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Title: Elucidation of the role of IL-33 in type 2 immunity in an ex-vivo model of differentiated human airway epithelial cells
Author: Zhang, Chu
Awarding Body: University of Aberdeen
Current Institution: University of Aberdeen
Date of Award: 2019
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Background: Airway epithelial cells play an important role in stimulating innate immune system responses, by producing DAMPs, which lead to asthma exacerbation and airway remodelling in the absence of Th2 T cell responses. Genome-wide association studies implicate the 'alarmin' IL-33 in asthma, but any role in human AEC function is unknown. Objectives: To develop an in vitro model representative of differentiated airway epithelia to examine IL-33 production and secretion following stimulation with house dust mite allergen. To compare IL-33 responses between asthmatic versus healthy donors. Methods: Submerged or air liquid interface (ALI) cultures were developed from cell lines, primary bronchial epithelia from excised tracheal tissue, or nasal epithelia isolated from nasal brushing or nasal polyps. Culture characteristics were examined by confocal microscopy, IHC, TEM and SEM. IL-33 production was assessed by flow cytometry, qPCR, ELISA and confocal microscopy. Analysis of AEC apoptosis after HDM stimulation was assessed by Annexin V/PI staining, while ALI models of AEC HDM stimulation used immunohistochemistry and immunofluorescence to detect goblet cell metaplasia and β catenin levels. Results: AEC from asthmatic vs. non-asthmatic donors expressed more IL-33 in submerged culture. Second, IL-33 increased in PBAEC nuclei based on long term exposure to HDM in the ALI model compared to IL-13 stimulation. In contrast, IL-13 induced more IL33 expression in mucus and cytoplasm compared to HDM and control PBAECs. Third, IL-33 was induced by HDM in sub-confluent AEC in submerged cultures whereas IL-33 was decreased by HDM or TNFα/IL-1β, when cells were fully confluent. Finally, HDM may also stimulate tissue remodelling according to A549 goblet cell metaplasia in ALI culture. Conclusion: IL-33 locates in the nucleus of AEC as an alarmin and HDM stimulation may contribute to airway remodelling by driving type 2 immune responses. This suggests that IL-33 may present an important target in asthma.
Supervisor: Walsh, Garry ; Ward, Frank J. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Asthma ; Interleukin-1 ; Interleukins ; Epithelial cells