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ADAP-STAT1 module maintains platelet homeostasis via restraint of macrophage phagocytic in ITP

ABSTRACT: Heightened platelet phagocytosis by macrophages accompanied with an increase in IFN-γ 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-FcγR 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 FcγRI/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.

ORGANISM(S): Mus musculus

PROVIDER: GSE183385 | GEO | 2022/06/21

REPOSITORIES: GEO

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Project description:Rituximab (RTX) is widely used as a first-line therapeutic strategy in B cell-mediated autoimmune diseases. However, a large proportion of patients either do not respond to the treatment or relapse during B cell reconstitution. Primary immune thrombocytopenia (ITP) is a prototypic B cell mediated autoimmune disease in which pathogenic antibodies directed against the platelet membrane glycoprotein IIb-IIIa (GPIIbIIIa) lead to platelet destruction by macrophages in the spleen. In ITP, RTX-mediated B-cell depletion leads to an immediate clinical response in 50% of patients but 80% of patients will subsequently relapse in the next following months. Patients failing to respond or relapsing after RTX treatment are splenectomized when alternative therapies are inefficient or unavailable. Therapeutic splenectomy, resulting in a durable platelet response in 60-70 % of ITP patients, offers a unique access to study the autoimmune response in the spleen. To understand the cellular basis of disease's relapse in secondary lymphoid organs in humans, memory B cells were sorted and analyzed by scRNAseq from the spleen of three different groups of splenectomized ITP patients: 1) Patients that achieved a complete response after a course of RTX and relapsed during B-cell reconstitution (hereafter referred to as “RTX relapse” patients), 2) patients with primary failure of RTX, i.e. who did not respond to treatment at the time of B-cell depletion (“RTX failure” patients), 3) patients with active ITP that were not treated with RTX (“ITP” patients). All were compared with sorted splenic memory B cells from organ donors with no immune disease who died from stroke or head trauma, hereafter referred to as healthy donors (“HD” patients). We also included in this analysis splenic memory B cells from children with sickle cell disease that underwent splenectomy and are known to have a high frequency of B cell activation secondary to classical childhood infections and vaccinations, reflected by an increased number of GC. Single-cell mRNA sequencing was performed according to an adapted version of the SORT-seq protocol (Muraro et al., 2016, Cell Systems 3, 385–394), with cDNA libraries generation, sequencing and reads alignment performed at Single Cell Discoveries (Utrecht, Netherlands).

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ADAP-STAT1 module maintains platelet homeostasis via restraint of macrophage phagocytic in ITP

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