CD47 Ligation Repositions the Inhibitory Receptor SIRPA to Suppress Integrin Activation and Phagocytosis

Immunity. 2020 Aug 18;53(2):290-302.e6. doi: 10.1016/j.immuni.2020.07.008. Epub 2020 Aug 7.


CD47 acts as a "don't eat me" signal that protects cells from phagocytosis by binding and activating its receptor SIPRA on macrophages. CD47 suppresses multiple different pro-engulfment "eat me" signals, including immunoglobulin G (IgG), complement, and calreticulin, on distinct target cells. This complexity has limited understanding of how the "don't eat me" signal is transduced biochemically. Here, we utilized a reconstituted system with a defined set of signals to interrogate the mechanism of SIRPA activation and its downstream targets. CD47 ligation altered SIRPA localization, positioning SIRPA for activation at the phagocytic synapse. At the phagocytic synapse, SIRPA inhibited integrin activation to limit macrophage spreading across the surface of the engulfment target. Chemical reactivation of integrin bypassed CD47-mediated inhibition and rescued engulfment, similar to the effect of a CD47 function-blocking antibody. Thus, the CD47-SIRPA axis suppresses phagocytosis by inhibiting inside-out activation of integrin signaling in the macrophage, with implications to cancer immunotherapy applications.

Keywords: CD47; Fc Receptor; Macrophage; SIRPA; checkpoint blockade; engulfment; immunological synapse; immunotherapy; integrin; phagocytosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD47 Antigen / metabolism*
  • Calreticulin / immunology
  • Cell Line
  • Complement System Proteins / immunology
  • HEK293 Cells
  • Humans
  • Immunoglobulin G / immunology
  • Integrins / metabolism*
  • Macrophage Activation / immunology
  • Macrophages / immunology*
  • Macrophages / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Phagocytosis / immunology*
  • Phosphatidylserines / immunology
  • RAW 264.7 Cells
  • Receptors, Immunologic / metabolism*
  • Signal Transduction / immunology


  • CD47 Antigen
  • Calreticulin
  • Cd47 protein, mouse
  • Immunoglobulin G
  • Integrins
  • Phosphatidylserines
  • Ptpns1 protein, mouse
  • Receptors, Immunologic
  • Complement System Proteins