Neutrophil Extracellular Traps (NETs) as drivers of atherosclerosis: Pathogenic mechanisms and therapeutic
Shravya Shetty1, Manikandan Subramanian2
1Barts and The London School of Medicine and Dentistry, Queen Mary University of London, UK.
Insights
Neutrophil extracellular traps (NETs) play a critical role in atherosclerosis progression and adverse cardiovascular events. Targeting NETs offers a novel therapeutic strategy to combat these life-threatening conditions.
Area of Science:
- Cardiovascular Science
- Immunology
- Pathology
Background:
- Cardiovascular diseases (CVDs) are the leading global cause of mortality.
- Atherosclerosis, a chronic inflammatory condition, underlies most CVDs, characterized by arterial plaque buildup.
- While immune cells like macrophages and lymphocytes are studied, neutrophils' role in atherosclerosis is less understood.
Purpose of the Study:
- To review the critical role of neutrophil extracellular traps (NETs) in atherosclerosis.
- To examine the mechanisms driving NETosis in this condition.
- To explore novel therapeutic strategies targeting NETs for atherothrombosis.
Main Methods:
- Comprehensive literature review of studies on neutrophils, NETs, and atherosclerosis.
- Analysis of mechanisms of NETosis and NET clearance.
- Examination of NETs' pathogenic role in plaque progression and clinical outcomes.
Main Results:
- Neutrophil extracellular traps (NETs) are increasingly recognized for their role in inflammasome activation and plaque instability.
- NETs contribute to the progression of atherosclerosis and increase the risk of atherothrombotic events.
- Dysfunctional NET clearance exacerbates their pathogenic effects.
Conclusions:
- Neutrophils and their extracellular traps (NETs) are significant contributors to atherosclerosis pathogenesis.
- Targeting NET formation or promoting NET clearance presents a promising avenue for novel cardiovascular therapies.
- Further research into NET-targeted interventions could mitigate atherothrombosis and its complications.
Abstract:
Cardiovascular diseases (CVDs) are the leading cause of death globally. The primary pathological process underlying CVDs is atherosclerosis, a chronic lipid-driven inflammatory condition that results in the narrowing of medium- and large-arteries due to a build-up of fibrofatty, leukocyte-rich plaques. Adverse clinical outcomes are usually a result of plaque erosion or rupture which result in acute luminal thrombosis with ensuing tissue ischaemia. Immune cell infiltration and the associated inflammation are recognized as key drivers of the development of unstable plaques. Whilst the role of macrophages, dendritic cells, T- and B-lymphocytes are extensively documented in the progression of atherosclerosis, the role of neutrophils, which are the dominant leukocyte subset in humans, is relatively understudied. Interestingly, studies in the last decade have shed light on the critical role of neutrophil extracellular traps (NETs) in mediating inflammasome activation, plaque progression, and adverse clinical outcomes. NETs are complex extracellular DNA structures released by neutrophils undergoing death by a specialized process of NETosis. This review will comprehensively examine the key drivers of NETosis in atherosclerosis, mechanisms of NET clearance, the pathogenic role of NETs in plaque progression, and finally novel pharmacological approaches to target NETs to prevent atherothrombosis and its associated clinical complications.
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