O019 IL-17A at crossroad between keratinocytes and fibroblasts in human skin within systemic sclerosis. (21st February 2018)

• Record Type: Journal Article
• Authors: Dufour, AM; Alvarez, M; Truchetet, M-E; Brembilla, NC; Chizzolini, C
• Is Part Of: Annals of the rheumatic diseases. Volume 77(2018)Supplement 1
• Page Start: A10
• Page End: A10
• Publication Date: 2018-02-21
• Subjects: Rheumatism -- Periodicals; 616.723005
• DOI: 10.1136/annrheumdis-2018-EWRR2018.19
• Languages: English
• ISSNs: 0003-4967

Abstract

Abstract : Introduction: Increased levels of IL-17A have been reported in systemic sclerosis (SSc) but its role in fibrosis development is still debated. 1 Recent findings suggest a role for keratinocytes in the development of fibrosis. 2 Of interest, epithelial cells are preferential targets of IL-17A. Objectives: Our aim was to investigate the interactions between epidermis and dermis in the presence of IL-17A, taking into perspective the fibrotic process. Methods: Conditioned-media of primary human keratinocytes primed with IL-17A and/or TGF-β were used to stimulate healthy donors (HD) and SSc fibroblasts. Alternatively, organotypic cultures of HD full human skin were treated with these cytokines. Responses were assessed by quantifying inflammatory mediators and type I collagen (Col-I) levels. The factors produced by keratinocytes were identified by a proteomic approach and their contribution was evaluated by their neutralisation. MicroRNA expression was examined by µParaflo technology platform. Results: Unstimulated HD- and SSc-derived keratinocyte-conditioned media (KCM) promoted collagen production by fibroblasts to a similar extent and in a dose-dependent manner. Cytokine array analysis and neutralising assays showed that TGF-β was, at least in part, responsible for the pro-fibrotic effect of KCM. Although priming of keratinocytes with IL-17A alone did not influence Col-I, it significantly decreased Col-I production induced by TGF-β by fibroblasts (p=0.02). In full human skin, IL-17A promoted pro-inflammatory responses by inducing 2- to 4-fold increase of IL-8, IL-6, MCP-1 and MMP-1 levels, while showing direct anti-fibrotic effects and decreasing by 2-fold collagen production triggered by TGF-β (p=0.02). The combined injection of IL-17A and TGF-β in the full human skin resulted in a distinct pattern of miRNA expression, particularly driven by miR-4343, when compared to the expression induced by the separate injection of IL-17A and TGF-β. Conclusions: Keratinocytes profoundly influence dermal fibroblast responses, which are further modulated in the presence of IL-17A. These data support a role for keratinocytes in the pathogenesis of SSc. IL-17A acts as a potent anti-fibrotic factor in the model of keratinocyte – fibroblast interactions, as well as in the full human skin, which mechanisms are currently explored. References: . Truchetet ME, et al. Arthritis & Rheumatol 2013. . Takahashi T, et al. J Exp Med 2017. Acknowledgements: Work supported in part by grant 310030–1 59 999 from the SNF to CC. Disclosure of interest: None declared