CD47-signal regulatory protein alpha (SIRPalpha) regulates Fcgamma and complement receptor-mediated phagocytosis.
In autoimmune hemolytic anemia (AIHA), circulating red blood cells (RBCs) opsonized with autoantibody are recognized by macrophage Fcgamma 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 (SIRPalpha), generating a negative signal that prevents phagocytosis of the unopsonized RBCs. We show here that clearance and phagocytosis of opsonized RBCs is also regulated by CD47-SIRPalpha. The inhibition generated by CD47-SIRPalpha interaction is strongly attenuated 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 SIRPalpha signaling in this system is mediated by SHP-1 phosphatase activity. The macrophage phagocytic response is controlled by an integration of the inhibitory SIRPalpha signal with prophagocytic signals such as from Fcgamma and complement receptor activation. Thus, augmentation of inhibitory CD47-SIRPalpha signaling may prevent or attenuate RBC clearance in AIHA.
Division of Infectious Diseases, Department of Internal Medicine and Department of Molecular Microbiology and Pathogenesis, Washington University School of Medicine, St. Louis, Missouri 63110, USA. per-arne.oldenborg@histocel.umu.se
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D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D000943:Antigens, Differentiation; D001854:Bone Marrow Cells / Q000276:immunology; D051928:CD47 Antigen; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002470:Cell Survival; D003433:Crosses, Genetic; D004912:Erythrocytes / Q000166:cytology; D005260:Female; D047908:Intracellular Signaling Peptides and Proteins; D008264:Macrophages / Q000276:immunology*; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D039842:Neural Cell Adhesion Molecule L1; D019006:Neural Cell Adhesion Molecules / Q000378:metabolism*; D009895:Opsonin Proteins; D010587:Phagocytosis / Q000276:immunology*; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D011951:Receptors, Complement / Q000378:metabolism*; D017452:Receptors, IgG / Q000378:metabolism*; D011971:Receptors, Immunologic; D015398:Signal Transduction
D015703:Antigens, CD; D000943:Antigens, Differentiation; D051928:CD47 Antigen; D002352:Carrier Proteins; C497895:Cd47 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D039842:Neural Cell Adhesion Molecule L1; D019006:Neural Cell Adhesion Molecules; D009895:Opsonin Proteins; D011951:Receptors, Complement; D017452:Receptors, IgG; D011971:Receptors, Immunologic; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; C509248:Ptpn6 protein, mouse