title: IL-17 drives psoriatic inflammation via distinct, target cell-specific mechanisms.
abstract: Psoriasis is a chronic inflammatory skin disease characterized by abnormal keratinocyte proliferation and differentiation and by an influx of inflammatory cells. The mechanisms underlying psoriasis in humans and in mouse models are poorly understood, although evidence strongly points to crucial contributions of IL-17 cytokines, which signal via the obligatory adaptor CIKS/Act1. Here we identify critical roles of CIKS/Act1-mediated signaling in imiquimod-induced psoriatic inflammation, a mouse model that shares features with the human disease. We found that IL-17 cytokines/CIKS-mediated signaling into keratinocytes is essential for neutrophilic microabscess formation and contributes to hyperproliferation and markedly attenuated differentiation of keratinocytes, at least in part via direct effects. In contrast, IL-17 cytokines/CIKS-mediated signaling into nonkeratinocytes, particularly into dermal fibroblasts, promotes cellular infiltration and, importantly, leads to enhanced the accumulation of IL-17-producing γδT cells in skin, comprising a positive feed-forward mechanism. Thus, CIKS-mediated signaling is central in the development of both dermal and epidermal hallmarks of psoriasis, inducing distinct pathologies via target cell-specific effects. CIKS-mediated signaling represents a potential therapeutic target in psoriasis.
authors.affiliation: Immune Activation Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases.
authors.forename: Hye-Lin
authors.initials: HL
authors.lastname: Ha
authors.affiliation: Immune Activation Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases.
authors.forename: Hongshan
authors.initials: H
authors.lastname: Wang
authors.affiliation: Immune Activation Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases,Division of Allergy, Immunology, and Rheumatology, Department of Medicine, Ramathibodi Hospital, Mahidol University, Ratchatewi, Bangkok 10400 Thailand.
authors.forename: Prapaporn
authors.initials: P
authors.lastname: Pisitkun
authors.affiliation: Laboratory of Skin Biology, National Institute of Arthritis and Musculoskeletal and Skin Diseases, and.
authors.forename: Jin-Chul
authors.initials: JC
authors.lastname: Kim
authors.affiliation: Immune Activation Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Tassi
authors.affiliation: Immune Activation Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases.
authors.forename: Wanhu
authors.initials: W
authors.lastname: Tang
authors.affiliation: Laboratory of Skin Biology, National Institute of Arthritis and Musculoskeletal and Skin Diseases, and.
authors.forename: Maria I
authors.initials: MI
authors.lastname: Morasso
authors.affiliation: Dermatology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; and.
authors.forename: Mark C
authors.initials: MC
authors.lastname: Udey
authors.affiliation: Immune Activation Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, usiebenlist@niaid.nih.gov.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Siebenlist
mesh_terms: D000634:Aminoquinolines / Q000008:administration & dosage; D000818:Animals; D002454:Cell Differentiation / Q000276:immunology; D049109:Cell Proliferation; D004195:Disease Models, Animal; D004817:Epidermis / Q000187:drug effects / Q000473:pathology; D000077271:Imiquimod; D020381:Interleukin-17 / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011565:Psoriasis / Q000139:chemically induced / Q000276:immunology*; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D000634:Aminoquinolines; D020381:Interleukin-17; D000077271:Imiquimod
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