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

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^*

^*Corresponding author for this work

33 Citations (Scopus)

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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.

Original language	English
Article number	1420
Journal	Nature Communications
Volume	9
Issue number	1
Pages (from-to)	1-18
Number of pages	18
ISSN	2041-1723
DOIs	https://doi.org/10.1038/s41467-018-03704-z
Publication status	Published - 2018

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Epigenetic control of IL-23 expression in keratinocytes is important for chronic skin inflammationFinal published version, 5.69 MBLicence: CC BY

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Li, H., Yao, Q., Mariscal, A. G., Wu, X., Hülse, J., Pedersen, E., Helin, K., Waisman, A., Vinkel, C., Thomsen, S. F., Avgustinova, A., Benitah, S. A., Lovato, P., Norsgaard, H., Mortensen, M. S., Veng, L., Rozell, B., & Brakebusch, C. (2018). Epigenetic control of IL-23 expression in keratinocytes is important for chronic skin inflammation. Nature Communications, 9(1), 1-18. [1420]. https://doi.org/10.1038/s41467-018-03704-z

Li, H, Yao, Q, Mariscal, AG, Wu, X, Hülse, J, Pedersen, E, Helin, K, Waisman, A, Vinkel, C, Thomsen, SF, Avgustinova, A, Benitah, SA, Lovato, P, Norsgaard, H, Mortensen, MS, Veng, L, Rozell, B & Brakebusch, C 2018, 'Epigenetic control of IL-23 expression in keratinocytes is important for chronic skin inflammation', Nature Communications, vol. 9, no. 1, 1420, pp. 1-18. https://doi.org/10.1038/s41467-018-03704-z

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title = "Epigenetic control of IL-23 expression in keratinocytes is important for chronic skin inflammation",

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.",

author = "Hui Li and Qi Yao and Mariscal, {Alberto Garcia} and Xudong Wu and Justus H{\"u}lse and Esben Pedersen and Kristian Helin and Ari Waisman and Caroline Vinkel and Thomsen, {Simon Francis} and Alexandra Avgustinova and Benitah, {Salvador Aznar} and Paola Lovato and Hanne Norsgaard and Mortensen, {Mette Sidsel} and Lone Veng and Bj{\"o}rn Rozell and Cord Brakebusch",

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T1 - Epigenetic control of IL-23 expression in keratinocytes is important for chronic skin inflammation

AU - Li, Hui

AU - Yao, Qi

AU - Mariscal, Alberto Garcia

AU - Wu, Xudong

AU - Hülse, Justus

AU - Pedersen, Esben

AU - Helin, Kristian

AU - Waisman, Ari

AU - Vinkel, Caroline

AU - Thomsen, Simon Francis

AU - Avgustinova, Alexandra

AU - Benitah, Salvador Aznar

AU - Lovato, Paola

AU - Norsgaard, Hanne

AU - Mortensen, Mette Sidsel

AU - Veng, Lone

AU - Rozell, Björn

AU - Brakebusch, Cord

PY - 2018

Y1 - 2018

N2 - 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.

AB - 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.

U2 - 10.1038/s41467-018-03704-z

DO - 10.1038/s41467-018-03704-z

M3 - Journal article

C2 - 29650963

AN - SCOPUS:85045508146

SN - 2041-1723

VL - 9

SP - 1

EP - 18

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 1420

ER -

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

Abstract

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