Histamine and T helper cytokine-driven epithelial barrier dysfunction in allergic rhinitis

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:141

Article

Steelant, Brecht¹  Seys, Sven F.¹  Van Gerven, Laura^1,2  Van Woensel, Matthias^3,4  Farre, Ricard⁵  Wawrzyniak, Paulina⁶  Krohn, Inge Kortekaas¹  Bullens, Dominique M.^7,8  Talavera, Karel⁹  Raap, Ulrike¹⁰  Boon, Louis¹¹  Akdis, Cezmi A.⁶  Boeckxstaens, Guy⁵  Ceuppens, Jan L.¹  Hellings, Peter W.^1,2,12,13 

[1] KU, Dept Microbiol & Immunol, Lab Clin Immunol, Leuven, Belgium

[2] Univ Hosp Leuven, Clin Dept Otorhinolaryngol Head & Neck Surg, Leuven, Belgium

[3] Katholieke Univ Leuven, Lab Expt Neurosurg & Neuroanat, Leuven, Belgium

[4] Univ Libre Bruxelles, Lab Galen Pharm & Biopharm, Brussels, Belgium

[5] Katholieke Univ Leuven, Translat Res Ctr Gastro Intestinal Disorders, Leuven, Belgium

[6] Univ Zurich, Swiss Inst Allergy & Asthma Res, Davos, Switzerland

[7] Katholieke Univ Leuven, Dept Microbiol & Immunol, Lab Pediat Immunol, Leuven, Belgium

[8] Univ Hosp Leuven, Clin Dept Pediat, Leuven, Belgium

[9] Katholieke Univ Leuven, Dept Cellular & Mol Med, Lab Ion Channel Res, Leuven, Belgium

[10] Carl von Ossietzky Univ Oldenburg, Dept Dermatol, Oldenburg, Germany

[11] Epirus Biopharmaceut Netherlands, Utrecht, Netherlands

[12] Univ Amsterdam, Acad Med Ctr, Dept Otorhinolaryngol, Amsterdam, Netherlands

[13] Univ Hosp Ghent, Dept Otorhinolaryngol, Ghent, Belgium

关键词: Allergic rhinitis;    idiopathic rhinitis;    tight junctions;    histamine;    T(H)2 cells;    primary nasal epithelial cells;   

DOI  :  10.1016/j.jaci.2017.08.039

来源: Elsevier

【 摘 要 】

Background: Allergic rhinitis (AR) is characterized by mucosal inflammation, driven by activated immune cells. Mast cells and T(H)2 cells might decrease epithelial barrier integrity in AR, maintaining a leaky epithelial barrier. Objective: We sought to investigate the role of histamine and T(H)2 cells in driving epithelial barrier dysfunction in AR. Methods: Air-liquid interface cultures of primary nasal epithelial cells were used to measure transepithelial electrical resistance, paracellular flux of fluorescein isothiocyanate-dextran 4 kDa, and mRNA expression of tight junctions. Nasal secretions were collected from healthy control subjects, AR patients, and idiopathic rhinitis patients and were tested in vitro. In addition, the effect of activated T(H)1 and T(H)2 cells, mast cells, and neurons was tested in vitro. The effect of IL-4, IL-13, IFN-gamma, and TNF-alpha on mucosal permeability was tested in vivo. Results: Histamine as well as nasal secretions of AR but not idiopathic rhinitis patients rapidly decreased epithelial barrier integrity in vitro. Pretreatment with histamine receptor-1 antagonist, azelastine prevented the early effect of nasal secretions of AR patients on epithelial integrity. Supernatant of activated T(H)1 and T(H)2 cells impaired epithelial integrity, while treatment with anti-TNF-alpha or anti-IL-4R alpha monoclonal antibodies restored the T(H)1- and T(H)2-induced epithelial barrier dysfunction, respectively. IL-4, IFN-gamma, and TNF-alpha enhanced mucosal permeability in mice. Antagonizing IL-4 prevented mucosal barrier disruption and tight junction downregulation in a mouse model of house dust mite allergic airway inflammation. Conclusions: Our data indicate a key role for allergic inflammatory mediators in modulating nasal epithelial barrier integrity in the pathophysiology in AR.

【 授权许可】

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