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.