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RESEARCH PRODUCT

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

Xudong WuEsben PedersenQi YaoPaola LovatoMette Sidsel MortensenCaroline VinkelCaroline VinkelBjörn RozellSimon Francis ThomsenSimon Francis ThomsenAri WaismanLone VengJustus HülseCord BrakebuschHui LiAlberto Garcia MariscalSalvador Aznar BenitahAlexandra AvgustinovaHanne NorsgaardKristian Helin

subject

KeratinocytesMale0301 basic medicinemedicine.medical_treatmentWiskott-Aldrich Syndrome Protein NeuronalGeneral Physics and AstronomyEpigenesis GeneticHistonesMice0302 clinical medicineGenes ReporterInterleukin 23Promoter Regions Geneticlcsh:ScienceSkinMice KnockoutMultidisciplinaryInterleukin-17QMiddle AgedCytokine030220 oncology & carcinogenesisHistone methyltransferaseTumor necrosis factor alphaSignal transductionmedicine.symptomSignal TransductionAdultScienceGreen Fluorescent ProteinsPrimary Cell CultureInflammationBiologyArticleGeneral Biochemistry Genetics and Molecular Biology03 medical and health sciencesImmune systemPsoriasismedicineAnimalsHumansPsoriasisInflammationHistone-Lysine N-MethyltransferaseGeneral Chemistrybiochemical phenomena metabolism and nutritionmedicine.diseaseDisease Models AnimalHEK293 Cells030104 developmental biologyInterleukin-23 Subunit p19Cancer researchlcsh:Q

description

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.

https://doi.org/10.1038/s41467-018-03704-z