Signaling of multiple IL-17 family cytokines through IL-17RA drive psoriasis-related inflammatory pathways.

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The IL-23/IL-17 immune axis is of central importance in psoriasis. However, the impact of IL-17 family cytokines other than IL-17A in psoriasis has not been fully established.To elucidate the contribution of IL-17 family cytokines in psoriasis, we performed a comprehensive and systematic analysis of their expression, localization and functional activity.To address the expression and localization of IL-17 family cytokines, lesional and non-lesional skin samples from psoriasis patients were analyzed by several complementary methods, including qPCR, immunoassays, in situ hybridization, and immunohistochemistry. Mechanistic studies assessing functional activity of IL-17 family cytokines were performed using ex vivo cultured human skin biopsies and primary human keratinocytes.We demonstrate that IL-17A, IL-17F, IL-17AF and IL-17C are expressed at increased levels in psoriasis lesional skin and induce overlapping gene expression responses in ex vivo cultured human skin that correlate with the transcriptomic signature of psoriasis skin. Furthermore, we show that brodalumab, in contrast to ixekizumab, normalizes gene expression responses induced by the combination of IL-17A, IL-17F, IL-17AF and IL-17C in human keratinocytes.Several IL-17 ligands signaling through IL-17RA are over-expressed in psoriasis skin and induce similar psoriasis-related inflammatory pathways demonstrating their relevance in relation to therapeutic intervention in psoriasis.

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Authors: M A X Tollenaere, J Hebsgaard, D A Ewald, P Lovato, S Garcet, X Li, S D Pilger, M L Tiirikainen, M Bertelsen, J G Krueger, H Norsgaard


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