Human Lung Mast Cells Impair Corticosteroid Responsiveness in Human Airway Smooth Muscle Cells
The mechanisms underlying corticosteroid insensitivity in severe asthma have not been elucidated although some indirect clinical evidence points toward a role of mast cells. Here, we tested the hypothesis that mast cells can drive corticosteroid insensitivity in airway smooth muscle cells, a key pla...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-12-01
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| Series: | Frontiers in Allergy |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/falgy.2021.785100/full |
| _version_ | 1819175792258580480 |
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| author | Abdulrahman Alzahrani Abdulrahman Alzahrani Jameel Hakeem Michael Biddle Fahad Alhadian Aamir Hussain Latifa Khalfaoui Katy M. Roach Omar Tliba Peter Bradding Yassine Amrani |
| author_facet | Abdulrahman Alzahrani Abdulrahman Alzahrani Jameel Hakeem Michael Biddle Fahad Alhadian Aamir Hussain Latifa Khalfaoui Katy M. Roach Omar Tliba Peter Bradding Yassine Amrani |
| author_sort | Abdulrahman Alzahrani |
| collection | DOAJ |
| description | The mechanisms underlying corticosteroid insensitivity in severe asthma have not been elucidated although some indirect clinical evidence points toward a role of mast cells. Here, we tested the hypothesis that mast cells can drive corticosteroid insensitivity in airway smooth muscle cells, a key player in asthma pathogenesis. Conditioned media from resting or FcεR1-activated human lung mast cells were incubated with serum-deprived ASM cells (1:4 dilution, 24 h) to determine their impact on the anti-inflammatory action of fluticasone on ASM cell chemokine expression induced by TNFα (10 ng/ml). Conditioned media from FcεR1-activated mast cells (but not that from non-activated mast cells or control media) significantly reduced the ability of 100 nM fluticasone to suppress ASM TNFα-dependent CCL5 and CXCL10 production at both mRNA and protein levels. In contrast, fluticasone inhibition of CXCL-8 production by TNFα was still preserved in the presence of activated mast cell conditioned media. Transcriptomic analysis validated by individual qPCR assays revealed that activated mast cell conditioned media dramatically reduced the number of anti-inflammatory genes induced by fluticasone in ASM cells. Our study demonstrates for the first time that conditioned media from FcεR1-activated mast cells blunt the anti-inflammatory action of corticosteroids in ASM cells by altering their transactivation properties. Because infiltration of mast cells within the ASM bundles is a defining feature of asthma, mast cell-derived mediators may contribute to the glucocorticoid insensitivity present in severe asthma. |
| first_indexed | 2024-12-22T21:00:30Z |
| format | Article |
| id | doaj.art-2d6cc5806c3343ea905d61faa697cb69 |
| institution | Directory Open Access Journal |
| issn | 2673-6101 |
| language | English |
| last_indexed | 2024-12-22T21:00:30Z |
| publishDate | 2021-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Allergy |
| spelling | doaj.art-2d6cc5806c3343ea905d61faa697cb692022-12-21T18:12:51ZengFrontiers Media S.A.Frontiers in Allergy2673-61012021-12-01210.3389/falgy.2021.785100785100Human Lung Mast Cells Impair Corticosteroid Responsiveness in Human Airway Smooth Muscle CellsAbdulrahman Alzahrani0Abdulrahman Alzahrani1Jameel Hakeem2Michael Biddle3Fahad Alhadian4Aamir Hussain5Latifa Khalfaoui6Katy M. Roach7Omar Tliba8Peter Bradding9Yassine Amrani10Department of Respiratory Sciences, Clinical Sciences, University of Leicester, Glenfield Hospital, Leicester, United KingdomDepartment of Applied Medical Sciences, Applied College, Albaha University, Albaha, Saudi ArabiaDepartment of Respiratory Sciences, Clinical Sciences, University of Leicester, Glenfield Hospital, Leicester, United KingdomDepartment of Respiratory Sciences, Clinical Sciences, University of Leicester, Glenfield Hospital, Leicester, United KingdomDepartment of Respiratory Sciences, Clinical Sciences, University of Leicester, Glenfield Hospital, Leicester, United KingdomDepartment of Respiratory Sciences, Clinical Sciences, University of Leicester, Glenfield Hospital, Leicester, United KingdomDepartment of Respiratory Sciences, Clinical Sciences, University of Leicester, Glenfield Hospital, Leicester, United KingdomDepartment of Respiratory Sciences, Clinical Sciences, University of Leicester, Glenfield Hospital, Leicester, United KingdomDepartment of Biomedical Sciences, College of Veterinary Medicine, Long Island University, Brookville, NY, United StatesDepartment of Respiratory Sciences, Clinical Sciences, University of Leicester, Glenfield Hospital, Leicester, United KingdomDepartment of Respiratory Sciences, Clinical Sciences, University of Leicester, Glenfield Hospital, Leicester, United KingdomThe mechanisms underlying corticosteroid insensitivity in severe asthma have not been elucidated although some indirect clinical evidence points toward a role of mast cells. Here, we tested the hypothesis that mast cells can drive corticosteroid insensitivity in airway smooth muscle cells, a key player in asthma pathogenesis. Conditioned media from resting or FcεR1-activated human lung mast cells were incubated with serum-deprived ASM cells (1:4 dilution, 24 h) to determine their impact on the anti-inflammatory action of fluticasone on ASM cell chemokine expression induced by TNFα (10 ng/ml). Conditioned media from FcεR1-activated mast cells (but not that from non-activated mast cells or control media) significantly reduced the ability of 100 nM fluticasone to suppress ASM TNFα-dependent CCL5 and CXCL10 production at both mRNA and protein levels. In contrast, fluticasone inhibition of CXCL-8 production by TNFα was still preserved in the presence of activated mast cell conditioned media. Transcriptomic analysis validated by individual qPCR assays revealed that activated mast cell conditioned media dramatically reduced the number of anti-inflammatory genes induced by fluticasone in ASM cells. Our study demonstrates for the first time that conditioned media from FcεR1-activated mast cells blunt the anti-inflammatory action of corticosteroids in ASM cells by altering their transactivation properties. Because infiltration of mast cells within the ASM bundles is a defining feature of asthma, mast cell-derived mediators may contribute to the glucocorticoid insensitivity present in severe asthma.https://www.frontiersin.org/articles/10.3389/falgy.2021.785100/fullsevere asthmacorticosteroid resistancemast cell (MC)growth factorsgene array |
| spellingShingle | Abdulrahman Alzahrani Abdulrahman Alzahrani Jameel Hakeem Michael Biddle Fahad Alhadian Aamir Hussain Latifa Khalfaoui Katy M. Roach Omar Tliba Peter Bradding Yassine Amrani Human Lung Mast Cells Impair Corticosteroid Responsiveness in Human Airway Smooth Muscle Cells Frontiers in Allergy severe asthma corticosteroid resistance mast cell (MC) growth factors gene array |
| title | Human Lung Mast Cells Impair Corticosteroid Responsiveness in Human Airway Smooth Muscle Cells |
| title_full | Human Lung Mast Cells Impair Corticosteroid Responsiveness in Human Airway Smooth Muscle Cells |
| title_fullStr | Human Lung Mast Cells Impair Corticosteroid Responsiveness in Human Airway Smooth Muscle Cells |
| title_full_unstemmed | Human Lung Mast Cells Impair Corticosteroid Responsiveness in Human Airway Smooth Muscle Cells |
| title_short | Human Lung Mast Cells Impair Corticosteroid Responsiveness in Human Airway Smooth Muscle Cells |
| title_sort | human lung mast cells impair corticosteroid responsiveness in human airway smooth muscle cells |
| topic | severe asthma corticosteroid resistance mast cell (MC) growth factors gene array |
| url | https://www.frontiersin.org/articles/10.3389/falgy.2021.785100/full |
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