eprintid: 1543766 rev_number: 42 eprint_status: archive userid: 608 dir: disk0/01/54/37/66 datestamp: 2017-03-05 02:31:17 lastmod: 2021-12-13 02:59:19 status_changed: 2017-03-14 15:50:00 type: article metadata_visibility: show creators_name: Zhu, Y creators_name: Underwood, J creators_name: Macmillan, D creators_name: Shariff, L creators_name: O'Shaughnessy, R creators_name: Harper, JI creators_name: Pickard, C creators_name: Friedmann, PS creators_name: Healy, E creators_name: Di, WL title: Persistent kallikrein5 activation induces atopic dermatitis-like skin architecture independent of PAR2 activity. ispublished: pub divisions: UCL divisions: B02 divisions: D13 divisions: G24 divisions: B04 divisions: C06 divisions: F56 keywords: Kallikrein 5, SFTI, atopic dermatitis, serine protease inhibitor, skin barrier note: © 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. 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. date: 2017-11 date_type: published official_url: http://dx.doi.org/10.1016/j.jaci.2017.01.025 oa_status: green full_text_type: other language: eng primo: open primo_central: open_green article_type_text: Journal Article verified: verified_manual elements_id: 1211156 doi: 10.1016/j.jaci.2017.01.025 pii: S0091-6749(17)30315-9 lyricists_name: Di, Wei-Li lyricists_name: Harper, John lyricists_name: Macmillan, Derek lyricists_name: O'Shaughnessy, Ryan lyricists_id: WLDIX50 lyricists_id: JHARP52 lyricists_id: DMACM78 lyricists_id: RFLOS27 full_text_status: public publication: Journal of Allergy and Clinical Immunology volume: 140 number: 5 pagerange: 1310-1322.e5 event_location: United States issn: 1097-6825 citation: Zhu, Y; Underwood, J; Macmillan, D; Shariff, L; O'Shaughnessy, R; Harper, JI; Pickard, C; ... Di, WL; + view all <#> Zhu, Y; Underwood, J; Macmillan, D; Shariff, L; O'Shaughnessy, R; Harper, JI; Pickard, C; Friedmann, PS; Healy, E; Di, WL; - view fewer <#> (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 <https://doi.org/10.1016/j.jaci.2017.01.025>. Green open access document_url: https://discovery.ucl.ac.uk/id/eprint/1543766/1/O%27Shaughnessy_PIIS0091674917303159.pdf