多发性红细胞增多症（Polycythemia vera，PV）是一种造血干细胞肿瘤，由JAK2体细胞突变驱动，导致红细胞（RBC）增生解耦于调节生理性红细胞生成的机制。在稳态下，骨髓巨噬细胞促进红细胞成熟，而脾巨噬细胞吞噬老化或受损的RBC。RBC表达的抗吞噬（“不要吞噬我”）CD47配体与巨噬细胞上的SIRPα受体的结合抑制吞噬活动，保护RBC免受吞噬。在本研究中，我们探讨了CD47-SIRPα相互作用在PV RBC生命周期中的作用。我们的结果表明，由于抗CD47治疗或抑制性SIRPα信号的丢失，可以矫正PV小鼠模型中的红细胞性状。抗CD47治疗对PV RBC的生产影响较小，但不影响红细胞成熟。然而，在抗CD47治疗时，高参数单细胞细胞术识别到MerTK+脾单核细胞来源的效应细胞增加，这些细胞在炎症条件下由Ly6Chi单核细胞分化，获得炎症吞噬状态。此外，在体外功能实验中显示，脾JAK2突变巨噬细胞更具“前吞噬性”，表明PV RBC利用CD47-SIRPα相互作用逃脱克隆JAK2突变巨噬细胞的先天免疫攻击。©2023作者。

Polycythemia vera (PV) is a hematopoietic stem cell neoplasm driven by somatic mutations in JAK2, leading to increased red blood cell (RBC) production uncoupled from mechanisms that regulate physiological erythropoiesis. At steady-state, bone marrow macrophages promote erythroid maturation, whereas splenic macrophages phagocytose aged or damaged RBCs. The binding of the anti-phagocytic ("don't eat me") CD47 ligand expressed on RBCs to the SIRPα receptor on macrophages inhibits phagocytic activity protecting RBCs from phagocytosis. In this study, we explore the role of the CD47-SIRPα interaction on the PV RBC life cycle. Our results show that blocking CD47-SIRPα in a PV mouse model due to either anti-CD47 treatment or loss of the inhibitory SIRPα-signal corrects the polycythemia phenotype. Anti-CD47 treatment marginally impacted PV RBC production while not influencing erythroid maturation. However, upon anti-CD47 treatment, high-parametric single-cell cytometry identified an increase of MerTK+ splenic monocyte-derived effector cells, which differentiate from Ly6Chi monocytes during inflammatory conditions, acquire an inflammatory phagocytic state. Furthermore, in vitro, functional assays showed that splenic JAK2 mutant macrophages were more "pro-phagocytic," suggesting that PV RBCs exploit the CD47-SIRPα interaction to escape innate immune attacks by clonal JAK2 mutant macrophages.© 2023. The Author(s).