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.

IκBζ is a key driver in the development of psoriasis

“…The mechanism by which imiquimod induces psoriasis-like skin inflammation is not fully understood, although IL-17 cytokines like IL-17A, IL-17C, and IL-17F are believed to play important roles (23,43). The adaptor protein Act1 is one of the key components in the IL-17 signaling pathway (44), and recently Act1-mediated signaling was demonstrated to play an essential role in imiquimodinduced psoriasis-like skin inflammation (45). Although IL-17 has been demonstrated to regulate IκBζ through an Act1-dependent mechanism in mice (46,47) and humans (19), the exact signaling mechanism involved needs still to be determined.…”

The roles and functional mechanisms of interleukin-17 family cytokines in mucosal immunity

“…Studies have shown that Il23p19-, Il17ra-, and Act1-deficient mice are protected from IMQ-induced psoriasis compared with wildtype mice. [103][104][105] K5.Stat3C transgenic mice in which Stat3 is constitutively activated in keratinocytes develop skin lesions similar to those of human psoriasis. 106 Either neutralization of IL-17 or deletion of the Il17a gene ameliorates 12-O-tetradecanoylphorbol-13-acetate-induced psoriasis in these mice.…”

The AMPK enzyme-complex: from the regulation of cellular energy homeostasis to a possible new molecular target in the management of chronic inflammatory disorders

“…It is characterized by abnormal keratinocyte proliferation and differentiation, and by an influx of inflammatory cells [71]. Inhibition of the excessive keratinocyte proliferation represents a main target in the treatment of psoriasis [72].…”