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House Dust Mite–Promoted Epithelial-to-Mesenchymal Transition in Human Bronchial Epithelium

¹ Department of Allergology and Pumonary Diseases, ³ Department of Pulmonology, and ⁴ Department of Pathology and Laboratory Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; and ² Keenan Research Centre in the Li Ka Shing Knowledge Institute of St. Michael's Hospital and Department of Surgery, University of Toronto, Toronto, Ontario, Canada

Correspondence and requests for reprints should be addressed to I. H. Heijink, Department of Allergology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, NL-9713 GZ, Groningen, The Netherlands. E-mail: h.i.heijink{at}int.umcg.nl

The molecular basis of airway remodeling and loss of epithelial integrity in asthma is still undefined. We aimed to establish if exposure of human bronchial epithelium (16HBE cells) to asthma-related stimuli can induce epithelial-to-mesenchymal transition (EMT), a key process in tissue repair and remodeling associated with loss of intercellular contacts. We studied the effects of fibrogenic cytokine TGF-β and protease-containing aeroallergen house dust mite (HDM) on mesenchymal and epithelial markers, cytoskeleton organization, and activation of β-catenin–driven reporter TopFLASH. TGF-β alone up-regulated vimentin and fibronectin, modestly down-regulated E-cadherin, but did not affect cytokeratin. HDM alone did not affect these markers, but promoted stress fibers. Importantly, when added to TGF-β–primed epithelium, HDM induced E-cadherin internalization, enhanced β-catenin–dependent transcription, and down-regulated cytokeratin. Regarding the underlying mechanisms, the stimuli together induced sustained myosin light chain phosphorylation, which was crucial for E-cadherin internalization and β-catenin–dependent transcription. Previously, we showed that HDM signals through the epidermal growth factor receptor (EGFR). Accordingly, inhibition of EGFR prevented TGF-β/HDM-induced mesenchymalization. TGF-β facilitated uncoupling of EGFR from E-cadherin, its negative regulator, and prolonged EGFR signaling. Thus, we show that HDM promotes EMT in TGF-β–primed epithelium. Analysis of primary epithelium appears consistent with this phenotypic change. We propose that TGF-β secretion and dysregulated EGFR signaling may increase epithelial vulnerability to allergens and trigger the induction of EMT, a hitherto unrecognized contributor to airway remodeling in asthma.

Key Words: TGF-β • E-cadherin • myosin light chain • EGFR

CLINICAL RELEVANCE House dust mite and TGF-β–induced epithelial-to-mesenchymal transition may be a hitherto unrecognized mechanism contributing to asthmatic airway remodeling. The involvement of epidermal growth factor receptor and myosin light chain may offer novel avenues for therapeutic intervention strategies in allergic asthma.