Neutrophil Extracellular Trap Biology and Mechanisms

Neutrophil extracellular traps (NETs) are web‐like assemblies of decondensed chromatin decorated with antimicrobial proteins and enzymes, released by neutrophils in response to infection, sterile inflammation or tissue damage. NET formation, or NETosis, proceeds through a series of regulated events: stimulus recognition, reactive oxygen species (ROS) generation via NADPH oxidase or mitochondrial sources, histone citrullination by peptidylarginine deiminase 4 (PAD4), chromatin decondensation, and ultimately nuclear and plasma membrane rupture. Recent work distinguishes NOX-dependent and NOX-independent pathways, vital NETosis that preserves neutrophil viability, and the influence of ion fluxes, autophagy and DNA repair on trap release. Biophysical forces inherent to decondensed chromatin, notably entropic chromatin swelling, drive membrane rupture. While NETs immobilise and neutralise bacteria, fungi and viruses, their persistence contributes to thrombosis, autoimmunity, acute pancreatitis and pulmonary injury. A detailed mechanistic understanding is crucial to develop therapies that curb pathological NETosis without compromising host defence.

Research from Nature Portfolio

Real-time biophysical analyses have revealed that NETosis unfolds in three distinct phases: an initial latency, a “point of no return” marked by irreversible chromatin decondensation, and a rapid expansion phase during which entropic chromatin swelling provides the mechanical force to rupture both nuclear envelope and plasma membrane. Single‐cell fluorescence and atomic force microscopy demonstrate that the material properties of chromatin directly orchestrate membrane disruption, offering novel mechanical checkpoints for therapeutic intervention.

Neutrophil Extracellular Trap Biology and Mechanisms publication trend

The graph below shows the total number of articles in neutrophil extracellular trap biology and mechanisms across all publications each year (not limited to Nature Index journals).

Technical terms

NETosis: Programmed process leading to neutrophil release of decondensed chromatin adorned with antimicrobial proteins.

Peptidylarginine deiminase 4 (PAD4): Enzyme that converts arginine to citrulline on histones, promoting chromatin decondensation.

Reactive oxygen species (ROS): Chemically reactive oxygen derivatives that drive signalling and oxidative NET formation.

NADPH oxidase (NOX): Multicomponent enzyme complex in neutrophils generating ROS for NOX-dependent NETosis.

Chromatin swelling: Entropic expansion of decondensed DNA–protein complexes that physically drives membrane rupture during NETosis.

References

1. Citrullination of actin-ligand and nuclear structural proteins, cytoskeleton reorganization and protein redistribution across cellular fractions are early events in ionomycin-induced NETosis. Redox Biology (2023).
2. Radiation from UV-A to Red Light Induces ROS-Dependent Release of Neutrophil Extracellular Traps. International Journal of Molecular Sciences (2023).
3. How Do ROS Induce NETosis? Oxidative DNA Damage, DNA Repair, and Chromatin Decondensation. Biomolecules (2024).
4. Diverse stimuli engage different neutrophil extracellular trap pathways. eLife (2017).
5. Chromatin swelling drives neutrophil extracellular trap release. Nature Communications (2018).