2. Academic Validation
  3. MST4 kinase regulates immune thrombocytopenia by phosphorylating STAT1-mediated M1 polarization of macrophages

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

  • Cell Mol Immunol. 2023 Oct 13. doi: 10.1038/s41423-023-01089-8.
Jingjing Cao # 1,  Lili Ji # 1,  Yanxia Zhan # 1,  Xia Shao 1 2,  Pengcheng Xu 1 2,  Boting Wu 3,  Pu Chen 4,  Luya Cheng 1,  Xibing Zhuang 1 2,  Yang Ou 1 2,  Fanli Hua 5,  Lihua Sun 5,  Feng Li 1 5,  Hao Chen 6,  Zhaocai Zhou 7,  Yunfeng Cheng 8 9 10 11
Affiliations

Affiliations

  • 1 Department of Hematology, Fudan University, Shanghai, 200032, China.
  • 2 Center for Tumor Diagnosis & Therapy, Jinshan Hospital, Fudan University, Shanghai, 201508, China.
  • 3 Department of Transfusion Medicine, Fudan University, Shanghai, 200032, China.
  • 4 Department of Laboratory Medicine, Fudan University, Shanghai, 200032, China.
  • 5 Department of Hematology, Zhongshan Hospital Qingpu Branch, Fudan University, Shanghai, 201700, China.
  • 6 Department of Thoracic Surgery, Zhongshan-Xuhui Hospital, Fudan University, Shanghai, 200031, China. h.chen@fudan.edu.cn.
  • 7 State Key Laboratory of Genetic Engineering, Zhongshan Hospital, School of Life Sciences, Fudan University, Shanghai, 200438, China. zhouzhaocai@fudan.edu.cn.
  • 8 Department of Hematology, Fudan University, Shanghai, 200032, China. yfcheng@fudan.edu.cn.
  • 9 Center for Tumor Diagnosis & Therapy, Jinshan Hospital, Fudan University, Shanghai, 201508, China. yfcheng@fudan.edu.cn.
  • 10 Department of Hematology, Zhongshan Hospital Qingpu Branch, Fudan University, Shanghai, 201700, China. yfcheng@fudan.edu.cn.
  • 11 Institute of Clinical Science, Zhongshan Hospital, Fudan University, Shanghai, 200032, China. yfcheng@fudan.edu.cn.
  • # Contributed equally.
PMID: 37833401 DOI: 10.1038/s41423-023-01089-8
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.

Keywords

M1 polarization; Macrophages; Mammalian sterile-20-like kinase 4 (MST4); Primary immune thrombocytopenia; Signal transducer and activator of transcription-1 (STAT1).

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