Neutrophil Extracellular Trap Dynamics in Inflammatory and Immune Disorders

Neutrophil extracellular traps (NETs) are web-like structures composed of decondensed chromatin decorated with antimicrobial proteins. They represent a frontline defence against pathogens by immobilising and neutralising microbes, yet their unchecked formation or impaired clearance can drive tissue injury, autoimmunity and organ dysfunction. The balance between protective and pathological NET release hinges on tightly regulated pathways of chromatin decondensation, receptor-mediated feedback and nuclease-driven degradation. Dysregulated NET dynamics have been implicated in chronic obstructive pulmonary disease, rheumatoid arthritis, systemic lupus erythematosus, sepsis and acute lung injury. Emerging insights into the molecular sensors that recognise NET DNA, the proteases that tether NETs to the vasculature and the signalling cascades that amplify inflammation are guiding novel therapeutic approaches. Strategies under investigation include blockade of DNA-sensing receptors, inhibition of decondensation enzymes and targeted NET degradation to restore homeostasis without compromising host defence.

Research from Nature Portfolio

One recent investigation demonstrated that the inhibitory receptor MICL recognises DNA within NETs and restrains further neutrophil activation via the reactive oxygen species–PAD4 pathway. Loss or inhibition of MICL function precipitates uncontrolled NET release, creating an auto-inflammatory feedback loop that exacerbates rheumatoid arthritis pathology and is observed in lupus and severe viral pneumonia. Conversely, in models of fungal infection, reduced MICL-mediated restraint enhances microbial clearance, highlighting the context-dependent nature of NET regulation. Another foundational study employed intravital imaging to map NET formation within the liver microvasculature during bloodstream infection. It revealed that NETs anchor to endothelial surfaces through von Willebrand factor, with histones and neutrophil elastase persisting even after DNase-mediated DNA removal. Genetic ablation of PAD4 or neutrophil elastase diminished collateral tissue damage, underscoring key targets for mitigating NET-driven host injury.

Neutrophil Extracellular Trap Dynamics in Inflammatory and Immune Disorders publication trend

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

Technical terms

Neutrophil extracellular traps (NETs): Web-like assemblies of decondensed DNA and neutrophil-derived proteins released into the extracellular space.

NETosis: The specialised process of neutrophil cell death leading to NET formation, involving chromatin decondensation and nuclear membrane rupture.

Myeloid inhibitory C-type lectin-like receptor (MICL): An inhibitory receptor on neutrophils that recognises NET DNA and downregulates further neutrophil activation.

ROS–PAD4 pathway: A signalling cascade in which reactive oxygen species activate peptidylarginine deiminase 4, promoting histone citrullination and chromatin decondensation during NETosis.

cGAS–TLR9 axis: A DNA-sensing pathway whereby cyclic GMP-AMP synthase and toll-like receptor 9 detect extracellular DNA, triggering NF-κB activation and type I interferon responses.

References

1. Recognition and control of neutrophil extracellular trap formation by MICL. Nature (2024).
2. Molecular mechanisms of NET formation and degradation revealed by intravital imaging in the liver vasculature. Nature Communications (2015).
3. DNA of neutrophil extracellular traps promote NF-κB-dependent autoimmunity via cGAS/TLR9 in chronic obstructive pulmonary disease. Signal Transduction and Targeted Therapy (2024).
4. Moonlighting chromatin: when DNA escapes nuclear control. Cell Death & Differentiation (2023).
5. Neutrophil Extracellular Traps Induce Organ Damage during Experimental and Clinical Sepsis. PLOS ONE (2016).