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

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-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 T H 1 and T H 2 cells impaired epithelial integrity, while treatment with anti-TNF-α or anti-IL-4Rα monoclonal antibodies restored the T H 1- and T H 2-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.