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An Epidermal-Specific Role for Arginase1 during Cutaneous Wound Repair

  • Author Footnotes
    5 These authors contributed equally to this work.
    Rachel A. Crompton
    Footnotes
    5 These authors contributed equally to this work.
    Affiliations
    Lydia Becker Institute of Immunology and Inflammation, Manchester Academic Health Science Centre, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United Kingdom
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  • Author Footnotes
    5 These authors contributed equally to this work.
    Helen Williams
    Footnotes
    5 These authors contributed equally to this work.
    Affiliations
    Lydia Becker Institute of Immunology and Inflammation, Manchester Academic Health Science Centre, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United Kingdom
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  • Laura Campbell
    Affiliations
    Lydia Becker Institute of Immunology and Inflammation, Manchester Academic Health Science Centre, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United Kingdom
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  • Lim Hui Kheng
    Affiliations
    Skin Research Institute of Singapore, Agency for Science, Technology and Research (A∗STAR), Singapore, Singapore
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  • Charis Saville
    Affiliations
    Lydia Becker Institute of Immunology and Inflammation, Manchester Academic Health Science Centre, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United Kingdom
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  • David M. Ansell
    Affiliations
    Lydia Becker Institute of Immunology and Inflammation, Manchester Academic Health Science Centre, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United Kingdom

    Faculty of Life Sciences, School of Chemistry and Bioscience, University of Bradford, Bradford, United Kingdom
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  • Adam Reid
    Affiliations
    Lydia Becker Institute of Immunology and Inflammation, Manchester Academic Health Science Centre, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United Kingdom
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  • Jason Wong
    Affiliations
    Lydia Becker Institute of Immunology and Inflammation, Manchester Academic Health Science Centre, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United Kingdom
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  • Leah A. Vardy
    Affiliations
    Skin Research Institute of Singapore, Agency for Science, Technology and Research (A∗STAR), Singapore, Singapore
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  • Matthew J. Hardman
    Affiliations
    Centre for Atherothrombosis and Metabolic Disease, Hull York Medical School, University of Hull, Hull, United Kingdom
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  • Sheena M. Cruickshank
    Correspondence
    Correspondence: Sheena M. Cruickshank, Lydia Becker Institute of Immunology and Inflammation, Manchester Academic Health Science Centre, Faculty of Biology, Medicine and Health, The University of Manchester, AV Hill Building, Oxford Road, Manchester M13 9PT, United Kingdom.
    Affiliations
    Lydia Becker Institute of Immunology and Inflammation, Manchester Academic Health Science Centre, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United Kingdom
    Search for articles by this author
  • Author Footnotes
    5 These authors contributed equally to this work.
Published:October 25, 2021DOI:https://doi.org/10.1016/j.jid.2021.09.009
      Nonhealing wounds are a major area of unmet clinical need remaining problematic to treat. Improved understanding of prohealing mechanisms is invaluable. The enzyme arginase1 (ARG1) is involved in prohealing responses, with its role in macrophages best characterized. ARG1 is also expressed by keratinocytes; however, ARG1 function in these critical wound repair cells is not understood. We characterized ARG1 expression in keratinocytes during normal cutaneous repair and reveal de novo temporal and spatial expression at the epidermal wound edge. Interestingly, epidermal ARG1 expression was decreased in both human and murine delayed healing wounds. We therefore generated a keratinocyte-specific ARG1-null mouse model (K14-cre;Arg1fl/fl) to explore arginase function. Wound repair, linked to changes in keratinocyte proliferation, migration, and differentiation, was significantly delayed in K14-cre;Arg1fl/fl mice. Similarly, using the arginase inhibitor N(omega)-hydroxy-nor-L-arginine, human in vitro and ex vivo models further confirmed this finding, revealing the importance of the downstream polyamine pathway in repair. Indeed, restoring the balance in ARG1 activity through the addition of putrescine proved beneficial in wound closure. In summary, we show that epidermal ARG1 plays, to our knowledge, a previously unreported intrinsic role in cutaneous healing, highlighting epidermal ARG1 and the downstream mediators as potential targets for the therapeutic modulation of wound repair.

      Graphical abstract

      Abbreviations:

      ARG1 (Arginase1), DFU (diabetic foot ulcer), IHC (immunohistochemistry), K (keratin), KC (keratinocyte), Nor-NOHA (N(omega)-hydroxy-nor-L-arginine)
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