Please use this identifier to cite or link to this item:
http://doi.org/10.25358/openscience-8546
Authors: | Fleischer, Maria Isabel Röhrig, Nadine Raker, Verena K. Springer, Juliane Becker, Detlef Ritz, Sandra Bros, Matthias Stege, Henner Haist, Maximilian Grabbe, Stephan Haub, Jessica Becker, Christian Reyda, Sabine Disse, Jennifer Schmidt, Talkea Mahnke, Karsten Weiler, Hartmut Ruf, Wolfram Steinbrik, Kerstin |
Title: | Protease- and cell type–specific activation of protease-activated receptor 2 in cutaneous inflammation |
Online publication date: | 10-Jan-2023 |
Year of first publication: | 2022 |
Language: | english |
Abstract: | Background: Protease-activated receptor 2 (PAR2) signaling controls skin barrier function and inflammation, but the roles of immune cells and PAR2-activating pro teases in cutaneous diseases are poorly understood. Objective: To dissect PAR2 signaling contributions to skin inflammation with new ge netic and pharmacological tools. Methods/Results: We found markedly increased numbers of PAR2+ infiltrating my eloid cells in skin lesions of allergic contact dermatitis (ACD) patients and in the skin of contact hypersensitivity (CHS) in mice, a murine ACD model for T cell–mediated allergic skin inflammation. Cell type–specific deletion of PAR2 in myeloid immune cells as well as mutation-induced complete PAR2 cleavage insensitivity significantly re duced skin inflammation and hapten-specific Tc1/Th1 cell response. Pharmacological approaches identified individual proteases involved in PAR2 cleavage and demon strated a pivotal role of tissue factor (TF) and coagulation factor Xa (FXa) as upstream activators of PAR2 in both the induction and effector phase of CHS. PAR2 mutant mouse strains with differential cleavage sensitivity for FXa versus skin epithelial cell–expressed proteases furthermore uncovered a time-dependent regulation of CHS development with an important function of FXa-induced PAR2 activation during the late phase of skin inflammation. Conclusions: Myeloid cells and the TF–FXa–PAR2 axis are key mediators and poten tial therapeutic targets in inflammatory skin diseases |
DDC: | 610 Medizin 610 Medical sciences |
Institution: | Johannes Gutenberg-Universität Mainz |
Department: | FB 04 Medizin |
Place: | Mainz |
ROR: | https://ror.org/023b0x485 |
DOI: | http://doi.org/10.25358/openscience-8546 |
Version: | Published version |
Publication type: | Zeitschriftenaufsatz |
License: | CC BY-NC-ND |
Information on rights of use: | https://creativecommons.org/licenses/by-nc-nd/4.0/ |
Journal: | Journal of thrombosis and haemostasis 20 12 |
Pages or article number: | 2823 2836 |
Publisher: | Wiley-Blackwell |
Publisher place: | Oxford |
Issue date: | 2022 |
ISSN: | 1538-7836 |
Publisher DOI: | 10.1111/jth.15894 |
Appears in collections: | DFG-491381577-H |
Files in This Item:
File | Description | Size | Format | ||
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![]() | protease_and_cell_typespecifi-20230110123737986.pdf | 3.79 MB | Adobe PDF | View/Open |