IL-20-receptor signaling delimits IL-17 production in psoriatic inflammation.

Abstract

IL-17 cytokines, in particular IL-17A, are critical effectors in psoriasis. Antibodies blocking IL-17A are highly efficacious in treating psoriasis. Likewise, disruption of IL-17 cytokines signaling, such as via loss of the adaptor CIKS/Act1, ameliorates inflammation in mouse models of psoriasis. IL-17A promotes a cascade of effects, including robust production of IL-19 in both humans and mice. IL-19, along with IL-20 and IL-24 signal via IL-20 receptors and comprise a subgroup within the IL-10 cytokine family. The role of these three cytokines in psoriasis is unsettled. They have been linked to inflammatory processes, including psoriatic pathology, but these cytokines have also been reported to suppress inflammation in other contexts. Here we demonstrate that signaling via IL-20 receptors, including in response to IL-19, delimited aspects of imiquimod-induced psoriatic inflammation. IL-20 receptor-signaling suppressed dermal production of the CCL2 chemokine and thereby reduced CCL-2-driven infiltration of inflammatory cells into the dermis, including IL-17A-producing γδT cells. This constitutes a negative feedback, since IL-17A strongly induces IL-19 in keratinocytes. The effects of IL-17 cytokines in this inflammatory setting are dynamic, they are central to development of both dermal and epidermal hallmarks of psoriasis, but also initiate a path to mitigate inflammatory damage.