GSE183385
ADAP-STAT1 module maintains platelet homeostasis via restraint of macrophage phagocytic in ITP
Heightened platelet phagocytosis by macrophages accompanied with an increase in IFN-? is often attributed to the etiology of immune thrombocytopenia (ITP), an autoimmune disease characterized by low platelet counts. While deletion of the hematopoietic cell adaptor protein ADAP predisposes to ITP in mice, the mechanisms that underlie the functional role of ADAP during ITP remains largely unknown. Here we report that ADAP restrains platelet clearance by macrophages via modulation of STAT1-Fc?R signaling axis. We show that under-expression of ADAP in splenic macrophage was associated with low platelet counts in patients with ITP. Further, macrophages from Adap-/- mice had an elevated phagocytosis capacity and exhibited upregulated pro-inflammatory signaling, and the thrombocytopenia in Adap-/- mice was mitigated in vivo by depletion of macrophages. Mechanically, ADAP interacted and competed with STAT1 binding to importin a5, a nuclear shuttling receptor for activated STAT1. While having no effect on STAT1 tyrosine phosphorylation, loss of ADAP increased the assembly of STAT1-importin a5 complex and facilitated STAT1 nuclear entry, leading to a selective enhancement of transcription of Fc?RI/IV in macrophages. Moreover, pharmacological inhibition of STAT1 or disruption of STAT1-importin a5 interaction relieved the thrombocytopenia in Adap-/- mice. Thus, our findings reveal a critical role for ADAP as an intracellular immune checkpoint for shaping macrophage phagocytic ability in homeostatic maintenance of platelets. Overall design: RNA profiles of splenic macrophages from wild-type and Adap-KO mice