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

Hye Lin Ha, Hongshan Wang, Prapaporn Pisitkun, Jin Chul Kim, Ilaria Tassi, Wanhu Tang, Maria I. Morasso, Mark C. Udey, Ulrich Siebenlist

Research output: Contribution to journalArticlepeer-review

98 Scopus citations


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.

Original languageEnglish
Pages (from-to)E3422-E3431
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number33
StatePublished - Aug 19 2014


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