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IL-17A Dissociates Inflammation from Fibrogenesis in Systemic Sclerosis

Brembilla, Nicolò Costantino
Published in Journal of investigative dermatology. 2020, vol. 140, no. 1, p. 103-112.e8
Abstract IL-17A is abundant in scleroderma but its role in fibrogenesis is controversial. We interrogated the role of IL-17A in extracellular matrix deposition and inflammation by investigating its effects on keratinocytes and fibroblasts cross-talk and in organotypic skin cultures. Keratinocyte-conditioned media of resting, IL-17A-, and/or transforming growth factor-β-primed primary keratinocytes were used to stimulate healthy donors and scleroderma fibroblasts. Alternatively, organotypic cultures of full human skin were challenged with these cytokines. Keratinocyte-conditioned media tilted the balance of col-I to matrix metalloproteinase-1 production by fibroblasts in favor of matrix metalloproteinase-1, significantly more so in healthy donors than in scleroderma, resulting in enhanced extracellular matrix turnover, further increased by IL-17A. In organotypic skin, transforming growth factor-β induced an extensive pro-fibrotic gene signature, including the enhanced expression of several collagen genes associated with Wnt signaling. IL-17A strongly promoted the expression of pro-inflammatory genes, with no direct effects on collagen genes, and attenuated Wnt signaling induced by transforming growth factor-β. In this model, at the protein level, IL-17A significantly decreased col-I production. Our data strongly support a pro-inflammatory and antifibrogenic activity of IL-17A in the context of keratinocyte-fibroblast interaction and in full skin. These data help in directing and interpreting targeted therapeutic approaches in scleroderma.
PMID: 31276679
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Article (Published version) (3 MB) - document accessible for UNIGE members only Limited access to UNIGE
Research group Groupe Pittet Cuenod Brigitte (chirurgie plastique et reconstructive) (96)
Swiss National Science Foundation: 310030_159999
(ISO format)
DUFOUR, Aleksandra Maria et al. IL-17A Dissociates Inflammation from Fibrogenesis in Systemic Sclerosis. In: Journal of Investigative Dermatology, 2020, vol. 140, n° 1, p. 103-112.e8. doi: 10.1016/j.jid.2019.05.026 https://archive-ouverte.unige.ch/unige:126341

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Deposited on : 2019-11-15

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