Elevated PLAUR is observed in the airway epithelium of asthma patients and blocking improves barrier integrity
Abstract Background Expression 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. Objectives To determine (i) the expression profile of uP...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2023-10-01
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| Series: | Clinical and Translational Allergy |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/clt2.12293 |
| _version_ | 1797650781906665472 |
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| author | Michael A. Portelli Sangita Bhaker Vincent Pang David O. Bates Simon R. Johnson Andrew P. Mazar Dominick Shaw Christopher Brightling Ian Sayers |
| author_facet | Michael A. Portelli Sangita Bhaker Vincent Pang David O. Bates Simon R. Johnson Andrew P. Mazar Dominick Shaw Christopher Brightling Ian Sayers |
| author_sort | Michael A. Portelli |
| collection | DOAJ |
| description | Abstract Background Expression 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. Objectives To 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. Methods uPAR 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. Results Elevated 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. Conclusion This 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. |
| first_indexed | 2024-03-11T16:05:25Z |
| format | Article |
| id | doaj.art-b98b2138b6a345bba5e4c156f9115f19 |
| institution | Directory Open Access Journal |
| issn | 2045-7022 |
| language | English |
| last_indexed | 2024-03-11T16:05:25Z |
| publishDate | 2023-10-01 |
| publisher | Wiley |
| record_format | Article |
| series | Clinical and Translational Allergy |
| spelling | doaj.art-b98b2138b6a345bba5e4c156f9115f192023-10-25T03:52:37ZengWileyClinical and Translational Allergy2045-70222023-10-011310n/an/a10.1002/clt2.12293Elevated PLAUR is observed in the airway epithelium of asthma patients and blocking improves barrier integrityMichael A. Portelli0Sangita Bhaker1Vincent Pang2David O. Bates3Simon R. Johnson4Andrew P. Mazar5Dominick Shaw6Christopher Brightling7Ian Sayers8Centre for Respiratory Research NIHR Respiratory Biomedical Research Centre School of Medicine Biodiscovery Institute University Park University of Nottingham Nottingham UKCentre for Respiratory Research NIHR Respiratory Biomedical Research Centre School of Medicine Biodiscovery Institute University Park University of Nottingham Nottingham UKTumour Vascular Biology Group Biodiscovery Institute University Park University of Nottingham Nottingham UKTumour Vascular Biology Group Biodiscovery Institute University Park University of Nottingham Nottingham UKCentre for Respiratory Research NIHR Respiratory Biomedical Research Centre School of Medicine Biodiscovery Institute University Park University of Nottingham Nottingham UKDepartment of Pharmacology Feinberg School of Medicine Northwestern University Chicago Illinois USACentre for Respiratory Research NIHR Respiratory Biomedical Research Centre School of Medicine Biodiscovery Institute University Park University of Nottingham Nottingham UKDepartment of Respiratory Medicine University of Leicester University Hospitals of Leicester NHS Trust Leicester UKCentre for Respiratory Research NIHR Respiratory Biomedical Research Centre School of Medicine Biodiscovery Institute University Park University of Nottingham Nottingham UKAbstract Background Expression 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. Objectives To 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. Methods uPAR 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. Results Elevated 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. Conclusion This 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.https://doi.org/10.1002/clt2.12293asthmabarrierbronchial epithelial cellsurokinase plasminogen receptor |
| spellingShingle | Michael A. Portelli Sangita Bhaker Vincent Pang David O. Bates Simon R. Johnson Andrew P. Mazar Dominick Shaw Christopher Brightling Ian Sayers Elevated PLAUR is observed in the airway epithelium of asthma patients and blocking improves barrier integrity Clinical and Translational Allergy asthma barrier bronchial epithelial cells urokinase plasminogen receptor |
| title | Elevated PLAUR is observed in the airway epithelium of asthma patients and blocking improves barrier integrity |
| title_full | Elevated PLAUR is observed in the airway epithelium of asthma patients and blocking improves barrier integrity |
| title_fullStr | Elevated PLAUR is observed in the airway epithelium of asthma patients and blocking improves barrier integrity |
| title_full_unstemmed | Elevated PLAUR is observed in the airway epithelium of asthma patients and blocking improves barrier integrity |
| title_short | Elevated PLAUR is observed in the airway epithelium of asthma patients and blocking improves barrier integrity |
| title_sort | elevated plaur is observed in the airway epithelium of asthma patients and blocking improves barrier integrity |
| topic | asthma barrier bronchial epithelial cells urokinase plasminogen receptor |
| url | https://doi.org/10.1002/clt2.12293 |
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