MMP9High Neutrophils are Critical Mediators of Neutrophil Extracellular Traps Formation and Myocardial Ischemia/Reperfusion Injury
Abstract Neutrophil extracellular traps (NETs) are increasingly recognized as pivotal players and potential therapeutic targets in neutrophil‐mediated reperfusion injury. Despite their importance, the effects and variability of circulating neutrophils in relation to NET formation during myocardial i...
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| Format: | Article |
| Language: | English |
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Wiley
2025-06-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202415205 |
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| author | Shiyu Hu Feng Zhang Jingpu Wang Jian Zhang Chenguang Li Yang Lyu Yiwen Wang Rong Huang Yang Gao Hongbo Yang Juying Qian Wenwen Tang Jiatian Cao Junbo Ge |
| author_facet | Shiyu Hu Feng Zhang Jingpu Wang Jian Zhang Chenguang Li Yang Lyu Yiwen Wang Rong Huang Yang Gao Hongbo Yang Juying Qian Wenwen Tang Jiatian Cao Junbo Ge |
| author_sort | Shiyu Hu |
| collection | DOAJ |
| description | Abstract Neutrophil extracellular traps (NETs) are increasingly recognized as pivotal players and potential therapeutic targets in neutrophil‐mediated reperfusion injury. Despite their importance, the effects and variability of circulating neutrophils in relation to NET formation during myocardial ischemia/reperfusion injury (MI/RI) remain inadequately characterized. In this study, single‐cell transcriptomes of neutrophils isolated from the blood of healthy donors and MI/RI patients are analyzed. The results reveal that MI/RI neutrophils transition from a high IFIT1 expression profile into four distinct states, two of which exhibit elevated MMP9 transcription. These MMP9High neutrophil subpopulations are instrumental in the NET formation and correlate positively with the severity of MI/RI. Further investigation identifies the transcription factor SPI1 as a key regulator of this transition, acting through modulation of CST7 expression. Targeting SPI1 or CST7 significantly reduces the prevalence of MMP9High neutrophils and NET formation, resulting in improved MI/RI outcomes. These findings offer new insights into neutrophil heterogeneity and pinpoint a specific subset critical for NET formation, underscoring their potential as diagnostic biomarkers and therapeutic targets for MI/RI management. |
| format | Article |
| id | doaj-art-cee423e3fdcb424ca36c4c5845960b10 |
| institution | Kabale University |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-cee423e3fdcb424ca36c4c5845960b102025-08-20T03:26:10ZengWileyAdvanced Science2198-38442025-06-011221n/an/a10.1002/advs.202415205MMP9High Neutrophils are Critical Mediators of Neutrophil Extracellular Traps Formation and Myocardial Ischemia/Reperfusion InjuryShiyu Hu0Feng Zhang1Jingpu Wang2Jian Zhang3Chenguang Li4Yang Lyu5Yiwen Wang6Rong Huang7Yang Gao8Hongbo Yang9Juying Qian10Wenwen Tang11Jiatian Cao12Junbo Ge13Department of Cardiology Shanghai Institute of Cardiovascular Diseases Zhongshan Hospital Fudan University Shanghai 200032 ChinaDepartment of Cardiology Shanghai Institute of Cardiovascular Diseases Zhongshan Hospital Fudan University Shanghai 200032 ChinaDepartment of Cardiology Shanghai Institute of Cardiovascular Diseases Zhongshan Hospital Fudan University Shanghai 200032 ChinaDepartment of Cardiology Shanghai Institute of Cardiovascular Diseases Zhongshan Hospital Fudan University Shanghai 200032 ChinaDepartment of Cardiology Shanghai Institute of Cardiovascular Diseases Zhongshan Hospital Fudan University Shanghai 200032 ChinaDepartment of Cardiology Shanghai Fifth People's Hospital Fudan University Shanghai 200240 ChinaDepartment of Cardiology Shanghai Institute of Cardiovascular Diseases Zhongshan Hospital Fudan University Shanghai 200032 ChinaDepartment of Cardiology Shanghai Institute of Cardiovascular Diseases Zhongshan Hospital Fudan University Shanghai 200032 ChinaDepartment of Cardiology Shanghai Institute of Cardiovascular Diseases Zhongshan Hospital Fudan University Shanghai 200032 ChinaDepartment of Cardiology Shanghai Institute of Cardiovascular Diseases Zhongshan Hospital Fudan University Shanghai 200032 ChinaDepartment of Cardiology Shanghai Institute of Cardiovascular Diseases Zhongshan Hospital Fudan University Shanghai 200032 ChinaVascular Biology and Therapeutics Program Department of Pharmacology Yale University School of Medicine New Haven CT 06520 USADepartment of Cardiology Shanghai Institute of Cardiovascular Diseases Zhongshan Hospital Fudan University Shanghai 200032 ChinaDepartment of Cardiology Shanghai Institute of Cardiovascular Diseases Zhongshan Hospital Fudan University Shanghai 200032 ChinaAbstract Neutrophil extracellular traps (NETs) are increasingly recognized as pivotal players and potential therapeutic targets in neutrophil‐mediated reperfusion injury. Despite their importance, the effects and variability of circulating neutrophils in relation to NET formation during myocardial ischemia/reperfusion injury (MI/RI) remain inadequately characterized. In this study, single‐cell transcriptomes of neutrophils isolated from the blood of healthy donors and MI/RI patients are analyzed. The results reveal that MI/RI neutrophils transition from a high IFIT1 expression profile into four distinct states, two of which exhibit elevated MMP9 transcription. These MMP9High neutrophil subpopulations are instrumental in the NET formation and correlate positively with the severity of MI/RI. Further investigation identifies the transcription factor SPI1 as a key regulator of this transition, acting through modulation of CST7 expression. Targeting SPI1 or CST7 significantly reduces the prevalence of MMP9High neutrophils and NET formation, resulting in improved MI/RI outcomes. These findings offer new insights into neutrophil heterogeneity and pinpoint a specific subset critical for NET formation, underscoring their potential as diagnostic biomarkers and therapeutic targets for MI/RI management.https://doi.org/10.1002/advs.202415205cystatin F (CST7)myocardial ischemia/reperfusion injuryneutrophil extracellular trapssingle‐cell RNA sequencingSPI1 |
| spellingShingle | Shiyu Hu Feng Zhang Jingpu Wang Jian Zhang Chenguang Li Yang Lyu Yiwen Wang Rong Huang Yang Gao Hongbo Yang Juying Qian Wenwen Tang Jiatian Cao Junbo Ge MMP9High Neutrophils are Critical Mediators of Neutrophil Extracellular Traps Formation and Myocardial Ischemia/Reperfusion Injury Advanced Science cystatin F (CST7) myocardial ischemia/reperfusion injury neutrophil extracellular traps single‐cell RNA sequencing SPI1 |
| title | MMP9High Neutrophils are Critical Mediators of Neutrophil Extracellular Traps Formation and Myocardial Ischemia/Reperfusion Injury |
| title_full | MMP9High Neutrophils are Critical Mediators of Neutrophil Extracellular Traps Formation and Myocardial Ischemia/Reperfusion Injury |
| title_fullStr | MMP9High Neutrophils are Critical Mediators of Neutrophil Extracellular Traps Formation and Myocardial Ischemia/Reperfusion Injury |
| title_full_unstemmed | MMP9High Neutrophils are Critical Mediators of Neutrophil Extracellular Traps Formation and Myocardial Ischemia/Reperfusion Injury |
| title_short | MMP9High Neutrophils are Critical Mediators of Neutrophil Extracellular Traps Formation and Myocardial Ischemia/Reperfusion Injury |
| title_sort | mmp9high neutrophils are critical mediators of neutrophil extracellular traps formation and myocardial ischemia reperfusion injury |
| topic | cystatin F (CST7) myocardial ischemia/reperfusion injury neutrophil extracellular traps single‐cell RNA sequencing SPI1 |
| url | https://doi.org/10.1002/advs.202415205 |
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