The Journal of allergy and clinical immunology (November 2012)
IL-33 induces innate lymphoid cell-mediated airway inflammation by activating mammalian target of rapamycin. [BACKGROUND] The IL-1 family cytokine IL-33 is involved in the induction of airway inflammation in allergic patients and after viral infection. Several cell types, including CD4 (+) T (H) 2 cells and the recently described type 2 innate lymphoid cells (ILCs), are targets for IL-33, yet the mechanisms by which this cytokine modulates their activation are not clear. [OBJECTIVES] Our goal was to investigate a role for mammalian target of rapamycin (mTOR) signaling in the activation of T (H) 2 and ILC responses and the induction of airway inflammation by IL-33. [METHODS] We biochemically determined the effect of IL-33 on mTOR activation in T (H) 2 cells and ILCs and examined the effect of this signaling pathway in vivo using a murine model of IL-33-induced lung inflammation. [RESULTS] We found that IL-33 induces mTOR activation through p110d phosphoinositide 3-kinase and that blockade of the mTOR pathway inhibited IL-33-induced IL-5 and IL-13 production by T (H) 2 cells and ILCs. Furthermore, use of a ribosomal protein S6 kinase 1 inhibitor implicated a role for ribosomal protein S6 kinase 1 in IL-33-induced mTOR-dependent cytokine production. Intranasal administration of IL-33 to wild-type mice induced airway inflammation, whereas adoptive transfer of wild-type ILCs to IL-33 receptor-deficient (St2 (-/-)) mice recapitulated this response. Importantly, coadministration of the mTOR inhibitor rapamycin reduced IL-33-dependent ILC, macrophage, and eosinophil accumulation; cytokine secretion; and mucus deposition in the airways. [CONCLUSION] These data reveal a hitherto unrecognized role of mTOR signaling in IL-33-driven, ILC-dependent inflammation in vivo and suggest that manipulation of this pathway might represent a target for therapeutic intervention for airway inflammation.