Neutrophil Extracellular Traps in Diabetes Pathophysiology

Neutrophil extracellular traps (NETs) are web-like matrices of decondensed chromatin and granular proteins expelled by activated neutrophils. While NETs contribute to microbial defence, excessive or persistent NET formation in diabetes amplifies inflammation, promotes thrombosis and impairs tissue repair. Hyperglycaemia, oxidative stress and pro-inflammatory cytokines heighten NET production, driving vascular complications such as impaired endothelial function, atherosclerosis progression and microvascular injury in the retina. Chronic wounds and diabetic foot ulcers also show excessive NET deposition that hinders angiogenesis and closure. Therapeutic strategies aimed at modulating NETosis—through enzymatic degradation, inhibition of reactive oxygen species generators or regulation of inflammasome activation—offer promise in mitigating the vascular and reparative defects characteristic of diabetes.

Research from Nature Portfolio

Studies have shown that elevated plasma homocysteine in type 2 diabetes induces constitutive NETosis by both NADPH oxidase-dependent and ‑independent mechanisms, with enhanced neutrophil–platelet interplay exacerbating vascular inflammation. In a diet-induced obesity model, prevention of NET formation using peptide inhibitors, or enzymatic degradation with deoxyribonuclease 1, restored endothelium-dependent vasodilation of mesenteric arteries. These findings establish a causal role for NETs in obesity-related endothelial dysfunction and identify NET modulation as a therapeutic avenue.

Neutrophil Extracellular Traps in Diabetes Pathophysiology publication trend

The graph below shows the total number of articles in neutrophil extracellular traps in diabetes pathophysiology across all publications each year (not limited to Nature Index journals).

Technical terms

Neutrophil extracellular traps (NETs): web-like structures of decondensed chromatin decorated with neutrophil granule proteins released by activated neutrophils.

NETosis: the regulated process by which neutrophils expel chromatin and granular contents to form extracellular traps.

Hyperglycaemia: elevated blood glucose levels characteristic of diabetes that can trigger pro-inflammatory and pro-oxidant pathways.

NADPH oxidase: a multi-subunit enzyme complex in neutrophils that generates reactive oxygen species driving NET formation.

Inflammasome: a multiprotein cytosolic complex that activates inflammatory caspases and cytokines such as interleukin-1β.

Deoxyribonuclease 1 (DNase 1): an endonuclease that degrades extracellular DNA and dismantles NET structures.

Endothelial dysfunction: impaired vasodilatory and barrier functions of the vascular endothelium, often preceding atherosclerosis.

References

1. Neutrophil Extracellular Traps (NETs) promote macrophage inflammation and impair atherosclerosis resolution in mice with diabetes. JCI Insight (2020).
2. Hyperglycemia Induces Neutrophil Extracellular Traps Formation Through an NADPH Oxidase-Dependent Pathway in Diabetic Retinopathy. Frontiers in Immunology (2019).
3. Elevated homocysteine levels in type 2 diabetes induce constitutive neutrophil extracellular traps. Scientific Reports (2016).
4. Obesity-induced Endothelial Dysfunction is Prevented by Neutrophil Extracellular Trap Inhibition. Scientific Reports (2018).
5. MFG-E8 accelerates wound healing in diabetes by regulating “NLRP3 inflammasome-neutrophil extracellular traps” axis. Cell Death Discovery (2020).
6. Predictors of neutrophil extracellular traps markers in type 2 diabetes mellitus: associations with a prothrombotic state and hypofibrinolysis. Cardiovascular Diabetology (2019).