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.

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