• J. Allergy Clin. Immunol. · Jan 2018

    Type 2 innate lymphoid cells disrupt bronchial epithelial barrier integrity by targeting tight junctions through IL-13 in asthmatic patients.

    • 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, and Cezmi A Akdis.
    • Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland; Christine Kühne-Center for Allergy Research and Education, Davos, Switzerland; Division of Dermatology, Department of Medicine of Sensory and Motor Organs, Tottori University Faculty of Medicine, Yonago, Japan. Electronic address: sugita@med.tottori-u.ac.jp.
    • J. Allergy Clin. Immunol. 2018 Jan 1; 141 (1): 300-310.e11.

    BackgroundBronchial epithelial barrier leakiness and type 2 innate lymphoid cells (ILC2s) have been separately linked to asthma pathogenesis; however, the influence of ILC2s on the bronchial epithelial barrier has not been investigated previously.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 patients and healthy subjects and general innate lymphoid cell- and ILC2-deficient mice.MethodsCocultures of human ILC2s and bronchial epithelial cells were used to determine transepithelial electrical resistance, paracellular flux, and TJ mRNA and protein expressions. The effect of ILC2s on TJs was examined by using a murine model of IL-33-induced airway inflammation in wild-type, recombination-activating gene 2 (Rag2)-/-, Rag2-/-Il2rg-/-, and Rorasg/sg mice undergoing bone marrow transplantation to analyze the in vivo relevance of barrier disruption by ILC2s.ResultsILC2s significantly impaired the epithelial barrier, as demonstrated by reduced transepithelial electrical resistance and increased fluorescein isothiocyanate-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. Intranasal administration of recombinant IL-33 to wild-type and Rag2-/- mice lacking T and B cells triggered TJ disruption, whereas Rag2-/-Il2rg-/- and Rorasg/sg mice undergoing bone marrow transplantation that lack ILC2s did not show any barrier leakiness. Direct nasal administration of IL-13 was sufficient to induce deficiency in the TJ barrier in the 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 through IL-13.Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

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