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      A role for IL-25 and IL-33–driven type-2 innate lymphoid cells in atopic dermatitis

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          Abstract

          Type 2 innate lymphoid cells promote skin inflammation in mice and men, in part by producing IL-5 and IL-13 in response to IL-33

          Abstract

          Type 2 innate lymphoid cells (ILC2s, nuocytes, NHC) require RORA and GATA3 for their development. We show that human ILC2s express skin homing receptors and infiltrate the skin after allergen challenge, where they produce the type 2 cytokines IL-5 and IL-13. Skin-derived ILC2s express the IL-33 receptor ST2, which is up-regulated during activation, and are enriched in lesional skin biopsies from atopic patients. Signaling via IL-33 induces type 2 cytokine and amphiregulin expression, and increases ILC2 migration. Furthermore, we demonstrate that E-cadherin ligation on human ILC2 dramatically inhibits IL-5 and IL-13 production. Interestingly, down-regulation of E-cadherin is characteristic of filaggrin insufficiency, a cardinal feature of atopic dermatitis (AD). ILC2 may contribute to increases in type 2 cytokine production in the absence of the suppressive E-cadherin ligation through this novel mechanism of barrier sensing. Using Rag1 −/− and RORα-deficient mice, we confirm that ILC2s are present in mouse skin and promote AD-like inflammation. IL-25 and IL-33 are the predominant ILC2-inducing cytokines in this model. The presence of ILC2s in skin, and their production of type 2 cytokines in response to IL-33, identifies a role for ILC2s in the pathogenesis of cutaneous atopic disease.

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          Most cited references 33

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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 after infection with influenza virus

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              New insights into atopic dermatitis.

              Atopic dermatitis is a chronic inflammatory skin disease associated with cutaneous hyperreactivity to environmental triggers and is often the first step in the atopic march that results in asthma and allergic rhinitis. The clinical phenotype that characterizes atopic dermatitis is the product of interactions between susceptibility genes, the environment, defective skin barrier function, and immunologic responses. This review summarizes recent progress in our understanding of the pathophysiology of atopic dermatitis and the implications for new management strategies.
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                Author and article information

                Journal
                J Exp Med
                J. Exp. Med
                jem
                The Journal of Experimental Medicine
                The Rockefeller University Press
                0022-1007
                1540-9538
                16 December 2013
                : 210
                : 13
                : 2939-2950
                Affiliations
                [1 ]Medical Research Council (MRC) Human Immunology Unit, National Institute for Health Research Biomedical Research Centre, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DS, England, UK
                [2 ]MRC Laboratory of Molecular Biology, Cambridge University, Cambridge CB2 0QH, England, UK
                [3 ]Trinity Biomedical Sciences Institute, Trinity College, Dublin 2, Ireland
                [4 ]Institute of Molecular Medicine, St James’s Hospital, Dublin 2, Ireland
                [5 ]National Children’s Research Centre, Our Lady’s Children’s Hospital, Dublin 12, Ireland
                [6 ]Department of Plastic and Reconstructive Surgery, John Radcliffe Hospital, Oxford University Hospitals National Health Service Trust, Oxford OX3 9DU, England, UK
                [7 ]Department of Periodontology and Oral Medicine, School of Stomatology, the Fourth Military Medical University, Xi’an, Shaanxi 710032, People’s Republic of China
                Author notes
                CORRESPONDENCE Andrew N.J. McKenzie: anm@ 123456mrc-lmb.cam.ac.uk

                M. Salimi, J.L. Barlow, and S.P. Saunders contributed equally to this paper.

                Article
                20130351
                10.1084/jem.20130351
                3865470
                24323357
                © 2013 Salimi et al.

                This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

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