Type 2 innate Lymphoid Cells Disrupt Bronchial Epithelial Barrier Integrity by Targeting Tight Junctions Via IL-13 in Asthma

Publication date: Available online 6 April 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Kazunari Sugita, Catherine A. Steer, Itziar Martinez-Gonzalez, Can Altunbulakli, Hideaki Morita, Francesc Castro-Giner, Terufumi Kubo, Paulina Wawrzyniak, Beate Rückert, Katsuko Sudo, Susumu Nakae, Kenji Matsumoto, Liam O'Mahony, Mübeccel Akdis, Fumio Takei, Cezmi A. Akdis
BackgroundBronchial epithelial barrier leakiness and type 2 innate lymphoid cells (ILC2s) have been separately linked to asthma pathogenesis, however the influence of ILC2s on bronchial epithelial barrier has not been previously investigated.ObjectiveWe investigated the role of ILC2s in the regulation of bronchial epithelial tight junctions (TJs) and barrier function both in bronchial epithelial cells of asthmatic and healthy individuals and general ILC- and ILC2-deficient mice.MethodsCo-cultures of human ILC2s and bronchial epithelial cells were used to determine transepithelial resistance (TER), paracellular flux, TJ mRNA and protein expressions. To analyze the in vivo relevance of barrier disruption by ILC2s, the effect of ILC2s on TJs was examined using a murine model of IL-33-induced airway inflammation in wild-type (WT), Rag2^−/−, Rag2^−/−Il2rg^−/−, and Rora^sg/sg bone marrow-transplanted (BMT) mice.ResultsILC2s significantly impaired epithelial barrier as demonstrated by reduced TER and increased FITC-dextran permeability in air-liquid interface cultures of human bronchial epithelial cells. This was in parallel to decreased mRNAs and disrupted protein expression of TJ proteins, and was restored by neutralization of IL-13. The intranasal administration of recombinant IL-33 to WT and Rag2^−/− mice lacking T and B cells triggered TJ disruption, whereas Rag2^−/−Il2rg^−/− and Rora^sg/sg BMT mice that lack ILC2s did not show any barrier leakiness. Direct nasal administration of IL-13 was sufficient to induce deficiency in TJ barrier in bronchial epithelium of mice in vivo.ConclusionThese data highlight an essential mechanism in asthma pathogenesis by demonstrating that ILC2s are responsible for bronchial epithelial TJ barrier leakiness via IL-13.

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Teaser

Bronchial epithelial leakiness, an essential feature of asthma is induced by ILC2s targeting tight junctions via IL-13 both mice and humans. Our findings may contribute to asthma pathogenesis via hampered bronchial epithelial barrier. (33 words)


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