Pluto Bioinformatics

GSE122305: Dissociating fibrosis from inflammation in systemic sclerosis the case of interleukin-17A

Bulk RNA sequencing

Objectives. Interleukin-17A (IL-17A) levels are increased in SSc skin and other organs but its role in fibrosis development is highly debated. Since epithelial cells are preferential targets of IL-17A, we aimed at investigating the role of IL-17A in the interactions between epidermis and dermis.; Methods. Organotypic cultures of HD full human skin were challenged with IL-17A,TNF and TGF-. Inflammatory mediators and type I collagen (col-I) levels were quantified. IL-17A- and TGF--induced changes in gene expression in full human skin were analysed by RNA sequencing.; Results. In full human skin, TGF- induced pro-fibrotic gene signature dominated by Wnt signalling. While IL-17A strongly promoted expression of many pro-inflammatory genes, it did not affect collagen gene levels but decreased Wnt signalling. At the protein level, IL-17A showed direct anti-fibrotic effects, as well as decreased by 2-fold TGF--triggered col-I production.; Conclusions. We report here firstly, a novel model of fibrotic skin and secondly, that IL-17A acts as a potent anti-fibrotic factor in the full human skin. Furthermore, we show that IL-17A not only decreased ECM deposition by itself, but also counteracted TGF- pro-fibrotic activities. Thus, IL-17A seems to play a dual role in SSc skin strongly pro-inflammatory but anti-fibrotic, being an example that fibrosis and inflammation, although closely related, are two different processes. These data may help in directing and interpreting therapeutic approaches in SSc, since both, IL-17A and TGF-, are target candidates in clinical trials. SOURCE: Sylvain LEMEILLE University of Geneva Medical School