RED CELLS, IRON, AND ERYTHROPOIESIS

CD47 on erythrocytes inhibits phagocyto-sis through interaction with the inhibitory immunoreceptor SIRP expressed by macrophages. Thus, the CD47-SIRP in-teraction constitutes a negative signal for erythrocyte phagocytosis. However, we report here that CD47 does not only func-tion as a “do not eat me ” signal for uptake but can also act as an “eat me ” signal. In particular, a subset of old erythrocytes present in whole blood was shown to bind and to be phagocytosed via CD47-SIRP interactions. Furthermore, we pro-vide evidence that experimental aging of erythrocytes induces a conformational change in CD47 that switches the mol-ecule from an inhibitory signal into an activating one. Preincubation of experi-mentally aged erythrocytes with human serum before the binding assay was re-quired for this activation. We also demon-strate that aged erythrocytes have the capacity to bind the CD47-binding partner thrombospondin-1 (TSP-1) and that treat-ment of aged erythrocytes with a TSP-1– derived peptide enabled their phagocyto-sis by human red pulp macrophages. Finally, CD47 on erythrocytes that had been stored for prolonged time was shown to undergo a conformational change and bind TSP-1. These findings reveal a more complex role for CD47-SIRP interactions in erythrocyte phago-cytosis, with CD47 acting as a molecular switch for controlling erythrocyte phago-cytosis. (Blood. 2012;119(23):5512-5521