Neutrophil Extracellular Traps Emerge as Key Drivers of Reperfusion Injury, Review Finds

A comprehensive review published in Burns & Trauma on June 15, 2026, reveals that neutrophil extracellular traps (NETs)—web-like structures released by immune cells—play a central role in ischaemia–reperfusion injury (IRI), a damaging process that can occur when blood flow is restored after a heart attack, stroke, or organ transplantation. The research, conducted by scientists from Chongqing University Central Hospital, University Hospital Essen, and Ludwig-Maximilians-University Munich, among others, systematically examines how NETs contribute to IRI across multiple organs and identifies potential biomarkers and therapeutic targets.

IRI is a shared pathological process in conditions such as myocardial infarction, ischaemic stroke, acute kidney injury, and graft dysfunction after transplantation. While restoring blood flow is essential for tissue survival, the sudden return of oxygen can trigger sterile inflammation, production of reactive oxygen species, endothelial dysfunction, and immunothrombosis. Neutrophils, the immune system's first responders, are rapidly recruited to injured sites and can release NETs—structures composed of decondensed DNA, histones, myeloperoxidase, neutrophil elastase, and other granular proteins. Although NETs help trap microbes during infection, excessive NET formation in sterile injury can damage endothelial cells, promote microthrombus formation, and sustain inflammatory feedback loops.

The review's cross-organ perspective reveals that NETs can worsen cardiomyocyte injury in the heart, obstruct cerebral microvessels and disrupt the blood–brain barrier in the brain, and amplify inflammation and graft dysfunction in the kidney and liver. The authors also discuss the "NET–organ axis," where NET-driven inflammation and thrombosis extend damage beyond the original injury site and contribute to multiple organ dysfunction syndrome (MODS). Biomarkers such as cell-free DNA (cfDNA), citrullinated histone H3 (CitH3), and myeloperoxidase–DNA (MPO–DNA) complexes may help monitor disease severity and therapeutic response.

The findings have significant implications for the treatment of cardiovascular disease, stroke, transplantation, and critical care. Potential therapeutic approaches include limiting harmful neutrophil recruitment, blocking peptidyl arginine deiminase 4 (PAD4)-dependent NET formation, reducing ROS-driven activation, modulating complement-related pathways, and accelerating NET clearance with deoxyribonuclease I (DNase I)-based therapies. However, the review emphasizes that clinical translation will require organ-specific biomarkers, careful timing, and strong safety evaluation, because NETs also support antimicrobial defense.

"The therapeutic goal should not be to eliminate neutrophil function entirely, but to identify when NET formation becomes excessive, where it causes the greatest harm, and how it can be safely controlled," the authors stated. This perspective could help move NET-targeted treatment from broad immune suppression toward more precise, stage-specific intervention. With better patient stratification, NET-targeted therapies may offer a practical route to protecting organs after reperfusion.

The review, published in Burns & Trauma, is available at https://doi.org/10.1093/burnst/tkag022. The research was supported by grants from the Natural Science Foundation of Chongqing, the National Natural Science Foundation of China, and other sources.