DataSheet_1_Oxysterols Protect Epithelial Cells Against Pore-Forming Toxins.pdf
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.
History
References
- https://doi.org//10.1128/MMBR.00052-12
- https://doi.org//10.1038/nrmicro.2015.3
- https://doi.org//10.1128/IAI.73.10.6199-6209.2005
- https://doi.org//10.1073/pnas.1309273110
- https://doi.org//10.7554/eLife.02882
- https://doi.org//10.1021/bi5000096
- https://doi.org//10.1111/bph.15073
- https://doi.org//10.1126/science.1254790
- https://doi.org//10.1016/j.cell.2017.09.029
- https://doi.org//10.1038/s41564-020-0701-5
- https://doi.org//10.1126/science.1214935
- https://doi.org//10.1073/pnas.0404073101
- https://doi.org//10.1038/cdd.2009.30
- https://doi.org//10.1111/j.1462-5822.2011.01600.x
- https://doi.org//10.1093/infdis/jir434
- https://doi.org//10.1016/j.cub.2017.12.034
- https://doi.org//10.1371/journal.pone.0219275
- https://doi.org//10.1096/fj.202100164R
- https://doi.org//10.1128/jb.179.19.6100-6106.1997
- https://doi.org//10.1007/s10482-005-2316-5
- https://doi.org//10.1095/biolreprod.113.115972
- https://doi.org//10.1016/j.bbamem.2016.05.016
- https://doi.org//10.1073/pnas.2033520100
- https://doi.org//10.1096/fj.14-265207
- https://doi.org//10.1016/j.cell.2018.12.042
- https://doi.org//10.3389/fphys.2021.723224
- https://doi.org//10.1038/nri3755
- https://doi.org//10.1038/s41590-020-0695-4
- https://doi.org//10.1096/fj.202100036R
- https://doi.org//10.1093/biolre/ioy099
- https://doi.org//10.1371/journal.ppat.1002664
- https://doi.org//10.1101/gad.850400
- https://doi.org//10.1016/j.cell.2006.07.033
- https://doi.org//10.1038/s41598-017-17138-y
- https://doi.org//10.1016/S0021-9258%2817%2943530-7
- https://doi.org//10.1373/clinchem.2008.112797
- https://doi.org//10.1210/en.2011-1124
- https://doi.org//10.1038/nmeth.2019
- https://doi.org//10.1126/science.3513311
- https://doi.org//10.1093/emboj/16.18.5592
- https://doi.org//10.1006/abio.1995.1110
- https://doi.org//10.1074/jbc.M511431200
- https://doi.org//10.1165/rcmb.2014-0391OC
- https://doi.org//10.1128/iai.47.1.52-60.1985
- https://doi.org//10.1242/jcs.076182
- https://doi.org//10.1126/science.274.5294.1859
- https://doi.org//10.1016/j.semcdb.2017.04.003
- https://doi.org//10.1007/s10565-008-9063-0
- https://doi.org//10.1038/s41574-018-0037-x
- https://doi.org//10.1074/jbc.M105805200
- https://doi.org//10.1074/jbc.M706967200
- https://doi.org//10.1152/ajpendo.90926.2008
- https://doi.org//10.15252/embj.2020106057
- https://doi.org//10.1016/j.ceb.2009.04.003
- https://doi.org//10.1074/jbc.272.6.3137
- https://doi.org//10.1210/me.2007-0383
- https://doi.org//10.1158/1078-0432.Ccr-07-1950
- https://doi.org//10.1128/IAI.61.12.4972-4979.1993
- https://doi.org//10.1007/s00018-018-2992-8
Usage metrics
Read the peer-reviewed publication
Categories
- Transplantation Immunology
- Tumour Immunology
- Immunology not elsewhere classified
- Immunology
- Veterinary Immunology
- Animal Immunology
- Genetic Immunology
- Applied Immunology (incl. Antibody Engineering, Xenotransplantation and T-cell Therapies)
- Autoimmunity
- Cellular Immunology
- Humoural Immunology and Immunochemistry
- Immunogenetics (incl. Genetic Immunology)
- Innate Immunity