• DOI: 10.1016/j.intimp.2024.112935

•UCP2 expression was increased in the intestinal tissues of septic mice.•UCP2 knockout aggravated intestinal damage and intestinal permeability in septic mice.•UCP2 knockout aggravates intestinal oxidative stress, intestinal inflammation, and pyroptosis in septic mice.•UCP2 plays a protective role in sepsis-induced intestinal injury by modulating oxidative stress and inflammation through NLRP3 inflammasome-mediated pyroptosis. Sepsis-induced intestinal injury is a common complication that increases the morbidity and mortality associated with sepsis. UCP2, a mitochondrial membrane protein, is involved in numerous cellular processes, including metabolism, inflammation, and pyroptosis. According to our previous studies, UCP2 expression increases in septic intestinal tissue. However, its function in intestinal damage is not known. This work investigated UCP2′s role in intestinal injury caused by sepsis. A sepsis mouse model was established in wild-type and UCP2-knockout (UCP2-KO) animals using cecal ligation and puncture (CLP). MCC950, an NLRP3 inflammasome inhibitor, was injected intraperitoneally 3 h before CLP surgery. Overall, significantly higher levels of UCP2 were observed in the intestines of septic mice. UCP2-KO mice subjected to CLP exhibited exacerbated intestinal damage, characterized by enhanced mucosal erosion, inflammatory cell infiltration, and increased intestinal permeability. Furthermore, UCP2 knockout significantly increased oxidative stress, inflammation, and pyroptosis in the CLP mouse intestines. Interestingly, MCC950 not only inhibited pyroptosis but also reversed inflammation, oxidative stress as well as damage to intestinal tissues as a result of UCP2 knockout. Our results highlighted the protective functions of UCP2 in sepsis-associated intestinal injury through modulation of inflammation and oxidative stress via NLRP3 inflammasome-induced pyroptosis.