Is b‐arrestin‐2 a determining factor in PAR‐2 stimulated allergic asthma?

Abstract

PAR‐2 exhibits pro‐ and anti‐inflammatory effects in the airway and lungs. From a molecular standpoint, the anti‐inflammatory effects signal via PAR‐2/Gαq resulting in mobilization of intracellular calcium and prostaglandin production. Pro‐inflammatory effects include leukocyte migration and cytokine production. Our lab has demonstrated that PAR‐2 promotes leukocyte migration in a β‐arrestin‐dependent pathway as β‐arrestins scaffold the actin filament severing protein, cofilin, with its upstream activator, CIN at the leading edge. This brings CIN and cofilin into proximity leading to cofilin dephosphorylation and activation and is independent of classic Gαq signaling. We believe the PAR‐2 pro‐inflammatory effects are mediated by β‐arrestin‐dependent actin reorganization and chemotaxis, and will be abolished in mice lacking β‐arrestins.These studies illustrate β‐arrestin‐2 mediation of an allergic asthma inflammatory response to intranasal administration of allergen and PAR‐2 activating peptides. Wild type mice exposed to allergen and treated with PAR‐2 activating peptide have increased leukocyte recruitment to BAL and lung epithelium; while β‐arrestin‐2−/− mice do not. These data suggest that β‐arrestins facilitate PAR‐2 stimulated cell migration by recruitment of actin machinery to the leading edge. This pathway is important for PAR‐2 stimulated inflammatory responses in vivo.