ADAP restraint of STAT1 signaling regulates macrophage phagocytosis in immune thrombocytopenia

Heightened platelet phagocytosis by macrophages accompanied by an increase in IFN-γplay 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 importinα5.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-importinα5 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-importinα5 module as a promising therapeutic target in the treatment of ITP.