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

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 Benitah, Paola Lovato, Hanne Norsgaard, Mette Sidsel Mortensen, Lone Veng, Björn Rozell and Cord Brakebusch ()
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Hui Li: University of Copenhagen
Qi Yao: University of Copenhagen
Alberto Garcia Mariscal: University of Copenhagen
Xudong Wu: Biotech Research and Innovation Centre (BRIC)
Justus Hülse: University of Copenhagen
Esben Pedersen: University of Copenhagen
Kristian Helin: Biotech Research and Innovation Centre (BRIC)
Ari Waisman: Johannes Gutenberg-University Mainz
Caroline Vinkel: Copenhagen University Hospital Bispebjerg
Simon Francis Thomsen: Copenhagen University Hospital Bispebjerg
Alexandra Avgustinova: The Barcelona Institute of Science and Technology
Salvador Aznar Benitah: The Barcelona Institute of Science and Technology
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

Nature Communications, 2018, vol. 9, issue 1, 1-18

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-03704-z

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