Psoriasis is a skin disease characterized by abnormal keratinocyte (KC) proliferation and differentiation and by an influx of inflammatory immune cells. The IL-23/IL-17 axis is thought to play an important role in the pathogenesis of psoriasis. Imiquimod (IMQ) can induce/exacerbate psoriasis in patients and it induces a psoriasis-like condition in mice. In addition to IL-17A/F, IL-17C has also recently been implicated in IMQ-induced psoriasis. To determine by what mechanisms IL-17 cytokines critically contribute to psoriasis, we investigated a mouse model in which signaling by all IL-17 cytokines is abrogated due to the loss of the obligate adaptor protein CIKS/Act1. Importantly, the gene for CIKS has also been identified as a strong susceptibility locus in psoriasis. Here we show that IMQ induced many of the typical phenotypes of human psoriasis in wild-type mice, but largely failed to do so in CIKS-deficient mice. In addition to promoting the influx of inflammatory cells, IL-17 signaling via CIKS contributed to increased proliferation of KCs and inhibited their terminal differentiation. Mice lacking CIKS in KCs only were protected from some, but not all of the pathologic phenotypes associated with psoriasis in this model. These data demonstrate that CIKS is essential for IMQ-induced psoriasis by mediating the signaling of IL-17 cytokines in several distinct cell types. Thus our findings identify CIKS as a promising target for therapeutic intervention in this disease.
- Copyright © 2013 by The American Association of Immunologists, Inc.