Protease- and cell type-specific activation of protease-activated receptor 2 in cutaneous inflammation

被引:14
|
作者
Fleischer, Maria Isabel [1 ,2 ]
Roehrig, Nadine [1 ]
Raker, Verena K. [2 ,3 ]
Springer, Juliane [1 ,2 ]
Becker, Detlef [1 ]
Ritz, Sandra [4 ]
Bros, Matthias [1 ,5 ]
Stege, Henner [1 ]
Haist, Maximilian [1 ]
Grabbe, Stephan [1 ,5 ]
Haub, Jessica [1 ]
Becker, Christian [2 ,3 ]
Reyda, Sabine [2 ]
Disse, Jennifer [6 ]
Schmidt, Talkea [1 ]
Mahnke, Karsten [7 ]
Weiler, Hartmut [8 ]
Ruf, Wolfram [2 ,6 ]
Steinbrink, Kerstin [3 ,9 ]
机构
[1] Johannes Gutenberg Univ Mainz, Univ Med Ctr Mainz, Dept Dermatol, Mainz, Germany
[2] Univ Med Ctr Mainz, Ctr Thrombosis & Hemostasis, Mainz, Germany
[3] Univ Munster, Univ Hosp Muenster, Dept Dermatol, Munster, Germany
[4] Inst Mol Biol Mainz, Mainz, Germany
[5] Johannes Gutenberg Univ Mainz, Res Ctr Immunotherapy, Mainz, Germany
[6] Scripps Res, Dept Immunol & Microbiol, La Jolla, CA USA
[7] Heidelberg Univ, Univ Hosp Heidelberg, Dept Dermatol, Heidelberg, Germany
[8] Vers Blood Res Inst, Milwaukee, WI USA
[9] Univ Munster, Cells Mot Interfac Ctr, Munster, Germany
关键词
allergic contact dermatitis; contact hypersensitivity; factor Xa; protease-activated receptor 2; tissue factor; HEMATOLOGY; 2018; GUIDELINES; TISSUE FACTOR; SERINE-PROTEASE; FACTOR XA; COAGULATION INITIATION; SIGNALING CONTRIBUTES; AMERICAN SOCIETY; STRATUM-CORNEUM; MOUSE MODEL; DERMATITIS;
D O I
10.1111/jth.15894
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Background Protease-activated receptor 2 (PAR2) signaling controls skin barrier function and inflammation, but the roles of immune cells and PAR2-activating proteases in cutaneous diseases are poorly understood. Objective To dissect PAR2 signaling contributions to skin inflammation with new genetic and pharmacological tools. Methods/Results We found markedly increased numbers of PAR2(+) infiltrating myeloid 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 reduced skin inflammation and hapten-specific Tc1/Th1 cell response. Pharmacological approaches identified individual proteases involved in PAR2 cleavage and demonstrated 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 potential therapeutic targets in inflammatory skin diseases.
引用
收藏
页码:2823 / 2836
页数:14
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