Abstract
Aeroallergens such as house dust mite (HDM), cockroach, and grass or tree pollen are innocuous substances that can induce allergic sensitization upon inhalation. The serine proteases present in these allergens are thought to activate the protease-activated receptor (PAR)-2, on the airway epithelium, thereby potentially inducing allergic sensitization at the expense of inhalation tolerance. We hypothesized that the proteolytic activity of allergens may play an important factor in the allergenicity to house dust mite and is essential to overcome airway tolerance. Here, we aimed to investigate the role of PAR-2 activation in allergic sensitization and HDM-induced allergic airway inflammation. In our study, Par-2 deficient mice were treated with two different HDM extracts containing high and low serine protease activities twice a week for a period of 5 weeks. We determined airway inflammation through quantification of percentages of mononuclear cells, eosinophils and neutrophils in the bronchial alveolar lavage fluid and measured total IgE and HDM-specific IgE and IgG1 levels in serum. Furthermore, Th2 and pro-inflammatory cytokines including IL-5, IL-13, Eotaxin-1, IL-17, KC, Chemokine (C-C motif) ligand 17 (CCL17) and thymic stromal lymphopoietin (TSLP), were measured in lung tissue homogenates. We observed that independent of the serine protease content, HDM was able to induce elevated levels of eosinophils and neutrophils in the airways of both wild-type (WT) and Par-2 deficient mice. Furthermore, we show that induction of pro-inflammatory cytokines by HDM exposure is independent of Par-2 activation. In contrast, serine protease activity of HDM does contribute to enhanced levels of total IgE, but not HDM-specific IgE. We conclude that, while Par-2 activation contributes to the development of IgE responses, it is largely dispensable for the HDM-induced induction of pro-inflammatory cytokines and airway inflammation in an experimental mouse model of HDM-driven allergic airway disease.
Highlights
Allergic asthma is a chronic inflammatory pulmonary disease that is characterized by airway hyperreactivity (AHR), airway remodeling, eosinophillic and T helper 2 (Th2) cell infiltration into the airways and an allergen-specific IgE response [1]
We aimed to test whether activation of the Par-2 by the endogenous serine protease activity of House dust mite (HDM) extracts is required for allergic sensitization and the induction of airway inflammation
We investigated the role of Par-2 activation in HDM-induced allergic sensitization and airway inflammation in mice
Summary
Allergic asthma is a chronic inflammatory pulmonary disease that is characterized by airway hyperreactivity (AHR), airway remodeling, eosinophillic and T helper 2 (Th2) cell infiltration into the airways and an allergen-specific IgE response [1]. Inhaled allergens are in first contact with the airway epithelium, which functions as a barrier (towards the inhaled environment) and is an important part of the innate immune system [2]. The airway epithelium expresses several so-called pattern recognition receptors (PRRs), which in mouse models were found to be critical for the activation of the airway epithelium by HDM and the induction of an innate immune response [8,9]. One of the PRRs activated by proteases is protease-activated receptor (PAR)-2, which is expressed by airway epithelium [10] and is upregulated in the airways asthma patients [11]. PAR-2 is activated by serine proteases present in HDM [12], which stimulate the release of pro-inflammatory cytokines and chemokines including IL-6, IL-8, GM-CSF and TSLP in cultured airway epithelial cells [13,14]
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