IL-33 induces innate lymphoid cell-mediated airway inflammation by activating mammalian target of rapamycin

Robert J Salmond, Ananda S Mirchandani, Anne-Gaelle Besnard, Calum C Bain, Neil C Thomson, Foo Y Liew

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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 p110δ 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.

Original languageEnglish
Pages (from-to)1159-1166.e6
JournalJournal of Allergy and Clinical Immunology
Issue number5
Publication statusPublished - Nov 2012

Keywords / Materials (for Non-textual outputs)

  • Animals
  • Cells, Cultured
  • Class Ia Phosphatidylinositol 3-Kinase
  • Humans
  • Immunity, Cellular
  • Immunity, Innate
  • Interleukin-13
  • Interleukin-5
  • Interleukins
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Pneumonia
  • Receptors, Interleukin
  • Ribosomal Protein S6 Kinases
  • Signal Transduction
  • TOR Serine-Threonine Kinases
  • Th2 Cells


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