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Glucose Availability and AMP-Activated Protein Kinase Link Energy Metabolism and Innate Immunity in the Bovine Endometrium

Matthew Turner Orcid Logo, James Cronin Orcid Logo, Pablo G. Noleto, I. Martin Sheldon, Martin Sheldon Orcid Logo

PLOS ONE, Volume: 11, Issue: 3, Start page: e0151416

Swansea University Authors: Matthew Turner Orcid Logo, James Cronin Orcid Logo, Martin Sheldon Orcid Logo

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Abstract

Defences against the bacteria that usually infect the endometrium of postpartum cattle are impaired when there is metabolic energy stress, leading to endometritis and infertility. The endometrial response to bacteria depends on innate immunity, with recognition of pathogen-associated molecular patte...

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Published in: PLOS ONE
ISSN: 1932-6203
Published: 2016
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The endometrial response to bacteria depends on innate immunity, with recognition of pathogen-associated molecular patterns stimulating inflammation, characterised by secretion of interleukin (IL)-1&#x3B2;, IL-6 and IL-8. How metabolic stress impacts tissue responses to pathogens is unclear, but integration of energy metabolism and innate immunity means that stressing one system might affect the other. Here we tested the hypothesis that homeostatic pathways integrate energy metabolism and innate immunity in bovine endometrial tissue. Glucose deprivation reduced the secretion of IL-1&#x3B2;, IL-6 and IL-8 from ex vivo organ cultures of bovine endometrium challenged with the pathogen-associated molecular patterns lipopolysaccharide and bacterial lipopeptide. Endometrial inflammatory responses to lipopolysaccharide were also reduced by small molecules that activate or inhibit the intracellular sensor of energy, AMP-activated protein kinase (AMPK). However, inhibition of mammalian target of rapamycin, which is a more global metabolic sensor than AMPK, had little effect on inflammation. Similarly, endometrial inflammatory responses to lipopolysaccharide were not affected by insulin-like growth factor-1, which is an endocrine regulator of metabolism. Interestingly, the inflammatory responses to lipopolysaccharide increased endometrial glucose consumption and induced the Warburg effect, which could exacerbate deficits in glucose availability in the tissue. In conclusion, metabolic energy stress perturbed inflammatory responses to pathogen-associated molecular patterns in bovine endometrial tissue, and the most fundamental regulators of cellular energy, glucose availability and AMPK, had the greatest impact on innate immunity.</abstract><type>Journal Article</type><journal>PLOS ONE</journal><volume>11</volume><journalNumber>3</journalNumber><paginationStart>e0151416</paginationStart><publisher/><issnElectronic>1932-6203</issnElectronic><keywords/><publishedDay>14</publishedDay><publishedMonth>3</publishedMonth><publishedYear>2016</publishedYear><publishedDate>2016-03-14</publishedDate><doi>10.1371/journal.pone.0151416</doi><url/><notes>Doctoral training for MLT was funded by the Biotechnology and Biological Sciences Research Council (BB/F017596/1) under the direction of Sheldon, and the work was supported in part by a project grant to Sheldon funded by the Biotechnology and Biological Sciences Research Council (BB/I017240/1).</notes><college>COLLEGE NANME</college><department>Medicine</department><CollegeCode>COLLEGE CODE</CollegeCode><DepartmentCode>PMSC</DepartmentCode><institution>Swansea University</institution><degreesponsorsfunders>BBSRC</degreesponsorsfunders><apcterm/><lastEdited>2019-08-15T16:05:46.8352894</lastEdited><Created>2016-03-14T20:25:17.2883170</Created><path><level id="1">Swansea University Medical School</level><level id="2">Medicine</level></path><authors><author><firstname>Matthew</firstname><surname>Turner</surname><orcid>0000-0002-1369-4051</orcid><order>1</order></author><author><firstname>James</firstname><surname>Cronin</surname><orcid>0000-0002-0590-9462</orcid><order>2</order></author><author><firstname>Pablo G.</firstname><surname>Noleto</surname><order>3</order></author><author><firstname>I. 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spelling 2019-08-15T16:05:46.8352894 v2 26753 2016-03-14 Glucose Availability and AMP-Activated Protein Kinase Link Energy Metabolism and Innate Immunity in the Bovine Endometrium d6ee69e43774ed1124d27923140b1e0b 0000-0002-1369-4051 Matthew Turner Matthew Turner true false 9cfd17551c0d1f7438895121e4fbb6e8 0000-0002-0590-9462 James Cronin James Cronin true false ab0f74b794e59cc270c69e63ee1d9748 0000-0001-7902-5558 Martin Sheldon Martin Sheldon true false 2016-03-14 PMSC Defences against the bacteria that usually infect the endometrium of postpartum cattle are impaired when there is metabolic energy stress, leading to endometritis and infertility. The endometrial response to bacteria depends on innate immunity, with recognition of pathogen-associated molecular patterns stimulating inflammation, characterised by secretion of interleukin (IL)-1β, IL-6 and IL-8. How metabolic stress impacts tissue responses to pathogens is unclear, but integration of energy metabolism and innate immunity means that stressing one system might affect the other. Here we tested the hypothesis that homeostatic pathways integrate energy metabolism and innate immunity in bovine endometrial tissue. Glucose deprivation reduced the secretion of IL-1β, IL-6 and IL-8 from ex vivo organ cultures of bovine endometrium challenged with the pathogen-associated molecular patterns lipopolysaccharide and bacterial lipopeptide. Endometrial inflammatory responses to lipopolysaccharide were also reduced by small molecules that activate or inhibit the intracellular sensor of energy, AMP-activated protein kinase (AMPK). However, inhibition of mammalian target of rapamycin, which is a more global metabolic sensor than AMPK, had little effect on inflammation. Similarly, endometrial inflammatory responses to lipopolysaccharide were not affected by insulin-like growth factor-1, which is an endocrine regulator of metabolism. Interestingly, the inflammatory responses to lipopolysaccharide increased endometrial glucose consumption and induced the Warburg effect, which could exacerbate deficits in glucose availability in the tissue. In conclusion, metabolic energy stress perturbed inflammatory responses to pathogen-associated molecular patterns in bovine endometrial tissue, and the most fundamental regulators of cellular energy, glucose availability and AMPK, had the greatest impact on innate immunity. Journal Article PLOS ONE 11 3 e0151416 1932-6203 14 3 2016 2016-03-14 10.1371/journal.pone.0151416 Doctoral training for MLT was funded by the Biotechnology and Biological Sciences Research Council (BB/F017596/1) under the direction of Sheldon, and the work was supported in part by a project grant to Sheldon funded by the Biotechnology and Biological Sciences Research Council (BB/I017240/1). COLLEGE NANME Medicine COLLEGE CODE PMSC Swansea University BBSRC 2019-08-15T16:05:46.8352894 2016-03-14T20:25:17.2883170 Swansea University Medical School Medicine Matthew Turner 0000-0002-1369-4051 1 James Cronin 0000-0002-0590-9462 2 Pablo G. Noleto 3 I. Martin Sheldon 4 Martin Sheldon 0000-0001-7902-5558 5 0026753-15082019160438.PDF 26753.PDF 2019-08-15T16:04:38.8870000 Output 2065534 application/pdf Version of Record true 2019-08-14T00:00:00.0000000 Released under the terms of a Creative Commons Attribution License (CC-BY). true eng
title Glucose Availability and AMP-Activated Protein Kinase Link Energy Metabolism and Innate Immunity in the Bovine Endometrium
spellingShingle Glucose Availability and AMP-Activated Protein Kinase Link Energy Metabolism and Innate Immunity in the Bovine Endometrium
Matthew Turner
James Cronin
Martin Sheldon
title_short Glucose Availability and AMP-Activated Protein Kinase Link Energy Metabolism and Innate Immunity in the Bovine Endometrium
title_full Glucose Availability and AMP-Activated Protein Kinase Link Energy Metabolism and Innate Immunity in the Bovine Endometrium
title_fullStr Glucose Availability and AMP-Activated Protein Kinase Link Energy Metabolism and Innate Immunity in the Bovine Endometrium
title_full_unstemmed Glucose Availability and AMP-Activated Protein Kinase Link Energy Metabolism and Innate Immunity in the Bovine Endometrium
title_sort Glucose Availability and AMP-Activated Protein Kinase Link Energy Metabolism and Innate Immunity in the Bovine Endometrium
author_id_str_mv d6ee69e43774ed1124d27923140b1e0b
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author_id_fullname_str_mv d6ee69e43774ed1124d27923140b1e0b_***_Matthew Turner
9cfd17551c0d1f7438895121e4fbb6e8_***_James Cronin
ab0f74b794e59cc270c69e63ee1d9748_***_Martin Sheldon
author Matthew Turner
James Cronin
Martin Sheldon
author2 Matthew Turner
James Cronin
Pablo G. Noleto
I. Martin Sheldon
Martin Sheldon
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description Defences against the bacteria that usually infect the endometrium of postpartum cattle are impaired when there is metabolic energy stress, leading to endometritis and infertility. The endometrial response to bacteria depends on innate immunity, with recognition of pathogen-associated molecular patterns stimulating inflammation, characterised by secretion of interleukin (IL)-1β, IL-6 and IL-8. How metabolic stress impacts tissue responses to pathogens is unclear, but integration of energy metabolism and innate immunity means that stressing one system might affect the other. Here we tested the hypothesis that homeostatic pathways integrate energy metabolism and innate immunity in bovine endometrial tissue. Glucose deprivation reduced the secretion of IL-1β, IL-6 and IL-8 from ex vivo organ cultures of bovine endometrium challenged with the pathogen-associated molecular patterns lipopolysaccharide and bacterial lipopeptide. Endometrial inflammatory responses to lipopolysaccharide were also reduced by small molecules that activate or inhibit the intracellular sensor of energy, AMP-activated protein kinase (AMPK). However, inhibition of mammalian target of rapamycin, which is a more global metabolic sensor than AMPK, had little effect on inflammation. Similarly, endometrial inflammatory responses to lipopolysaccharide were not affected by insulin-like growth factor-1, which is an endocrine regulator of metabolism. Interestingly, the inflammatory responses to lipopolysaccharide increased endometrial glucose consumption and induced the Warburg effect, which could exacerbate deficits in glucose availability in the tissue. In conclusion, metabolic energy stress perturbed inflammatory responses to pathogen-associated molecular patterns in bovine endometrial tissue, and the most fundamental regulators of cellular energy, glucose availability and AMPK, had the greatest impact on innate immunity.
published_date 2016-03-14T03:37:49Z
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