SIRP alpha

Signal regulatory protein alpha (SIRPα, CD172a, SHPS-1) is an inhibitory immunoreceptor of the SIRP family, abundantly expressed on myeloid cells-monocytes, macrophages, dendritic cells and neutrophils-as well as on neurons and vascular endothelial cells. SIRPα comprises three extracellular Ig-like domains and a cytoplasmic tail bearing two ITIM motifs that, upon ligand binding, recruit SHP-1 and SHP-2 to inhibit phagocytosis, migration and inflammatory signaling. Its principal ligand is CD47, the widely expressed 'don't eat me' molecule; the CD47-SIRPα checkpoint suppresses macrophage-mediated engulfment of healthy cells, enables red blood cell and platelet homeostasis, and supports synapse maturation via neuronal pairing. Tumors hijack this axis to escape macrophage surveillance, spawning anti-CD47 and SIRPα-blocking antibodies now in clinical trials, which synergize with tumor-opsonizing antibodies. SIRPα ligation also restrains dendritic-cell cross-presentation and T-cell priming, and soluble SIRPα acts as a rheumatoid arthritis biomarker and potential decoy therapy.