title: 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.affiliation: Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.
authors.forename: Khalifa
authors.initials: K
authors.lastname: El Malki
authors.forename: Susanne H
authors.initials: SH
authors.lastname: Karbach
authors.forename: Jula
authors.initials: J
authors.lastname: Huppert
authors.forename: Morad
authors.initials: M
authors.lastname: Zayoud
authors.forename: Sonja
authors.initials: S
authors.lastname: Reissig
authors.forename: Rebecca
authors.initials: R
authors.lastname: Schüler
authors.forename: Alexej
authors.initials: A
authors.lastname: Nikolaev
authors.forename: Khalad
authors.initials: K
authors.lastname: Karram
authors.forename: Thomas
authors.initials: T
authors.lastname: Münzel
authors.forename: Christoph R W
authors.initials: CR
authors.lastname: Kuhlmann
authors.forename: Heiko J
authors.initials: HJ
authors.lastname: Luhmann
authors.forename: Esther
authors.initials: E
authors.lastname: von Stebut
authors.forename: Simone
authors.initials: S
authors.lastname: Wörtge
authors.forename: Florian C
authors.initials: FC
authors.lastname: Kurschus
authors.forename: Ari
authors.initials: A
authors.lastname: Waisman
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000634:Aminoquinolines / Q000494:pharmacology*; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D000077271:Imiquimod; D020381:Interleukin-17 / Q000276:immunology* / Q000378:metabolism; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism; D007378:Interleukins / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000187:drug effects / Q000276:immunology; D011565:Psoriasis / Q000139:chemically induced* / Q000235:genetics / Q000276:immunology*; D053722:Receptors, Interleukin-17 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D012867:Skin / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D000097043:Interleukin-22
chemical_list: D000276:Adjuvants, Immunologic; D000634:Aminoquinolines; D000077271:Imiquimod; D020381:Interleukin-17; D015850:Interleukin-6; D007378:Interleukins; D053722:Receptors, Interleukin-17; D000097043:Interleukin-22; C098680:Il17a protein, mouse; C491673:Il17ra protein, mouse; C577686:interleukin-6, mouse