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

Cellular & Molecular Immunology volume 20, pages 1339–1351 (2023)Cite this article

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Abstract

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.

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Data availability

The data are available upon reasonable request. All data relevant to the study are included in the paper or uploaded as supplementary information. The data are available from the corresponding author (email:zxpumch2003@sina.com ORCID: https://orcid.org/0000-0001-8775-1699) upon reasonable request.

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Acknowledgements

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), and National High Level Hospital Clinical Research Funding (BJ-2022-116, BJ-2023-084).

Author information

Author notes

  1. These authors contributed equally: Xu Jiang, Xinyue Xiao, Hao Li, Yiyi Gong.

Authors and Affiliations

  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

    Xu Jiang

  2. Department of Rheumatology, Key Laboratory of Myositis, China–Japan Friendship Hospital, Beijing, China

    Xinyue Xiao

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

    Hao Li & George C. Tsokos

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

    Yiyi Gong & Yanping Wei

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

    Min Wang, Shiliang Ma, Yue Xu, Yudong Liu & Xuan Zhang

  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

    Huaxia Yang & Lidan Zhao

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

    Ying Jiang

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

    Chongchong Zhao, Jin Li, Yuling Chen & Haiteng Deng

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

    Shan Feng

  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

    Minghong Jiang

Authors
  1. Xu Jiang
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  2. Xinyue Xiao
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  11. Jin Li
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  18. George C. Tsokos
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  20. Xuan Zhang
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Contributions

XZ, GCT, and MJ designed and supervised the study; XJ, XX, MW, HY, LZ, SM, YX, YL, YJ, and YW collected samples and performed clinical analysis; XJ, XX, and YG designed and performed experiments; XJ, YG, CZ, JL, YC, SF, and HD performed and analyzed the MS data; and XJ, XX, HL, YG, MJ, GCT and XZ drafted and revised the paper.

Corresponding authors

Correspondence to George C. Tsokos, Minghong Jiang or Xuan Zhang.

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Competing interests

The authors declare no competing interests.

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The study was approved by the Ethics Committee of PUMC Hospital Review Board.

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Jiang, X., Xiao, X., Li, H. et al. Oxidized galectin-1 in SLE fails to bind the inhibitory receptor VSTM1 and increases reactive oxygen species levels in neutrophils. Cell Mol Immunol 20, 1339–1351 (2023). https://doi.org/10.1038/s41423-023-01084-z

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