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SIRPα sequesters SHP-2 to promote IL-4 and IL-13 signaling and the alternative activation of macrophages

Description SIRPα enhances macrophage alternative activation by preventing a phosphatase from acting on cytokine receptors. Aiding alternative activation The cytokines interleukin-4 (IL-4) and IL-13 act through receptors that share a common subunit to generate alternatively activated macrophages, which play roles in wound healing and resolving inflammation. Shi et al. found that the immunoreceptor SIRPα was tyrosine-phosphorylated in IL-4– and IL-13–treated macrophages. This resulted in the recruitment to SIRPα of the phosphatase SHP-2, thereby preventing SHP-2 from interacting with and inhibiting receptors for IL-4 and IL-13. Loss of SIRPα in mice resulted in reduced numbers of alternatively activated macrophages and exacerbated inflammation in a model of colitis. Transfusing these mice with macrophages overexpressing SIRPα ameliorated disease. These data suggest potential strategies for the use of alternatively activated macrophages as cellular therapies to treat inflammatory diseases. The cytokines interleukin-4 (IL-4) and IL-13 bind to their shared receptor subunit IL-4Rα to direct the alternative activation of macrophages to promote immunosuppression and wound healing. Activated IL-4 and IL-13 receptors recruit the tyrosine phosphatases SHP-1 and SHP-2, which dephosphorylate and inhibit the IL-4Rα subunit. Here, we report that the immunoreceptor SIRPα spatially restricted SHP-2 to promote IL-4 and IL-13 signaling and the alternative activation of macrophages. This effect required the cytoplasmic ITIMs or ITSMs of SIRPα, which underwent tyrosine phosphorylation by Bruton’s tyrosine kinase (Btk) that was activated in response to IL-4 and IL-13. This phosphorylation event resulted in the recruitment of SHP-2 to SIRPα and prevented it from binding to and inhibiting IL-4R and IL-13R. Binding of the ligand CD47 to the SIRPα extracellular domain promoted the Btk-mediated phosphorylation of the SIRPα cytoplasmic domain and hence SHP-2 sequestration. Conversely, loss of SIRPα enabled SHP-2 to bind to the γC and IL-13Rα1 subunits of IL-4R and IL-13R, respectively, and dephosphorylate IL-4Rα, dampening its signaling. Impaired wound healing in Sirpα−/− mice with experimental colitis correlated with a deficit of immunosuppressive macrophages in the colon, a condition that was corrected by transfusion of ex vivo–produced, alternatively activated SIRPαhigh macrophages. These studies reveal a previously unappreciated role for SIRPα in promoting IL-4 and IL-13 signaling and reveal the mechanistic basis by which SIRPα enhances the alternative activation of macrophages.