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