2. Academic Validation
  3. Metabolic regulator LKB1 controls adipose tissue ILC2 PD-1 expression and mitochondrial homeostasis to prevent insulin resistance

Metabolic regulator LKB1 controls adipose tissue ILC2 PD-1 expression and mitochondrial homeostasis to prevent insulin resistance

  • Immunity. 2024 May 14:S1074-7613(24)00229-2. doi: 10.1016/j.immuni.2024.04.024.
Jiping Sun 1,  Youqin Zhang 1,  Qingbing Zhang 1,  Lin Hu 1,  Linfeng Zhao 1,  Hongdong Wang 2,  Yue Yuan 2,  Hongshen Niu 3,  Dongdi Wang 1,  Huasheng Zhang 3,  Jianyue Liu 3,  Xujiao Feng 3,  Xiaohui Su 1,  Ju Qiu 4,  Jing Sun 5,  Heping Xu 6,  Catherine Zhang 7,  Kathleen Wang 7,  Yan Bi 2,  Edgar G Engleman 7,  Lei Shen 8
Affiliations

Affiliations

  • 1 Center for Immune-Related Diseases at Shanghai Institute of Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Department of Immunology and Microbiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
  • 2 Department of Endocrinology, Drum Tower Hospital affiliated with Nanjing University Medical School, Branch of National Clinical Research Centre for Metabolic Diseases, Nanjing 210008, China.
  • 3 Department of Immunology and Microbiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
  • 4 CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
  • 5 Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
  • 6 Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang 310024, China.
  • 7 Department of Pathology, Stanford University, Stanford, CA 94305, USA.
  • 8 Center for Immune-Related Diseases at Shanghai Institute of Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Department of Immunology and Microbiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. Electronic address: lshen@shsmu.edu.cn.
PMID: 38772366 DOI: 10.1016/j.immuni.2024.04.024
Abstract

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.

Keywords

PD-1; group 2 innate lymphoid cells; insulin resistance; liver kinase B1; mitophagy.

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