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GITRL impairs the immunosuppressive function of MDSCs via PTEN-mediated signaling pathway in experimental Sjögren syndrome

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Abstract

Background

Recent studies have revealed a role of the ligand for glucocorticoid-induced TNFR family-related protein (GITRL) in mediating functional dysregulations of myeloid-derived suppressor cells (MDSCs) in the pathogenesis of primary Sjögren syndrome (pSS), but the underlying molecular mechanism is largely unclear. In this study, we aimed to elucidate GITRL-mediated signaling pathways in MDSCs during the development of experimental SS (ESS).

Methods

MDSCs were stimulated with recombinant GITRL, the activation of PTEN, AKT and STAT3 in MDSCs was analyzed by Western blot. MDSCs with different treatment were adoptively transferred to ESS mice. ELISA was used to detect the level of autoantibodies. Proportions of Th1 and Th17 cells were examined by flow cytometry. Histological evaluation of glandular destruction was analyzed by hematoxylin and eosin (HE) staining. The interaction of GITR, TRAF3 and PP2A was detected by CoIP.

Results

Upon the engagement of GITR on MDSCs, PTEN was activated and led to the inhibition of downstream AKT/STAT3 signaling pathway, therefore, resulting in the impaired immunosuppressive function of MDSCs. In ESS mice, blocking the activity of PTEN could efficiently restore the immunomodulatory effect of MDSCs and alleviate the progression of ESS. Furthermore, TRAF3 was found to bind to GITR, and then recruited PP2A to dephosphorylate PTEN, thus enhancing the activity of PTEN.

Conclusion

This study elucidated the molecular mechanism underlying the effect of GITRL in regulating the function of MDSCs, which may provide a new therapeutic target for the treatment of pSS.

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Funding

This work was supported by the National Natural Science Foundation of China (Grant Nos. 81971542, 82171771, 82271854, 82004171, 82071817), Young Elite Scientist Sponsorship Program by CACM (CACM-2020-QNRC2-05), Hong Kong Research Grants Council General Research Fund (17113319, 17103821, 17111222) and Theme-Based Research Scheme (T12-703/19R), Shenzhen Science and Technology Program (YCYJ20210324114602008).

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Author notes

  1. Jie Tian and Beibei Zhang contributed equally to this work.

Authors and Affiliations

  1. Institute of Medical Immunology, Affiliated Hospital of Jiangsu University, Zhenjiang, 212000, China

    Jie Tian & Ke Rui

  2. Department of Laboratory Medicine, Jiangsu Key Laboratory of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, China

    Jie Tian, Beibei Zhang, Qingfang Yuan, Xueqing Sun, Chang Liu & Shengjun Wang

  3. Department of Rheumatology, The Second People’s Hospital, China Three Gorges University, Yichang, China

    Na Peng & Xiaoran Wang

  4. Department of Laboratory Medicine, Affiliated Hospital of Jiangsu University, Zhenjiang, China

    Bo Zhu & Ke Rui

  5. Division of Rheumatology, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China

    Man Han

  6. Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China

    Meng Cao

  7. Department of Pathology, Faculty of Medicine and Shenzhen Hospital, The University of Hong Kong, Hong Kong, China

    Fan Xiao & Liwei Lu

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  1. Jie Tian
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Contributions

JT and BZ performed the experiments, analyzed the data, and wrote the paper; QY, XS and CL performed the experiments; NP, BZ, MH, FX, WX and MC analyzed the data; KR, SW and LL designed the study and revised the paper. All authors read and approved the final manuscript.

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Correspondence to Ke Rui.

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Tian, J., Zhang, B., Yuan, Q. et al. GITRL impairs the immunosuppressive function of MDSCs via PTEN-mediated signaling pathway in experimental Sjögren syndrome. Inflamm. Res. 71, 1577–1588 (2022). https://doi.org/10.1007/s00011-022-01660-5

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