CCR6 is required for IL-23-induced psoriasis-like inflammation in mice

J Clin Invest. 2009 Aug;119(8):2317-29. doi: 10.1172/jci37378.

Abstract

Psoriasis is a common immune-mediated chronic inflammatory skin disorder, but the mechanisms of pathogenesis are still poorly understood. IL-23 is expressed in psoriatic skin, and IL-23 injection produces IL-22-dependent psoriasiform changes in mouse skin. Th17 cells produce IL-22 and display CCR6, the CCL20 receptor; CCR6+ T cells and CCL20 are abundant in psoriatic skin. We investigated a possible role for CCR6 in recruiting Th17 cells and producing psoriasiform pathology by injecting IL-23 into the skin of WT and Ccr6-/- mice. Unlike for WT mice, IL-23-injected ears of Ccr6-/- mice showed neither substantial epidermal/dermal changes nor increased Il22 mRNA expression. However, injection of IL-22 yielded equivalent psoriasiform changes in WT and Ccr6-/- mice. Surprisingly, IL-23-injected ears of WT and Ccr6-/- mice contained similar numbers of Th cells able to make IL-17A and/or IL-22. Furthermore, in ears of Rag1-/- mice, IL-23 initially induced skin changes and levels of Il22 mRNA that were indistinguishable from WT mice, revealing at least one non-T cell source for IL-22. We conclude that CCR6 is essential in a model of IL-23-induced, IL-22-mediated dermatitis, which develops in sequential T cell-independent and T cell-dependent phases. These findings reveal an expanded role for CCR6 in IL-23-related responses and identify CCR6 as a potential therapeutic target in psoriasis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / physiology
  • Dendritic Cells / physiology
  • Homeodomain Proteins / physiology
  • Interleukin-17 / biosynthesis
  • Interleukin-23 / toxicity*
  • Interleukins / biosynthesis
  • Mice
  • Mice, Inbred C57BL
  • Psoriasis / etiology*
  • Receptors, CCR6 / physiology*

Substances

  • CCR6 protein, mouse
  • Homeodomain Proteins
  • Interleukin-17
  • Interleukin-23
  • Interleukins
  • Receptors, CCR6
  • RAG-1 protein
  • interleukin-22