Journal
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
Volume 128, Issue 6, Pages 1216-U546Publisher
MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2011.08.035
Keywords
Asthma; polyI:C; Toll-like receptor 3; epithelial permeability; protein kinase C; tight junctions; adherens junctions
Categories
Funding
- National Institutes of Health (NIH) [R01 HL071933, P30 ES 01247, R01 DK083968, DK084953, T32 HD057821, T32 HL066988]
- National Eczema Association
- University of Rochester Department of Pediatrics
- Centocor
- Regeneron
- Genentech
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Background: Disruption of the epithelial barrier might be a risk factor for allergen sensitization and asthma. Viral respiratory tract infections are strongly associated with asthma exacerbation, but the effects of respiratory viruses on airway epithelial barrier function are not well understood. Many viruses generate double-stranded RNA, which can lead to airway inflammation and initiate an antiviral immune response. Objectives: We investigated the effects of the synthetic double-stranded RNA polyinosinic:polycytidylic acid (polyI:C) on the structure and function of the airway epithelial barrier in vitro. Methods: 16HBE14o- human bronchial epithelial cells and primary airway epithelial cells at an air-liquid interface were grown to confluence on Transwell inserts and exposed to polyI:C. We studied epithelial barrier function by measuring transepithelial electrical resistance and paracellular flux of fluorescent markers and structure of epithelial apical junctions by means of immunofluorescence microscopy. Results: PolyI:C induced a profound decrease in transepithelial electrical resistance and increase in paracellular permeability. Immunofluorescence microscopy revealed markedly reduced junctional localization of zonula occludens-1, occludin, E-cadherin, beta-catenin, and disorganization of junction-associated actin filaments. PolyI:C induced protein kinase D (PKD) phosphorylation, and a PKD antagonist attenuated polyI:C-induced disassembly of apical junctions and barrier dysfunction. Conclusions: PolyI:C has a powerful and previously unsuspected disruptive effect on the airway epithelial barrier. PolyI:C-dependent barrier disruption is mediated by disassembly of epithelial apical junctions, which is dependent on PKD signaling. These findings suggest a new mechanism potentially underlying the associations between viral respiratory tract infections, airway inflammation, and allergen sensitization. (J Allergy Clin Immunol 2011;128:1216-24.)
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