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

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.

• Authors: 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
• Journal: The Journal of allergy and clinical immunology (J Allergy Clin Immunol) Vol. 140 Issue 1 Pg. 190-203.e5 (Jul 2017) ISSN: 1097-6825 [Electronic] United States
• PMID: 27865862 (Publication Type: Journal Article)
• Copyright: Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Chemical References

• Allergens
• Epithelial Sodium Channels
• Interleukin-13
• STAT6 Transcription Factor
• Scnn1b protein, mouse
• Sodium Channel Blockers
• Stat6 protein, mouse
• Amiloride

Topics

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