Particulate Allergens Potentiate Allergic Asthma through Sustained IgE Mediated Mast Cell Activation

Abstract

<p>In recent years, the incidence of allergic asthma as well as the severity of disease has rapidly increased worldwide. Numerous epidemiological studies have related the exacerbation of allergic asthma with exposure to increased ambient particles from air pollutants. However, the mechanism by which particulate allergens (pAg) exacerbate allergic asthma remains undefined. To evaluate this, we modeled environmental pAg induced allergic asthma by exposing mice to polystyrene beads coated with natural allergen extracts. Compared to equal amounts of soluble allergen extracts (sAg), pAg triggered markedly enhanced airway hyper-responsiveness and pulmonary eosinophila in allergen sensitized mice. The cellular basis for this effect was determined to be mast cells (MCs), as both airway allergic responses were attenuated in MC deficient Kit<super>W-sh</super>/Kit<super>W-sh</super> mice compared to mast cell reconstituted Kit<super>W-sh</super>/Kit<super>W-sh</super> mice. The divergent responses of MCs to pAg versus sAg were due to differences in the termination rate of IgE/Fc&epsilonRI initiated signaling. Following ligation of sAg, IgE/Fc&epsilonRI rapidly shuttled into a degradative endosome/lysosome pathway. However, following ligation by pAg, IgE/Fc&epsilonRI migrated into lipid raft enriched compartments and subsequently failed to follow a degradative pathway, which resulted in a prolonged signaling and heightened synthesis of proinflammatory mediators. These observations highlight the overlooked contributions of the particulate nature of allergens and mast cell endocytic circuitry to the aggravation of allergic asthma.</p>