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Oxysterols Protect Epithelial Cells Against Pore-Forming Toxins

Thomas J. R. Ormsby, Sian-eleri Owens Orcid Logo, Liam Clement, Tom J. Mills, James Cronin Orcid Logo, John J. Bromfield, Martin Sheldon Orcid Logo

Frontiers in Immunology, Volume: 13, Issue: 815775, Start page: 815775

Swansea University Authors: Sian-eleri Owens Orcid Logo, Liam Clement, James Cronin Orcid Logo, Martin Sheldon Orcid Logo

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DOI (Published version): 10.3389/fimmu.2022.815775

Abstract

Many species of bacteria produce toxins such as cholesterol-dependent cytolysins that form pores in cell membranes. Membrane pores facilitate infection by releasing nutrients, delivering virulence factors, and causing lytic cell damage - cytolysis. Oxysterols are oxidized forms of cholesterol that r...

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Published in: Frontiers in Immunology
ISSN: 1664-3224
Published: Frontiers Media SA 2022
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URI: https://cronfa.swan.ac.uk/Record/cronfa59255
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Membrane pores facilitate infection by releasing nutrients, delivering virulence factors, and causing lytic cell damage - cytolysis. Oxysterols are oxidized forms of cholesterol that regulate cellular cholesterol and alter immune responses to bacteria. Whether oxysterols also influence the protection of cells against pore-forming toxins is unresolved. Here we tested the hypothesis that oxysterols stimulate the intrinsic protection of epithelial cells against damage caused by cholesterol-dependent cytolysins. We treated epithelial cells with oxysterols and then challenged them with the cholesterol-dependent cytolysin, pyolysin. Treating HeLa cells with 27-hydroxycholesterol, 25-hydroxycholesterol, 7&#x3B1;-hydroxycholesterol, or 7&#x3B2;-hydroxycholesterol reduced pyolysin-induced leakage of lactate dehydrogenase and reduced pyolysin-induced cytolysis. Specifically, treatment with 10 ng/ml 27-hydroxycholesterol for 24 h reduced pyolysin-induced lactate dehydrogenase leakage by 88%, and reduced cytolysis from 74% to 1%. Treating HeLa cells with 27-hydroxycholesterol also reduced pyolysin-induced leakage of potassium ions, prevented mitogen-activated protein kinase cell stress responses, and limited alterations in the cytoskeleton. Furthermore, 27-hydroxycholesterol reduced pyolysin-induced damage in lung and liver epithelial cells, and protected against the cytolysins streptolysin O and Staphylococcus aureus &#x3B1;-hemolysin. Although oxysterols regulate cellular cholesterol by activating liver X receptors, cytoprotection did not depend on liver X receptors or changes in total cellular cholesterol. However, oxysterol cytoprotection was partially dependent on acyl-CoA:cholesterol acyltransferase (ACAT) reducing accessible cholesterol in cell membranes. 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spelling 2022-10-27T11:39:10.0731950 v2 59255 2022-01-27 Oxysterols Protect Epithelial Cells Against Pore-Forming Toxins 721deb4604d122019244cfdf08820cbe 0000-0003-1806-5235 Sian-eleri Owens Sian-eleri Owens true false fa86f6f84a36f8e3649ba144e0d81529 Liam Clement Liam Clement true false 9cfd17551c0d1f7438895121e4fbb6e8 0000-0002-0590-9462 James Cronin James Cronin true false ab0f74b794e59cc270c69e63ee1d9748 0000-0001-7902-5558 Martin Sheldon Martin Sheldon true false 2022-01-27 BMS Many species of bacteria produce toxins such as cholesterol-dependent cytolysins that form pores in cell membranes. Membrane pores facilitate infection by releasing nutrients, delivering virulence factors, and causing lytic cell damage - cytolysis. Oxysterols are oxidized forms of cholesterol that regulate cellular cholesterol and alter immune responses to bacteria. Whether oxysterols also influence the protection of cells against pore-forming toxins is unresolved. Here we tested the hypothesis that oxysterols stimulate the intrinsic protection of epithelial cells against damage caused by cholesterol-dependent cytolysins. We treated epithelial cells with oxysterols and then challenged them with the cholesterol-dependent cytolysin, pyolysin. Treating HeLa cells with 27-hydroxycholesterol, 25-hydroxycholesterol, 7α-hydroxycholesterol, or 7β-hydroxycholesterol reduced pyolysin-induced leakage of lactate dehydrogenase and reduced pyolysin-induced cytolysis. Specifically, treatment with 10 ng/ml 27-hydroxycholesterol for 24 h reduced pyolysin-induced lactate dehydrogenase leakage by 88%, and reduced cytolysis from 74% to 1%. Treating HeLa cells with 27-hydroxycholesterol also reduced pyolysin-induced leakage of potassium ions, prevented mitogen-activated protein kinase cell stress responses, and limited alterations in the cytoskeleton. Furthermore, 27-hydroxycholesterol reduced pyolysin-induced damage in lung and liver epithelial cells, and protected against the cytolysins streptolysin O and Staphylococcus aureus α-hemolysin. Although oxysterols regulate cellular cholesterol by activating liver X receptors, cytoprotection did not depend on liver X receptors or changes in total cellular cholesterol. However, oxysterol cytoprotection was partially dependent on acyl-CoA:cholesterol acyltransferase (ACAT) reducing accessible cholesterol in cell membranes. Collectively, these findings imply that oxysterols stimulate the intrinsic protection of epithelial cells against pore-forming toxins and may help protect tissues against pathogenic bacteria. Journal Article Frontiers in Immunology 13 815775 815775 Frontiers Media SA 1664-3224 oxysterol, epithelial cells, cholesterol, liver X receptor, pore-forming toxins, cholesterol-dependent cytolysin, cytoprotection 26 1 2022 2022-01-26 10.3389/fimmu.2022.815775 COLLEGE NANME Biomedical Sciences COLLEGE CODE BMS Swansea University Other This study was supported in part by the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health under Award Number R01HD084316. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. R01HD084316 2022-10-27T11:39:10.0731950 2022-01-27T11:05:07.0412327 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Thomas J. R. Ormsby 1 Sian-eleri Owens 0000-0003-1806-5235 2 Liam Clement 3 Tom J. Mills 4 James Cronin 0000-0002-0590-9462 5 John J. Bromfield 6 Martin Sheldon 0000-0001-7902-5558 7 59255__22231__9852d62588374511866d4e7dee20efc8.pdf OrmsbyFIc2022.pdf 2022-01-27T11:10:53.3091670 Output 8462766 application/pdf Version of Record true © 2022 Ormsby, Owens, Clement, Mills, Cronin, Bromfield and Sheldon. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) true eng https://creativecommons.org/licenses/by/4.0/
title Oxysterols Protect Epithelial Cells Against Pore-Forming Toxins
spellingShingle Oxysterols Protect Epithelial Cells Against Pore-Forming Toxins
Sian-eleri Owens
Liam Clement
James Cronin
Martin Sheldon
title_short Oxysterols Protect Epithelial Cells Against Pore-Forming Toxins
title_full Oxysterols Protect Epithelial Cells Against Pore-Forming Toxins
title_fullStr Oxysterols Protect Epithelial Cells Against Pore-Forming Toxins
title_full_unstemmed Oxysterols Protect Epithelial Cells Against Pore-Forming Toxins
title_sort Oxysterols Protect Epithelial Cells Against Pore-Forming Toxins
author_id_str_mv 721deb4604d122019244cfdf08820cbe
fa86f6f84a36f8e3649ba144e0d81529
9cfd17551c0d1f7438895121e4fbb6e8
ab0f74b794e59cc270c69e63ee1d9748
author_id_fullname_str_mv 721deb4604d122019244cfdf08820cbe_***_Sian-eleri Owens
fa86f6f84a36f8e3649ba144e0d81529_***_Liam Clement
9cfd17551c0d1f7438895121e4fbb6e8_***_James Cronin
ab0f74b794e59cc270c69e63ee1d9748_***_Martin Sheldon
author Sian-eleri Owens
Liam Clement
James Cronin
Martin Sheldon
author2 Thomas J. R. Ormsby
Sian-eleri Owens
Liam Clement
Tom J. Mills
James Cronin
John J. Bromfield
Martin Sheldon
format Journal article
container_title Frontiers in Immunology
container_volume 13
container_issue 815775
container_start_page 815775
publishDate 2022
institution Swansea University
issn 1664-3224
doi_str_mv 10.3389/fimmu.2022.815775
publisher Frontiers Media SA
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
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 - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
document_store_str 1
active_str 0
description Many species of bacteria produce toxins such as cholesterol-dependent cytolysins that form pores in cell membranes. Membrane pores facilitate infection by releasing nutrients, delivering virulence factors, and causing lytic cell damage - cytolysis. Oxysterols are oxidized forms of cholesterol that regulate cellular cholesterol and alter immune responses to bacteria. Whether oxysterols also influence the protection of cells against pore-forming toxins is unresolved. Here we tested the hypothesis that oxysterols stimulate the intrinsic protection of epithelial cells against damage caused by cholesterol-dependent cytolysins. We treated epithelial cells with oxysterols and then challenged them with the cholesterol-dependent cytolysin, pyolysin. Treating HeLa cells with 27-hydroxycholesterol, 25-hydroxycholesterol, 7α-hydroxycholesterol, or 7β-hydroxycholesterol reduced pyolysin-induced leakage of lactate dehydrogenase and reduced pyolysin-induced cytolysis. Specifically, treatment with 10 ng/ml 27-hydroxycholesterol for 24 h reduced pyolysin-induced lactate dehydrogenase leakage by 88%, and reduced cytolysis from 74% to 1%. Treating HeLa cells with 27-hydroxycholesterol also reduced pyolysin-induced leakage of potassium ions, prevented mitogen-activated protein kinase cell stress responses, and limited alterations in the cytoskeleton. Furthermore, 27-hydroxycholesterol reduced pyolysin-induced damage in lung and liver epithelial cells, and protected against the cytolysins streptolysin O and Staphylococcus aureus α-hemolysin. Although oxysterols regulate cellular cholesterol by activating liver X receptors, cytoprotection did not depend on liver X receptors or changes in total cellular cholesterol. However, oxysterol cytoprotection was partially dependent on acyl-CoA:cholesterol acyltransferase (ACAT) reducing accessible cholesterol in cell membranes. Collectively, these findings imply that oxysterols stimulate the intrinsic protection of epithelial cells against pore-forming toxins and may help protect tissues against pathogenic bacteria.
published_date 2022-01-26T04:16:25Z
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