Impaired barrier function in patients with house dust mite–induced allergic rhinitis is accompanied by decreased occludin and zonula occludens-1 expression

doi:10.1016/j.jaci.2015.10.050

Journal of Allergy and Clinical Immunology

Volume 137, Issue 4, April 2016, Pages 1043-1053.e5

https://doi.org/10.1016/j.jaci.2015.10.050 Get rights and content

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Background

Tight junction (TJ) defects have recently been associated with asthma and chronic rhinosinusitis. The expression, function, and regulation of nasal epithelial TJs remain unknown in patients with allergic rhinitis (AR).

Objective

We investigated the expression, function, and regulation of TJs in the nasal epithelium of patients with house dust mite (HDM)–induced AR and in an HDM-induced murine model of allergic airway disease.

Methods

Air-liquid interface cultures of primary nasal epithelial cells of control subjects and patients with HDM-induced AR were used for measuring transepithelial resistance and passage to fluorescein isothiocyanate–dextran 4 kDa (FD4). Ex vivo transtissue resistance and FD4 permeability of nasal mucosal explants were measured. TJ expression was evaluated by using real-time quantitative PCR and immunofluorescence. In addition, the effects of IL-4, IFN-γ, and fluticasone propionate (FP) on nasal epithelial cells were investigated in vitro. An HDM murine model was used to study the effects of allergic inflammation and FP treatment on transmucosal passage of FD4 in vivo.

Results

A decreased resistance in vitro and ex vivo was found in patients with HDM-induced AR, with increased FD4 permeability and reduced occludin and zonula occludens-1 expression. AR symptoms correlated inversely with resistance in patients with HDM-induced AR. In vitro IL-4 decreased transepithelial resistance and increased FD4 permeability, whereas IFN-γ had no effect. FP prevented IL-4–induced barrier dysfunction in vitro. In an HDM murine model FP prevented the allergen-induced increased mucosal permeability.

Conclusion

We found impaired nasal epithelial barrier function in patients with HDM-induced AR, with lower occludin and zonula occludens-1 expression. IL-4 disrupted epithelial integrity in vitro, and FP restored barrier function. Better understanding of nasal barrier regulation might lead to a better understanding and treatment of AR.

Key words

Allergic rhinitis

tight junctions

fluticasone propionate

IL-4

leak pathway

epithelial resistance

epithelial permeability

Abbreviations used

ALI

Air-liquid interface

Allergic rhinitis

FD4

Fluorescein isothiocyanate–dextran 4 kDa

Fluticasone propionate

HDM

House dust mite

INS

Intranasal steroid

NEC

Nasal epithelial cell

RT-qPCR

Real-time quantitative PCR

TER

Transepithelial resistance

Tight junction

Zonula occludens

Cited by (0)

: The authors' laboratories are supported by grants from the Belgian Federal Government (IUAP P6/28), IWT (TBM project 130260), and the research council of the KU Leuven (GOA 2009/07 and 14/011). P.W.H. and D.M.A.B. are recipients of a senior researcher fellowship from the Fund of Scientific Research (FWO), Flanders, Belgium.

: Disclosure of potential conflict of interest: B. Steelant and I. Kortekaas Krohn have received grants from the Belgian government (IUAP P7/30), the Agency for Innovation by Science and Technology (TBM project 130260), and the University of Leuven (GOA 2009/07 and GOA 14/011). D. M. A. Bullens is employed by the Fund for Scientific Research; has received payment for manuscript preparation from Merck Sharpe & Dohme; has received travel support from Phadia, Thermo Fisher, and Mead Johnson; and has received payment for organizing symposia from Meda, ALK-Abelló, Thermo Fisher, Novartis, Shire, Hal, Stallergenes, and VWR. C. A. Akdis has consultant arrangements with Actellion, Aventis, Stallergenes, Allergopharma, and Circacia; is employed by the Swiss Institute of Allergy and Asthma Research, University of Zurich; and has received grants from Novartis, PREDICTA: European Commission's Seventh Framework Programme no. 260895, Swiss National Science Foundation, MeDALL: European Commission's Seventh Framework Programme no. 261357, and the Christine Kühne-Center for Allergy Research and Education. S. F. Seys has received grants from the Belgian government (IUAP P7/30) and the University of Leuven (GOA 2009/07 and GOA 2014/011) and is employed by the Research Council, University of Leuven (PDMK/14/189). P. W. Hellings has received grants from the Belgian government (IUAP P7/30) and the University of Leuven (GOA 2009/07 and GOA 2014/011). The rest of the authors declare that they have no relevant conflicts of interest.