2. Academic Validation
  3. MMP9High Neutrophils are Critical Mediators of Neutrophil Extracellular Traps Formation and Myocardial Ischemia/Reperfusion Injury

MMP9High Neutrophils are Critical Mediators of Neutrophil Extracellular Traps Formation and Myocardial Ischemia/Reperfusion Injury

  • Adv Sci (Weinh). 2025 Jun;12(21):e2415205. doi: 10.1002/advs.202415205.
Shiyu Hu 1 2 3 4 5,  Feng Zhang 1 2 3 4 5,  Jingpu Wang 1 2 3 4 5,  Jian Zhang 1 2 3 4 5,  Chenguang Li 1 2 3 4 5,  Yang Lyu 6,  Yiwen Wang 1 2 3 4 5,  Rong Huang 1 2 3 4 5,  Yang Gao 1 2 3 4 5,  Hongbo Yang 1 2 3 4 5,  Juying Qian 1 2 3 4 5,  Wenwen Tang 7,  Jiatian Cao 1 2 3 4 5,  Junbo Ge 1 3 4 5 6
Affiliations

Affiliations

  • 1 Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
  • 2 National Clinical Research Center for Interventional Medicine, Shanghai, 200032, China.
  • 3 State Key Laboratory of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
  • 4 NHC Key Laboratory of Ischemic Heart Diseases, Shanghai, 200032, China.
  • 5 Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, Shanghai, 200032, China.
  • 6 Department of Cardiology, Shanghai Fifth People's Hospital, Fudan University, Shanghai, 200240, China.
  • 7 Vascular Biology and Therapeutics Program, Department of Pharmacology, Yale University School of Medicine, New Haven, CT, 06520, USA.
PMID: 40151877 DOI: 10.1002/advs.202415205
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.

Keywords

SPI1; cystatin F (CST7); myocardial ischemia/reperfusion injury; neutrophil extracellular traps; single‐cell RNA sequencing.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-124629
    99.48%, PU.1 Inhibitor