Neutrophils and Neutrophil Extracellular Traps in Cardiovascular Disease: An Overview and Potential Therapeutic
Kohsuke Shirakawa1, Motoaki Sano1
1Department of Cardiology, Keio University School of Medicine, Shinjuku-ku, Tokyo 1608582, Japan.
Insights
Inflammation plays a key role in cardiovascular disease (CVD) pathogenesis. Targeting neutrophil extracellular traps (NETs) offers a promising therapeutic strategy for managing residual risk in CVD patients.
Area of Science:
- Immunology
- Cardiovascular Medicine
- Inflammation Research
Background:
- Pharmacotherapy has improved cardiovascular disease (CVD) outcomes, yet residual risk persists.
- Inflammation, particularly neutrophil-driven processes, is crucial in CVD pathogenesis.
- The NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome pathway is a validated target for secondary CVD prevention.
Purpose of the Study:
- To review the diverse roles of neutrophils in cardiovascular disease progression.
- To explore the therapeutic potential of targeting neutrophil extracellular traps (NETs) for CVD.
- To discuss the clinical implications and challenges of NET-targeted therapies in CVD.
Main Methods:
- This narrative review synthesizes current research on neutrophils and NETs in CVD.
- Literature search focused on neutrophil diversity, activation, NET formation, and their role in cardiovascular pathologies.
- Analysis of preclinical data on NET-targeted therapies in animal models of CVD.
Main Results:
- Neutrophils exhibit diverse functions influenced by circadian rhythms and disease microenvironments.
- Activated neutrophils contribute to CVD via degranulation, ROS generation, phagocytosis, and NET release.
- NETs promote immunothrombosis and are implicated in acute coronary syndrome, deep vein thrombosis, and heart failure.
Conclusions:
- NETs represent a significant therapeutic target for mitigating inflammation and residual risk in CVD.
- Preclinical studies demonstrate the efficacy of targeting NETs in various CVD models.
- Clinical translation of NET-targeted therapies for CVD requires further investigation and development.
Abstract:
Recent advances in pharmacotherapy have markedly improved the prognosis of cardiovascular disease (CVD) but have not completely conquered it. Therapies targeting the NOD-like receptor family pyrin domain containing 3 inflammasome and its downstream cytokines have proven effective in the secondary prevention of cardiovascular events, suggesting that inflammation is a target for treating residual risk in CVD. Neutrophil-induced inflammation has long been recognized as important in the pathogenesis of CVD. Circadian rhythm-related and disease-specific microenvironment changes give rise to neutrophil diversity. Neutrophils are primed by various stimuli, such as chemokines, cytokines, and damage-related molecular patterns, and the activated neutrophils contribute to the inflammatory response in CVD through degranulation, phagocytosis, reactive oxygen species generation, and the release of neutrophil extracellular traps (NETs). In particular, NETs promote immunothrombosis through the interaction with vascular endothelial cells and platelets and are implicated in the development of various types of CVD, such as acute coronary syndrome, deep vein thrombosis, and heart failure. NETs are promising candidates for anti-inflammatory therapy in CVD, and their efficacy has already been demonstrated in various animal models of the disease; however, they have yet to be clinically applied in humans. This narrative review discusses the diversity and complexity of neutrophils in the trajectory of CVD, the therapeutic potential of targeting NETs, and the related clinical issues.
