Oxidized galectin-1 in SLE fails to bind the inhibitory receptor VSTM1 and increases reactive oxygen species levels in neutrophils  

作　　者：Xu Jiang Xinyue Xiao Hao Li Yiyi Gong Min Wang Huaxia Yang Lidan Zhao Ying Jiang Yanping Wei Chongchong Zhao Jin Li Yuling Chen Shan Feng Haiteng Deng Shiliang Ma Yue Xu Yudong Liu George C.Tsokos Minghong Jiang Xuan Zhan 

机构地区：[1]Medical Research Center,State Key Laboratory of Complex Severe and Rare Diseases,Peking Union Medical College Hospital,Department of Rheumatology,Beijing Hospital,National Center of Gerontology,Institute of Geriatric Medicine,Chinese Academy of Medical Sciences,Beijing,China [2]Department of Rheumatology,Key Laboratory of Myositis,China-Japan Friendship Hospital,Beijing,China [3]Department of Medicine,Beth Israel Deaconess Medical Center,Harvard Medical School,Boston,MA,USA [4]Medical Research Center,Peking Union Medical College Hospital,Chinese Academy of Medical Sciences,Beijing,China [5]Department of Rheumatology,Beijing Hospital,National Center of Gerontology,Institute of Geriatric Medicine,Clinical Immunology Center,Chinese Academy of Medical Sciences,Beijing,China [6]Department of Rheumatology and Clinical Immunology,Peking Union Medical College Hospital,Clinical Immunology Center,Chinese Academy of Medical Sciences and Peking Union Medical College,The Ministry of Education Key Laboratory,Beijing,China [7]Department of Rheumatology,Xiangya Hospital,Central South University,Hunan,China [8]MOE Key Laboratory of Bioinformatics,Center for Synthetic&Systems Biology,School of Life Sciences,Tsinghua University,Beijing,China [9]Key Laboratory of Structural Biology of Zhejiang Province,School of Life Sciences,Westlake University,Hangzhou,Zhejiang,China [10]State Key Laboratory of Common Mechanism Research for Major Diseases,Institute of Basic Medical Sciences Chinese Academy of Medical Sciences,School of Basic Medicine Peking Union Medical College,Beijing,China

出　　处：《Cellular & Molecular Immunology》2023年第11期1339-1351,共13页中国免疫学杂志（英文版）

基　　金：The authors are grateful to all of the patients who participated in the study.We thank Prof Dalong Ma Lab and Prof Wenling Han Lab at Peking University Health Science Center for providing plasmids and helpful discussions.We also thank the Center for Biomarker Discovery and Validation,National Infrastructures for Translational Medicine(PUMCH),Institute of Clinical Medicine,Peking Union Medical College Hospital for instrument support and assistance.This study was supported by grants from the National Natural Science Foundation of China(81788101,82171799,82100942,82171726,82171798,82230060,32141004);National Key R&D Program of China(2022YFC3602000);Chinese Academy of Medical Science Innovation Fund for Medical Sciences(2021-I2M-1-017,2022-I2M-JB-003,2021-I2M-1-047,2021-I2M-1-040,2021-I2M-1-016,and 2021-I2M-1-026);Capital’s Funds for Health Improvement and Research(2020-2-4019);National High Level Hospital Clinical Research Funding(BJ-2022-116,BJ-2023-084).

摘　　要：Inhibitory immune receptors set thresholds for immune cell activation,and their deficiency predisposes a person to autoimmune responses.However,the agonists of inhibitory immune receptors remain largely unknown,representing untapped sources of treatments for autoimmune diseases.Here,we show that V-set and transmembrane domain-containing 1(VSTM1)is an inhibitory receptor and that its binding by the competent ligand soluble galectin-1(Gal1)is essential for maintaining neutrophil viability mediated by downregulated reactive oxygen species production.However,in patients with systemic lupus erythematosus(SLE),circulating Gal1 is oxidized and cannot be recognized by VSTM1,leading to increased intracellular reactive oxygen species levels and reduced neutrophil viability.Dysregulated neutrophil function or death contributes significantly to the pathogenesis of SLE by providing danger molecules and autoantigens that drive the production of inflammatory cytokines and the activation of autoreactive lymphocytes.Interestingly,serum levels of glutathione,an antioxidant able to convert oxidized Gal1 to its reduced form,were negatively correlated with SLE disease activity.Taken together,our findings reveal failed inhibitory Gal1/VSTM1 pathway activation in patients with SLE and provide important insights for the development of effective targeted therapies.

关 键 词：Systemic lupus erythematosus ROS VSTM1 GALECTIN-1 GLUTATHIONE 

分 类 号：R392[医药卫生—免疫学]