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

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          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 H2 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.


          Our goal was to investigate a role for mammalian target of rapamycin (mTOR) signaling in the activation of T H2 and ILC responses and the induction of airway inflammation by IL-33.


          We biochemically determined the effect of IL-33 on mTOR activation in T H2 cells and ILCs and examined the effect of this signaling pathway in vivo using a murine model of IL-33–induced lung inflammation.


          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 H2 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.


          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.

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          Most cited references 25

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          Human IL-25- and IL-33-responsive type 2 innate lymphoid cells are defined by expression of CRTH2 and CD161.

          Innate lymphoid cells (ILCs) are emerging as a family of effectors and regulators of innate immunity and tissue remodeling. Interleukin 22 (IL-22)- and IL-17-producing ILCs, which depend on the transcription factor RORγt, express CD127 (IL-7 receptor α-chain) and the natural killer cell marker CD161. Here we describe another lineage-negative CD127(+)CD161(+) ILC population found in humans that expressed the chemoattractant receptor CRTH2. These cells responded in vitro to IL-2 plus IL-25 and IL-33 by producing IL-13. CRTH2(+) ILCs were present in fetal and adult lung and gut. In fetal gut, these cells expressed IL-13 but not IL-17 or IL-22. There was enrichment for CRTH2(+) ILCs in nasal polyps of chronic rhinosinusitis, a typical type 2 inflammatory disease. Our data identify a unique type of human ILC that provides an innate source of T helper type 2 (T(H)2) cytokines.
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            Innate lymphoid cells promote lung tissue homeostasis following acute influenza virus infection

            Innate lymphoid cells (ILCs), a recently identified heterogeneous cell population, are critical in orchestrating immunity and inflammation in the intestine but whether ILCs can influence immune responses or tissue homeostasis at other mucosal sites remains poorly characterized. Here we identify a population of lung-resident ILCs in mice and humans that expressed CD90, CD25, CD127 and T1-ST2. Strikingly, mouse ILCs accumulated in the lung following influenza virus infection and depletion of ILCs resulted in loss of airway epithelial integrity, decreased lung function and impaired airway remodeling. These defects could be restored by administration of the lung ILC product amphiregulin. Collectively, these results demonstrate a critical role for lung ILCs in restoring airway epithelial integrity and tissue homeostasis following influenza virus infection.
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              Interleukin 9 fate reporter reveals induction of innate IL-9 response in lung inflammation

              Interleukin 9 (IL-9) is a cytokine implicated in lung inflammation, but its cellular origin and function remain unclear. Here we describe a reporter mouse strain designed to fate map cells that have activated IL-9. We show that during papain-induced lung inflammation IL-9 production was largely restricted to innate lymphoid cells (ILC). IL-9 production by ILC was dependent on IL-2 from adaptive immune cells and was rapidly lost in favor of other cytokines, such as IL-13 and IL-5. Blockade of IL-9 production via neutralizing antibodies substantially reduced IL-13 and IL-5, suggesting that ILC provide the missing link between the well-established functions of IL-9 on the regulation of TH2 cytokines and responses.

                Author and article information

                J Allergy Clin Immunol
                J. Allergy Clin. Immunol
                The Journal of Allergy and Clinical Immunology
                1 November 2012
                November 2012
                : 130
                : 5
                : 1159-1166.e6
                [a ]Division of Immunology, Infection and Inflammation, University of Glasgow, Glasgow, United Kingdom
                [b ]CEGMR, King Abdulaziz University, Jeddah, Saudi Arabia
                Author notes
                []Corresponding author: Foo Y. Liew, PhD, Division of Immunology, Infection and Inflammation, Glasgow Biomedical Research Centre, 120 University Place, Glasgow G12 8TA, United Kingdom. foo.liew@ 123456glasgow.ac.uk

                These authors contributed equally to this work.

                © 2012 Mosby, Inc.

                This document may be redistributed and reused, subject to certain conditions.

                Mechanisms of Allergy and Clinical Immunology


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