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Keratinocytes Counteract UVB-Induced Immunosuppression in Mice Via HIF-1a Signaling

  • Sonja Faßbender
    Correspondence
    Corresponding author Sonja Fassbender IUF Leibniz Research Institute for Environmental Medicine, Auf´m Hennekamp 50, D-40225 Duesseldorf, Germany phone: +49 (0) 211 – 3389 251
    Affiliations
    Immunology and Environment, Life and Medical Sciences (LIMES) Institute, University of Bonn, Carl-Troll-Strasse 31, D-53115 Bonn, Germany

    IUF Leibniz Research Institute for Environmental Medicine, Auf´m Hennekamp 50, D-40225 Duesseldorf, Germany
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  • Kevin Sondenheimer
    Affiliations
    IUF Leibniz Research Institute for Environmental Medicine, Auf´m Hennekamp 50, D-40225 Duesseldorf, Germany
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  • Marc Majora
    Affiliations
    IUF Leibniz Research Institute for Environmental Medicine, Auf´m Hennekamp 50, D-40225 Duesseldorf, Germany
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  • Jennifer Schindler
    Affiliations
    IUF Leibniz Research Institute for Environmental Medicine, Auf´m Hennekamp 50, D-40225 Duesseldorf, Germany
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  • Author Footnotes
    # currently: Institute of Pathology, University Hospital Duesseldorf, Germany
    Friederike V. Opitz
    Footnotes
    # currently: Institute of Pathology, University Hospital Duesseldorf, Germany
    Affiliations
    Immunology and Environment, Life and Medical Sciences (LIMES) Institute, University of Bonn, Carl-Troll-Strasse 31, D-53115 Bonn, Germany

    IUF Leibniz Research Institute for Environmental Medicine, Auf´m Hennekamp 50, D-40225 Duesseldorf, Germany
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  • Marius Pollet
    Affiliations
    IUF Leibniz Research Institute for Environmental Medicine, Auf´m Hennekamp 50, D-40225 Duesseldorf, Germany
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  • Thomas Haarmann-Stemmann
    Affiliations
    IUF Leibniz Research Institute for Environmental Medicine, Auf´m Hennekamp 50, D-40225 Duesseldorf, Germany
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  • Jean Krutmann
    Affiliations
    IUF Leibniz Research Institute for Environmental Medicine, Auf´m Hennekamp 50, D-40225 Duesseldorf, Germany
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  • Heike Weighardt
    Affiliations
    Immunology and Environment, Life and Medical Sciences (LIMES) Institute, University of Bonn, Carl-Troll-Strasse 31, D-53115 Bonn, Germany

    IUF Leibniz Research Institute for Environmental Medicine, Auf´m Hennekamp 50, D-40225 Duesseldorf, Germany
    Search for articles by this author
  • Author Footnotes
    # currently: Institute of Pathology, University Hospital Duesseldorf, Germany
Published:September 24, 2021DOI:https://doi.org/10.1016/j.jid.2021.07.185

      ABSTRACT

      The transcription factor Hypoxia-Inducible Factor-1alpha (HIF-1a) regulates cellular metabolism under hypoxia but also immune responses and UVB-induced skin reactions. In keratinocytes, HIF-1a is an environmental sensor orchestrating the adaptation to environmental changes. Here, we investigated the role of HIF-1a in keratinocytes for skin reactions to acute and chronic UVB exposure in mice.
      The function of HIF-1a in keratinocytes under UVB exposure was analyzed in conditional keratinocyte-specific HIF-1a-KO (in short “cKO”) mice.
      cKO mice were hypersensitive to acute high-dose UVB irradiation compared to wildtype (WT), displaying increased cell death and delayed barrier repair. After chronic low-dose UVB treatment, cKO mice also had stronger epidermal damage but reduced infiltration of dermal macrophages and T helper cells compared to WT mice. Irradiated cKO mice revealed accumulation of regulatory lymphocytes in dorsal skin-draining lymph nodes compared to WT and unirradiated mice. This was reflected by augmented IL-10 release of lymph node cells and a weaker contact hypersensitivity reaction to DNFB in UVB-exposed cKO mice compared to WT and unirradiated controls.
      In summary, we found that keratinocyte-specific HIF-1a expression is crucial for adaptation to UVB exposure and inhibits the development of UVB-induced immunosuppression in mice. Therefore, HIF-1a signaling in keratinocytes could ameliorate photoaging-related skin disorders.

      Graphical abstract

      Abbreviations:

      bLN (brachial lymph node), cKO (conditional knock-out), CPD (Cyclobutane Pyrimidine Dimer), DNFB (2,4-Dinitro-1-Fluorobenzene), HIF (Hypoxia-inducible factor), LC (Langerhans cells), LN (lymph node), LNC (lymph node cells), sdLN (skin-draining lymph node), SW (South-Western (blot))
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