Requirement Of G Alpha I1 And G Alpha I3 In Interleukin-4-Induced Signaling, Macrophage M2 Polarization And Allergic Asthma Response

IL-4 induces Akt activation in macrophages, required for full M2 (alternative) polarization. We examined the roles of G alpha i1 and G alpha i3 in M2 polarization using multiple genetic methods.Methods and Results: In MEFs and primary murine BMDMs, G alpha i1/3 shRNA, knockout or dominant negative mutations attenuated IL-4-induced IL4R alpha endocytosis, Gab1 recruitment as well as Akt activation, leaving STAT6 signaling unaffected. Following IL-4 stimulation, G alpha i1/3 proteins associated with the intracellular domain of IL-4R alpha and the APPL1 adaptor, to mediate IL-4R alpha endosomal traffic and Gab1-Akt activation in BMDMs. In contrast, gene silencing of G alpha i1/3 with shRNA or knockout resulted in BMDMs that were refractory to IL-4-induced M2 polarization. Conversely, G alpha i1/3-overexpressed BMDMs displayed preferred M2 response with IL-4 stimulation. In primary human macrophages IL-4-induced Akt activation and Th2 genes expression were inhibited with G alpha i1/3 silencing, but augmented with G alpha i1/3 overexpression. In G alpha i1/3 double knockout (DKO) mice, M2 polarization, by injection of IL-4 complex or chitin, was potently inhibited. Moreover, in a murine model of asthma, ovalbumin-induced airway inflammation and hyperresponsiveness were largely impaired in G alpha i1/3 DKO mice.Conclusion: These findings highlight novel and essential roles for G alpha i1/3 in regulating IL-4-induced signaling, macrophage M2 polarization and allergic asthma response.