Compromised Anti-inflammatory Action of Neutrophil Extracellular Traps in PAD4-Deficient Mice Contributes to Aggravated Acute Inflammation After Myocardial Infarction
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...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-10-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2019.02313/full |
| _version_ | 1818305006773731328 |
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| author | Kaveh Eghbalzadeh Leena Georgi Theresa Louis Haizhi Zhao Ugur Keser Carolyn Weber Martin Mollenhauer Martin Mollenhauer Andreas Conforti Thorsten Wahlers Adnana Paunel-Görgülü |
| author_facet | Kaveh Eghbalzadeh Leena Georgi Theresa Louis Haizhi Zhao Ugur Keser Carolyn Weber Martin Mollenhauer Martin Mollenhauer Andreas Conforti Thorsten Wahlers Adnana Paunel-Görgülü |
| author_sort | Kaveh Eghbalzadeh |
| collection | DOAJ |
| description | 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 in vitro 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 TGF-ß expression under hypoxic culture conditions. PAD4−/− mice subjected to permanent ligation of the left anterior descending artery suffered from overwhelming inflammation in the acute phase of MI. Noteworthy, PAD4−/− neutrophils were unable to release NETs upon ex vivo 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−/− mice in the acute phase of MI when compared to WT mice. Reduced cardiac expression of IL-6, IL-10, and M2 marker genes, as well as increased TNF-α expression, suggested a pro-inflammatory state. PAD4−/− mice displayed significantly increased cardiac MMP-2 expression under baseline conditions. At day 1, post-MI, PAD4−/− 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. |
| first_indexed | 2024-12-13T06:19:44Z |
| format | Article |
| id | doaj.art-955aeaaad3f64568962a9c826d0e6c77 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-13T06:19:44Z |
| publishDate | 2019-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-955aeaaad3f64568962a9c826d0e6c772022-12-21T23:56:52ZengFrontiers Media S.A.Frontiers in Immunology1664-32242019-10-011010.3389/fimmu.2019.02313480998Compromised Anti-inflammatory Action of Neutrophil Extracellular Traps in PAD4-Deficient Mice Contributes to Aggravated Acute Inflammation After Myocardial InfarctionKaveh Eghbalzadeh0Leena Georgi1Theresa Louis2Haizhi Zhao3Ugur Keser4Carolyn Weber5Martin Mollenhauer6Martin Mollenhauer7Andreas Conforti8Thorsten Wahlers9Adnana Paunel-Görgülü10Department of Cardiothoracic Surgery, Heart Center, University of Cologne, Cologne, GermanyDepartment of Cardiothoracic Surgery, Heart Center, University of Cologne, Cologne, GermanyDepartment of Cardiothoracic Surgery, Heart Center, University of Cologne, Cologne, GermanyDepartment of Cardiothoracic Surgery, Heart Center, University of Cologne, Cologne, GermanyDepartment of Cardiothoracic Surgery, Heart Center, University of Cologne, Cologne, GermanyDepartment of Cardiothoracic Surgery, Heart Center, University of Cologne, Cologne, GermanyDepartment of Cardiology, Heart Center, University of Cologne, Cologne, GermanyCenter for Molecular Medicine Cologne, University of Cologne, Cologne, GermanyDepartment of Cardiothoracic Surgery, Heart Center, University of Cologne, Cologne, GermanyDepartment of Cardiothoracic Surgery, Heart Center, University of Cologne, Cologne, GermanyDepartment of Cardiothoracic Surgery, Heart Center, University of Cologne, Cologne, GermanyInnate 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 in vitro 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 TGF-ß expression under hypoxic culture conditions. PAD4−/− mice subjected to permanent ligation of the left anterior descending artery suffered from overwhelming inflammation in the acute phase of MI. Noteworthy, PAD4−/− neutrophils were unable to release NETs upon ex vivo 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−/− mice in the acute phase of MI when compared to WT mice. Reduced cardiac expression of IL-6, IL-10, and M2 marker genes, as well as increased TNF-α expression, suggested a pro-inflammatory state. PAD4−/− mice displayed significantly increased cardiac MMP-2 expression under baseline conditions. At day 1, post-MI, PAD4−/− 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.https://www.frontiersin.org/article/10.3389/fimmu.2019.02313/fullneutrophil extracellular trapsinflammationPAD4myocardial infarctionmacrophages |
| spellingShingle | Kaveh Eghbalzadeh Leena Georgi Theresa Louis Haizhi Zhao Ugur Keser Carolyn Weber Martin Mollenhauer Martin Mollenhauer Andreas Conforti Thorsten Wahlers Adnana Paunel-Görgülü Compromised Anti-inflammatory Action of Neutrophil Extracellular Traps in PAD4-Deficient Mice Contributes to Aggravated Acute Inflammation After Myocardial Infarction Frontiers in Immunology neutrophil extracellular traps inflammation PAD4 myocardial infarction macrophages |
| title | Compromised Anti-inflammatory Action of Neutrophil Extracellular Traps in PAD4-Deficient Mice Contributes to Aggravated Acute Inflammation After Myocardial Infarction |
| title_full | Compromised Anti-inflammatory Action of Neutrophil Extracellular Traps in PAD4-Deficient Mice Contributes to Aggravated Acute Inflammation After Myocardial Infarction |
| title_fullStr | Compromised Anti-inflammatory Action of Neutrophil Extracellular Traps in PAD4-Deficient Mice Contributes to Aggravated Acute Inflammation After Myocardial Infarction |
| title_full_unstemmed | Compromised Anti-inflammatory Action of Neutrophil Extracellular Traps in PAD4-Deficient Mice Contributes to Aggravated Acute Inflammation After Myocardial Infarction |
| title_short | Compromised Anti-inflammatory Action of Neutrophil Extracellular Traps in PAD4-Deficient Mice Contributes to Aggravated Acute Inflammation After Myocardial Infarction |
| title_sort | compromised anti inflammatory action of neutrophil extracellular traps in pad4 deficient mice contributes to aggravated acute inflammation after myocardial infarction |
| topic | neutrophil extracellular traps inflammation PAD4 myocardial infarction macrophages |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2019.02313/full |
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