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ADAP restraint of STAT1 signaling regulates macrophage phagocytosis in immune thrombocytopenia

Cellular & Molecular Immunology volume 19, pages 898–912 (2022)Cite this article

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Abstract

Heightened platelet phagocytosis by macrophages accompanied by an increase in IFN-γ play key roles in the etiology of immune thrombocytopenia (ITP); however, it remains elusive how macrophage-mediated platelet clearance is regulated in ITP. Here, we report that adhesion and degranulation-protein adaptor protein (ADAP) restrains platelet phagocytosis by macrophages in ITP via modulation of signal transducer and activator of transcription 1 (STAT1)-FcγR signaling. We show that ITP was associated with the underexpression of ADAP in splenic macrophages. Furthermore, macrophages from Adap−/− mice exhibited elevated platelet phagocytosis and upregulated proinflammatory signaling, and thrombocytopenia in Adap−/− mice was mitigated by the depletion of macrophages. Mechanistically, ADAP interacted and competed with STAT1 binding to importin α5. ADAP deficiency potentiated STAT1 nuclear entry, leading to a selective enhancement of FcγRI/IV transcription in macrophages. Moreover, pharmacological inhibition of STAT1 or disruption of the STAT1-importin α5 interaction relieved thrombocytopenia in Adap−/− mice. Thus, our findings not only reveal a critical role for ADAP as an intracellular immune checkpoint for shaping macrophage phagocytosis in ITP but also identify the ADAP-STAT1-importin α5 module as a promising therapeutic target in the treatment of ITP.

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Data availability

RNA-seq data have been deposited in the GEO database under accession number GSE183385. All related data, code, and materials used in the analyses are available from the corresponding author (Dr. Hebin Liu, hbliu@suda.edu.cn) upon reasonable request.

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Acknowledgements

This work was supported by grants from Natural Science Foundation of Jiangsu Higher Education Institution-Key Program under 21KJA310002 to H.L, the Suzhou Key Program Special Funds in XJTLU under KSF-A-21 and KSF-E-30 to H.L, Soochow University Research Development Funds under Q424900220 to H.L, National Natural Science Foundation of China (NSFC) under Grant 31470840 to H.L, and the Priority Academic Program Development of Jiangsu Higher Education Institutions. The authors would like to thank Dr. Dongqing Ma (Merck, Shanghai) for technical support on PLA ligation assay.

Funding

This work was supported by grants from Natural Science Foundation of Jiangsu Higher Education Institution-Key Program under 21KJA310002 (H.L.), the Suzhou Key Program Special Funds in XJTLU under KSF-A-21 and KSF-E-30 (H.L.), Soochow University Research Development Funds under Q424900220 (H.L.), National Natural Science Foundation of China (NSFC) under Grant 31470840 (H.L.), and the Priority Academic Program Development of Jiangsu Higher Education Institutions.

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Authors and Affiliations

  1. Institutes of Biology and Medical Sciences, Soochow University, Suzhou, 215123, China

    Yiwei Xiong, Yanli Li, Xinxing Cui & Hebin Liu

  2. Department of General Surgery, Dushu Lake Hospital Affiliated to Soochow University, Medical Center of Soochow University, Suzhou, 215123, China

    Lifeng Zhang

  3. Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, China

    Xiaodong Yang

  4. Department of Biological Sciences, Xi’an Jiaotong-Liverpool University, Suzhou, 215123, China

    Hebin Liu

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  1. Yiwei Xiong
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Contributions

H.L. and Y.X. conceived the study; Y.X. and H.L. designed experiments; Y.X., Y.L., and X.C. performed experiments; Y.X., L.Z., and H.L. analyzed and interpreted data; L.Z. and X.Y. performed pathologic examination and provided patient tissue samples; Y.X. and H.L. wrote and edited the manuscript with intellectual input from the other authors; H.L. supervised and acquired funding for the study.

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Correspondence to Hebin Liu.

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Xiong, Y., Li, Y., Cui, X. et al. ADAP restraint of STAT1 signaling regulates macrophage phagocytosis in immune thrombocytopenia. Cell Mol Immunol 19, 898–912 (2022). https://doi.org/10.1038/s41423-022-00881-2

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