IL-17 drives psoriatic inflammation via distinct, target cell-specific mechanisms

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 cont...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2014-08, Vol.111 (33), p.11922-11922
Main Authors: Ha, Hye-Lin, Wang, Hongshan, Pisitkun, Prapaporn, Kim, Jin-Chul, Tassi, Ilaria, Tang, Wanhu, Morasso, Maria I., Udey, Mark C., Siebenlist, Ulrich
Format: Article
Language:English
Subjects:
Aminoquinolines - administration & dosage
Animals
Biological Sciences
Cell Differentiation - immunology
Cell Proliferation
Cellular biology
Disease Models, Animal
Epidermis - drug effects
Epidermis - pathology
Interleukin-17 - immunology
Mice
Mice, Inbred C57BL
Mice, Knockout
Pathology
PNAS Plus
PNAS PLUS: Significance Statements
Psoriasis
Psoriasis - chemically induced
Psoriasis - immunology
Real-Time Polymerase Chain Reaction
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Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1400513111