- (1) University of Copenhagen, grid.5254.6, KU
- (2) Centre for Epigenetics, Ole Maaløes Vej 5, 2200, Copenhagen, Denmark
- (3) Johannes Gutenberg University of Mainz, grid.5802.f
- (4) Bispebjerg Hospital, grid.411702.1, Capital Region
- (5) Catalan Institution for Research and Advanced Studies, grid.425902.8
- (6) Institute for Research in Biomedicine, grid.7722.0
- (7) Leo Pharma (Denmark), grid.420009.f
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.