Skin fibrosis characterizes systemic sclerosis (SSc). This thesis addresses the question of whether dysfunctional keratinocyte-fibroblast interactions may participate in fibrogenesis and investigates whether epithelial-derived IL-25 may affect skin homeostasis. By using a novel tissue-engineered epidermal-equivalent (EE) generated from SSc and healthy donor (HD) keratinocytes, we found that in vitro SSc-EE reproduces a morphological phenotype characterized by aberrant differentiation and keratinocyte activation mimicking alterations found in vivo. Unbiased transcriptomic analysis showed profound alterations in SSc-EE, including downregulation of homeobox gene expression. Compared to HD, SSc-EE induced enhanced production of inflammatory mediators and matrix metalloproteinases by fibroblasts, but similar production of matrix components. IL-25 enhanced the pro-inflammatory activity of EE and directly inhibited matrix deposition by fibroblasts. The decreased expression of IL-25 in SSc skin suggested that its relative lack could play a role in skin fibrosis. Thèse Results strongly support a role for keratinocytes to modulate matrix turnover amenable to therapeutic intervention.