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

Zhu, Y; Underwood, J; Macmillan, D; Shariff, L; O'Shaughnessy, R; Harper, JI; Pickard, C; ... Di, WL; + view all (2017) Persistent kallikrein5 activation induces atopic dermatitis-like skin architecture independent of PAR2 activity. Journal of Allergy and Clinical Immunology , 140 (5) 1310-1322.e5. 10.1016/j.jaci.2017.01.025. Green open access

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Abstract

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.

Type: Article
Title: Persistent kallikrein5 activation induces atopic dermatitis-like skin architecture independent of PAR2 activity.
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.jaci.2017.01.025
Publisher version: http://dx.doi.org/10.1016/j.jaci.2017.01.025
Language: English
Additional information: © 2017. This manuscript version is published under a Creative Commons Attribution Non-commercial Non-derivative 4.0 International licence (CC BY-NC-ND 4.0). This licence allows you to share, copy, distribute and transmit the work for personal and non-commercial use providing author and publisher attribution is clearly stated. Further details about CC BY licences are available at http://creativecommons.org/licenses/by/4.0. Access may be initially restricted by the publisher.
Keywords: Kallikrein 5, SFTI, atopic dermatitis, serine protease inhibitor, skin barrier
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Infection, Immunity and Inflammation Dept
UCL > Provost and Vice Provost Offices > UCL BEAMS
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences > Dept of Chemistry
URI: https://discovery.ucl.ac.uk/id/eprint/1543766
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