Brecht Steelant1, Sven F Seys1, Laura Van Gerven2, Matthias Van Woensel3, Ricard Farré4, Paulina Wawrzyniak5, Inge Kortekaas Krohn1, Dominique M Bullens6, Karel Talavera7, Ulrike Raap8, Louis Boon9, Cezmi A Akdis5, Guy Boeckxstaens4, Jan L Ceuppens1, Peter W Hellings10. 1. Laboratory of Clinical Immunology, Department of Microbiology and Immunology, Katholieke Universiteit (KU) Leuven, Leuven, Belgium. 2. Laboratory of Clinical Immunology, Department of Microbiology and Immunology, Katholieke Universiteit (KU) Leuven, Leuven, Belgium; Clinical Department of Otorhinolaryngology, Head and Neck Surgery, University Hospitals Leuven, Leuven, Belgium. 3. Laboratory of Experimental Neurosurgery and Neuroanatomy, KU Leuven, Leuven, Belgium; Laboratory of Galenic Pharmacy and Biopharmacy, Université libre de Bruxelles, Brussels, Belgium. 4. Translational Research Center for Gastro Intestinal Disorders, KU Leuven, Leuven, Belgium. 5. Swiss Institute of Allergy and Asthma Research, University of Zurich, Davos, Switzerland. 6. Laboratory of Pediatric Immunology, Department of Microbiology and Immunology, KU Leuven, Leuven, Belgium; Clinical Department of Pediatrics, University Hospitals Leuven, Leuven, Belgium. 7. Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium. 8. Department of Dermatology, University of Oldenburg, Oldenburg. 9. Epirus Biopharmaceuticals Netherlands, Utrecht, The Netherlands. 10. Laboratory of Clinical Immunology, Department of Microbiology and Immunology, Katholieke Universiteit (KU) Leuven, Leuven, Belgium; Clinical Department of Otorhinolaryngology, Head and Neck Surgery, University Hospitals Leuven, Leuven, Belgium; Department of Otorhinolaryngology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Department of Otorhinolaryngology, University Hospitals Ghent, Ghent, Belgium. Electronic address: Peter.hellings@kuleuven.be.
Abstract
BACKGROUND: Allergic rhinitis (AR) is characterized by mucosal inflammation, driven by activated immune cells. Mast cells and TH2 cells might decrease epithelial barrier integrity in AR, maintaining a leaky epithelial barrier. OBJECTIVE: We sought to investigate the role of histamine and TH2 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 TH1 and TH2 cells, mast cells, and neurons was tested in vitro. The effect of IL-4, IL-13, IFN-γ, and TNF-α 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 TH1 and TH2 cells impaired epithelial integrity, while treatment with anti-TNF-α or anti-IL-4Rα monoclonal antibodies restored the TH1- and TH2-induced epithelial barrier dysfunction, respectively. IL-4, IFN-γ, and TNF-α 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.
BACKGROUND:Allergic rhinitis (AR) is characterized by mucosal inflammation, driven by activated immune cells. Mast cells and TH2 cells might decrease epithelial barrier integrity in AR, maintaining a leaky epithelial barrier. OBJECTIVE: We sought to investigate the role of histamine and TH2 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 rhinitispatients and were tested in vitro. In addition, the effect of activated TH1 and TH2 cells, mast cells, and neurons was tested in vitro. The effect of IL-4, IL-13, IFN-γ, and TNF-α on mucosal permeability was tested in vivo. RESULTS:Histamine as well as nasal secretions of AR but not idiopathic rhinitispatients 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 TH1 and TH2 cells impaired epithelial integrity, while treatment with anti-TNF-α or anti-IL-4Rα monoclonal antibodies restored the TH1- and TH2-induced epithelial barrier dysfunction, respectively. IL-4, IFN-γ, and TNF-α 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.
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