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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 111; no. 33; p. 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: Journal Article
• Language: English
• Published: United States National Academy of Sciences 19-08-2014; National Acad Sciences
• Series: PNAS Plus
• 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
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1400513111

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.