%0 Journal Article
%@ 1097-6825
%A Zhu, Y
%A Underwood, J
%A Macmillan, D
%A Shariff, L
%A O'Shaughnessy, R
%A Harper, JI
%A Pickard, C
%A Friedmann, PS
%A Healy, E
%A Di, WL
%D 2017
%F discovery:1543766
%J Journal of Allergy and Clinical Immunology
%K Kallikrein 5, SFTI, atopic dermatitis, serine protease inhibitor, skin barrier
%N 5
%P 1310-1322.e5
%T Persistent kallikrein5 activation induces atopic dermatitis-like skin architecture independent of PAR2 activity.
%U https://discovery.ucl.ac.uk/id/eprint/1543766/
%V 140
%X BACKGROUND: Up-regulation of kallikreins (KLK) including KLK5 has been reported in atopic dermatitis (AD). KLK5 has biological functions which include degrading desmosomal proteins and inducing pro-inflammatory cytokine secretion through protease activated receptor 2 (PAR2). However, due to the complex interactions between various cells in AD inflamed skin, it is difficult to dissect the precise and multiple roles of up-regulated KLK5 in AD skin. OBJECTIVE: We investigated the effect of up-regulated KLK5 on the expression of epidermal related proteins and cytokines in keratinocytes and on skin architecture. METHODS: Lesional and non-lesional AD skin biopsies were collected for analysis of morphology and protein expression. The relationship between KLK5 and barrier related molecules was investigated using an ex-vivo dermatitis skin model with transient KLK5 expression and a cell model with persistent KLK5 expression. The influence of up-regulated KLK5 on epidermal morphology was investigated using an in vivo skin graft model. RESULTS: Up-regulation of KLK5 and abnormal expression of desmoglein 1 (DSG1) and filaggrin (FLG), but not PAR2 were identified in AD skin. PAR2 was increased in response to transient up-regulation of KLK5, while persistently up-regulated KLK5 did not show this effect. Persistently up-regulated KLK5 degraded DSG1 and stimulated secretion of IL-8, IL-10 and TSLP independent of PAR2 activity. With control of higher KLK5 activity by the inhibitor SFTI-G, restoration of DSG1 expression and a reduction in AD-related cytokine IL-8, TLSP and IL-10 secretion were observed. Furthermore, persistently elevated KLK5 could induce AD-like skin architecture in an in vivo skin graft model. . CONCLUSION: Persistently up-regulated KLK5 resulted in AD-like skin architecture and secretion of AD-related cytokines from keratinocytes in a PAR-2 independent manner. Inhibition of KLK5-mediated effects may offer potential as a therapeutic approach in AD.
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