Persistent kallikrein5 activation induces atopic dermatitis-like skin architecture independent of PAR2 activity

Publication date: Available online 24 February 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Yanan Zhu, Joanne Underwood, Derek Macmillan, Leila Shariff, Ryan O'Shaughnessy, John I. Harper, Chris Pickard, Peter S. Friedmann, Eugene Healy, Wei-Li Di
BackgroundUp-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.ObjectiveWe investigated the effect of up-regulated KLK5 on the expression of epidermal related proteins and cytokines in keratinocytes and on skin architecture.MethodsLesional 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.ResultsUp-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. .ConclusionPersistently 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.

Teaser

Persistently increased serine protease kallikrein 5 modifies skin barrier proteins, upregulates AD-related cytokine expression and induces AD-like skin architecture. Inhibition of KLK5 may offer potential as a treatment strategy in AD.


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