3 years ago

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

Histamine and T helper cytokine driven epithelial barrier dysfunction in allergic rhinitis
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 (ALI) cultures of primary nasal epithelial cells (pNECs) were used to measure trans-epithelial electrical resistance, paracellular flux of FITC-dextran 4kDa and mRNA expression of tight junctions. Nasal secretions were collected from healthy controls, AR patients and idiopathic rhinitis (IR) 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 TNFα on mucosal permeability was tested in vivo. Results Histamine as well as nasal secretions of AR but not IR 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-TNFα or anti-IL-4Rα monoclonal antibodies restored the TH1 and TH2 induced epithelial barrier dysfunction respectively. IL-4, IFN-γ and TNFα 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. Conclusion 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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Capsule summary: A defective epithelial barrier is demonstrated in allergic rhinitis, and we here show that histamine, released during the early allergic immune reaction, together with T cell cytokines, released during chronic inflammation, contribute to this defect.

Publisher URL: www.sciencedirect.com/science

DOI: S0091674917316226

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