Psoriasiform dermatitis is driven by IL-36-mediated DC-keratinocyte crosstalk

J Clin Invest. 2012 Nov;122(11):3965-76. doi: 10.1172/JCI63451. Epub 2012 Oct 15.

Abstract

Psoriasis is a chronic inflammatory disorder of the skin affecting approximately 2% of the world's population. Accumulating evidence has revealed that the IL-23/IL-17/IL-22 pathway is key for development of skin immunopathology. However, the role of keratinocytes and their crosstalk with immune cells at the onset of disease remains poorly understood. Here, we show that IL-36R-deficient (Il36r-/-) mice were protected from imiquimod-induced expansion of dermal IL-17-producing γδ T cells and psoriasiform dermatitis. Furthermore, IL-36R antagonist-deficient (Il36rn-/-) mice showed exacerbated pathology. TLR7 ligation on DCs induced IL-36-mediated crosstalk with keratinocytes and dermal mesenchymal cells that was crucial for control of the pathological IL-23/IL-17/IL-22 axis and disease development. Notably, mice lacking IL-23, IL-17, or IL-22 were less well protected from disease compared with Il36r-/- mice, indicating an additional distinct activity of IL-36 beyond induction of the pathological IL-23 axis. Moreover, while the absence of IL-1R1 prevented neutrophil infiltration, it did not protect from acanthosis and hyperkeratosis, demonstrating that neutrophils are dispensable for disease manifestation. These results highlight a central and unique IL-1-independent role for IL-36 in control of the IL-23/IL-17/IL-22 pathway and development of psoriasiform dermatitis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Communication / genetics
  • Cell Communication / immunology*
  • Dendritic Cells / immunology*
  • Dendritic Cells / metabolism
  • Dendritic Cells / pathology
  • Dermatitis / genetics
  • Dermatitis / immunology*
  • Dermatitis / metabolism
  • Dermatitis / pathology
  • Interleukin-1 / genetics
  • Interleukin-1 / immunology*
  • Interleukin-1 / metabolism
  • Interleukin-17 / genetics
  • Interleukin-17 / immunology
  • Interleukin-17 / metabolism
  • Interleukin-22
  • Interleukin-23 / genetics
  • Interleukin-23 / immunology
  • Interleukin-23 / metabolism
  • Interleukins / genetics
  • Interleukins / immunology
  • Interleukins / metabolism
  • Keratinocytes / immunology*
  • Keratinocytes / metabolism
  • Keratinocytes / pathology
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / immunology
  • Membrane Glycoproteins / metabolism
  • Mice
  • Mice, Knockout
  • Psoriasis / genetics
  • Psoriasis / immunology*
  • Psoriasis / metabolism
  • Psoriasis / pathology
  • Receptors, Interleukin-1 / genetics
  • Receptors, Interleukin-1 / immunology
  • Receptors, Interleukin-1 / metabolism
  • Toll-Like Receptor 7 / genetics
  • Toll-Like Receptor 7 / immunology
  • Toll-Like Receptor 7 / metabolism

Substances

  • Interleukin-1
  • Interleukin-17
  • Interleukin-23
  • Interleukins
  • Membrane Glycoproteins
  • Receptors, Interleukin-1
  • Tlr7 protein, mouse
  • Toll-Like Receptor 7
  • interleukin-36 receptor, mouse