Mitochondrial GRIM-19 loss in parietal cells promotes spasmolytic polypeptide-expressing metaplasia through NLR family pyrin domain-containing 3 (NLRP3)-mediated IL-33 activation via a reactive oxygen species (ROS)-NRF2-Heme oxygenase-1(HO-1)-NF-kappa B axis

作者全名："Zeng, Xin; Yang, Meihua; Ye, Tingbo; Feng, Jinmei; Xu, Xiaohui; Yang, Huaan; Wang, Xin; Bao, Liming; Li, Rui; Xue, Bingqian; Zang, Jinbao; Huang, Yi"

作者地址："[Zeng, Xin; Feng, Jinmei; Xu, Xiaohui; Zang, Jinbao; Huang, Yi] Chongqing Med Univ, Inst Paediat, Natl Clin Res Ctr Child Hlth & Disorders, Minist Educ,Key Lab Child Dev & Disorders,Children, Chongqing 400014, Peoples R China; [Zeng, Xin; Ye, Tingbo; Li, Rui; Xue, Bingqian] Third Peoples Hosp Chengdu, Dept Lab Med, Chengdu 610031, Peoples R China; [Yang, Meihua] Washington Univ, Dept Neurol, Sch Med, St Louis, MO 63110 USA; [Yang, Meihua] Barnes Jewish Hosp, St Louis, MO 63110 USA; [Yang, Huaan] Yubei Dist Peoples Hosp, Dept Urol Surg, Chongqing 401120, Peoples R China; [Wang, Xin] Chongqing Med Univ, Minist Educ, Key Lab Mol Biol Infect Dis, Chongqing 40016, Peoples R China; [Bao, Liming] Cornell Univ, Dept Pathol & Lab Med, Weill Cornell Med Coll, New York, NY 10065 USA; [Huang, Yi] Chongqing Med Univ, Childrens Hosp, 136 Zhongshan Erd Rd, Chongqing 400014, Peoples R China"

通信作者："Huang, Y (通讯作者)，Chongqing Med Univ, Childrens Hosp, 136 Zhongshan Erd Rd, Chongqing 400014, Peoples R China."

来源：FREE RADICAL BIOLOGY AND MEDICINE

ESI学科分类：BIOLOGY & BIOCHEMISTRY

WOS号：WOS:000971239300001

JCR分区：Q1

影响因子：7.1

年份：2023

卷号：202

期号：　

开始页：46

结束页：61

文献类型：Article

关键词：Chronic atrophic gastritis (CAG); GRIM-19; NLRP3 inflammasome; SPEM; IL-33

摘要："Spasmolytic polypeptide-expressing metaplasia (SPEM), as a pre-neoplastic precursor of intestinal metaplasia (IM), plays critical roles in the development of chronic atrophic gastritis (CAG) and gastric cancer (GC). However, the pathogenetic targets responsible for the SPEM pathogenesis remain poorly understood. Gene associated with retinoid-IFN-induced mortality 19 (GRIM-19), an essential subunit of the mitochondrial respiratory chain complex I, was progressively lost along with malignant transformation of human CAG, little is known about the potential link between GRIM-19 loss and CAG pathogenesis. Here, we show that lower GRIM-19 is associated with higher NF-kappa B RelA/p65 and NLR family pyrin domain-containing 3 (NLRP3) levels in CAG lesions. Functionally, GRIM-19 deficiency fails to drive direct differentiation of human GES-1 cells into IM or SPEM-like cell lineages in vitro, whereas parietal cells (PCs)-specific GRIM-19 knockout disturbs gastric glandular differentiation and promotes spontaneous gastritis and SPEM pathogenesis without intestinal characteristics in mice. Mechanistically, GRIM-19 loss causes chronic mucosal injury and aberrant NRF2 (Nuclear factor erythroid 2-related factor 2)- HO-1 (Heme oxygenase-1) activation via reactive oxygen species (ROS)-mediated oxidative stress, resulting in aberrant NF-kappa B activation by inducing p65 nuclear translocation via an IKK/I kappa B partner, while NRF2-HO-1 activation contributes to GRIM-19 loss-driven NF-kappa B activation via a positive feedback NRF2-HO-1 loop. Furthermore, GRIM-19 loss did not cause obvious PCs loss but triggers NLRP3 inflammasome activation in PCs via a ROS-NRF2-HO-1-NF-kappa B axis, leading to NLRP3-dependent IL-33 expression, a key mediator for SPEM formation. Moreover, intraperitoneal administration of NLRP3 inhibitor MCC950 drastically attenuates GRIM-19 loss-driven gastritis and SPEM in vivo. Our study suggests that mitochondrial GRIM-19 maybe a potential pathogenetic target for the SPEM pathogenesis, and its deficiency promotes SPEM through NLRP3/IL-33 pathway via a ROS-NRF2-HO-1-NF-kappa B axis. This finding not only provides a causal link between GRIM-19 loss and SPEM pathogenesis, but offers potential therapeutic strategies for the early prevention of intestinal GC."

基金机构："National Nature Science Foundation of China [32171119]; Science and Technology Research Program of Chongqing Municipal Education Commission [KJZD-K202100401]; Ministry of Education Key Laboratory of Child Development [GBRP-202104, GBRP-202116]; Nature Science Foundation of Chongqing Science and Technology Bureau [CSTB2022NSCQ-MSX0838]; Program for Youth Innovation in Future Medicine, Chongqing Medical University [W1075]"

基金资助正文："This study was partly supported by National Nature Science Foundation of China [Grant No.32171119] ; The Science and Technology Research Program of Chongqing Municipal Education Commission [Grant No. KJZD-K202100401] ; The general basic research project from Ministry of Education Key Laboratory of Child Development and Disorders [Grant No. GBRP-202104 and GBRP-202116] ; Nature Science Foundation of Chongqing Science and Technology Bureau [Grant No. CSTB2022NSCQ-MSX0838] ; Program for Youth Innovation in Future Medicine, Chongqing Medical University [Grant No.W1075] ."