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

Abstract

The Th2 cytokines IL-4 and IL-13 through activation of their shared receptor IL-4R direct macrophage alternative activation to promote immunosuppression and wound healing. However, the mechanisms that control macrophage responses to IL-4/13 are not fully understood. Apart from driving JAK-STAT and PI3K-Akt pathways to polarize macrophages toward the alternative phenotype, the activated IL-4/13 receptors recruit negative regulators SHP-1 and SHP-2, which dephosphorylate IL-4R and decrease its signaling. Here we report that SIRP spatially restricts SHP-2 and, by such, promotes IL-4/13 signaling and macrophage alternative activation. SIRP executes this regulation via its cytoplasmic ITIMs/ITSMs that undergo phosphorylation by IL-4/13-induced, Src kinase-activated Brutons tyrosine kinase (Btk), resulting in recruitment of SHP-2 and preclusion of SHP-2 from binding to and inhibiting IL-4/13 receptors. Despite that this regulation occurs independent of CD47, extracellular CD47 ligation of SIRP facilitates its cytoplasmic phosphorylation and SHP-2 sequestration, leading to stronger IL-4/13 signaling and enhanced macrophage expression of IL-10, TGF{beta}, CD206, arginase-1, etc. Conversely, deficiency of SIRP allows SHP-2 to freely bind to {gamma}C or IL-13R1 and through which dephosphorylate IL-4R, dampening its signaling. Consistent with these findings, impaired wound healing in Sirp-/- mice under experimental colitis correlated with a deficit of immunosuppressive macrophages in the colon, a condition that was corrected by transfusion of ex vivo-produced SIRPhigh alternatively activated macrophages.