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      Epidermal ADAM17 maintains the skin barrier by regulating EGFR ligand–dependent terminal keratinocyte differentiation

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          Abstract

          EGFR requires ADAM17 activity to preserve skin barrier homeostasis.

          Abstract

          ADAM17 (a disintegrin and metalloproteinase 17) is ubiquitously expressed and cleaves membrane proteins, such as epidermal growth factor receptor (EGFR) ligands, l-selectin, and TNF, from the cell surface, thus regulating responses to tissue injury and inflammation. However, little is currently known about its role in skin homeostasis. We show that mice lacking ADAM17 in keratinocytes ( A17 ΔKC ) have a normal epidermal barrier and skin architecture at birth but develop pronounced defects in epidermal barrier integrity soon after birth and develop chronic dermatitis as adults. The dysregulated expression of epidermal differentiation proteins becomes evident 2 d after birth, followed by reduced transglutaminase (TGM) activity, transepidermal water loss, up-regulation of the proinflammatory cytokine IL-36α, and inflammatory immune cell infiltration. Activation of the EGFR was strongly reduced in A17 ΔKC skin, and topical treatment of A17 ΔKC mice with recombinant TGF-α significantly improved TGM activity and decreased skin inflammation. Finally, we show that mice lacking the EGFR in keratinocytes ( Egfr ΔKC ) closely resembled A17 ΔKC mice. Collectively, these results identify a previously unappreciated critical role of the ADAM17–EGFR signaling axis in maintaining the homeostasis of the postnatal epidermal barrier and suggest that this pathway could represent a good target for treatment of epidermal barrier defects.

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          Most cited references59

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          The cornified envelope: a model of cell death in the skin.

          The epidermis functions as a barrier against the environment by means of several layers of terminally differentiated, dead keratinocytes - the cornified layer, which forms the endpoint of epidermal differentiation and death. The cornified envelope replaces the plasma membrane of differentiating keratinocytes and consists of keratins that are enclosed within an insoluble amalgam of proteins, which are crosslinked by transglutaminases and surrounded by a lipid envelope. New insights into the molecular mechanisms and the physiological endpoints of cornification are increasing our understanding of the pathological defects of this unique form of programmed cell death, which is associated with barrier malfunctions and ichthyosis.
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            The IL-1 family: regulators of immunity.

            Over recent years it has become increasingly clear that innate immune responses can shape the adaptive immune response. Among the most potent molecules of the innate immune system are the interleukin-1 (IL-1) family members. These evolutionarily ancient cytokines are made by and act on innate immune cells to influence their survival and function. In addition, they act directly on lymphocytes to reinforce certain adaptive immune responses. This Review provides an overview of both the long-established and more recently characterized members of the IL-1 family. In addition to their effects on immune cells, their involvement in human disease and disease models is discussed.
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              Epidermal homeostasis: a balancing act of stem cells in the skin.

              The skin epidermis and its array of appendages undergo ongoing renewal by a process called homeostasis. Stem cells in the epidermis have a crucial role in maintaining tissue homeostasis by providing new cells to replace those that are constantly lost during tissue turnover or following injury. Different resident skin stem cell pools contribute to the maintenance and repair of the various epidermal tissues of the skin, including interfollicular epidermis, hair follicles and sebaceous glands. Interestingly, the basic mechanisms and signalling pathways that orchestrate epithelial morphogenesis in the skin are reused during adult life to regulate skin homeostasis.
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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
                4 June 2012
                : 209
                : 6
                : 1105-1119
                Affiliations
                [1 ]Department of Dermatology and [2 ]Centre of Chronic Immunodeficiency, University Freiburg Medical Center, D-79104 Freiburg, Germany
                [3 ]Department of Orthopedic Surgery and Anti-aging Orthopedic Research, School of Medicine, Keio University, Tokyo 160-8582, Japan
                [4 ]Department of Genetics, North Carolina State University, Raleigh, NC 27695
                [5 ]Core Facility Genomics, Centre for Systems Biology, University Freiburg, D-79104 Freiburg, Germany
                [6 ]Department of Molecular Cell Biology, Faculty of Medicine, Vrije Universiteit, 1081 BT Amsterdam, Netherlands
                [7 ]Freiburg Institute for Advanced Studies FRIAS, School of Life Sciences – LifeNet, D-79104 Freiburg, Germany
                [8 ]Arthritis and Tissue Degeneration Program, Hospital for Special Surgery , [9 ]Department of Medicine , and [10 ]Department of Physiology and Biophysics, Weill Medical College of Cornell University, New York, NY 10021
                Author notes
                CORRESPONDENCE Claus-Werner Franzke: claus-werner.franzke@ 123456uniklinik-freiburg.de OR Carl P. Blobel: blobelc@ 123456hss.edu

                T. Kurz’s present address is Next Generation Sequencing Technologies, GATC Biotech AG, 78467 Konstanz, Germany.

                Article
                20112258
                10.1084/jem.20112258
                3371728
                22565824
                8f9b5868-0fd9-431c-9f0f-1ce000d62a31
                © 2012 Franzke 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/).

                History
                : 24 October 2011
                : 16 April 2012
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                Medicine
                Medicine

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