title: Epidermal growth factor receptor signalling contributes to house dust mite-induced epithelial barrier dysfunction.
abstract: Impaired airway epithelial barrier function has emerged as a key factor in the pathogenesis of allergic asthma. We aimed to discern the involvement of the epidermal growth factor receptor (EGFR) in allergen-induced epithelial barrier impairment, as we previously observed that house dust mite (HDM) signals through EGFR. We investigated the junctional integrity of human bronchial epithelial cells using electric cell-substrate impedance sensing and immunofluorescent staining. HDM induced a rapid, transient fall in epithelial resistance, concomitant with delocalisation of E-cadherin and zona occludens (ZO)-1, and proteolytic cleavage of the latter. EGFR inhibition by AG1478 reduced the HDM-triggered decrease in epithelial resistance and improved restoration of epithelial junctions. Similarly, AG1478 increased epithelial barrier recovery upon electroporation-induced injury, although it delayed the migration phase of the wound healing response. HDM-promoted redistribution of E-cadherin was mediated via EGFR-dependent activation of protease-activated receptor (PAR)-2, while the concomitant ZO-1 degradation was PAR-2/EGFR-independent. Importantly, the fibrogenic cytokine transforming growth factor (TGF)-β prolonged HDM-induced EGFR phosphorylation and inhibited ligand-induced EGFR internalisation/degradation, which resulted in sustained E-cadherin and ZO-1 redistribution. Thus, allergen-induced, PAR-2/EGFR-mediated signalling decreases epithelial resistance and promotes junction disassembly. The TGF-β-enhanced EGFR signalling may be an important contributor to barrier dysfunction and increased epithelial vulnerability in response to HDM.
authors.affiliation: Laboratory of Allergology and Pulmonary Diseases, Dept of Pathology and Medical Biology,University Medical Center Groningen, University of Groningen, Hanzeplein 1, NL-9713 GZ Groningen, The Netherlands. h.i.heijink@int.umcg.nl
authors.forename: I H
authors.initials: IH
authors.lastname: Heijink
authors.forename: A
authors.initials: A
authors.lastname: van Oosterhout
authors.forename: A
authors.initials: A
authors.lastname: Kapus
mesh_terms: D000818:Animals; D001980:Bronchi / Q000166:cytology; D015820:Cadherins / Q000378:metabolism; D002450:Cell Communication / Q000276:immunology; D002460:Cell Line; D018274:Electroporation; D066246:ErbB Receptors / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007365:Intercellular Junctions / Q000276:immunology / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D010539:Permeability; D010750:Phosphoproteins / Q000378:metabolism; D039981:Pyroglyphidae / Q000276:immunology*; D020545:Respiratory Mucosa / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014945:Wound Healing / Q000502:physiology; D062826:Zonula Occludens-1 Protein
chemical_list: D015820:Cadherins; D008565:Membrane Proteins; D010750:Phosphoproteins; C569042:TJP1 protein, human; D016212:Transforming Growth Factor beta; D062826:Zonula Occludens-1 Protein; C512478:EGFR protein, human; D066246:ErbB Receptors