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

J Allergy Clin Immunol. 2012 Nov;130(5):1159-1166.e6. doi: 10.1016/j.jaci.2012.05.018. Epub 2012 Jun 26.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Class Ia Phosphatidylinositol 3-Kinase / metabolism
  • Humans
  • Immunity, Cellular / drug effects
  • Immunity, Cellular / genetics
  • Immunity, Innate / drug effects
  • Immunity, Innate / genetics
  • Interleukin-1 Receptor-Like 1 Protein
  • Interleukin-13 / metabolism
  • Interleukin-33
  • Interleukin-5 / metabolism
  • Interleukins / administration & dosage*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Pneumonia / chemically induced
  • Pneumonia / drug therapy*
  • Pneumonia / immunology*
  • Receptors, Interleukin / genetics
  • Ribosomal Protein S6 Kinases / metabolism
  • Signal Transduction / drug effects
  • TOR Serine-Threonine Kinases / metabolism*
  • Th2 Cells / drug effects*
  • Th2 Cells / immunology
  • Th2 Cells / transplantation

Substances

  • Il1rl1 protein, mouse
  • Il33 protein, mouse
  • Interleukin-1 Receptor-Like 1 Protein
  • Interleukin-13
  • Interleukin-33
  • Interleukin-5
  • Interleukins
  • Receptors, Interleukin
  • mTOR protein, mouse
  • Class Ia Phosphatidylinositol 3-Kinase
  • Ribosomal Protein S6 Kinases
  • TOR Serine-Threonine Kinases