ADAP restraint of STAT1 signaling regulates macrophage phagocytosis in immune thrombocytopenia
Open accessAbstract
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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ADAP deficiency skews macrophages toward a pro-inflammatory M1 phenotype, amplifying production of inflammatory cytokines.
“Our prior work firmly established that ADAP deficiency skews macrophages toward a pro-inflammatory M1 phenotype, amplifying their production of inflammatory cytokines [14, 15].”
From Inhibition of SPI1 by ADAP Regulates S100A8/A9 Signaling in Macrophages to Control the Development of Colitis (2026) · cites this paper as [14]
The Results section reports enriched proinflammatory signaling pathways in Adap−/− splenic macrophages, and the Discussion says this suggests a shift toward a proinflammatory phenotype. The cited passages do not establish an M1 phenotype or show increased inflammatory cytokine production; pathway enrichment is not a measurement of cytokine output. Page numbers were not available in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredIn immune thrombocytopenia, ADAP inhibits STAT1 signaling to regulate macrophage phagocytosis.
“in immune thrombocytopenia, we demonstrated that ADAP inhibits STAT1 signaling to regulate macrophage phagocytosis [14].”
From Inhibition of SPI1 by ADAP Regulates S100A8/A9 Signaling in Macrophages to Control the Development of Colitis (2026) · cites this paper as [14]
ADAP modulates macrophage polarization and phagocytic capacity through direct interactions with STAT3 and STAT1.
“Furthermore, ADAP modulates macrophage polarization and phagocytic capacity through direct interactions with the STAT family members STAT3 and STAT1 [14, 15].”
From Inhibition of SPI1 by ADAP Regulates S100A8/A9 Signaling in Macrophages to Control the Development of Colitis (2026) · cites this paper as [14]
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References 77 · Cited by 27
- Authors
- Xiong, Y., Li, Y., Cui, X., Zhang, L., Yang, X., & Liu, H.
- Affiliations
- Soochow University (CN)
- Second Affiliated Hospital of Soochow University (CN)
- Corresponding author
- Liu, Hebin
- Venue
- Cellular & Molecular Immunology
- Published
- 2022-05-30
- Volume
- 19
- Issue
- 8
- Pages
- 898-912
- ISSN
- 1672-7681 (ISSN-L)
- 2042-0226
- PMC
- PMC9149338
- OpenAlex
- W4281669050
- Cited by
- 27
- References
- 77
- Citations by year
- 2026: 9 · 2025: 7 · 2024: 10 · 2023: 1
- FWCI
- 3.28
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cellular and Molecular Immunology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (31470840)
- Xi’an Jiaotong-Liverpool University
- Soochow University (Q424900220)
- Priority Academic Program Development of Jiangsu Higher Education Institutions (KSF-E-30, KSF-A-21)
- Topics
- Health Sciences › Medicine › Hematology › Platelet Disorders and Treatments
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Keywords
- idiopathic thrombocytopenic purpura, ADAP, STAT1 signaling, macrophage phagocytosis, platelet clearance, Fcγ receptor signaling, thrombocytopenia, splenic macrophages, immune checkpoint, interferon-gamma, therapeutic target
- MeSH terms
- Animals, Macrophages, Phagocytosis, Thrombocytopenia, Purpura, Thrombocytopenic, Idiopathic, Karyopherins, Adaptor Proteins, Signal Transducing, STAT1 Transcription Factor, Mice
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