title: Type 2 innate lymphoid cells disrupt bronchial epithelial barrier integrity by targeting tight junctions through IL-13 in asthmatic patients.
abstract: 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.
  
  
  
  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.
  
  
  
  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 Rorasg/sgmice undergoing bone marrow transplantation to analyze the in vivo relevance of barrier disruption by ILC2s.
  
  
  
  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 Rorasg/sgmice 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.
  
  
  
  These data highlight an essential mechanism in asthma pathogenesis by demonstrating that ILC2s are responsible for bronchial epithelial TJ barrier leakiness through IL-13.
authors.affiliation: 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.
authors.forename: Kazunari
authors.initials: K
authors.lastname: Sugita
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia and Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Steer
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia and Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Itziar
authors.initials: I
authors.lastname: Martinez-Gonzalez
authors.affiliation: Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland; Christine Kühne-Center for Allergy Research and Education, Davos, Switzerland.
authors.forename: Can
authors.initials: C
authors.lastname: Altunbulakli
authors.affiliation: 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.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Morita
authors.affiliation: 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.
authors.forename: Francesc
authors.initials: F
authors.lastname: Castro-Giner
authors.affiliation: Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland; Christine Kühne-Center for Allergy Research and Education, Davos, Switzerland.
authors.forename: Terufumi
authors.initials: T
authors.lastname: Kubo
authors.affiliation: Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland; Christine Kühne-Center for Allergy Research and Education, Davos, Switzerland.
authors.forename: Paulina
authors.initials: P
authors.lastname: Wawrzyniak
authors.affiliation: Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland; Christine Kühne-Center for Allergy Research and Education, Davos, Switzerland.
authors.forename: Beate
authors.initials: B
authors.lastname: Rückert
authors.affiliation: Animal Research Center, Tokyo Medical University, Tokyo, Japan.
authors.forename: Katsuko
authors.initials: K
authors.lastname: Sudo
authors.affiliation: 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.
authors.forename: Susumu
authors.initials: S
authors.lastname: Nakae
authors.affiliation: Department of Allergy and Clinical Immunology, National Research Institute for Child Health and Development, Tokyo, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Matsumoto
authors.affiliation: Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland; Christine Kühne-Center for Allergy Research and Education, Davos, Switzerland.
authors.forename: Liam
authors.initials: L
authors.lastname: O'Mahony
authors.affiliation: Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland; Christine Kühne-Center for Allergy Research and Education, Davos, Switzerland.
authors.forename: Mübeccel
authors.initials: M
authors.lastname: Akdis
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia and Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Fumio
authors.initials: F
authors.lastname: Takei
authors.affiliation: 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.
authors.forename: Cezmi A
authors.initials: CA
authors.lastname: Akdis
mesh_terms: D000818:Animals; D001249:Asthma / Q000276:immunology* / Q000378:metabolism*; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate; D018793:Interleukin-13 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016131:Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009093:Mucus / Q000378:metabolism; D020545:Respiratory Mucosa / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D019108:Tight Junctions / Q000378:metabolism*
chemical_list: D018793:Interleukin-13
keywords: IL-13; Innate lymphoid cell; barrier; bronchial epithelium; tight junction