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; Cord Brakebusch

doi:10.1038/s41467-018-03704-z

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

Nat Commun. 2018 Apr 12;9(1):1420. doi: 10.1038/s41467-018-03704-z.

Authors

Hui Li^{1

2}, Qi Yao^{1

2

3}, Alberto Garcia Mariscal^{1

2}, Xudong Wu^{2

4}, Justus Hülse^{1

2}, Esben Pedersen^{1

2}, Kristian Helin^{2

4}, Ari Waisman⁵, Caroline Vinkel^{6

7}, Simon Francis Thomsen^{6

7}, Alexandra Avgustinova^{8

9}, Salvador Aznar Benitah^{8

9}, Paola Lovato¹⁰, Hanne Norsgaard¹⁰, Mette Sidsel Mortensen¹⁰, Lone Veng¹⁰, Björn Rozell¹¹, Cord Brakebusch^{12

13}

Affiliations

¹ Department of Biomedical Sciences, University of Copenhagen, Ole Maaløes Vej 5, 2200, Copenhagen, Denmark.
² Biotech Research and Innovation Centre (BRIC), Ole Maaløes Vej 5, 2200, Copenhagen, Denmark.
³ Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, 2200, Denmark.
⁴ Centre for Epigenetics, Ole Maaløes Vej 5, 2200, Copenhagen, Denmark.
⁵ Institute for Molecular Medicine, Johannes Gutenberg-University Mainz, Obere Zahlbacher Straße 67, 55131, Mainz, Germany.
⁶ Department of Dermatology, Copenhagen University Hospital Bispebjerg, Bispebjerg Bakke 23, 2400, Copenhagen, Denmark.
⁷ Department of Biomedical Sciences, University of Copenhagen, Blegdamsvej 3, 2200, Copenhagen, Denmark.
⁸ Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, 08028, Spain.
⁹ Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, 08010, Spain.
¹⁰ LEO Pharma A/S, Industriparken 55, 2750, Ballerup, Denmark.
¹¹ Department of Experimental Medicine, University of Copenhagen, Blegdamsvej 3, 2200, Copenhagen, Denmark.
¹² Department of Biomedical Sciences, University of Copenhagen, Ole Maaløes Vej 5, 2200, Copenhagen, Denmark. [email protected].
¹³ Biotech Research and Innovation Centre (BRIC), Ole Maaløes Vej 5, 2200, Copenhagen, Denmark. [email protected].

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Animals
Disease Models, Animal
Epigenesis, Genetic*
Genes, Reporter
Green Fluorescent Proteins / genetics
Green Fluorescent Proteins / metabolism
HEK293 Cells
Histone-Lysine N-Methyltransferase / deficiency
Histone-Lysine N-Methyltransferase / genetics*
Histone-Lysine N-Methyltransferase / metabolism
Histones / genetics
Histones / metabolism
Humans
Inflammation
Interleukin-17 / genetics
Interleukin-17 / metabolism
Interleukin-23 Subunit p19 / deficiency
Interleukin-23 Subunit p19 / genetics*
Keratinocytes / metabolism
Keratinocytes / pathology
Male
Mice
Mice, Knockout
Middle Aged
Primary Cell Culture
Promoter Regions, Genetic
Psoriasis / genetics*
Psoriasis / metabolism
Psoriasis / pathology
Signal Transduction
Skin / metabolism*
Skin / pathology
Wiskott-Aldrich Syndrome Protein, Neuronal / deficiency
Wiskott-Aldrich Syndrome Protein, Neuronal / genetics*

Substances

Histones
IL23A protein, human
Interleukin-17
Interleukin-23 Subunit p19
Wasl protein, mouse
Wiskott-Aldrich Syndrome Protein, Neuronal
Green Fluorescent Proteins
G9a protein, mouse
GLP protein, mouse
Histone-Lysine N-Methyltransferase