. 2018 Jan;141(1):300-310.e11.

doi: 10.1016/j.jaci.2017.02.038. Epub 2017 Apr 6.

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

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

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

Kazunari Sugita et al. J Allergy Clin Immunol. 2018 Jan.

. 2018 Jan;141(1):300-310.e11.

doi: 10.1016/j.jaci.2017.02.038. Epub 2017 Apr 6.

Authors

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.

PubMed Disclaimer

Cited by

Epithelial barrier hypothesis: Effect of the external exposome on the microbiome and epithelial barriers in allergic disease.
Celebi Sozener Z, Ozdel Ozturk B, Cerci P, Turk M, Gorgulu Akin B, Akdis M, Altiner S, Ozbey U, Ogulur I, Mitamura Y, Yilmaz I, Nadeau K, Ozdemir C, Mungan D, Akdis CA. Celebi Sozener Z, et al. Allergy. 2022 May;77(5):1418-1449. doi: 10.1111/all.15240. Epub 2022 Feb 16. Allergy. 2022. PMID: 35108405 Free PMC article. Review.
Acute Respiratory Barrier Disruption by Ozone Exposure in Mice.
Sokolowska M, Quesniaux VFJ, Akdis CA, Chung KF, Ryffel B, Togbe D. Sokolowska M, et al. Front Immunol. 2019 Sep 13;10:2169. doi: 10.3389/fimmu.2019.02169. eCollection 2019. Front Immunol. 2019. PMID: 31608051 Free PMC article. Review.
IL-13 Impairs Tight Junctions in Airway Epithelia.
Schmidt H, Braubach P, Schilpp C, Lochbaum R, Neuland K, Thompson K, Jonigk D, Frick M, Dietl P, Wittekindt OH. Schmidt H, et al. Int J Mol Sci. 2019 Jun 30;20(13):3222. doi: 10.3390/ijms20133222. Int J Mol Sci. 2019. PMID: 31262043 Free PMC article.
Knob protein enhances epithelial barrier integrity and attenuates airway inflammation.
Ha SG, Dileepan M, Ge XN, Kang BN, Greenberg YG, Rao A, Muralidhar G, Medina-Kauwe L, Thompson MA, Pabelick CM, O'Grady SM, Rao SP, Sriramarao P. Ha SG, et al. J Allergy Clin Immunol. 2018 Dec;142(6):1808-1817.e3. doi: 10.1016/j.jaci.2018.01.049. Epub 2018 Mar 6. J Allergy Clin Immunol. 2018. PMID: 29522849 Free PMC article.
Innate Type-2 Cytokines: From Immune Regulation to Therapeutic Targets.
Kim HY, Jeong D, Kim JH, Chung DH. Kim HY, et al. Immune Netw. 2024 Jan 31;24(1):e6. doi: 10.4110/in.2024.24.e6. eCollection 2024 Feb. Immune Netw. 2024. PMID: 38455467 Free PMC article. Review.

See all "Cited by" articles

Publication types

Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions

Grants and funding

LinkOut - more resources

Full Text Sources
Other Literature Sources
- H1 Connect - Access expert opinions and insights on biomedical research.
- scite Smart Citations
Medical
- MedlinePlus Consumer Health Information
- MedlinePlus Health Information

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

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

Affiliations

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

Authors

Affiliations

Abstract

Similar articles

Cited by

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Abstract

Similar articles

Cited by

Publication types

MeSH terms

Substances

Related information

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical