CD47 promotes RBC survival by preventing DC-mediated retention and macrophage-mediated phagocytosis of RBC in the spleen Open Access

• Transfer of Cd47^–/– RBCs to WT mice activates cDCs and promotes retention and macrophage-mediated phagocytosis of the RBCs in the spleen.

• Interaction of CD47 on circulating RBCs with SIRPα on cDCs promotes RBC survival by preventing their cDC-mediated retention in the spleen.

The interaction of CD47 on red blood cells (RBCs) with SIRPα on macrophages prevents phagocytosis of RBCs by macrophages. The transfusion of CD47-deficient (Cd47^–/–) RBCs into wild-type (WT) mice indeed results in marked phagocytosis of these cells by splenic red pulp macrophages (RPMs) and their consequent rapid elimination from the recipients. We confirmed that transfusion of Cd47^–/– RBCs resulted in the activation of conventional dendritic cells (cDCs) in the spleen of WT recipient mice as previously reported. In addition, we here found that the clearance of the transferred Cd47^–/– RBCs was prevented by depletion of both cDCs and RPMs but only partially attenuated by that of RPMs alone. We also found that the transfusion of Cd47^–/– RBCs into WT recipients resulted in marked retention of the RBCs in the spleen before their phagocytosis by RPMs. Such retention was not affected by depletion of RPMs alone but was greatly attenuated by depletion of both cDCs and RPMs. SIRPα-expressing CD4⁺ cDC2s appeared to contribute to the retention and rapid clearance of transfused Cd47^–/– RBCs. Collectively, our findings indicate that the interaction of CD47 on RBCs with SIRPα on cDCs promotes the survival of circulating RBCs by preventing the cDC-dependent retention and RPM-mediated phagocytosis of these cells.