A fungal protease allergen provokes airway hyper-responsiveness in asthma.

Nariman A Balenga,Eunice C Chan,Michael Klichinsky,Michel Laviolette,Ming Zhao,Zhihui Xie,Reynold A Panettieri,Kirk M Druey,Joseph Jude

doi:10.1038/ncomms7763

Abstract

Asthma, a common disorder that affects more than 250 million people worldwide, is defined by exaggerated bronchoconstriction to inflammatory mediators including acetylcholine, bradykinin, and histamine—also termed airway hyper-responsiveness Nearly 10% of people with asthma have severe, treatment-resistant disease, which is frequently associated with IgE sensitization to ubiquitous fungi, typically Aspergillus fumigatus. Here we show that a major Aspergillus fumigatus allergen, Asp f13, which is a serine protease, alkaline protease 1 (Alp 1), promotes airway hyper-responsiveness by infiltrating the bronchial submucosa and disrupting airway smooth muscle cell-extracellular matrix interactions. Alp 1-mediated extracellular matrix degradation evokes pathophysiological RhoA-dependent Ca2+ sensitivity and bronchoconstriction. These findings support a pathogenic mechanism in asthma and other lung diseases associated with epithelial barrier impairment, whereby airway smooth muscle cells respond directly to inhaled environmental allergens to generate airway hyper-responsiveness.

Highlights

Asthma, a common disorder that affects 4250 million people worldwide, is defined by exaggerated bronchoconstriction to inflammatory mediators including acetylcholine (ACh), bradykinin and histamine— termed airway hyper-responsiveness
Our results suggest a novel pathophysiological mechanism whereby inflammation associated with respiratory mucosal exposure to Aspergillus fumigatus (Af) allergen leads to extracellular matrix (ECM) degradation through direct contact between a protease component and the bronchial submucosa
The serine protease alkaline protease 1 (Alp 1) secreted by Af digested ECM components directly and stimulated MMP1 release from airway smooth muscle (ASM) cells

Summary

Introduction

A common disorder that affects 4250 million people worldwide, is defined by exaggerated bronchoconstriction to inflammatory mediators including acetylcholine (ACh), bradykinin and histamine— termed airway hyper-responsiveness. Intraperitoneal immunization of mice with a diverse array of allergens including ovalbumin (OVA), house dust mite (HDM) or Aspergillus fumigatus (Af) followed by respiratory mucosal challenge induces what is termed as ‘allergic sensitization’: expansion of allergen-specific T helper type 2 (TH2) cells, synthesis of allergen-specific immunoglobulin-E (IgE) and production of cytokines in lung including interleukin-4 (IL-4), IL-5 and IL-13 These events result in allergic inflammation including goblet cell metaplasia, increased mucous production, leukocyte infiltration (predominantly eosinophils) and collagen deposition in the bronchial submucosa[4,5,6,7]. The purified, secreted Af protease, which itself is poorly immunogenic[13], induced AHR in the presence of OVA despite recruiting markedly fewer airway eosinophils to the lung than OVA plus crude Af allergen These results suggest that proteolytic activity of certain allergens, while not sufficient to elicit AHR in the absence of lung inflammation, contribute to AHR through mechanisms independent of allergic sensitization. We detect an Af-derived protease (Alp 1) in the bronchial smooth muscle layer of human subjects with asthma and allergenchallenged mice but not in control subjects or naıve mice, and we provide a potential mechanism by which Alp 1 induces a pro-contractile phenotype of ASM cells

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