Protease- and cell type–specific activation of protease-activated receptor 2 in cutaneous inflammation
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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
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Journal of thrombosis and haemostasis, 20, 12, Wiley-Blackwell, Oxford, 2022, https://doi.org/10.1111/jth.15894