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

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Abstract

Background

Type 2 airway inflammation plays a central role in the pathogenesis of allergen-induced asthma, but the underlying mechanisms remain poorly understood. Recently, we demonstrated that reduced mucociliary clearance, a characteristic feature of asthma, produces spontaneous type 2 airway inflammation in juvenile β-epithelial Na+ channel (Scnn1b)-transgenic (Tg) mice.

Objective

We sought to 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.

Methods

We challenged juvenile Scnn1b-Tg and wild-type mice with Aspergillus fumigatus and house dust mite allergen and compared the effects on airway eosinophilia, type 2 cytokine levels, goblet cell metaplasia, and airway hyperresponsiveness. Furthermore, we determined cellular sources of IL-13 and effects of genetic deletion of the key type 2 signal-transducing molecule signal transducer and activator of transcription 6 (STAT6) and evaluated the effects of therapeutic improvement of mucus clearance.

Results

Reduced mucociliary allergen clearance exacerbated Stat6-dependent secretion of type 2 cytokines, airway eosinophilia, and airway hyperresponsiveness in juvenile Scnn1b-Tg mice. IL-13 levels were increased in airway epithelial cells, macrophages, type 2 innate lymphoid cells, and TH2 cells along with increased Il33 expression 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 mice.

Conclusion

Our data support that impaired clearance of inhaled allergens triggering IL-13 production by multiple cell types in the airways plays an important role in the pathogenesis of type 2 airway inflammation and suggests therapeutic improvement of mucociliary clearance as a novel treatment strategy for children with allergen-induced asthma.

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