Lactate Buildup at the Site of Chronic Inflammation Promotes Disease by Inducing CD4+ T Cell Metabolic Rewiring
Identifieur interne : 000642 ( Pmc/Checkpoint ); précédent : 000641; suivant : 000643Lactate Buildup at the Site of Chronic Inflammation Promotes Disease by Inducing CD4+ T Cell Metabolic Rewiring
Auteurs : Valentina Pucino [Royaume-Uni] ; Michelangelo Certo [Royaume-Uni] ; Vinay Bulusu [Royaume-Uni] ; Danilo Cucchi [Royaume-Uni] ; Katriona Goldmann [Royaume-Uni] ; Elena Pontarini [Royaume-Uni] ; Robert Haas [Royaume-Uni] ; Joanne Smith [Royaume-Uni] ; Sarah E. Headland [Royaume-Uni] ; Kevin Blighe [Royaume-Uni] ; Massimiliano Ruscica [Italie] ; Frances Humby [Royaume-Uni] ; Myles J. Lewis [Royaume-Uni] ; Jurre J. Kamphorst [Royaume-Uni] ; Michele Bombardieri [Royaume-Uni] ; Costantino Pitzalis [Royaume-Uni] ; Claudio Mauro [Royaume-Uni]Source :
- Cell Metabolism [ 1550-4131 ] ; 2019.
Abstract
Accumulation of lactate in the tissue microenvironment is a feature of both inflammatory disease and cancer. Here, we assess the response of immune cells to lactate in the context of chronic inflammation. We report that lactate accumulation in the inflamed tissue contributes to the upregulation of the lactate transporter SLC5A12 by human CD4+ T cells. SLC5A12-mediated lactate uptake into CD4+ T cells induces a reshaping of their effector phenotype, resulting in increased IL17 production via nuclear PKM2/STAT3 and enhanced fatty acid synthesis. It also leads to CD4+ T cell retention in the inflamed tissue as a consequence of reduced glycolysis and enhanced fatty acid synthesis. Furthermore, antibody-mediated blockade of SLC5A12 ameliorates the disease severity in a murine model of arthritis. Finally, we propose that lactate/SLC5A12-induced metabolic reprogramming is a distinctive feature of lymphoid synovitis in rheumatoid arthritis patients and a potential therapeutic target in chronic inflammatory disorders.
Url:
DOI: 10.1016/j.cmet.2019.10.004
PubMed: 31708446
PubMed Central: 6899510
Affiliations:
- Italie, Royaume-Uni
- Angleterre, Grand Londres, Lombardie, Midlands de l'Ouest, Écosse
- Birmingham, Glasgow, Londres, Milan
- Université de Birmingham, Université de Glasgow, Université de Londres
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PMC:6899510Le document en format XML
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<author><name sortKey="Bombardieri, Michele" sort="Bombardieri, Michele" uniqKey="Bombardieri M" first="Michele" last="Bombardieri">Michele Bombardieri</name>
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<author><name sortKey="Mauro, Claudio" sort="Mauro, Claudio" uniqKey="Mauro C" first="Claudio" last="Mauro">Claudio Mauro</name>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Lactate Buildup at the Site of Chronic Inflammation Promotes Disease by Inducing CD4<sup>+</sup>
T Cell Metabolic Rewiring</title>
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<author><name sortKey="Bulusu, Vinay" sort="Bulusu, Vinay" uniqKey="Bulusu V" first="Vinay" last="Bulusu">Vinay Bulusu</name>
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<placeName><settlement type="city">Londres</settlement>
<region type="country">Angleterre</region>
<region type="région" nuts="1">Grand Londres</region>
</placeName>
<orgName type="university">Université de Londres</orgName>
</affiliation>
</author>
<author><name sortKey="Pontarini, Elena" sort="Pontarini, Elena" uniqKey="Pontarini E" first="Elena" last="Pontarini">Elena Pontarini</name>
<affiliation wicri:level="4"><nlm:aff id="aff2">William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London</wicri:regionArea>
<placeName><settlement type="city">Londres</settlement>
<region type="country">Angleterre</region>
<region type="région" nuts="1">Grand Londres</region>
</placeName>
<orgName type="university">Université de Londres</orgName>
</affiliation>
</author>
<author><name sortKey="Haas, Robert" sort="Haas, Robert" uniqKey="Haas R" first="Robert" last="Haas">Robert Haas</name>
<affiliation wicri:level="4"><nlm:aff id="aff2">William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London</wicri:regionArea>
<placeName><settlement type="city">Londres</settlement>
<region type="country">Angleterre</region>
<region type="région" nuts="1">Grand Londres</region>
</placeName>
<orgName type="university">Université de Londres</orgName>
</affiliation>
</author>
<author><name sortKey="Smith, Joanne" sort="Smith, Joanne" uniqKey="Smith J" first="Joanne" last="Smith">Joanne Smith</name>
<affiliation wicri:level="4"><nlm:aff id="aff2">William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London</wicri:regionArea>
<placeName><settlement type="city">Londres</settlement>
<region type="country">Angleterre</region>
<region type="région" nuts="1">Grand Londres</region>
</placeName>
<orgName type="university">Université de Londres</orgName>
</affiliation>
</author>
<author><name sortKey="Headland, Sarah E" sort="Headland, Sarah E" uniqKey="Headland S" first="Sarah E." last="Headland">Sarah E. Headland</name>
<affiliation wicri:level="4"><nlm:aff id="aff2">William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London</wicri:regionArea>
<placeName><settlement type="city">Londres</settlement>
<region type="country">Angleterre</region>
<region type="région" nuts="1">Grand Londres</region>
</placeName>
<orgName type="university">Université de Londres</orgName>
</affiliation>
</author>
<author><name sortKey="Blighe, Kevin" sort="Blighe, Kevin" uniqKey="Blighe K" first="Kevin" last="Blighe">Kevin Blighe</name>
<affiliation wicri:level="4"><nlm:aff id="aff2">William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London</wicri:regionArea>
<placeName><settlement type="city">Londres</settlement>
<region type="country">Angleterre</region>
<region type="région" nuts="1">Grand Londres</region>
</placeName>
<orgName type="university">Université de Londres</orgName>
</affiliation>
</author>
<author><name sortKey="Ruscica, Massimiliano" sort="Ruscica, Massimiliano" uniqKey="Ruscica M" first="Massimiliano" last="Ruscica">Massimiliano Ruscica</name>
<affiliation wicri:level="3"><nlm:aff id="aff5">Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy</nlm:aff>
<country xml:lang="fr">Italie</country>
<wicri:regionArea>Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan</wicri:regionArea>
<placeName><settlement type="city">Milan</settlement>
<region nuts="2">Lombardie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Humby, Frances" sort="Humby, Frances" uniqKey="Humby F" first="Frances" last="Humby">Frances Humby</name>
<affiliation wicri:level="4"><nlm:aff id="aff2">William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London</wicri:regionArea>
<placeName><settlement type="city">Londres</settlement>
<region type="country">Angleterre</region>
<region type="région" nuts="1">Grand Londres</region>
</placeName>
<orgName type="university">Université de Londres</orgName>
</affiliation>
</author>
<author><name sortKey="Lewis, Myles J" sort="Lewis, Myles J" uniqKey="Lewis M" first="Myles J." last="Lewis">Myles J. Lewis</name>
<affiliation wicri:level="4"><nlm:aff id="aff2">William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London</wicri:regionArea>
<placeName><settlement type="city">Londres</settlement>
<region type="country">Angleterre</region>
<region type="région" nuts="1">Grand Londres</region>
</placeName>
<orgName type="university">Université de Londres</orgName>
</affiliation>
</author>
<author><name sortKey="Kamphorst, Jurre J" sort="Kamphorst, Jurre J" uniqKey="Kamphorst J" first="Jurre J." last="Kamphorst">Jurre J. Kamphorst</name>
<affiliation wicri:level="1"><nlm:aff id="aff3">Cancer Research UK Beatson Institute, Glasgow, UK</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Cancer Research UK Beatson Institute, Glasgow</wicri:regionArea>
<wicri:noRegion>Glasgow</wicri:noRegion>
</affiliation>
<affiliation wicri:level="4"><nlm:aff id="aff4">Institute of Cancer Sciences, University of Glasgow, Glasgow, UK</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Institute of Cancer Sciences, University of Glasgow, Glasgow</wicri:regionArea>
<orgName type="university">Université de Glasgow</orgName>
<placeName><settlement type="city">Glasgow</settlement>
<region type="country">Écosse</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Bombardieri, Michele" sort="Bombardieri, Michele" uniqKey="Bombardieri M" first="Michele" last="Bombardieri">Michele Bombardieri</name>
<affiliation wicri:level="4"><nlm:aff id="aff2">William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London</wicri:regionArea>
<placeName><settlement type="city">Londres</settlement>
<region type="country">Angleterre</region>
<region type="région" nuts="1">Grand Londres</region>
</placeName>
<orgName type="university">Université de Londres</orgName>
</affiliation>
</author>
<author><name sortKey="Pitzalis, Costantino" sort="Pitzalis, Costantino" uniqKey="Pitzalis C" first="Costantino" last="Pitzalis">Costantino Pitzalis</name>
<affiliation wicri:level="4"><nlm:aff id="aff2">William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London</wicri:regionArea>
<placeName><settlement type="city">Londres</settlement>
<region type="country">Angleterre</region>
<region type="région" nuts="1">Grand Londres</region>
</placeName>
<orgName type="university">Université de Londres</orgName>
</affiliation>
</author>
<author><name sortKey="Mauro, Claudio" sort="Mauro, Claudio" uniqKey="Mauro C" first="Claudio" last="Mauro">Claudio Mauro</name>
<affiliation wicri:level="4"><nlm:aff id="aff1">Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham</wicri:regionArea>
<placeName><settlement type="city">Birmingham</settlement>
<region type="country">Angleterre</region>
<region type="région" nuts="1">Midlands de l'Ouest</region>
</placeName>
<orgName type="university">Université de Birmingham</orgName>
</affiliation>
<affiliation wicri:level="4"><nlm:aff id="aff2">William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London</wicri:regionArea>
<placeName><settlement type="city">Londres</settlement>
<region type="country">Angleterre</region>
<region type="région" nuts="1">Grand Londres</region>
</placeName>
<orgName type="university">Université de Londres</orgName>
</affiliation>
<affiliation wicri:level="4"><nlm:aff id="aff6">Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham</wicri:regionArea>
<placeName><settlement type="city">Birmingham</settlement>
<region type="country">Angleterre</region>
<region type="région" nuts="1">Midlands de l'Ouest</region>
</placeName>
<orgName type="university">Université de Birmingham</orgName>
</affiliation>
<affiliation wicri:level="4"><nlm:aff id="aff7">Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham</wicri:regionArea>
<placeName><settlement type="city">Birmingham</settlement>
<region type="country">Angleterre</region>
<region type="région" nuts="1">Midlands de l'Ouest</region>
</placeName>
<orgName type="university">Université de Birmingham</orgName>
</affiliation>
</author>
</analytic>
<series><title level="j">Cell Metabolism</title>
<idno type="ISSN">1550-4131</idno>
<idno type="eISSN">1932-7420</idno>
<imprint><date when="2019">2019</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass></textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en"><title>Summary</title>
<p>Accumulation of lactate in the tissue microenvironment is a feature of both inflammatory disease and cancer. Here, we assess the response of immune cells to lactate in the context of chronic inflammation. We report that lactate accumulation in the inflamed tissue contributes to the upregulation of the lactate transporter SLC5A12 by human CD4<sup>+</sup>
T cells. SLC5A12-mediated lactate uptake into CD4<sup>+</sup>
T cells induces a reshaping of their effector phenotype, resulting in increased IL17 production via nuclear PKM2/STAT3 and enhanced fatty acid synthesis. It also leads to CD4<sup>+</sup>
T cell retention in the inflamed tissue as a consequence of reduced glycolysis and enhanced fatty acid synthesis. Furthermore, antibody-mediated blockade of SLC5A12 ameliorates the disease severity in a murine model of arthritis. Finally, we propose that lactate/SLC5A12-induced metabolic reprogramming is a distinctive feature of lymphoid synovitis in rheumatoid arthritis patients and a potential therapeutic target in chronic inflammatory disorders.</p>
</div>
</front>
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<pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Cell Metab</journal-id>
<journal-id journal-id-type="iso-abbrev">Cell Metab</journal-id>
<journal-title-group><journal-title>Cell Metabolism</journal-title>
</journal-title-group>
<issn pub-type="ppub">1550-4131</issn>
<issn pub-type="epub">1932-7420</issn>
<publisher><publisher-name>Cell Press</publisher-name>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">31708446</article-id>
<article-id pub-id-type="pmc">6899510</article-id>
<article-id pub-id-type="publisher-id">S1550-4131(19)30559-5</article-id>
<article-id pub-id-type="doi">10.1016/j.cmet.2019.10.004</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Article</subject>
</subj-group>
</article-categories>
<title-group><article-title>Lactate Buildup at the Site of Chronic Inflammation Promotes Disease by Inducing CD4<sup>+</sup>
T Cell Metabolic Rewiring</article-title>
</title-group>
<contrib-group><contrib contrib-type="author" id="au1"><name><surname>Pucino</surname>
<given-names>Valentina</given-names>
</name>
<xref rid="aff1" ref-type="aff">1</xref>
<xref rid="aff2" ref-type="aff">2</xref>
<xref rid="fn2" ref-type="fn">9</xref>
</contrib>
<contrib contrib-type="author" id="au2"><name><surname>Certo</surname>
<given-names>Michelangelo</given-names>
</name>
<xref rid="aff1" ref-type="aff">1</xref>
<xref rid="aff2" ref-type="aff">2</xref>
<xref rid="fn2" ref-type="fn">9</xref>
</contrib>
<contrib contrib-type="author" id="au3"><name><surname>Bulusu</surname>
<given-names>Vinay</given-names>
</name>
<xref rid="aff3" ref-type="aff">3</xref>
<xref rid="aff4" ref-type="aff">4</xref>
</contrib>
<contrib contrib-type="author" id="au4"><name><surname>Cucchi</surname>
<given-names>Danilo</given-names>
</name>
<xref rid="aff2" ref-type="aff">2</xref>
</contrib>
<contrib contrib-type="author" id="au5"><name><surname>Goldmann</surname>
<given-names>Katriona</given-names>
</name>
<xref rid="aff2" ref-type="aff">2</xref>
</contrib>
<contrib contrib-type="author" id="au6"><name><surname>Pontarini</surname>
<given-names>Elena</given-names>
</name>
<xref rid="aff2" ref-type="aff">2</xref>
</contrib>
<contrib contrib-type="author" id="au7"><name><surname>Haas</surname>
<given-names>Robert</given-names>
</name>
<xref rid="aff2" ref-type="aff">2</xref>
</contrib>
<contrib contrib-type="author" id="au8"><name><surname>Smith</surname>
<given-names>Joanne</given-names>
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<xref rid="aff2" ref-type="aff">2</xref>
</contrib>
<contrib contrib-type="author" id="au9"><name><surname>Headland</surname>
<given-names>Sarah E.</given-names>
</name>
<xref rid="aff2" ref-type="aff">2</xref>
</contrib>
<contrib contrib-type="author" id="au10"><name><surname>Blighe</surname>
<given-names>Kevin</given-names>
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<xref rid="aff2" ref-type="aff">2</xref>
</contrib>
<contrib contrib-type="author" id="au11"><name><surname>Ruscica</surname>
<given-names>Massimiliano</given-names>
</name>
<xref rid="aff5" ref-type="aff">5</xref>
</contrib>
<contrib contrib-type="author" id="au12"><name><surname>Humby</surname>
<given-names>Frances</given-names>
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<xref rid="aff2" ref-type="aff">2</xref>
</contrib>
<contrib contrib-type="author" id="au13"><name><surname>Lewis</surname>
<given-names>Myles J.</given-names>
</name>
<xref rid="aff2" ref-type="aff">2</xref>
</contrib>
<contrib contrib-type="author" id="au14"><name><surname>Kamphorst</surname>
<given-names>Jurre J.</given-names>
</name>
<xref rid="aff3" ref-type="aff">3</xref>
<xref rid="aff4" ref-type="aff">4</xref>
</contrib>
<contrib contrib-type="author" id="au15"><name><surname>Bombardieri</surname>
<given-names>Michele</given-names>
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<xref rid="aff2" ref-type="aff">2</xref>
<xref rid="fn1" ref-type="fn">8</xref>
</contrib>
<contrib contrib-type="author" id="au16"><name><surname>Pitzalis</surname>
<given-names>Costantino</given-names>
</name>
<xref rid="aff2" ref-type="aff">2</xref>
<xref rid="fn1" ref-type="fn">8</xref>
</contrib>
<contrib contrib-type="author" id="au17"><name><surname>Mauro</surname>
<given-names>Claudio</given-names>
</name>
<email>c.mauro@bham.ac.uk</email>
<xref rid="aff1" ref-type="aff">1</xref>
<xref rid="aff2" ref-type="aff">2</xref>
<xref rid="aff6" ref-type="aff">6</xref>
<xref rid="aff7" ref-type="aff">7</xref>
<xref rid="fn1" ref-type="fn">8</xref>
<xref rid="fn3" ref-type="fn">10</xref>
<xref rid="cor1" ref-type="corresp">∗</xref>
</contrib>
</contrib-group>
<aff id="aff1"><label>1</label>
Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK</aff>
<aff id="aff2"><label>2</label>
William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK</aff>
<aff id="aff3"><label>3</label>
Cancer Research UK Beatson Institute, Glasgow, UK</aff>
<aff id="aff4"><label>4</label>
Institute of Cancer Sciences, University of Glasgow, Glasgow, UK</aff>
<aff id="aff5"><label>5</label>
Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy</aff>
<aff id="aff6"><label>6</label>
Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK</aff>
<aff id="aff7"><label>7</label>
Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK</aff>
<author-notes><corresp id="cor1"><label>∗</label>
Corresponding author <email>c.mauro@bham.ac.uk</email>
</corresp>
<fn id="fn1"><label>8</label>
<p id="ntpara0010">Senior author</p>
</fn>
<fn id="fn2"><label>9</label>
<p id="ntpara0015">These authors contributed equally</p>
</fn>
<fn id="fn3"><label>10</label>
<p id="ntpara0020">Lead Contact</p>
</fn>
</author-notes>
<pub-date pub-type="pmc-release"><day>03</day>
<month>12</month>
<year>2019</year>
</pub-date>
<pmc-comment> PMC Release delay is 0 months and 0 days and was based on .</pmc-comment>
<pub-date pub-type="ppub"><day>03</day>
<month>12</month>
<year>2019</year>
</pub-date>
<volume>30</volume>
<issue>6</issue>
<fpage>1055</fpage>
<lpage>1074.e8</lpage>
<history><date date-type="received"><day>30</day>
<month>12</month>
<year>2018</year>
</date>
<date date-type="rev-recd"><day>21</day>
<month>6</month>
<year>2019</year>
</date>
<date date-type="accepted"><day>12</day>
<month>10</month>
<year>2019</year>
</date>
</history>
<permissions><copyright-statement>© 2019 The Authors</copyright-statement>
<copyright-year>2019</copyright-year>
<license license-type="CC BY-NC-ND" xlink:href="http://creativecommons.org/licenses/by-nc-nd/4.0/"><license-p>This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).</license-p>
</license>
</permissions>
<abstract id="abs0010"><title>Summary</title>
<p>Accumulation of lactate in the tissue microenvironment is a feature of both inflammatory disease and cancer. Here, we assess the response of immune cells to lactate in the context of chronic inflammation. We report that lactate accumulation in the inflamed tissue contributes to the upregulation of the lactate transporter SLC5A12 by human CD4<sup>+</sup>
T cells. SLC5A12-mediated lactate uptake into CD4<sup>+</sup>
T cells induces a reshaping of their effector phenotype, resulting in increased IL17 production via nuclear PKM2/STAT3 and enhanced fatty acid synthesis. It also leads to CD4<sup>+</sup>
T cell retention in the inflamed tissue as a consequence of reduced glycolysis and enhanced fatty acid synthesis. Furthermore, antibody-mediated blockade of SLC5A12 ameliorates the disease severity in a murine model of arthritis. Finally, we propose that lactate/SLC5A12-induced metabolic reprogramming is a distinctive feature of lymphoid synovitis in rheumatoid arthritis patients and a potential therapeutic target in chronic inflammatory disorders.</p>
</abstract>
<abstract abstract-type="graphical" id="abs0015"><title>Graphical Abstract</title>
<fig id="undfig1" position="anchor"><graphic xlink:href="fx1"></graphic>
</fig>
</abstract>
<abstract abstract-type="author-highlights" id="abs0020"><title>Highlights</title>
<p><list list-type="simple" id="ulist0010"><list-item id="u0010"><label>•</label>
<p id="p0010">Lactate induces the expression of SLC5A12 on human CD4<sup>+</sup>
T cells in the inflamed tissue</p>
</list-item>
<list-item id="u0015"><label>•</label>
<p id="p0015">Lactate promotes CD4<sup>+</sup>
T cell IL17 production via PKM2/STAT3 signaling and FA synthesis</p>
</list-item>
<list-item id="u0020"><label>•</label>
<p id="p0020">Lactate inhibits CD4<sup>+</sup>
T cell motility via increased FA synthesis and reduced glycolysis</p>
</list-item>
<list-item id="u0025"><label>•</label>
<p id="p0025">SLC5A12 blockade ameliorates the disease severity in a murine model of arthritis</p>
</list-item>
</list>
</p>
</abstract>
<abstract abstract-type="teaser" id="abs0030"><p>With buildup in the inflamed tissue, lactate can exacerbate the inflammatory response. Pucino et al. report that lactate induces expression of its own transporter, SLC5A12, driving lactate uptake into CD4<sup>+</sup>
T cells and resulting in increased IL17 production via PKM2/STAT3 signaling and enhanced fatty acid synthesis. They provide evidence that targeting SLC5A12 may ameliorate chronic inflammatory disorders.</p>
</abstract>
<kwd-group id="kwrds0010"><title>Keywords</title>
<kwd>lactate</kwd>
<kwd>lactate transporter</kwd>
<kwd>signaling</kwd>
<kwd>inflammation</kwd>
<kwd>immunometabolism</kwd>
<kwd>T cell</kwd>
<kwd>translational research</kwd>
<kwd>cytokines</kwd>
<kwd>metabolic crosstalk</kwd>
</kwd-group>
</article-meta>
<notes><p id="misc0010">Published: November 7, 2019</p>
</notes>
</front>
</pmc>
<affiliations><list><country><li>Italie</li>
<li>Royaume-Uni</li>
</country>
<region><li>Angleterre</li>
<li>Grand Londres</li>
<li>Lombardie</li>
<li>Midlands de l'Ouest</li>
<li>Écosse</li>
</region>
<settlement><li>Birmingham</li>
<li>Glasgow</li>
<li>Londres</li>
<li>Milan</li>
</settlement>
<orgName><li>Université de Birmingham</li>
<li>Université de Glasgow</li>
<li>Université de Londres</li>
</orgName>
</list>
<tree><country name="Royaume-Uni"><region name="Angleterre"><name sortKey="Pucino, Valentina" sort="Pucino, Valentina" uniqKey="Pucino V" first="Valentina" last="Pucino">Valentina Pucino</name>
</region>
<name sortKey="Blighe, Kevin" sort="Blighe, Kevin" uniqKey="Blighe K" first="Kevin" last="Blighe">Kevin Blighe</name>
<name sortKey="Bombardieri, Michele" sort="Bombardieri, Michele" uniqKey="Bombardieri M" first="Michele" last="Bombardieri">Michele Bombardieri</name>
<name sortKey="Bulusu, Vinay" sort="Bulusu, Vinay" uniqKey="Bulusu V" first="Vinay" last="Bulusu">Vinay Bulusu</name>
<name sortKey="Bulusu, Vinay" sort="Bulusu, Vinay" uniqKey="Bulusu V" first="Vinay" last="Bulusu">Vinay Bulusu</name>
<name sortKey="Certo, Michelangelo" sort="Certo, Michelangelo" uniqKey="Certo M" first="Michelangelo" last="Certo">Michelangelo Certo</name>
<name sortKey="Certo, Michelangelo" sort="Certo, Michelangelo" uniqKey="Certo M" first="Michelangelo" last="Certo">Michelangelo Certo</name>
<name sortKey="Cucchi, Danilo" sort="Cucchi, Danilo" uniqKey="Cucchi D" first="Danilo" last="Cucchi">Danilo Cucchi</name>
<name sortKey="Goldmann, Katriona" sort="Goldmann, Katriona" uniqKey="Goldmann K" first="Katriona" last="Goldmann">Katriona Goldmann</name>
<name sortKey="Haas, Robert" sort="Haas, Robert" uniqKey="Haas R" first="Robert" last="Haas">Robert Haas</name>
<name sortKey="Headland, Sarah E" sort="Headland, Sarah E" uniqKey="Headland S" first="Sarah E." last="Headland">Sarah E. Headland</name>
<name sortKey="Humby, Frances" sort="Humby, Frances" uniqKey="Humby F" first="Frances" last="Humby">Frances Humby</name>
<name sortKey="Kamphorst, Jurre J" sort="Kamphorst, Jurre J" uniqKey="Kamphorst J" first="Jurre J." last="Kamphorst">Jurre J. Kamphorst</name>
<name sortKey="Kamphorst, Jurre J" sort="Kamphorst, Jurre J" uniqKey="Kamphorst J" first="Jurre J." last="Kamphorst">Jurre J. Kamphorst</name>
<name sortKey="Lewis, Myles J" sort="Lewis, Myles J" uniqKey="Lewis M" first="Myles J." last="Lewis">Myles J. Lewis</name>
<name sortKey="Mauro, Claudio" sort="Mauro, Claudio" uniqKey="Mauro C" first="Claudio" last="Mauro">Claudio Mauro</name>
<name sortKey="Mauro, Claudio" sort="Mauro, Claudio" uniqKey="Mauro C" first="Claudio" last="Mauro">Claudio Mauro</name>
<name sortKey="Mauro, Claudio" sort="Mauro, Claudio" uniqKey="Mauro C" first="Claudio" last="Mauro">Claudio Mauro</name>
<name sortKey="Mauro, Claudio" sort="Mauro, Claudio" uniqKey="Mauro C" first="Claudio" last="Mauro">Claudio Mauro</name>
<name sortKey="Pitzalis, Costantino" sort="Pitzalis, Costantino" uniqKey="Pitzalis C" first="Costantino" last="Pitzalis">Costantino Pitzalis</name>
<name sortKey="Pontarini, Elena" sort="Pontarini, Elena" uniqKey="Pontarini E" first="Elena" last="Pontarini">Elena Pontarini</name>
<name sortKey="Pucino, Valentina" sort="Pucino, Valentina" uniqKey="Pucino V" first="Valentina" last="Pucino">Valentina Pucino</name>
<name sortKey="Smith, Joanne" sort="Smith, Joanne" uniqKey="Smith J" first="Joanne" last="Smith">Joanne Smith</name>
</country>
<country name="Italie"><region name="Lombardie"><name sortKey="Ruscica, Massimiliano" sort="Ruscica, Massimiliano" uniqKey="Ruscica M" first="Massimiliano" last="Ruscica">Massimiliano Ruscica</name>
</region>
</country>
</tree>
</affiliations>
</record>
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