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      Keratin 6, 16 and 17—Critical Barrier Alarmin Molecules in Skin Wounds and Psoriasis

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          Abstract

          Located at the skin surface, keratinocytes (KCs) are constantly exposed to external stimuli and are the first responders to invading pathogens and injury. Upon skin injury, activated KCs secrete an array of alarmin molecules, providing a rapid and specific innate immune response against danger signals. However, dysregulation of the innate immune response of KCs may lead to uncontrolled inflammation and psoriasis pathogenesis. Keratins (KRT) are the major structural intermediate filament proteins in KCs and are expressed in a highly specific pattern at different differentiation stages of KCs. While KRT14-KRT5 is restricted to basal proliferative KCs, and KRT10-KRT1 is restricted to suprabasal differentiated KCs in normal skin epidermis, the wound proximal KCs downregulate KRT10-K1 and upregulate KRT16/KRT17-KRT6 upon skin injury. Recent studies have recognized KRT6/16/17 as key early barrier alarmins and upregulation of these keratins alters proliferation, cell adhesion, migration and inflammatory features of KCs, contributing to hyperproliferation and innate immune activation of KCs in response to an epidermal barrier breach, followed by the autoimmune activation of T cells that drives psoriasis. Here, we have reviewed how keratins are dysregulated during skin injury, their roles in wound repairs and in initiating the innate immune system and the subsequent autoimmune amplification that arises in psoriasis.

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          Wound healing--aiming for perfect skin regeneration.

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          The healing of an adult skin wound is a complex process requiring the collaborative efforts of many different tissues and cell lineages. The behavior of each of the contributing cell types during the phases of proliferation, migration, matrix synthesis, and contraction, as well as the growth factor and matrix signals present at a wound site, are now roughly understood. Details of how these signals control wound cell activities are beginning to emerge, and studies of healing in embryos have begun to show how the normal adult repair process might be readjusted to make it less like patching up and more like regeneration.
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            Pathogenesis and clinical features of psoriasis.

            Psoriasis, a papulosquamous skin disease, was originally thought of as a disorder primarily of epidermal keratinocytes, but is now recognised as one of the commonest immune-mediated disorders. Tumour necrosis factor alpha, dendritic cells, and T-cells all contribute substantially to its pathogenesis. In early-onset psoriasis (beginning before age 40 years), carriage of HLA-Cw6 and environmental triggers, such as beta-haemolytic streptococcal infections, are major determinants of disease expression. Moreover, at least nine chromosomal psoriasis susceptibility loci have been identified. Several clinical phenotypes of psoriasis are recognised, with chronic plaque (psoriasis vulgaris) accounting for 90% of cases. Comorbidities of psoriasis are attracting interest, and include impairment of quality of life and associated depressive illness, cardiovascular disease, and a seronegative arthritis known as psoriatic arthritis. A more complete understanding of underlying pathomechanisms is leading to new treatments, which will be discussed in the second part of this Series.
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              The catalog of human cytokeratins: patterns of expression in normal epithelia, tumors and cultured cells.

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                Author and article information

                Journal
                Cells
                Cells
                cells
                Cells
                MDPI
                2073-4409
                01 August 2019
                August 2019
                : 8
                : 8
                : 807
                Affiliations
                [1 ]School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, China
                [2 ]Department of Dermatology, University of California, San Diego, La Jolla, CA 92093, USA
                Author notes
                [†]

                These authors contribute equally to this work.

                Author information
                https://orcid.org/0000-0001-6937-4578
                Article
                cells-08-00807
                10.3390/cells8080807
                6721482
                31374826
                70fe78f9-739a-4837-804f-fdee75e10767
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 10 July 2019
                : 28 July 2019
                Categories
                Review

                keratins,epidermal keratinocytes,barrier alarmins,skin wounds,psoriasis,proliferation,innate immune responses,autoimmune

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