The SIRP family: from structural diversity and signaling mechanisms to implications in immune-related disease targeted therapeutics

TL;DR

This review explains how different SIRP proteins regulate immune responses and how targeting them could help treat diseases like cancer and autoimmunity.

Contribution

The paper provides a comprehensive overview of SIRP family signaling mechanisms and their therapeutic implications in immune-related diseases.

Findings

SIRPα inhibits phagocytosis via CD47 binding, making it a target for cancer immunotherapy.

SIRPβ activates cells through DAP12, linking it to inflammation and bone metabolism.

SIRPγ modulates T cell adhesion and migration without typical signaling motifs.

Abstract

Signal regulatory proteins (SIRPs) are membrane receptors on immune cells that control immune homeostasis and inflammation. Although SIRP family members share homologous extracellular domains, they differ in intracellular motifs and function: SIRPα transduces inhibitory signals, SIRPβ associates with DAP12 to trigger activation, and SIRPγ primarily modulates adhesion and T cell responses. This review compares the structure, ligand interactions, and signaling mechanisms of SIRPα, SIRPβ, and SIRPγ, summarizes their roles in cancer, autoimmunity and neurodegeneration, and surveys therapeutic strategies that target the CD47–SIRPα axis. We highlight current clinical progress, common toxicities, and open questions that must be addressed to advance SIRP-targeted therapies.

The core biological characteristics and functions of the SIRP protein family. Upon binding to CD47, SIRPα transduces an inhibitory signal that suppresses phagocytosis by macrophages. SIRPβ binds to the adaptor protein DAP12 through its transmembrane domain, thereby transmitting activation signals to promote cell activation and the release of inflammatory mediators. SIRPγ exhibits relatively low binding affinity to CD47 and lacks typical signaling motifs. Its primary function is to enhance adhesion between T cells and endothelial cells, thereby facilitating T cell activation and migration.Infographic diagram illustrating the SIRP family signaling pathways: SIRPα with CD47 delivers inhibitory signals affecting phagocytosis and cancer immunotherapy; SIRPβ with DAP12 generates active signals leading to cell activation and inflammatory release involved in bone metabolism and inflammatory diseases; SIRPγ shows no signaling, involved in T cell and endothelial cell adhesion, with consequences for autoimmune diseases.

The core biological characteristics and functions of the SIRP protein family. Upon binding to CD47, SIRPα transduces an inhibitory signal that suppresses phagocytosis by macrophages. SIRPβ binds to the adaptor protein DAP12 through its transmembrane domain, thereby transmitting activation signals to promote cell activation and the release of inflammatory mediators. SIRPγ exhibits relatively low binding affinity to CD47 and lacks typical signaling motifs. Its primary function is to enhance adhesion between T cells and endothelial cells, thereby facilitating T cell activation and migration.

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