CD47通过去磷酸化Vav抑制吞噬作用

CD47 on viable cells protects against phagocytosis. CD47 is recognized by SIRPα, an inhibitory receptor expressed by macrophages and other myeloid cells. Activated SIRPα recruits SHP-1 and SHP-2 phosphatases, but the inhibitory signaling cascade downstream of these phosphatases is unclear. Here, we used time-lapse imaging to measure how CD47 impacts the kinetics of phagocytosis. Targets with IgG antibodies were primarily phagocytosed through a Rac-based reaching mechanism. Targets also containing CD47 were only phagocytosed through a less frequent Rho-based sinking mechanism. Hyperactivating Rac2 eliminated the suppressive effect of CD47, suggesting that CD47 prevents activation of Rac and reaching phagocytosis. During IgG-mediated phagocytosis, the tyrosine kinase Syk phosphorylates the GEF Vav, which activates Rac to drive F-actin rearrangement and target internalization. CD47 inhibited Vav phosphorylation without impacting Vav recruitment to the phagocytic synapse or Syk phosphorylation. Macrophages expressing a hyperactive Vav were no longer sensitive to CD47. These data suggest that Vav is a key target of the CD47 signaling pathway.