An alternative pathway of imiquimod-induced psoriasis-like skin inflammation in the absence of interleukin-17 receptor a signaling

J Invest Dermatol. 2013 Feb;133(2):441-51. doi: 10.1038/jid.2012.318. Epub 2012 Sep 6.

Abstract

Topical application of imiquimod (IMQ) on the skin of mice induces inflammation with common features found in psoriatic skin. Recently, it was postulated that IL-17 has an important role both in psoriasis and in the IMQ model. To further investigate the impact of IL-17RA signaling in psoriasis, we generated IL-17 receptor A (IL-17RA)-deficient mice (IL-17RA(del)) and challenged these mice with IMQ. Interestingly, the disease was only partially reduced and delayed but not abolished when compared with controls. In the absence of IL-17RA, we found persisting signs of inflammation such as neutrophil and macrophage infiltration within the skin. Surprisingly, already in the naive state, the skin of IL-17RA(del) mice contained significantly elevated numbers of Th17- and IL-17-producing γδ T cells, assuming that IL-17RA signaling regulates the population size of Th17 and γδ T cells. Upon IMQ treatment of IL-17RA(del) mice, these cells secreted elevated amounts of tumor necrosis factor-α, IL-6, and IL-22, accompanied by increased levels of the chemokine CXCL2, suggesting an alternative pathway of neutrophil and macrophage skin infiltration. Hence, our findings have major implications in the potential long-term treatment of psoriasis by IL-17-targeting drugs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adjuvants, Immunologic / pharmacology
  • Aminoquinolines / pharmacology*
  • Animals
  • Disease Models, Animal
  • Female
  • Imiquimod
  • Interleukin-17 / immunology*
  • Interleukin-17 / metabolism
  • Interleukin-6 / immunology
  • Interleukin-6 / metabolism
  • Interleukins / immunology
  • Interleukins / metabolism
  • Macrophages / drug effects
  • Macrophages / immunology
  • Mice
  • Mice, Knockout
  • Neutrophil Infiltration / drug effects
  • Neutrophil Infiltration / immunology
  • Psoriasis / chemically induced*
  • Psoriasis / genetics
  • Psoriasis / immunology*
  • Receptors, Interleukin-17 / genetics
  • Receptors, Interleukin-17 / immunology*
  • Receptors, Interleukin-17 / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / immunology*
  • Skin / immunology
  • Skin / metabolism
  • Skin / pathology

Substances

  • Adjuvants, Immunologic
  • Aminoquinolines
  • Il17a protein, mouse
  • Il17ra protein, mouse
  • Interleukin-17
  • Interleukin-6
  • Interleukins
  • Receptors, Interleukin-17
  • interleukin-6, mouse
  • Imiquimod
  • interleukin-22