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

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外文摘要：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.

外文关键词：

Systemic lupus erythematosusROSVSTM1Galectin-1Glutathione

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 Zhang

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作者单位：

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

Department of Rheumatology,Key Laboratory of Myositis,China-Japan Friendship Hospital,Beijing,China

Department of Medicine,Beth Israel Deaconess Medical Center,Harvard Medical School,Boston,MA,USA

Medical Research Center,Peking Union Medical College Hospital,Chinese Academy of Medical Sciences,Beijing,China

Department of Rheumatology,Beijing Hospital,National Center of Gerontology,Institute of Geriatric Medicine,Clinical Immunology Center,Chinese Academy of Medical Sciences,Beijing,China

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

Department of Rheumatology,Xiangya Hospital,Central South University,Hunan,China

MOE Key Laboratory of Bioinformatics,Center for Synthetic&Systems Biology,School of Life Sciences,Tsinghua University,Beijing,China

Key Laboratory of Structural Biology of Zhejiang Province,School of Life Sciences,Westlake University,Hangzhou,Zhejiang,China

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

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基金：

National Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Key R&D Program of ChinaChinese Academy of Medical Science Innovation Fund for Medical SciencesChinese Academy of Medical Science Innovation Fund for Medical SciencesChinese Academy of Medical Science Innovation Fund for Medical SciencesChinese Academy of Medical Science Innovation Fund for Medical SciencesChinese Academy of Medical Science Innovation Fund for Medical SciencesChinese Academy of Medical Science Innovation Fund for Medical SciencesCapital's Funds for Health Improvement and ResearchNational High Level Hospital Clinical Research FundingNational High Level Hospital Clinical Research Funding

项目编号：

817881018217179982100942821717268217179882230060321410042022YFC36020002021-I2M-1-0172022-I2M-JB-0032021-I2M-1-0472021-I2M-1-0402021-I2M-1-0162021-I2M-1-0262020-2-4019BJ-2022-116BJ-2023-084

出版年：

2023

DOI：

10.1038/s41423-023-01084-z

中国免疫学杂志(英文版)

中国免疫学会

中国免疫学杂志(英文版)

CSTPCDCSCDSCI

影响因子：0.731

ISSN：1672-7681

年,卷(期)：2023.20(11)

参考文献量68