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Manipulating bovine granulosa cell energy metabolism limits inflammation

Anthony Horlock Orcid Logo, Anthony D Horlock, Thomas Ormsby, Martin Clift Orcid Logo, José E P Santos, John J Bromfield, Martin Sheldon Orcid Logo

Reproduction, Volume: 161, Issue: 5, Pages: 499 - 512

Swansea University Authors: Anthony Horlock Orcid Logo, Thomas Ormsby, Martin Clift Orcid Logo, Martin Sheldon Orcid Logo

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DOI (Published version): 10.1530/rep-20-0554

Abstract

Bovine granulosa cells are often exposed to energy stress, due to the energy demands of lactation, and exposed to lipopolysaccharide from postpartum bacterial infections. Granulosa cells mount innate immune responses to lipopolysaccharide, including the phosphorylation of mitogen-activated protein k...

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Published in: Reproduction
ISSN: 1470-1626 1741-7899
Published: Bioscientifica 2021
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URI: https://cronfa.swan.ac.uk/Record/cronfa56383
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Granulosa cells mount innate immune responses to lipopolysaccharide, including the phosphorylation of mitogen-activated protein kinases and production of pro-inflammatory interleukins. Cellular energy depends on glycolysis, and energy stress activates intracellular AMPK (AMP-activated protein kinase), which in turn inhibits mTOR (mechanistic target of rapamycin). Here, we tested the hypothesis that manipulating glycolysis, AMPK or mTOR to mimic energy stress in bovine granulosa cells limits the inflammatory responses to lipopolysaccharide. We inhibited glycolysis, activated AMPK or inhibited mTOR in granulosa cells isolated from 4&#x2013;8 mm and &gt; 8.5 mm diameter ovarian follicles, and then challenged the cells with lipopolysaccharide and measured the production of interleukins IL-1&#x3B1;, IL-1&#x3B2;, and IL-8. We found that inhibiting glycolysis with 2-deoxy-D-glucose reduced lipopolysaccharide-stimulated IL-1&#x3B1; &gt; 80%, IL-1&#x3B2; &gt; 90%, and IL-8 &gt; 65% in granulosa cells from 4&#x2013;8 mm and &gt; 8.5 mm diameter ovarian follicles. Activating AMPK with AICAR also reduced lipopolysaccharide-stimulated IL-1&#x3B1; &gt; 60%, IL-1&#x3B2; &gt; 75%, and IL-8 &gt; 20%, and shortened the duration of lipopolysaccharide-stimulated phosphorylation of the mitogen-activated protein kinase ERK1/2 and JNK. However, only the mTOR inhibitor Torin 1, and not rapamycin, reduced lipopolysaccharide-stimulated IL-1&#x3B1; and IL-1&#x3B2;. In conclusion, manipulating granulosa cell energy metabolism with a glycolysis inhibitor, an AMPK activator, or an mTOR inhibitor, limited inflammatory responses to lipopolysaccharide. Our findings imply that energy stress compromises ovarian follicle immune defences.</abstract><type>Journal Article</type><journal>Reproduction</journal><volume>161</volume><journalNumber>5</journalNumber><paginationStart>499</paginationStart><paginationEnd>512</paginationEnd><publisher>Bioscientifica</publisher><placeOfPublication/><isbnPrint/><isbnElectronic/><issnPrint>1470-1626</issnPrint><issnElectronic>1741-7899</issnElectronic><keywords>Ovary, Innate immunity, Lipopolysaccharide, AMPK, mTOR, Cattle</keywords><publishedDay>1</publishedDay><publishedMonth>5</publishedMonth><publishedYear>2021</publishedYear><publishedDate>2021-05-01</publishedDate><doi>10.1530/rep-20-0554</doi><url/><notes/><college>COLLEGE NANME</college><department>Biomedical Sciences</department><CollegeCode>COLLEGE CODE</CollegeCode><DepartmentCode>BMS</DepartmentCode><institution>Swansea University</institution><apcterm/><funders>NIH</funders><lastEdited>2021-06-09T16:37:27.9889785</lastEdited><Created>2021-03-08T20:22:06.7108990</Created><path><level id="1">Faculty of Medicine, Health and Life Sciences</level><level id="2">Swansea University Medical School - Medicine</level></path><authors><author><firstname>Anthony</firstname><surname>Horlock</surname><orcid>0000-0001-9580-552X</orcid><order>1</order></author><author><firstname>Anthony D</firstname><surname>Horlock</surname><order>2</order></author><author><firstname>Thomas</firstname><surname>Ormsby</surname><order>3</order></author><author><firstname>Martin</firstname><surname>Clift</surname><orcid>0000-0001-6133-3368</orcid><order>4</order></author><author><firstname>Jos&#xE9; E P</firstname><surname>Santos</surname><order>5</order></author><author><firstname>John J</firstname><surname>Bromfield</surname><order>6</order></author><author><firstname>Martin</firstname><surname>Sheldon</surname><orcid>0000-0001-7902-5558</orcid><order>7</order></author></authors><documents><document><filename>56383__19448__7475c01704014e1a98f5e9a086465d6d.pdf</filename><originalFilename>Horlock manuscript deposit.pdf</originalFilename><uploaded>2021-03-08T20:27:27.1305848</uploaded><type>Output</type><contentLength>1405820</contentLength><contentType>application/pdf</contentType><version>Accepted Manuscript</version><cronfaStatus>true</cronfaStatus><embargoDate>2021-03-01T00:00:00.0000000</embargoDate><copyrightCorrect>true</copyrightCorrect><language>eng</language></document></documents><OutputDurs/></rfc1807>
spelling 2021-06-09T16:37:27.9889785 v2 56383 2021-03-08 Manipulating bovine granulosa cell energy metabolism limits inflammation 4191b316c42c893bec2cada92597ad44 0000-0001-9580-552X Anthony Horlock Anthony Horlock true false c8a0f774d8ff66a2193a035018cc6cda Thomas Ormsby Thomas Ormsby true false 71bf49b157691e541950f5c3f49c9169 0000-0001-6133-3368 Martin Clift Martin Clift true false ab0f74b794e59cc270c69e63ee1d9748 0000-0001-7902-5558 Martin Sheldon Martin Sheldon true false 2021-03-08 BMS Bovine granulosa cells are often exposed to energy stress, due to the energy demands of lactation, and exposed to lipopolysaccharide from postpartum bacterial infections. Granulosa cells mount innate immune responses to lipopolysaccharide, including the phosphorylation of mitogen-activated protein kinases and production of pro-inflammatory interleukins. Cellular energy depends on glycolysis, and energy stress activates intracellular AMPK (AMP-activated protein kinase), which in turn inhibits mTOR (mechanistic target of rapamycin). Here, we tested the hypothesis that manipulating glycolysis, AMPK or mTOR to mimic energy stress in bovine granulosa cells limits the inflammatory responses to lipopolysaccharide. We inhibited glycolysis, activated AMPK or inhibited mTOR in granulosa cells isolated from 4–8 mm and > 8.5 mm diameter ovarian follicles, and then challenged the cells with lipopolysaccharide and measured the production of interleukins IL-1α, IL-1β, and IL-8. We found that inhibiting glycolysis with 2-deoxy-D-glucose reduced lipopolysaccharide-stimulated IL-1α > 80%, IL-1β > 90%, and IL-8 > 65% in granulosa cells from 4–8 mm and > 8.5 mm diameter ovarian follicles. Activating AMPK with AICAR also reduced lipopolysaccharide-stimulated IL-1α > 60%, IL-1β > 75%, and IL-8 > 20%, and shortened the duration of lipopolysaccharide-stimulated phosphorylation of the mitogen-activated protein kinase ERK1/2 and JNK. However, only the mTOR inhibitor Torin 1, and not rapamycin, reduced lipopolysaccharide-stimulated IL-1α and IL-1β. In conclusion, manipulating granulosa cell energy metabolism with a glycolysis inhibitor, an AMPK activator, or an mTOR inhibitor, limited inflammatory responses to lipopolysaccharide. Our findings imply that energy stress compromises ovarian follicle immune defences. Journal Article Reproduction 161 5 499 512 Bioscientifica 1470-1626 1741-7899 Ovary, Innate immunity, Lipopolysaccharide, AMPK, mTOR, Cattle 1 5 2021 2021-05-01 10.1530/rep-20-0554 COLLEGE NANME Biomedical Sciences COLLEGE CODE BMS Swansea University NIH 2021-06-09T16:37:27.9889785 2021-03-08T20:22:06.7108990 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Anthony Horlock 0000-0001-9580-552X 1 Anthony D Horlock 2 Thomas Ormsby 3 Martin Clift 0000-0001-6133-3368 4 José E P Santos 5 John J Bromfield 6 Martin Sheldon 0000-0001-7902-5558 7 56383__19448__7475c01704014e1a98f5e9a086465d6d.pdf Horlock manuscript deposit.pdf 2021-03-08T20:27:27.1305848 Output 1405820 application/pdf Accepted Manuscript true 2021-03-01T00:00:00.0000000 true eng
title Manipulating bovine granulosa cell energy metabolism limits inflammation
spellingShingle Manipulating bovine granulosa cell energy metabolism limits inflammation
Anthony Horlock
Thomas Ormsby
Martin Clift
Martin Sheldon
title_short Manipulating bovine granulosa cell energy metabolism limits inflammation
title_full Manipulating bovine granulosa cell energy metabolism limits inflammation
title_fullStr Manipulating bovine granulosa cell energy metabolism limits inflammation
title_full_unstemmed Manipulating bovine granulosa cell energy metabolism limits inflammation
title_sort Manipulating bovine granulosa cell energy metabolism limits inflammation
author_id_str_mv 4191b316c42c893bec2cada92597ad44
c8a0f774d8ff66a2193a035018cc6cda
71bf49b157691e541950f5c3f49c9169
ab0f74b794e59cc270c69e63ee1d9748
author_id_fullname_str_mv 4191b316c42c893bec2cada92597ad44_***_Anthony Horlock
c8a0f774d8ff66a2193a035018cc6cda_***_Thomas Ormsby
71bf49b157691e541950f5c3f49c9169_***_Martin Clift
ab0f74b794e59cc270c69e63ee1d9748_***_Martin Sheldon
author Anthony Horlock
Thomas Ormsby
Martin Clift
Martin Sheldon
author2 Anthony Horlock
Anthony D Horlock
Thomas Ormsby
Martin Clift
José E P Santos
John J Bromfield
Martin Sheldon
format Journal article
container_title Reproduction
container_volume 161
container_issue 5
container_start_page 499
publishDate 2021
institution Swansea University
issn 1470-1626
1741-7899
doi_str_mv 10.1530/rep-20-0554
publisher Bioscientifica
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 Bovine granulosa cells are often exposed to energy stress, due to the energy demands of lactation, and exposed to lipopolysaccharide from postpartum bacterial infections. Granulosa cells mount innate immune responses to lipopolysaccharide, including the phosphorylation of mitogen-activated protein kinases and production of pro-inflammatory interleukins. Cellular energy depends on glycolysis, and energy stress activates intracellular AMPK (AMP-activated protein kinase), which in turn inhibits mTOR (mechanistic target of rapamycin). Here, we tested the hypothesis that manipulating glycolysis, AMPK or mTOR to mimic energy stress in bovine granulosa cells limits the inflammatory responses to lipopolysaccharide. We inhibited glycolysis, activated AMPK or inhibited mTOR in granulosa cells isolated from 4–8 mm and > 8.5 mm diameter ovarian follicles, and then challenged the cells with lipopolysaccharide and measured the production of interleukins IL-1α, IL-1β, and IL-8. We found that inhibiting glycolysis with 2-deoxy-D-glucose reduced lipopolysaccharide-stimulated IL-1α > 80%, IL-1β > 90%, and IL-8 > 65% in granulosa cells from 4–8 mm and > 8.5 mm diameter ovarian follicles. Activating AMPK with AICAR also reduced lipopolysaccharide-stimulated IL-1α > 60%, IL-1β > 75%, and IL-8 > 20%, and shortened the duration of lipopolysaccharide-stimulated phosphorylation of the mitogen-activated protein kinase ERK1/2 and JNK. However, only the mTOR inhibitor Torin 1, and not rapamycin, reduced lipopolysaccharide-stimulated IL-1α and IL-1β. In conclusion, manipulating granulosa cell energy metabolism with a glycolysis inhibitor, an AMPK activator, or an mTOR inhibitor, limited inflammatory responses to lipopolysaccharide. Our findings imply that energy stress compromises ovarian follicle immune defences.
published_date 2021-05-01T04:11:18Z
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score 11.016593

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