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Elevated PLAUR is observed in the airway epithelium of asthma patients and blocking improves barrier integrity

Portelli, Michael A.; Bhaker, Sangita; Pang, Vincent; Bates, David O.; Johnson, Simon R.; Mazar, Andrew P.; Shaw, Dominick; Brightling, Christopher; Sayers, Ian

Elevated PLAUR is observed in the airway epithelium of asthma patients and blocking improves barrier integrity Thumbnail


Authors

Sangita Bhaker

Vincent Pang

DAVID BATES David.Bates@nottingham.ac.uk
Professor of Oncology

SIMON JOHNSON simon.johnson@nottingham.ac.uk
Professor of Respiratory Medicine

Andrew P. Mazar

Dominick Shaw

Christopher Brightling



Abstract

AbstractBackgroundExpression of the urokinase plasminogen activator receptor (uPAR) is elevated in the airway epithelium in asthma; however, the contribution of uPAR to asthma pathogenesis and scope for therapeutic targeting remains unknown.ObjectivesTo determine (i) the expression profile of uPAR in cultured human bronchial epithelial cells (HBEC) from asthma patients, (ii) the relationship between uPAR and the epithelial barrier, including blocking uPAR functions and (iii) the function of different uPAR isoforms.MethodsuPAR levels in HBECs isolated from asthma patients and cells at air liquid interface (ALI) during differentiation were quantified. Transepithelial electrical resistance or electrical cell impedance sensing was used to relate uPAR levels to barrier properties, including effects of uPAR blocking antibodies. The functional effects of gain of function was determined using transcriptomics, in cells over‐expressing membrane (muPAR), soluble cleaved (scuPAR) or soluble spliced (ssuPAR) isoforms.ResultsElevated expression of uPAR was a feature of cultured HBECs from asthma patients, suggesting intrinsic alterations in asthma patient cells. Soluble uPAR levels inversely correlated with barrier properties of the HBEC layer in 2D and ALI. Blocking uPAR‐integrin interactions enhanced barrier formation. The gain of function cells showed limited transcriptomic changes.ConclusionThis study provides a significant advance in our understanding of the relationship between asthma, uPAR and the epithelial barrier, where elevated circulating uPAR results in a reduced cell barrier, a phenotype prevalent in asthma.

Citation

Portelli, M. A., Bhaker, S., Pang, V., Bates, D. O., Johnson, S. R., Mazar, A. P., …Sayers, I. (2023). Elevated PLAUR is observed in the airway epithelium of asthma patients and blocking improves barrier integrity. Clinical and Translational Allergy, 13(10), Article e12293. https://doi.org/10.1002/clt2.12293

Journal Article Type Article
Acceptance Date Jul 31, 2023
Online Publication Date Oct 1, 2023
Publication Date 2023-10
Deposit Date Sep 27, 2023
Publicly Available Date Oct 2, 2023
Journal Clinical and Translational Allergy
Print ISSN 2045-7022
Electronic ISSN 2045-7022
Publisher Springer Verlag
Peer Reviewed Peer Reviewed
Volume 13
Issue 10
Article Number e12293
DOI https://doi.org/10.1002/clt2.12293
Keywords Asthma; barrier; bronchial epithelial cells; urokinase plasminogen receptor
Public URL https://nottingham-repository.worktribe.com/output/25377586
Publisher URL https://onlinelibrary.wiley.com/doi/full/10.1002/clt2.12293

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