Impaired mucus clearance exacerbates allergen-induced type 2 airway inflammation in juvenile mice

Publication date: Available online 16 November 2016
Source:Journal of Allergy and Clinical Immunology
Author(s): Benedikt Fritzsching, Matthias Hagner, Lu Dai, Sandra Christochowitz, Raman Agrawal, Charlotte van Bodegom, Simone Schmidt, Jolanthe Schatterny, Stephanie Hirtz, Ryan Brown, Michelle Goritzka, Julia Duerr, Zhe Zhou-Suckow, Marcus A. Mall
BackgroundType 2 airway inflammation plays a central role in the pathogenesis of allergen-induced asthma, but the underlying mechanisms remain poorly understood. We recently demonstrated that reduced mucociliary clearance, a characteristic feature of asthma, produces spontaneous type 2 airway inflammation in juvenile Scnn1b-transgenic (Scnn1b-Tg) mice.ObjectiveTo determine the role of impaired mucus clearance in the pathogenesis of allergen-induced type 2 airway inflammation and identify cellular sources of the signature cytokine IL-13.MethodsWe challenged juvenile Scnn1b-Tg and wild-type mice with Aspergillus fumigatus and house dust mite allergen and compared effects on airway eosinophilia, type 2 cytokine levels, goblet cell metaplasia and airway hyperresponsiveness. Further, we determined cellular sources of IL-13 and effects of genetic deletion of the key type 2 signal transducing molecule STAT6, and evaluated effects of therapeutic improvement of mucus clearance.ResultsReduced mucociliary allergen clearance exacerbated Stat6-dependent secretion of type 2 cytokines, airway eosinophilia and airway hyperresponsiveness in juvenile Scnn1b-Tg mice. IL-13 was elevated in airway epithelial cells, macrophages, type 2 innate lymphoid cells and Th2 cells along with increased Il33 in the airway epithelium of Scnn1b-Tg mice. Treatment with the epithelial Na⁺ channel blocker amiloride improving airway surface hydration and mucus clearance reduced allergen-induced inflammation in Scnn1b-Tg.ConclusionOur data support that impaired clearance of inhaled allergen triggering IL-13 production by multiple cell types in the airways plays an important role in the pathogenesis of type 2 airway inflammation and suggest therapeutic improvement of mucociliary clearance as a novel treatment strategy for children with allergen-induced asthma.

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Teaser

This study identifies impaired mucus clearance as a risk factor for allergen-induced type 2 airway inflammation in mice and suggests that pharmacological improvement of mucociliary clearance may be an effective treatment strategy for allergic asthma.


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