Systemic sclerosis (SSc) is a disorder of systemic and dermal fibrosis of uncertain etiology. Recently, we found that SSc epidermis is abnormal, taking on an activated phenotype observed during wound healing and tissue repair. As epithelial-fibroblast interactions are important during wound repair and in fibrosis in general, we investigated further the phenotype of the SSc epidermis, and tested whether the SSc epidermis provides a pro-fibrotic stimulus to fibroblasts. In this study we show that in SSc epidermis keratinocyte maturation is delayed, and wound-associated keratins 6 and 16 are induced, in both involved and clinically uninvolved skin. Phosphorylation array analysis revealed induction of stress-induced mitogen-activated protein kinase signaling and mesenchymal feedback through hepatocyte growth factor/c-Met in SSc epidermis. SSc epidermal cells maintained with normal fibroblasts in three-dimensional co-culture were found to stimulate fibroblasts, leading to contractility and connective tissue growth factor expression. These effects depend on elevation of IL-1alpha by the epidermal cells and induction of endothelin-1 and transforming growth factor-beta in fibroblasts. Antagonism of endogenous IL-1alpha using IL-1 receptor antagonist blocked gel contraction by SSc epidermis. We propose that in SSc, epidermal cells are in a persistently activated state and are able to promote dermal fibrosis. These findings are important because biologic therapies could target epithelial-fibroblast interactions in the disease.

Consistent with previous models of SSc pathogenesis these data are showing increased contractility, increased extracellular matrix and response to oxidative stress in the involved skin of recent onset SSc patients. In addition, we show that SSc epidermis has an activated, wound healing phenotype. These findings are important because epidermal cells activated by injury induce and regulate local fibroblasts during wound repair.

The results suggest that the antioxidant, EGCG, can reduce ECM production, the fibrotic marker CTGF and inhibit contraction of dermal fibroblasts from SSc patients. Furthermore, EGCG was able to suppress intracellular ROS, ERK1/2 kinase signalling and NF-κB activity. Taken together, EGCG may be a possible candidate for therapeutic treatment aimed at reducing both oxidant stress and the fibrotic effects associated with SSc.