Compromised Anti-inflammatory Action of Neutrophil Extracellular Traps in PAD4-Deficient Mice Contributes to Aggravated Acute Inflammation After Myocardial Infarction
Identifieur interne : 000543 ( Pmc/Curation ); précédent : 000542; suivant : 000544Compromised Anti-inflammatory Action of Neutrophil Extracellular Traps in PAD4-Deficient Mice Contributes to Aggravated Acute Inflammation After Myocardial Infarction
Auteurs : Kaveh Eghbalzadeh [Allemagne] ; Leena Georgi [Allemagne] ; Theresa Louis [Allemagne] ; Haizhi Zhao [Allemagne] ; Ugur Keser [Allemagne] ; Carolyn Weber [Allemagne] ; Martin Mollenhauer [Allemagne] ; Andreas Conforti [Allemagne] ; Thorsten Wahlers [Allemagne] ; Adnana Paunel-Görgülü [Allemagne]Source :
- Frontiers in Immunology [ 1664-3224 ] ; 2019.
Abstract
Innate immune responses and rapid recruitment of leukocytes, which regulate inflammation and subsequent healing, play a key role in acute myocardial infarction (MI). Peptidylarginine deiminase 4 (PAD4) is critically involved in chromatin decondensation during the release of Neutrophil Extracellular Traps (NETs) by activated neutrophils. Alternatively, activated macrophages (M2) and accurate collagen deposition determine the repair of the infarcted heart. In this study, we investigated the impact of NETs on macrophage polarization and their role for acute cardiac inflammation and subsequent cardiac healing in a mouse model of acute MI. NETs were found to promote
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DOI: 10.3389/fimmu.2019.02313
PubMed: 31632398
PubMed Central: 6779806
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Compromised Anti-inflammatory Action of Neutrophil Extracellular Traps in PAD4-Deficient Mice Contributes to Aggravated Acute Inflammation After Myocardial Infarction</title><author><name sortKey="Eghbalzadeh, Kaveh" sort="Eghbalzadeh, Kaveh" uniqKey="Eghbalzadeh K" first="Kaveh" last="Eghbalzadeh">Kaveh Eghbalzadeh</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Department of Cardiothoracic Surgery, Heart Center, University of Cologne</institution>,<addr-line>Cologne</addr-line>,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Georgi, Leena" sort="Georgi, Leena" uniqKey="Georgi L" first="Leena" last="Georgi">Leena Georgi</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Department of Cardiothoracic Surgery, Heart Center, University of Cologne</institution>,<addr-line>Cologne</addr-line>,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Louis, Theresa" sort="Louis, Theresa" uniqKey="Louis T" first="Theresa" last="Louis">Theresa Louis</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Department of Cardiothoracic Surgery, Heart Center, University of Cologne</institution>,<addr-line>Cologne</addr-line>,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Zhao, Haizhi" sort="Zhao, Haizhi" uniqKey="Zhao H" first="Haizhi" last="Zhao">Haizhi Zhao</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Department of Cardiothoracic Surgery, Heart Center, University of Cologne</institution>,<addr-line>Cologne</addr-line>,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Keser, Ugur" sort="Keser, Ugur" uniqKey="Keser U" first="Ugur" last="Keser">Ugur Keser</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Department of Cardiothoracic Surgery, Heart Center, University of Cologne</institution>,<addr-line>Cologne</addr-line>,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Weber, Carolyn" sort="Weber, Carolyn" uniqKey="Weber C" first="Carolyn" last="Weber">Carolyn Weber</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Department of Cardiothoracic Surgery, Heart Center, University of Cologne</institution>,<addr-line>Cologne</addr-line>,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Mollenhauer, Martin" sort="Mollenhauer, Martin" uniqKey="Mollenhauer M" first="Martin" last="Mollenhauer">Martin Mollenhauer</name><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Department of Cardiology, Heart Center, University of Cologne</institution>,<addr-line>Cologne</addr-line>,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff3"><institution>Center for Molecular Medicine Cologne, University of Cologne</institution>,<addr-line>Cologne</addr-line>,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Conforti, Andreas" sort="Conforti, Andreas" uniqKey="Conforti A" first="Andreas" last="Conforti">Andreas Conforti</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Department of Cardiothoracic Surgery, Heart Center, University of Cologne</institution>,<addr-line>Cologne</addr-line>,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Wahlers, Thorsten" sort="Wahlers, Thorsten" uniqKey="Wahlers T" first="Thorsten" last="Wahlers">Thorsten Wahlers</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Department of Cardiothoracic Surgery, Heart Center, University of Cologne</institution>,<addr-line>Cologne</addr-line>,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Paunel Gorgulu, Adnana" sort="Paunel Gorgulu, Adnana" uniqKey="Paunel Gorgulu A" first="Adnana" last="Paunel-Görgülü">Adnana Paunel-Görgülü</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Department of Cardiothoracic Surgery, Heart Center, University of Cologne</institution>,<addr-line>Cologne</addr-line>,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">31632398</idno><idno type="pmc">6779806</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6779806</idno><idno type="RBID">PMC:6779806</idno><idno type="doi">10.3389/fimmu.2019.02313</idno><date when="2019">2019</date><idno type="wicri:Area/Pmc/Corpus">000543</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" 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uniqKey="Georgi L" first="Leena" last="Georgi">Leena Georgi</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Department of Cardiothoracic Surgery, Heart Center, University of Cologne</institution>,<addr-line>Cologne</addr-line>,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Louis, Theresa" sort="Louis, Theresa" uniqKey="Louis T" first="Theresa" last="Louis">Theresa Louis</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Department of Cardiothoracic Surgery, Heart Center, University of Cologne</institution>,<addr-line>Cologne</addr-line>,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Zhao, Haizhi" sort="Zhao, Haizhi" uniqKey="Zhao H" first="Haizhi" last="Zhao">Haizhi Zhao</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Department of Cardiothoracic Surgery, Heart Center, University of Cologne</institution>,<addr-line>Cologne</addr-line>,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Keser, Ugur" sort="Keser, Ugur" uniqKey="Keser U" first="Ugur" last="Keser">Ugur Keser</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Department of Cardiothoracic Surgery, Heart Center, University of Cologne</institution>,<addr-line>Cologne</addr-line>,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Weber, Carolyn" sort="Weber, Carolyn" uniqKey="Weber C" first="Carolyn" last="Weber">Carolyn Weber</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Department of Cardiothoracic Surgery, Heart Center, University of Cologne</institution>,<addr-line>Cologne</addr-line>,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Mollenhauer, Martin" sort="Mollenhauer, Martin" uniqKey="Mollenhauer M" first="Martin" last="Mollenhauer">Martin Mollenhauer</name><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Department of Cardiology, Heart Center, University of Cologne</institution>,<addr-line>Cologne</addr-line>,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff3"><institution>Center for Molecular Medicine Cologne, University of Cologne</institution>,<addr-line>Cologne</addr-line>,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Conforti, Andreas" sort="Conforti, Andreas" uniqKey="Conforti A" first="Andreas" last="Conforti">Andreas Conforti</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Department of Cardiothoracic Surgery, Heart Center, University of Cologne</institution>,<addr-line>Cologne</addr-line>,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Wahlers, Thorsten" sort="Wahlers, Thorsten" uniqKey="Wahlers T" first="Thorsten" last="Wahlers">Thorsten Wahlers</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Department of Cardiothoracic Surgery, Heart Center, University of Cologne</institution>,<addr-line>Cologne</addr-line>,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Paunel Gorgulu, Adnana" sort="Paunel Gorgulu, Adnana" uniqKey="Paunel Gorgulu A" first="Adnana" last="Paunel-Görgülü">Adnana Paunel-Görgülü</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Department of Cardiothoracic Surgery, Heart Center, University of Cologne</institution>,<addr-line>Cologne</addr-line>,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author></analytic><series><title level="j">Frontiers in Immunology</title><idno type="eISSN">1664-3224</idno><imprint><date when="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Innate immune responses and rapid recruitment of leukocytes, which regulate inflammation and subsequent healing, play a key role in acute myocardial infarction (MI). Peptidylarginine deiminase 4 (PAD4) is critically involved in chromatin decondensation during the release of Neutrophil Extracellular Traps (NETs) by activated neutrophils. Alternatively, activated macrophages (M2) and accurate collagen deposition determine the repair of the infarcted heart. In this study, we investigated the impact of NETs on macrophage polarization and their role for acute cardiac inflammation and subsequent cardiac healing in a mouse model of acute MI. NETs were found to promote <italic>in vitro</italic> macrophage polarization toward a reparative phenotype. NETs suppressed pro-inflammatory macrophages (M1) under hypoxia and diminished IL-6 and TNF-α expression. Further on, NETs strongly supported M2b polarization and IL-10 expression. In cardiac fibroblasts, NETs increased <italic>TGF-ß</italic> expression under hypoxic culture conditions. PAD4<sup>−/−</sup> mice subjected to permanent ligation of the left anterior descending artery suffered from overwhelming inflammation in the acute phase of MI. Noteworthy, PAD4<sup>−/−</sup> neutrophils were unable to release NETs upon <italic>ex vivo</italic> stimulation with ionomycin or PMA, but produced significantly higher amounts of reactive oxygen species (ROS). Increased levels of circulating cell-free DNA, mitochondrial DNA and cardiac troponin were found in PAD4<sup>−/−</sup> mice in the acute phase of MI when compared to WT mice. Reduced cardiac expression of <italic>IL-6, IL-10</italic>, and M2 marker genes, as well as increased <italic>TNF-</italic>α expression, suggested a pro-inflammatory state. PAD4<sup>−/−</sup> mice displayed significantly increased cardiac <italic>MMP-2</italic> expression under baseline conditions. At day 1, post-MI, PAD4<sup>−/−</sup> mice showed increased end-diastolic volume and increased thinning of the left ventricular wall. Interestingly, improved cardiac function, as demonstrated by significantly increased ejection fraction, was found at day 21. Altogether, our results indicate that NETs support macrophage polarization toward an M2 phenotype, thus displaying anti-inflammatory properties. PAD4 deficiency aggravates acute inflammation and increases tissue damage post-MI, partially due to the lack of NETs.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Laflamme, Ma" uniqKey="Laflamme M">MA Laflamme</name></author><author><name sortKey="Murry, Ce" uniqKey="Murry C">CE Murry</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lewis, Ef" uniqKey="Lewis E">EF Lewis</name></author><author><name sortKey="Moye, La" uniqKey="Moye L">LA Moye</name></author><author><name sortKey="Rouleau, Jl" uniqKey="Rouleau J">JL Rouleau</name></author><author><name sortKey="Sacks, Fm" uniqKey="Sacks F">FM Sacks</name></author><author><name sortKey="Arnold, Jm" uniqKey="Arnold J">JM Arnold</name></author><author><name sortKey="Warnica, Jw" uniqKey="Warnica J">JW Warnica</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Brill, A" uniqKey="Brill A">A 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uniqKey="Subramanian V">V Subramanian</name></author><author><name sortKey="Thompson, Pr" uniqKey="Thompson P">PR Thompson</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Jang, B" uniqKey="Jang B">B Jang</name></author><author><name sortKey="Kim, Hw" uniqKey="Kim H">HW Kim</name></author><author><name sortKey="Kim, Js" uniqKey="Kim J">JS Kim</name></author><author><name sortKey="Kim, Ws" uniqKey="Kim W">WS Kim</name></author><author><name sortKey="Lee, Br" uniqKey="Lee B">BR Lee</name></author><author><name sortKey="Kim, S" uniqKey="Kim S">S Kim</name></author></analytic></biblStruct></listBibl></div1></back></TEI><pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Front Immunol</journal-id><journal-id journal-id-type="iso-abbrev">Front Immunol</journal-id><journal-id journal-id-type="publisher-id">Front. Immunol.</journal-id><journal-title-group><journal-title>Frontiers in Immunology</journal-title></journal-title-group><issn pub-type="epub">1664-3224</issn><publisher><publisher-name>Frontiers Media S.A.</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">31632398</article-id><article-id pub-id-type="pmc">6779806</article-id><article-id pub-id-type="doi">10.3389/fimmu.2019.02313</article-id><article-categories><subj-group subj-group-type="heading"><subject>Immunology</subject><subj-group><subject>Original Research</subject></subj-group></subj-group></article-categories><title-group><article-title>Compromised Anti-inflammatory Action of Neutrophil Extracellular Traps in PAD4-Deficient Mice Contributes to Aggravated Acute Inflammation After Myocardial Infarction</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Eghbalzadeh</surname><given-names>Kaveh</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><uri xlink:type="simple" xlink:href="http://loop.frontiersin.org/people/785727/overview"></uri></contrib><contrib contrib-type="author"><name><surname>Georgi</surname><given-names>Leena</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Louis</surname><given-names>Theresa</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><uri xlink:type="simple" xlink:href="http://loop.frontiersin.org/people/803016/overview"></uri></contrib><contrib contrib-type="author"><name><surname>Zhao</surname><given-names>Haizhi</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><uri xlink:type="simple" xlink:href="http://loop.frontiersin.org/people/814513/overview"></uri></contrib><contrib contrib-type="author"><name><surname>Keser</surname><given-names>Ugur</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><uri xlink:type="simple" xlink:href="http://loop.frontiersin.org/people/801602/overview"></uri></contrib><contrib contrib-type="author"><name><surname>Weber</surname><given-names>Carolyn</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><uri xlink:type="simple" xlink:href="http://loop.frontiersin.org/people/625438/overview"></uri></contrib><contrib contrib-type="author"><name><surname>Mollenhauer</surname><given-names>Martin</given-names></name><xref ref-type="aff" rid="aff2"><sup>2</sup></xref><xref ref-type="aff" rid="aff3"><sup>3</sup></xref><uri xlink:type="simple" xlink:href="http://loop.frontiersin.org/people/814321/overview"></uri></contrib><contrib contrib-type="author"><name><surname>Conforti</surname><given-names>Andreas</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Wahlers</surname><given-names>Thorsten</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Paunel-Görgülü</surname><given-names>Adnana</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="corresp" rid="c001"><sup>*</sup></xref><uri xlink:type="simple" xlink:href="http://loop.frontiersin.org/people/751214/overview"></uri></contrib></contrib-group><aff id="aff1"><sup>1</sup><institution>Department of Cardiothoracic Surgery, Heart Center, University of Cologne</institution>,<addr-line>Cologne</addr-line>,<country>Germany</country></aff><aff id="aff2"><sup>2</sup><institution>Department of Cardiology, Heart Center, University of Cologne</institution>,<addr-line>Cologne</addr-line>,<country>Germany</country></aff><aff id="aff3"><sup>3</sup><institution>Center for Molecular Medicine Cologne, University of Cologne</institution>,<addr-line>Cologne</addr-line>,<country>Germany</country></aff><author-notes><fn fn-type="edited-by"><p>Edited by: Takayuki Yoshimoto, Tokyo Medical University, Japan</p></fn><fn fn-type="edited-by"><p>Reviewed by: Marko Radic, University of Tennessee College of Medicine, United States; Harumichi Ishigame, RIKEN, Japan</p></fn><corresp id="c001">*Correspondence: Adnana Paunel-Görgülü <email>adnana.paunel-goerguelue@uk-koeln.de</email></corresp><fn fn-type="other" id="fn001"><p>This article was submitted to Inflammation, a section of the journal Frontiers in Immunology</p></fn></author-notes><pub-date pub-type="epub"><day>01</day><month>10</month><year>2019</year></pub-date><pub-date pub-type="collection"><year>2019</year></pub-date><volume>10</volume><elocation-id>2313</elocation-id><history><date date-type="received"><day>26</day><month>6</month><year>2019</year></date><date date-type="accepted"><day>12</day><month>9</month><year>2019</year></date></history><permissions><copyright-statement>Copyright © 2019 Eghbalzadeh, Georgi, Louis, Zhao, Keser, Weber, Mollenhauer, Conforti, Wahlers and Paunel-Görgülü.</copyright-statement><copyright-year>2019</copyright-year><copyright-holder>Eghbalzadeh, Georgi, Louis, Zhao, Keser, Weber, Mollenhauer, Conforti, Wahlers and Paunel-Görgülü</copyright-holder><license xlink:href="http://creativecommons.org/licenses/by/4.0/"><license-p>This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.</license-p></license></permissions><abstract><p>Innate immune responses and rapid recruitment of leukocytes, which regulate inflammation and subsequent healing, play a key role in acute myocardial infarction (MI). Peptidylarginine deiminase 4 (PAD4) is critically involved in chromatin decondensation during the release of Neutrophil Extracellular Traps (NETs) by activated neutrophils. Alternatively, activated macrophages (M2) and accurate collagen deposition determine the repair of the infarcted heart. In this study, we investigated the impact of NETs on macrophage polarization and their role for acute cardiac inflammation and subsequent cardiac healing in a mouse model of acute MI. NETs were found to promote <italic>in vitro</italic> macrophage polarization toward a reparative phenotype. NETs suppressed pro-inflammatory macrophages (M1) under hypoxia and diminished IL-6 and TNF-α expression. Further on, NETs strongly supported M2b polarization and IL-10 expression. In cardiac fibroblasts, NETs increased <italic>TGF-ß</italic> expression under hypoxic culture conditions. PAD4<sup>−/−</sup> mice subjected to permanent ligation of the left anterior descending artery suffered from overwhelming inflammation in the acute phase of MI. Noteworthy, PAD4<sup>−/−</sup> neutrophils were unable to release NETs upon <italic>ex vivo</italic> stimulation with ionomycin or PMA, but produced significantly higher amounts of reactive oxygen species (ROS). Increased levels of circulating cell-free DNA, mitochondrial DNA and cardiac troponin were found in PAD4<sup>−/−</sup> mice in the acute phase of MI when compared to WT mice. Reduced cardiac expression of <italic>IL-6, IL-10</italic>, and M2 marker genes, as well as increased <italic>TNF-</italic>α expression, suggested a pro-inflammatory state. PAD4<sup>−/−</sup> mice displayed significantly increased cardiac <italic>MMP-2</italic> expression under baseline conditions. At day 1, post-MI, PAD4<sup>−/−</sup> mice showed increased end-diastolic volume and increased thinning of the left ventricular wall. Interestingly, improved cardiac function, as demonstrated by significantly increased ejection fraction, was found at day 21. Altogether, our results indicate that NETs support macrophage polarization toward an M2 phenotype, thus displaying anti-inflammatory properties. PAD4 deficiency aggravates acute inflammation and increases tissue damage post-MI, partially due to the lack of NETs.</p></abstract><kwd-group><kwd>neutrophil extracellular traps</kwd><kwd>inflammation</kwd><kwd>PAD4</kwd><kwd>myocardial infarction</kwd><kwd>macrophages</kwd></kwd-group><counts><fig-count count="8"></fig-count><table-count count="0"></table-count><equation-count count="0"></equation-count><ref-count count="62"></ref-count><page-count count="17"></page-count><word-count count="10290"></word-count></counts></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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