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

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

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4 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)190-203.e5
JournalThe Journal of allergy and clinical immunology
Volume140
Issue number1
Early online date16 Nov 2016
DOIs
Publication statusPublished - Jul 2017

Bibliographical note

Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Keywords

  • Allergens/immunology
  • Amiloride/pharmacology
  • Animals
  • Aspergillus fumigatus/immunology
  • Asthma/drug therapy
  • Bronchoalveolar Lavage Fluid/cytology
  • Cell Count
  • Cells, Cultured
  • Disease Models, Animal
  • Epithelial Cells/drug effects
  • Epithelial Sodium Channels/genetics
  • Interleukin-13/immunology
  • Lung/cytology
  • Mice, Transgenic
  • Mucociliary Clearance
  • Pyroglyphidae/immunology
  • STAT6 Transcription Factor/genetics
  • Sodium Channel Blockers/pharmacology

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    Fritzsching, B., Hagner, M., Dai, L., Christochowitz, S., Agrawal, R., van Bodegom, C., Schmidt, S., Schatterny, J., Hirtz, S., Brown, R., Goritzka, M., Duerr, J., Zhou-Suckow, Z., & Mall, M. A. (2017). Impaired mucus clearance exacerbates allergen-induced type 2 airway inflammation in juvenile mice. The Journal of allergy and clinical immunology, 140(1), 190-203.e5. https://doi.org/10.1016/j.jaci.2016.09.045