Mucosal Allergic Sensitization to Cockroach Allergens Is Dependent on Proteinase Activity and Proteinase-Activated Receptor-2 Activation

Abstract

We have shown that proteinase-activated receptor-2 (PAR2) activation in the airways leads to allergic sensitization to concomitantly inhaled Ags, thus implicating PAR2 in the pathogenesis of asthma. Many aeroallergens with proteinase activity activate PAR2. To study the role of PAR2 in allergic sensitization to aeroallergens, we developed a murine model of mucosal sensitization to cockroach proteins. We hypothesized that PAR2 activation in the airways by natural allergens with serine proteinase activity plays an important role in allergic sensitization. Cockroach extract (CE) was administered to BALB/c mice intranasally on five consecutive days (sensitization phase) and a week later for four more days (challenge phase). Airway hyperresponsiveness (AHR) and allergic airway inflammation were assessed after the last challenge. To study the role of PAR2, mice were exposed intranasally to a receptor-blocking anti-PAR2 Ab before each administration of CE during the sensitization phase. Mucosal exposure to CE induced eosinophilic airway inflammation, AHR, and cockroach-specific IgG1. Heat-inactivated or soybean trypsin inhibitor-treated CE failed to induce these effects, indicating that proteinase activity plays an important role. The use of an anti-PAR2 blocking Ab during the sensitization phase completely inhibited airway inflammation and also decreased AHR and the production of cockroach-specific IgG1. PAR2 activation by CE acts as an adjuvant for allergic sensitization even in the absence of functional TLR4. We conclude that CE induces PAR2-dependent allergic airway sensitization in a mouse model of allergic airway inflammation. PAR2 activation may be a general mechanism used by aeroallergens to induce allergic sensitization.

Pulmonary Endotoxin Tolerance Protects against Cockroach Allergen-Induced Asthma-Like Inflammation in a Mouse Model

“…Most models utilize ovalbumin, which is not an environmental allergen, and employ an average of 6 exposures and a total of 2,000 µg of allergen, while our model requires 3 exposures and a total of only 4 µg of allergen [39,40,41]. This is potentially explained by the inherent protease activity present in cockroach frass and gastrointestinal proteins, which may facilitate antigen uptake by dendritic cells in the lung [42,43]. The ability to induce asthma-like pulmonary inflammation with relatively low concentrations of allergen may lie not only in the use of an environmentally relevant allergen, but also in the substantial LPS contamination naturally present in the allergen preparation.…”

Functional inhibition of PAR2 alleviates allergen‐induced airway hyperresponsiveness and inflammation

“…One of the members of the family, PAR 2 , can be activated by a variety of allergens [9][10][11] and endogenous serine proteinases [12,13]. PAR 2 is expressed by a variety of cells in the lung [14][15][16][17] and is involved in inflammation [18][19][20].…”

Challenges and Opportunities in Protease-Activated Receptor Drug Development

“…However, PAR2 activation is also beneficial under certain conditions. Several studies using animal models are highly suggestive of important roles for PAR2 in arthritis (53), inflammatory bowel disease including colitis and radiation-induced intestinal inflammation (54,55), and allergen-induced asthma (56). Similar to research on PAR1, diverse strategies have been taken to perturb PAR2 function, including the use of function-blocking antibodies, small-molecule inhibitors, and pepducins.…”