Zhu, Y; (2015) The role of serine protease Kallikrein 5 in skin barrier dysfunction - a potential therapeutic intervention for atopic dermatitis. Doctoral thesis , UCL (University College London).

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Abstract

Atopic dermatitis (AD) is a common, chronic inflammatory skin disorder caused by both genetic and environmental factors. The primary cause of AD is epidermal barrier dysfunction, which leads to impaired protective function of skin and promotes Th2 immune response. The barrier defect in AD can be induced by dysregulations of numerous molecules, including imbalance between serine proteases kallikreins (KLKs) and their inhibitor LEKTI. The importance of serine protease-protease inhibitor balance has also been revealed in Netherton Syndrome (NS), which is caused by loss-of-function mutations in the LEKTI encoding gene SPINK5. Hyperactivity of KLKs in NS can result in severe skin barrier defect. AD and NS both exhibit up-regulated activity of KLKs, and they share some clinical features including atopy and skin inflammation. Therefore, it was speculated that up-regulated KLKs might play an important role in AD pathogenesis. In this project, up-regulation of a key epidermal protease kallikrein 5 (KLK5) and disturbed expression of barrier-related proteins were confirmed in AD skin. In order to eliminate the influences of other causes of AD and investigate the role of up-regulated KLK5 in barrier defect, keratinocytes overexpressing KLK5 (KLK5-cells) were generated. Over-degradation of desmoglein 1 (DSG1) and impaired function of protease activated receptor 2 (PAR2) were found in KLK5-cells. In vitro organotypic cultures and in vivo skin grafts generated from KLK5-cells exhibited AD-like histological features and barrier abnormalities including disrupted keratinocyte growth. In order to further study the influences of up-regulated KLK5 on keratinocyte growth and cytokine production, related phospho-kinase and cytokine arrays were performed. There were increased levels of p53, heat shock protein 60 (HSP60) and elevated secretion of IL-8, thymic stromal lymphopoietin (TSLP) and IL-10 in KLK5-cells. As p53 and HSP60 are involved in the regulation of cell growth and cytokine production respectively, up-regulation of KLK5 could result in disorganized keratinocyte proliferation/differentiation and aberrant cytokine levels by up-regulating p53 and HSP60, consequently exacerbating the skin barrier dysfunction in AD. Finally, sunflower trypsin inhibitor analogue (SFTI-G) was used to inhibit the unopposed activity of KLK5. The results showed restored level of DSG1, reduced expression of p53/HSP60 and decreased production of inflammatory cytokines in KLK5-cells treated with SFTI-G. Therefore, improvement of epidermal barrier function by inhibiting up-regulated KLK5 is a promising therapeutic intervention for AD.

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