IL-33 induces innate lymphoid cellamediated 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+ TH2 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 TH2 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 TH2 cells and ILCs and examined the effectANBof this signaling pathway inANBvivo using a murine model of IL-33ainduced lung inflammation. Results: We found that IL-33 induces mTOR activation through p110[d] phosphoinositide 3-kinase and that blockade of the mTOR pathway inhibited IL-33ainduced IL-5 and IL-13 production by TH2 cells and ILCs. Furthermore, use of a ribosomal protein S6 kinase 1 inhibitor implicated a role for ribosomal protein S6 kinase 1 in IL-33ainduced 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 receptoradeficient (St2-/-) mice recapitulated this response. Importantly, coadministration of the mTOR inhibitor rapamycin reduced IL-33adependent ILC, macrophage, and eosinophil accumulation; cytokine secretion; and mucus deposition in the airways. Conclusions: These data reveal a hitherto unrecognized role of mTOR signaling in IL-33adriven, ILC-dependent inflammation inANBvivo and suggest that manipulation of this pathway might represent a target for therapeutic intervention for airway inflammation.