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Glucocorticoids increase tissue cell protection against pore-forming toxins from pathogenic bacteria

THOMAS ORMSBY, Sian-eleri Owens Orcid Logo, Matthew Turner Orcid Logo, James Cronin Orcid Logo, John J. Bromfield Orcid Logo, Martin Sheldon

Communications Biology, Volume: 6, Issue: 1, Pages: 1 - 15

Swansea University Authors: THOMAS ORMSBY, Sian-eleri Owens Orcid Logo, Matthew Turner Orcid Logo, James Cronin Orcid Logo, Martin Sheldon

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DOI (Published version): 10.1038/s42003-023-04568-w

Abstract

Many species of pathogenic bacteria damage tissue cells by secreting toxins that form pores in plasma membranes. Here we show that glucocorticoids increase the intrinsic protection of tissue cells against pore-forming toxins. Dexamethasone protected several cell types against the cholesterol-depende...

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Published in: Communications Biology
ISSN: 2399-3642
Published: Springer Science and Business Media LLC 2023
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URI: https://cronfa.swan.ac.uk/Record/cronfa62675
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Here we show that glucocorticoids increase the intrinsic protection of tissue cells against pore-forming toxins. Dexamethasone protected several cell types against the cholesterol-dependent cytolysin, pyolysin, from Trueperella pyogenes. Dexamethasone treatment reduced pyolysin-induced leakage of potassium and lactate dehydrogenase, limited actin cytoskeleton alterations, reduced plasma membrane blebbing, and prevented cytolysis. Hydrocortisone and fluticasone also protected against pyolysin-induced cell damage. Furthermore, dexamethasone protected HeLa and A549 cells against the pore-forming toxins streptolysin O from Streptococcus pyogenes, and alpha-hemolysin from Staphylococcus aureus. Dexamethasone cytoprotection was not associated with changes in cellular cholesterol or activating mitogen-activated protein kinase (MAPK) cell stress responses. However, cytoprotection was dependent on the glucocorticoid receptor and 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR). Collectively, our findings imply that glucocorticoids could be exploited to limit tissue damage caused by pathogens secreting pore-forming toxins.</abstract><type>Journal Article</type><journal>Communications Biology</journal><volume>6</volume><journalNumber>1</journalNumber><paginationStart>1</paginationStart><paginationEnd>15</paginationEnd><publisher>Springer Science and Business Media LLC</publisher><placeOfPublication/><isbnPrint/><isbnElectronic/><issnPrint/><issnElectronic>2399-3642</issnElectronic><keywords/><publishedDay>17</publishedDay><publishedMonth>2</publishedMonth><publishedYear>2023</publishedYear><publishedDate>2023-02-17</publishedDate><doi>10.1038/s42003-023-04568-w</doi><url/><notes>Data availability:All data generated or analyzed during this study, and uncropped Western blots, are included in this published article and its supplementary information files. The datasets generated and analyzed during the current study are available in Supplementary Data 1. 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spelling v2 62675 2023-02-16 Glucocorticoids increase tissue cell protection against pore-forming toxins from pathogenic bacteria 559dbd7b55ce6aa38eca17712d4f06c5 THOMAS ORMSBY THOMAS ORMSBY true false 721deb4604d122019244cfdf08820cbe 0000-0003-1806-5235 Sian-eleri Owens Sian-eleri Owens true false d6ee69e43774ed1124d27923140b1e0b 0000-0002-1369-4051 Matthew Turner Matthew Turner true false 9cfd17551c0d1f7438895121e4fbb6e8 0000-0002-0590-9462 James Cronin James Cronin true false ab0f74b794e59cc270c69e63ee1d9748 Martin Sheldon Martin Sheldon true false 2023-02-16 Many species of pathogenic bacteria damage tissue cells by secreting toxins that form pores in plasma membranes. Here we show that glucocorticoids increase the intrinsic protection of tissue cells against pore-forming toxins. Dexamethasone protected several cell types against the cholesterol-dependent cytolysin, pyolysin, from Trueperella pyogenes. Dexamethasone treatment reduced pyolysin-induced leakage of potassium and lactate dehydrogenase, limited actin cytoskeleton alterations, reduced plasma membrane blebbing, and prevented cytolysis. Hydrocortisone and fluticasone also protected against pyolysin-induced cell damage. Furthermore, dexamethasone protected HeLa and A549 cells against the pore-forming toxins streptolysin O from Streptococcus pyogenes, and alpha-hemolysin from Staphylococcus aureus. Dexamethasone cytoprotection was not associated with changes in cellular cholesterol or activating mitogen-activated protein kinase (MAPK) cell stress responses. However, cytoprotection was dependent on the glucocorticoid receptor and 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR). Collectively, our findings imply that glucocorticoids could be exploited to limit tissue damage caused by pathogens secreting pore-forming toxins. Journal Article Communications Biology 6 1 1 15 Springer Science and Business Media LLC 2399-3642 17 2 2023 2023-02-17 10.1038/s42003-023-04568-w Data availability:All data generated or analyzed during this study, and uncropped Western blots, are included in this published article and its supplementary information files. The datasets generated and analyzed during the current study are available in Supplementary Data 1. All other data are available from the corresponding author on reasonable request. COLLEGE NANME COLLEGE CODE Swansea University External research funder(s) paid the OA fee (includes OA grants disbursed by the Library) This study was supported by the Biotechnology and Biological Sciences Research Council (BB/K006592/1) and the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health (R01HD084316). 2024-07-15T12:06:07.8274854 2023-02-16T11:39:34.3795822 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Biomedical Science THOMAS ORMSBY 1 Sian-eleri Owens 0000-0003-1806-5235 2 Matthew Turner 0000-0002-1369-4051 3 James Cronin 0000-0002-0590-9462 4 John J. Bromfield 0000-0001-5438-2137 5 Martin Sheldon 6 62675__26626__3689a24197e44085a2119af9af0a4173.pdf OrmsbyComBiol.pdf 2023-02-20T09:37:37.5965704 Output 2282871 application/pdf Version of Record true This article is licensed under a Creative Commons Attribution 4.0 International License true eng http://creativecommons.org/licenses/by/4.0/
title Glucocorticoids increase tissue cell protection against pore-forming toxins from pathogenic bacteria
spellingShingle Glucocorticoids increase tissue cell protection against pore-forming toxins from pathogenic bacteria
THOMAS ORMSBY
Sian-eleri Owens
Matthew Turner
James Cronin
Martin Sheldon
title_short Glucocorticoids increase tissue cell protection against pore-forming toxins from pathogenic bacteria
title_full Glucocorticoids increase tissue cell protection against pore-forming toxins from pathogenic bacteria
title_fullStr Glucocorticoids increase tissue cell protection against pore-forming toxins from pathogenic bacteria
title_full_unstemmed Glucocorticoids increase tissue cell protection against pore-forming toxins from pathogenic bacteria
title_sort Glucocorticoids increase tissue cell protection against pore-forming toxins from pathogenic bacteria
author_id_str_mv 559dbd7b55ce6aa38eca17712d4f06c5
721deb4604d122019244cfdf08820cbe
d6ee69e43774ed1124d27923140b1e0b
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ab0f74b794e59cc270c69e63ee1d9748
author_id_fullname_str_mv 559dbd7b55ce6aa38eca17712d4f06c5_***_THOMAS ORMSBY
721deb4604d122019244cfdf08820cbe_***_Sian-eleri Owens
d6ee69e43774ed1124d27923140b1e0b_***_Matthew Turner
9cfd17551c0d1f7438895121e4fbb6e8_***_James Cronin
ab0f74b794e59cc270c69e63ee1d9748_***_Martin Sheldon
author THOMAS ORMSBY
Sian-eleri Owens
Matthew Turner
James Cronin
Martin Sheldon
author2 THOMAS ORMSBY
Sian-eleri Owens
Matthew Turner
James Cronin
John J. Bromfield
Martin Sheldon
format Journal article
container_title Communications Biology
container_volume 6
container_issue 1
container_start_page 1
publishDate 2023
institution Swansea University
issn 2399-3642
doi_str_mv 10.1038/s42003-023-04568-w
publisher Springer Science and Business Media LLC
college_str Faculty of Medicine, Health and Life Sciences
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hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Biomedical Science{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Biomedical Science
document_store_str 1
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description Many species of pathogenic bacteria damage tissue cells by secreting toxins that form pores in plasma membranes. Here we show that glucocorticoids increase the intrinsic protection of tissue cells against pore-forming toxins. Dexamethasone protected several cell types against the cholesterol-dependent cytolysin, pyolysin, from Trueperella pyogenes. Dexamethasone treatment reduced pyolysin-induced leakage of potassium and lactate dehydrogenase, limited actin cytoskeleton alterations, reduced plasma membrane blebbing, and prevented cytolysis. Hydrocortisone and fluticasone also protected against pyolysin-induced cell damage. Furthermore, dexamethasone protected HeLa and A549 cells against the pore-forming toxins streptolysin O from Streptococcus pyogenes, and alpha-hemolysin from Staphylococcus aureus. Dexamethasone cytoprotection was not associated with changes in cellular cholesterol or activating mitogen-activated protein kinase (MAPK) cell stress responses. However, cytoprotection was dependent on the glucocorticoid receptor and 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR). Collectively, our findings imply that glucocorticoids could be exploited to limit tissue damage caused by pathogens secreting pore-forming toxins.
published_date 2023-02-17T12:06:06Z
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