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MST4 kinase regulates immune thrombocytopenia by phosphorylating STAT1-mediated M1 polarization of macrophages

Cellular & Molecular Immunology volume 20, pages 1413–1427 (2023)Cite this article

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A Correction to this article was published on 31 October 2023

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Abstract

Primary immune thrombocytopenia (ITP) is an autoimmune hemorrhagic disorder in which macrophages play a critical role. Mammalian sterile-20-like kinase 4 (MST4), a member of the germinal-center kinase STE20 family, has been demonstrated to be a regulator of inflammation. Whether MST4 participates in the macrophage-dependent inflammation of ITP remains elusive. The expression and function of MST4 in macrophages of ITP patients and THP-1 cells, and of a macrophage-specific Mst4−/− (Mst4ΔM/ΔM) ITP mouse model were determined. Macrophage phagocytic assays, RNA sequencing (RNA-seq) analysis, immunofluorescence analysis, coimmunoprecipitation (co-IP), mass spectrometry (MS), bioinformatics analysis, and phosphoproteomics analysis were performed to reveal the underlying mechanisms. The expression levels of the MST4 gene were elevated in the expanded M1-like macrophages of ITP patients, and this elevated expression of MST4 was restored to basal levels in patients with remission after high-dose dexamethasone treatment. The expression of the MST4 gene was significantly elevated in THP-1-derived M1 macrophages. Silencing of MST4 decreased the expression of M1 macrophage markers and cytokines, and impaired phagocytosis, which could be increased by overexpression of MST4. In a passive ITP mouse model, macrophage-specific depletion of Mst4 reduced the numbers of M1 macrophages in the spleen and peritoneal lavage fluid, attenuated the expression of M1 cytokines, and promoted the predominance of FcγRIIb in splenic macrophages, which resulted in amelioration of thrombocytopenia. Downregulation of MST4 directly inhibited STAT1 phosphorylation, which is essential for M1 polarization of macrophages. Our study elucidates a critical role for MST4 kinase in the pathology of ITP and identifies MST4 kinase as a potential therapeutic target for refractory ITP.

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Acknowledgements

This study was conducted at the Institute of Clinical Science of Zhongshan Hospital, Fudan University. The study was supported by the Medical Science Data Center of Shanghai Medical College of Fudan University. We sincerely thank all staff and participants for their important contributions.

Funding

This work was supported by grants from the National Natural Science Foundation of China (82370130, 81870098, 82300146), the Program of the Shanghai Academic/Technology Researcher Leader (20XD1401000), the Shanghai Engineering Research Center of Tumor Multi-Target Gene Diagnosis (20DZ2254300), the Key Subject Construction Program of the Shanghai Health Administrative Authority (ZK2019B30), and the Science and Technology Commission of the Shanghai Municipality (21ZR1459000). All authors obtained permission to acknowledge all those mentioned in the acknowledgments.

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  1. These authors contributed equally: Jingjing Cao, Lili Ji, Yanxia Zhan.

Authors and Affiliations

  1. Department of Hematology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China

    Jingjing Cao, Lili Ji, Yanxia Zhan, Xia Shao, Pengcheng Xu, Luya Cheng, Xibing Zhuang, Yang Ou, Feng Li & Yunfeng Cheng

  2. Center for Tumor Diagnosis & Therapy, Jinshan Hospital, Fudan University, Shanghai, 201508, China

    Xia Shao, Pengcheng Xu, Xibing Zhuang, Yang Ou & Yunfeng Cheng

  3. Department of Transfusion Medicine, Zhongshan Hospital, Fudan University, Shanghai, 200032, China

    Boting Wu

  4. Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai, 200032, China

    Pu Chen

  5. Department of Hematology, Zhongshan Hospital Qingpu Branch, Fudan University, Shanghai, 201700, China

    Fanli Hua, Lihua Sun, Feng Li & Yunfeng Cheng

  6. Department of Thoracic Surgery, Zhongshan-Xuhui Hospital, Fudan University, Shanghai, 200031, China

    Hao Chen

  7. State Key Laboratory of Genetic Engineering, Zhongshan Hospital, School of Life Sciences, Fudan University, Shanghai, 200438, China

    Zhaocai Zhou

  8. Institute of Clinical Science, Zhongshan Hospital, Fudan University, Shanghai, 200032, China

    Yunfeng Cheng

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Contributions

YC, ZZ, JC, LJ, YZ, and HC performed the literature review and drafted and revised the manuscript; JC, YC, HC, and ZZ contributed to the critical revision of the manuscript; YZ, LJ, PX, HC, YO, XZ, XS, BW, PC, LC, LS, FH, FL, and YC performed the experiments and analyzed the data. All the authors have read and approved the final manuscript.

Corresponding authors

Correspondence to Hao Chen, Zhaocai Zhou or Yunfeng Cheng.

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Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

The study was in accordance with the ethical standards formulated in the Helsinki Declaration and was approved by the respective local Medical Ethics Committees of Zhongshan Hospital of Fudan University (#B2020-279R). Written informed consent was obtained from each patient upon enrollment.

Additional information

Data sharing statement All data in this study are included in this published article and its supplementary information files. Original data are available from the corresponding author upon reasonable request.

The original online version of this article was revised: In this article, the details for Affiliation 1 were incorrectly given as ‘Department of Hematology, Fudan University, Shanghai 200032, China’ but should have been ‘Department of Hematology, Zhongshan Hospital, Fudan University, Shanghai 200032, China’; the details for Affiliation 3 were incorrectly given as ‘Department of Transfusion Medicine, Fudan University, Shanghai 200032, China’ but should have been ‘Department of Transfusion Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, China’; the details for Affiliation 4 were incorrectly given as ‘Department of Laboratory Medicine, Fudan University, Shanghai 200032, China’ but should have been ‘Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, China’. The original article has been corrected.

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Cao, J., Ji, L., Zhan, Y. et al. MST4 kinase regulates immune thrombocytopenia by phosphorylating STAT1-mediated M1 polarization of macrophages. Cell Mol Immunol 20, 1413–1427 (2023). https://doi.org/10.1038/s41423-023-01089-8

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