CD47-signal regulatory protein α (SIRPα) regulates Fcγ and complement receptor-mediated phagocytosis

In autoimmune hemolytic anemia (AIHA), circulating red blood cells (RBCs) opsonized with autoantibody are recognized by macrophage Fc gamma and complement receptors. This triggers phagocytosis and elimination of RBCs from the circulation by splenic macrophages. We recently found that CD47 on unopsonized RBCs binds macrophage signal regulatory protein alpha (SIRP alpha), generating a negative signal that prevents phagocytosis of thr unopsonized RBCs. We show here that clearance and phagocytosis of opsonized RBCs is also regulated by CD47-SIRP alpha. The inhibition generated by CD47-SIRP alpha interaction is strongly attentuated but not absent in mice with only residual activity of the phosphatase Src homology 2 domain-containing protein tyrosine phosphatase (SHP)-1, suggesting that most SIRP alpha signaling in this system is mediated by SHP-1 phosphatase activity. The macrophage phagocytic response is controlled by an integration of the inhibitory SIRP alpha signal with prophagocytic signals such as from Fc gamma and complement receptor activation, Thus, augmentation of inhibitory CD47-SIRP alpha signaling may prevent or attenuate RBC clearance in AIHA.