SIRPCD47SIRPalpha

SIRPCD47SIRPalpha refers to the functional interaction between the cell surface receptor Signal Regulatory Protein alpha (SIRPA) and its ligand Cytoglobin Immunoglobulin Domain 47 (CD47), often discussed in the context of the “don’t eat me” signaling mechanism. SIRPA is a transmembrane protein expressed on myeloid cells such as macrophages and neutrophils. Its cytoplasmic domain contains immunoreceptor tyrosine-based inhibitory motifs (ITIMs) that recruit SHP-1 and SHP-2 phosphatases upon phosphorylation. CD47, a ubiquitously expressed transmembrane protein, presents a conserved extracellular IgV-like domain that engages SIRPA with high affinity.

The SIRPA–CD47 axis inhibits phagocytosis and other innate immune effector functions. When CD47 on target cells binds SIRPA, the ITIMs of SIRPA become phosphorylated and the recruited phosphatases dephosphorylate key signaling molecules downstream of the Fcγ receptors. This results in suppression of actin remodeling and fusion pore formation, thereby protecting normal cells from being engulfed. The pathway is exploited by many cancer cells to evade immune clearance; overexpression of CD47 on tumor surfaces can engage SIRPA on infiltrating macrophages and impair phagocytosis. In contrast, pathogenic microbes that express CD47-like proteins can also trigger SIRPA signaling to dampen host defenses.

Therapeutically, blockade of the SIRPA–CD47 interaction by monoclonal antibodies or small molecules restores macrophage‑mediated tumor clearance and is being investigated in several clinical trials for hematologic malignancies and solid tumors. Moreover, soluble SIRPα variants fused to Fc domains are being developed as therapeutics to modulate immune responses in autoimmune diseases. Understanding the structural basis of SIRPA–CD47 binding and downstream signaling continues to inform both basic immunology and translational applications.