Jiping Sun, Youqin Zhang, Qingbing Zhang, Lin Hu, Linfeng Zhao, Hongdong Wang, Yue Yuan, Hongshen Niu, Dongdi Wang, Huasheng Zhang, Jianyue Liu, Xujiao Feng, Xiaohui Su, Ju Qiu, Jing Sun, Heping Xu, Catherine Zhang, Kathleen Wang, Yan Bi, Edgar G. Engleman, Lei Shen
{"title":"代谢调节因子 LKB1 控制脂肪组织 ILC2 PD-1 的表达和线粒体稳态,以防止胰岛素抵抗","authors":"Jiping Sun, Youqin Zhang, Qingbing Zhang, Lin Hu, Linfeng Zhao, Hongdong Wang, Yue Yuan, Hongshen Niu, Dongdi Wang, Huasheng Zhang, Jianyue Liu, Xujiao Feng, Xiaohui Su, Ju Qiu, Jing Sun, Heping Xu, Catherine Zhang, Kathleen Wang, Yan Bi, Edgar G. Engleman, Lei Shen","doi":"10.1016/j.immuni.2024.04.024","DOIUrl":null,"url":null,"abstract":"<p>Adipose tissue group 2 innate lymphoid cells (ILC2s) help maintain metabolic homeostasis by sustaining type 2 immunity and promoting adipose beiging. Although impairment of the ILC2 compartment contributes to obesity-associated insulin resistance, the underlying mechanisms have not been elucidated. Here, we found that ILC2s in obese mice and humans exhibited impaired liver kinase B1 (LKB1) activation. Genetic ablation of LKB1 disrupted ILC2 mitochondrial metabolism and suppressed ILC2 responses, resulting in exacerbated insulin resistance. Mechanistically, LKB1 deficiency induced aberrant PD-1 expression through activation of NFAT, which in turn enhanced mitophagy by suppressing Bcl-xL expression. Blockade of PD-1 restored the normal functions of ILC2s and reversed obesity-induced insulin resistance in mice. Collectively, these data present the LKB1-PD-1 axis as a promising therapeutic target for the treatment of metabolic disease.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":null,"pages":null},"PeriodicalIF":25.5000,"publicationDate":"2024-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Metabolic regulator LKB1 controls adipose tissue ILC2 PD-1 expression and mitochondrial homeostasis to prevent insulin resistance\",\"authors\":\"Jiping Sun, Youqin Zhang, Qingbing Zhang, Lin Hu, Linfeng Zhao, Hongdong Wang, Yue Yuan, Hongshen Niu, Dongdi Wang, Huasheng Zhang, Jianyue Liu, Xujiao Feng, Xiaohui Su, Ju Qiu, Jing Sun, Heping Xu, Catherine Zhang, Kathleen Wang, Yan Bi, Edgar G. Engleman, Lei Shen\",\"doi\":\"10.1016/j.immuni.2024.04.024\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>Adipose tissue group 2 innate lymphoid cells (ILC2s) help maintain metabolic homeostasis by sustaining type 2 immunity and promoting adipose beiging. Although impairment of the ILC2 compartment contributes to obesity-associated insulin resistance, the underlying mechanisms have not been elucidated. Here, we found that ILC2s in obese mice and humans exhibited impaired liver kinase B1 (LKB1) activation. Genetic ablation of LKB1 disrupted ILC2 mitochondrial metabolism and suppressed ILC2 responses, resulting in exacerbated insulin resistance. Mechanistically, LKB1 deficiency induced aberrant PD-1 expression through activation of NFAT, which in turn enhanced mitophagy by suppressing Bcl-xL expression. Blockade of PD-1 restored the normal functions of ILC2s and reversed obesity-induced insulin resistance in mice. Collectively, these data present the LKB1-PD-1 axis as a promising therapeutic target for the treatment of metabolic disease.</p>\",\"PeriodicalId\":13269,\"journal\":{\"name\":\"Immunity\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":25.5000,\"publicationDate\":\"2024-05-20\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Immunity\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1016/j.immuni.2024.04.024\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"IMMUNOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Immunity","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.immuni.2024.04.024","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
Metabolic regulator LKB1 controls adipose tissue ILC2 PD-1 expression and mitochondrial homeostasis to prevent insulin resistance
Adipose tissue group 2 innate lymphoid cells (ILC2s) help maintain metabolic homeostasis by sustaining type 2 immunity and promoting adipose beiging. Although impairment of the ILC2 compartment contributes to obesity-associated insulin resistance, the underlying mechanisms have not been elucidated. Here, we found that ILC2s in obese mice and humans exhibited impaired liver kinase B1 (LKB1) activation. Genetic ablation of LKB1 disrupted ILC2 mitochondrial metabolism and suppressed ILC2 responses, resulting in exacerbated insulin resistance. Mechanistically, LKB1 deficiency induced aberrant PD-1 expression through activation of NFAT, which in turn enhanced mitophagy by suppressing Bcl-xL expression. Blockade of PD-1 restored the normal functions of ILC2s and reversed obesity-induced insulin resistance in mice. Collectively, these data present the LKB1-PD-1 axis as a promising therapeutic target for the treatment of metabolic disease.
期刊介绍:
Immunity is a publication that focuses on publishing significant advancements in research related to immunology. We encourage the submission of studies that offer groundbreaking immunological discoveries, whether at the molecular, cellular, or whole organism level. Topics of interest encompass a wide range, such as cancer, infectious diseases, neuroimmunology, autoimmune diseases, allergies, mucosal immunity, metabolic diseases, and homeostasis.