The pro‐inflammatory but not protective effects of protease‐activated‐ receptor‐2 in the airway require β‐arrestin‐2

As asthma prevalence, health care use, and mortality increase therapeutics with a distinct target are needed. One attractive target is a G Protein Coupled Receptor (GPCR) known to play both protective and pro‐inflammatory roles in the airways. Namely, Proteinase Activated Receptor‐2 (PAR 2 ) is activated by serine‐like proteases such as trypsin, mast cell tryptase, and those found in cockroach frass and Alternaria alternata . Given the dual and apparently opposing actions, both inhibitors and activators of PAR 2 have already been proposed as therapeutics for asthma. PAR 2 can signal through two independent pathways: a G‐protein‐dependent and a β‐arrestin‐dependent/G‐protein‐independent one. The β‐arrestin‐dependent pathway promotes leukocyte migration, while bronchiolar smooth muscle relaxation requires G‐protein signaling intermediates. We use a mouse ovalbumin model for PAR 2 ‐modulated airway inflammation to address the hypothesis that inflammatory responses to PAR 2 activation are β‐arrestin dependent while ‘protective’ anti‐constrictor effect of bronchial epithelial PAR 2 are β‐arrestin‐independent. We show that PAR 2 ‐ induced lung inflammation, mucus production, Th2 cytokines, airway responsiveness and cellular inflammation were abolished in β‐arrestin‐2 −/− mice while tracheal smooth muscle relaxation and PGE2 production were equivalent in wild type and β‐arrestin‐2 −/− mice.