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.
Highlights
The chronic skin inflammation psoriasis is crucially dependent on the IL-23/IL-17 cytokine axis
Mice with a keratinocyte-restricted deletion of the neural Wiskott-Aldrich syndrome protein (N-WASP) gene (N-WASP fl/fl K5 cre; called ko) show increased transforming growth factor-β (TGFβ) signaling in the epidermis, suggesting the possibility of a local inflammatory reaction[18]
The tumor necrosis factor (TNF)/IL-23/IL-17 cytokine cascade is suggested to be important for different inflammatory diseases
Summary
The chronic skin inflammation psoriasis is crucially dependent on the IL-23/IL-17 cytokine axis. 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. TNF and IL-23 are produced by activated innate immune cells, and by psoriatic keratinocytes[8,9], which may contribute to the development of the disease. In addition to these cytoplasmic functions, N-WASP might have a nuclear role, since it was reported to shuttle between the nucleus and the cytoplasm and to bind to a nuclear complex containing actin and RNA polymerase II16
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
