The psoriasis-associated IL-17A induces and cooperates with IL-36 cytokines to control keratinocyte differentiation and function

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Abstract

Psoriasis is a TH17-driven inflammatory disease affecting a significant proportion of the world population. The molecular consequences of IL-17 signaling in the skin are only partially understood. Therefore, we evaluated the IL-17A effects on organotypic 3-dimensional skin models and observed that IL-17A interfered with keratinocyte differentiation. In agreement with this phenotype, IL-17A repressed the expression of many genes encoding structural proteins. Moreover, genes encoding anti-microbial peptides were induced, resulting in a strengthening of the chemical barrier. Finally, we observed enhanced expression of the three IL-36 cytokines IL-36α, β and γ. We found that IL-36γ was secreted from keratinocytes in an inactive form and that neutrophilic proteases, including elastase, were capable of activating this cytokine. Functionally and similar to IL-17A, truncated IL-36 cytokines interfered with keratinocyte differentiation in 3D models. The molecular analysis revealed strong cooperative effects of IL-17A and IL-36 cytokines in regulating target genes, which was dependent on the proteolytic activation of the latter. Together these findings suggest an amplification cycle that can be initiated by IL-17A, involving IL-36 cytokines and immune cell derived proteases and resulting in active IL-36 cytokines which synergize with IL-17A. This amplification cycle might be relevant for a persistent psoriatic phenotype.

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Pfaff, C. M., Marquardt, Y., Fietkau, K., Baron, J. M., & Lüscher, B. (2017). The psoriasis-associated IL-17A induces and cooperates with IL-36 cytokines to control keratinocyte differentiation and function. Scientific Reports, 7(1). https://doi.org/10.1038/s41598-017-15892-7

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