Salmond, R.J., Mirchandani, A.S., Besnard, A.-G., Bain, C.C., Thomson, N.C. and Liew, F.Y. (2012) IL-33 induces innate lymphoid cell–mediated airway inflammation by activating mammalian target of rapamycin. Journal of Allergy and Clinical Immunology, 130(5), pp. 1159-1166. (doi: 10.1016/j.jaci.2012.05.018)
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Publisher's URL: http://dx.doi.org/10.1016/j.jaci.2012.05.018
Abstract
<b>Background:</b> 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.<p></p> <b>Objectives:</b> 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.<p></p> <b>Methods:</b> We biochemically determined the effect of IL-33 on mTOR activation in TH2 cells and ILCs and examined the effect of this signaling pathway in vivo using a murine model of IL-33–induced lung inflammation.<p></p> <b>Results:</b> 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 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-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.<p></p> <b>Conclusion:</b> 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.<p></p>
| Item Type: | Articles |
|---|---|
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Liew, Prof Foo and Mirchandani, Dr Ananda and Besnard, Dr Anne-Gaelle and Thomson, Professor Neil and Bain, Mr Calum and Salmond, Dr Robert |
| Authors: | Salmond, R.J., Mirchandani, A.S., Besnard, A.-G., Bain, C.C., Thomson, N.C., and Liew, F.Y. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Infection & Immunity |
| Journal Name: | Journal of Allergy and Clinical Immunology |
| Journal Abbr.: | J. Allergy Clin. Immunol. |
| Publisher: | Mosby, Inc. |
| ISSN: | 0091-6749 |
| ISSN (Online): | 1097-6825 |
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