Journal
JOURNAL OF INVESTIGATIVE DERMATOLOGY
Volume 140, Issue 1, Pages 103-+Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jid.2019.05.026
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Funding
- Swiss National Science Foundation [310030-159999]
- Swiss Scleroderma Patient organization
- Swiss National Science Foundation (SNF) [310030_159999] Funding Source: Swiss National Science Foundation (SNF)
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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-beta-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-beta 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 proinflammatory genes, with no direct effects on collagen genes, and attenuated Wnt signaling induced by transforming growth factor-beta. 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.
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