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Multiple IL-17 family cytokines signaling through IL-17RA drive inflammatory pathways in psoriasis

ABSTRACT: The IL-23/IL-17 immune axis is of central importance in psoriasis. However, the contribution of IL-17 family cytokines other than IL-17A to drive skin inflammation in psoriasis has not been fully established. To further elucidate the role of individual IL-17 family cytokines in psoriasis, we investigated their expression and localization in psoriasis skin at the mRNA and protein level. Moreover, we investigated the gene expression signatures induced by individual IL-17 family cytokines in human skin ex vivo as well as modulation of responses induced by the combination of IL-17 family cytokines in human keratinocytes by brodalumab, a human monoclonal antibody targeting the IL-17RA, versus the IL-17A blocking antibody ixekizumab. We demonstrate that IL-17A, IL-17AF, IL-17F and IL-17C are expressed at increased levels in psoriasis lesional skin and induce inflammatory gene expression signatures in human skin ex vivo that correlate with those observed in psoriasis. Furthermore, we show that brodalumab, in contrast to ixekizumab, fully blocks gene expression responses induced by the combination of IL-17A, IL-17AF, IL-17F and IL-17C in human keratinocytes. These findings suggest that inhibition of several IL-17 family cytokines, e.g. by targeting of the IL-17RA receptor, could be a favored mechanism to obtain a profound suppression of the inflammatory processes in psoriasis and thereby achieve high levels of skin clearance and sustained efficacy in patients with psoriasis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE158448 | GEO | 2021/04/07

REPOSITORIES: GEO

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