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Epigenetic control of IL-23 expression in keratinocytes is important for chronic skin inflammation

Author

Listed:
  • Hui Li

    (University of Copenhagen
    Biotech Research and Innovation Centre (BRIC))

  • Qi Yao

    (University of Copenhagen
    Biotech Research and Innovation Centre (BRIC)
    University of Copenhagen)

  • Alberto Garcia Mariscal

    (University of Copenhagen
    Biotech Research and Innovation Centre (BRIC))

  • Xudong Wu

    (Biotech Research and Innovation Centre (BRIC)
    Centre for Epigenetics)

  • Justus Hülse

    (University of Copenhagen
    Biotech Research and Innovation Centre (BRIC))

  • Esben Pedersen

    (University of Copenhagen
    Biotech Research and Innovation Centre (BRIC))

  • Kristian Helin

    (Biotech Research and Innovation Centre (BRIC)
    Centre for Epigenetics)

  • Ari Waisman

    (Johannes Gutenberg-University Mainz)

  • Caroline Vinkel

    (Copenhagen University Hospital Bispebjerg
    University of Copenhagen)

  • Simon Francis Thomsen

    (Copenhagen University Hospital Bispebjerg
    University of Copenhagen)

  • Alexandra Avgustinova

    (The Barcelona Institute of Science and Technology
    Catalan Institution for Research and Advanced Studies (ICREA))

  • Salvador Aznar Benitah

    (The Barcelona Institute of Science and Technology
    Catalan Institution for Research and Advanced Studies (ICREA))

  • Paola Lovato

    (LEO Pharma A/S)

  • Hanne Norsgaard

    (LEO Pharma A/S)

  • Mette Sidsel Mortensen

    (LEO Pharma A/S)

  • Lone Veng

    (LEO Pharma A/S)

  • Björn Rozell

    (University of Copenhagen)

  • Cord Brakebusch

    (University of Copenhagen
    Biotech Research and Innovation Centre (BRIC))

Abstract

The chronic skin inflammation psoriasis is crucially dependent on the IL-23/IL-17 cytokine axis. Although IL-23 is expressed by psoriatic keratinocytes and immune cells, only the immune cell-derived IL-23 is believed to be disease relevant. Here we use a genetic mouse model to show that keratinocyte-produced IL-23 is sufficient to cause a chronic skin inflammation with an IL-17 profile. Furthermore, we reveal a cell-autonomous nuclear function for the actin polymerizing molecule N-WASP, which controls IL-23 expression in keratinocytes by regulating the degradation of the histone methyltransferases G9a and GLP, and H3K9 dimethylation of the IL-23 promoter. This mechanism mediates the induction of IL-23 by TNF, a known inducer of IL-23 in psoriasis. Finally, in keratinocytes of psoriatic lesions a decrease in H3K9 dimethylation correlates with increased IL-23 expression, suggesting relevance for disease. Taken together, our data describe a molecular pathway where epigenetic regulation of keratinocytes can contribute to chronic skin inflammation.

Suggested Citation

  • Hui Li & Qi Yao & Alberto Garcia Mariscal & Xudong Wu & Justus Hülse & Esben Pedersen & Kristian Helin & Ari Waisman & Caroline Vinkel & Simon Francis Thomsen & Alexandra Avgustinova & Salvador Aznar , 2018. "Epigenetic control of IL-23 expression in keratinocytes is important for chronic skin inflammation," Nature Communications, Nature, vol. 9(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-03704-z
    DOI: 10.1038/s41467-018-03704-z
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