Proteinase-activated receptor-2 activation participates in allergic sensitization to house dust mite allergens in a murine model

BackgroundMany aeroallergens contain proteinase activity and are able to induce allergic sensitization when presented to mucosal surfaces. Some of these allergens activate proteinase-activated receptor-2 (PAR(2)). ObjectiveTo determine the role of PAR(2) activation in a murine house dust mite (HDM) allergy model. MethodsWe sensitized and challenged PAR(2)-deficient mice with HDM, and examined allergic outcomes compared to wild-type animals. To focus on the role of PAR(2) in allergic sensitization, we administered a PAR(2) blocking antibody to wild-type animals during the sensitization phase and examined the outcomes immediately after sensitization or following subsequent allergen challenge. ResultsWe found PAR(2)-deficient mice sensitized and challenged with HDM failed to develop airway inflammation, did not produce HDM-specific IgG1 and had less IL-4 mRNA in the lungs than wild-type animals. Prevention of PAR(2) activation during sensitization in wild-type mice diminished the levels of Th2 mediators, including IL-4, IL-5 and IL-13, in the lungs. Blocking PAR(2) during the sensitization phase also led to decreased manifestations of allergic disease, including airway hyperresponsiveness (AHR) and airway inflammation following subsequent allergen challenge. HDM-induced proliferation of splenocytes obtained from animals sensitized in the presence of PAR(2) antibody was reduced relative to those that did not receive antibody. The effect of PAR(2) blockade could be transferred to naive mice through splenic CD4(+) T cells from sensitized mice. Conclusions and Clinical RelevancePAR(2) activation plays a key role during the sensitization phase of our HDM allergy model, leading to increased lung cytokine production and augmented lung reactivity. PAR(2) activation is a common mechanism for sensitization to a wide variety of allergens and is therefore a potential pharmacological target to prevent allergy.