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Mevalonate Biosynthesis Intermediates Are Key Regulators of Innate Immunity in Bovine Endometritis

Gareth Healey Orcid Logo, Christine Collier, Sholeem Griffin, Hans-Joachim Schuberth, Olivier Sandra, David G. Smith, Suman Mahan, Isabelle Dieuzy-Labaye, Martin Sheldon

The Journal of Immunology, Volume: 196, Issue: 2, Pages: 823 - 831

Swansea University Authors: Gareth Healey Orcid Logo, Martin Sheldon

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DOI (Published version): 10.4049/jimmunol.1501080

Abstract

Metabolic changes can influence inflammatory responses to bacteria. To examine whether localized manipulation of the mevalonate pathway impacts innate immunity, we exploited a unique mucosal disease model, endometritis, where inflammation is a consequence of innate immunity. IL responses to pathogen...

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Published in: The Journal of Immunology
ISSN: 0022-1767 1550-6606
Published: 2016
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URI: https://cronfa.swan.ac.uk/Record/cronfa25016
first_indexed 2015-12-11T01:56:24Z
last_indexed 2020-05-22T18:35:38Z
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To examine whether localized manipulation of the mevalonate pathway impacts innate immunity, we exploited a unique mucosal disease model, endometritis, where inflammation is a consequence of innate immunity. IL responses to pathogenic bacteria and LPS were modulated in bovine endometrial cell and organ cultures by small molecules that target the mevalonate pathway. Treatment with multiple statins, bisphosphonates, squalene synthase inhibitors, and small interfering RNA showed that inhibition of farnesyl-diphosphate farnesyl transferase (squalene synthase), but not 3-hydroxy-3-methylglutaryl-CoA reductase or farnesyl diphosphate synthase, reduced endometrial organ and cellular inflammatory responses to pathogenic bacteria and LPS. Although manipulation of the mevalonate pathway reduced cellular cholesterol, impacts on inflammation were independent of cholesterol concentration as cholesterol depletion using cyclodextrins did not alter inflammatory responses. Treatment with the isoprenoid mevalonate pathway-intermediates, farnesyl diphosphate and geranylgeranyl diphosphate, also reduced endometrial cellular inflammatory responses to LPS. These data imply that manipulating the mevalonate pathway regulates innate immunity within the endometrium, and that isoprenoids are regulatory molecules in this process, knowledge that could be exploited for novel therapeutic strategies.</abstract><type>Journal Article</type><journal>The Journal of Immunology</journal><volume>196</volume><journalNumber>2</journalNumber><paginationStart>823</paginationStart><paginationEnd>831</paginationEnd><publisher/><issnPrint>0022-1767</issnPrint><issnElectronic>1550-6606</issnElectronic><keywords/><publishedDay>15</publishedDay><publishedMonth>1</publishedMonth><publishedYear>2016</publishedYear><publishedDate>2016-01-15</publishedDate><doi>10.4049/jimmunol.1501080</doi><url/><notes>This work was funded by Sheldon's grant "iPUD" from Biotechnology and Biological Sciences Research Council, Grant BB/1017240/1. 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spelling 2020-05-22T16:08:33.8519868 v2 25016 2015-12-10 Mevalonate Biosynthesis Intermediates Are Key Regulators of Innate Immunity in Bovine Endometritis 5926519f89187489cfd5e1478aa188b1 0000-0001-9531-1220 Gareth Healey Gareth Healey true false ab0f74b794e59cc270c69e63ee1d9748 Martin Sheldon Martin Sheldon true false 2015-12-10 MEDS Metabolic changes can influence inflammatory responses to bacteria. To examine whether localized manipulation of the mevalonate pathway impacts innate immunity, we exploited a unique mucosal disease model, endometritis, where inflammation is a consequence of innate immunity. IL responses to pathogenic bacteria and LPS were modulated in bovine endometrial cell and organ cultures by small molecules that target the mevalonate pathway. Treatment with multiple statins, bisphosphonates, squalene synthase inhibitors, and small interfering RNA showed that inhibition of farnesyl-diphosphate farnesyl transferase (squalene synthase), but not 3-hydroxy-3-methylglutaryl-CoA reductase or farnesyl diphosphate synthase, reduced endometrial organ and cellular inflammatory responses to pathogenic bacteria and LPS. Although manipulation of the mevalonate pathway reduced cellular cholesterol, impacts on inflammation were independent of cholesterol concentration as cholesterol depletion using cyclodextrins did not alter inflammatory responses. Treatment with the isoprenoid mevalonate pathway-intermediates, farnesyl diphosphate and geranylgeranyl diphosphate, also reduced endometrial cellular inflammatory responses to LPS. These data imply that manipulating the mevalonate pathway regulates innate immunity within the endometrium, and that isoprenoids are regulatory molecules in this process, knowledge that could be exploited for novel therapeutic strategies. Journal Article The Journal of Immunology 196 2 823 831 0022-1767 1550-6606 15 1 2016 2016-01-15 10.4049/jimmunol.1501080 This work was funded by Sheldon's grant "iPUD" from Biotechnology and Biological Sciences Research Council, Grant BB/1017240/1. Gareth Healey was a postdoctoral assistant working for Sheldon, and funded by Sheldon's BBSRC grant. COLLEGE NANME Medical School COLLEGE CODE MEDS Swansea University BBSRC 2020-05-22T16:08:33.8519868 2015-12-10T17:50:42.7020440 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Gareth Healey 0000-0001-9531-1220 1 Christine Collier 2 Sholeem Griffin 3 Hans-Joachim Schuberth 4 Olivier Sandra 5 David G. Smith 6 Suman Mahan 7 Isabelle Dieuzy-Labaye 8 Martin Sheldon 9 0025016-22012016142614.pdf HealeyJI2016v4.pdf 2016-01-22T14:26:14.8570000 Output 2213901 application/pdf Version of Record true 2016-01-16T00:00:00.0000000 true 0025016-10122015180116.pdf HealeyEuropePMCversion.pdf 2015-12-10T18:01:16.3170000 Output 4833574 application/pdf Accepted Manuscript true 2015-12-16T00:00:00.0000000 true
title Mevalonate Biosynthesis Intermediates Are Key Regulators of Innate Immunity in Bovine Endometritis
spellingShingle Mevalonate Biosynthesis Intermediates Are Key Regulators of Innate Immunity in Bovine Endometritis
Gareth Healey
Martin Sheldon
title_short Mevalonate Biosynthesis Intermediates Are Key Regulators of Innate Immunity in Bovine Endometritis
title_full Mevalonate Biosynthesis Intermediates Are Key Regulators of Innate Immunity in Bovine Endometritis
title_fullStr Mevalonate Biosynthesis Intermediates Are Key Regulators of Innate Immunity in Bovine Endometritis
title_full_unstemmed Mevalonate Biosynthesis Intermediates Are Key Regulators of Innate Immunity in Bovine Endometritis
title_sort Mevalonate Biosynthesis Intermediates Are Key Regulators of Innate Immunity in Bovine Endometritis
author_id_str_mv 5926519f89187489cfd5e1478aa188b1
ab0f74b794e59cc270c69e63ee1d9748
author_id_fullname_str_mv 5926519f89187489cfd5e1478aa188b1_***_Gareth Healey
ab0f74b794e59cc270c69e63ee1d9748_***_Martin Sheldon
author Gareth Healey
Martin Sheldon
author2 Gareth Healey
Christine Collier
Sholeem Griffin
Hans-Joachim Schuberth
Olivier Sandra
David G. Smith
Suman Mahan
Isabelle Dieuzy-Labaye
Martin Sheldon
format Journal article
container_title The Journal of Immunology
container_volume 196
container_issue 2
container_start_page 823
publishDate 2016
institution Swansea University
issn 0022-1767
1550-6606
doi_str_mv 10.4049/jimmunol.1501080
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 - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
document_store_str 1
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description Metabolic changes can influence inflammatory responses to bacteria. To examine whether localized manipulation of the mevalonate pathway impacts innate immunity, we exploited a unique mucosal disease model, endometritis, where inflammation is a consequence of innate immunity. IL responses to pathogenic bacteria and LPS were modulated in bovine endometrial cell and organ cultures by small molecules that target the mevalonate pathway. Treatment with multiple statins, bisphosphonates, squalene synthase inhibitors, and small interfering RNA showed that inhibition of farnesyl-diphosphate farnesyl transferase (squalene synthase), but not 3-hydroxy-3-methylglutaryl-CoA reductase or farnesyl diphosphate synthase, reduced endometrial organ and cellular inflammatory responses to pathogenic bacteria and LPS. Although manipulation of the mevalonate pathway reduced cellular cholesterol, impacts on inflammation were independent of cholesterol concentration as cholesterol depletion using cyclodextrins did not alter inflammatory responses. Treatment with the isoprenoid mevalonate pathway-intermediates, farnesyl diphosphate and geranylgeranyl diphosphate, also reduced endometrial cellular inflammatory responses to LPS. These data imply that manipulating the mevalonate pathway regulates innate immunity within the endometrium, and that isoprenoids are regulatory molecules in this process, knowledge that could be exploited for novel therapeutic strategies.
published_date 2016-01-15T12:53:17Z
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