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

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.

• Authors: Khalifa El Malki, Susanne H Karbach, Jula Huppert, Morad Zayoud, Sonja Reissig, Rebecca Schüler, Alexej Nikolaev, Khalad Karram, Thomas Münzel, Christoph R W Kuhlmann, Heiko J Luhmann, Esther von Stebut, Simone Wörtge, Florian C Kurschus, Ari Waisman
• Journal: The Journal of investigative dermatology (J Invest Dermatol) Vol. 133 Issue 2 Pg. 441-51 (Feb 2013) ISSN: 1523-1747 [Electronic] United States
• PMID: 22951726 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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