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; Cezmi A Akdis

doi:10.1016/j.jaci.2017.02.038

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

J Allergy Clin Immunol. 2018 Jan;141(1):300-310.e11. doi: 10.1016/j.jaci.2017.02.038. Epub 2017 Apr 6.

Authors

Kazunari Sugita¹, Catherine A Steer², Itziar Martinez-Gonzalez², Can Altunbulakli³, Hideaki Morita⁴, Francesc Castro-Giner⁵, Terufumi Kubo³, Paulina Wawrzyniak³, Beate Rückert³, Katsuko Sudo⁶, Susumu Nakae⁷, Kenji Matsumoto⁸, Liam O'Mahony³, Mübeccel Akdis³, Fumio Takei², Cezmi A Akdis⁹

Affiliations

¹ 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.
² Department of Pathology and Laboratory Medicine, University of British Columbia and Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
³ Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland; Christine Kühne-Center for Allergy Research and Education, Davos, Switzerland.
⁴ Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland; Christine Kühne-Center for Allergy Research and Education, Davos, Switzerland; Department of Allergy and Clinical Immunology, National Research Institute for Child Health and Development, Tokyo, Japan.
⁵ Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland; Christine Kühne-Center for Allergy Research and Education, Davos, Switzerland; University of Zurich, Functional Genomics Center Zurich, Zurich, Switzerland.
⁶ Animal Research Center, Tokyo Medical University, Tokyo, Japan.
⁷ Laboratory of Systems Biology, Center for Experimental Medicine and Systems Biology, Institute of Medical Science, University of Tokyo, Tokyo, Japan; Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency, Saitama, Japan.
⁸ Department of Allergy and Clinical Immunology, National Research Institute for Child Health and Development, Tokyo, Japan.
⁹ Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland; Christine Kühne-Center for Allergy Research and Education, Davos, Switzerland. Electronic address: akdisac@siaf.uzh.ch.

PMID: 28392332
DOI: 10.1016/j.jaci.2017.02.038

Abstract

Background: Bronchial 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.

Objective: We 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.

Methods: Cocultures 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 Rora^sg/sg mice undergoing bone marrow transplantation to analyze the in vivo relevance of barrier disruption by ILC2s.

Results: ILC2s 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 Rora^sg/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.

Conclusion: These data highlight an essential mechanism in asthma pathogenesis by demonstrating that ILC2s are responsible for bronchial epithelial TJ barrier leakiness through IL-13.

Keywords: IL-13; Innate lymphoid cell; barrier; bronchial epithelium; tight junction.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Asthma / immunology*
Asthma / metabolism*
Disease Models, Animal
Epithelial Cells / metabolism
Humans
Immunity, Innate*
Interleukin-13 / antagonists & inhibitors
Interleukin-13 / metabolism*
Lymphocyte Subsets / immunology*
Lymphocyte Subsets / metabolism*
Mice
Mice, Transgenic
Mucus / metabolism
Respiratory Mucosa / immunology*
Respiratory Mucosa / metabolism*
Respiratory Mucosa / pathology
Tight Junctions / metabolism*

Substances

Interleukin-13

Abstract

Publication types

MeSH terms

Substances

Grants and funding