A comprehensive review published in Burns & Trauma on 15 June 2026 synthesizes evidence that neutrophil extracellular traps (NETs) are central mediators of ischaemia-reperfusion injury (IRI), a damaging inflammatory response that can occur when blood flow is restored after an interruption such as a heart attack, stroke, transplantation, or severe injury. The review, authored by researchers from Chongqing University Central Hospital, Chongqing University, University Hospital Essen, University of Duisburg-Essen, and Ludwig-Maximilians-University Munich, systematically examines how neutrophils and NETs contribute to IRI across multiple organs and assesses their potential as biomarkers and therapeutic targets.
Ischaemia-reperfusion injury is a shared pathological process in myocardial infarction, ischaemic stroke, acute kidney injury, lung injury, and graft dysfunction after transplantation. Although rapid reperfusion is essential for tissue survival, the sudden return of oxygen can trigger sterile inflammation, production of reactive oxygen species, endothelial dysfunction, and immunothrombosis. Neutrophils, as the immune system's first responders, arrive early at injured sites and release inflammatory mediators, proteases, and NETs. These NETs are web-like structures composed of decondensed DNA, histones, myeloperoxidase, neutrophil elastase, and other granular proteins. While 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 highlights that reperfusion injury often begins at the vascular interface. Damaged tissues and activated endothelial cells release damage-associated molecular patterns (DAMPs), cytokines, and chemokines, recruiting neutrophils into vulnerable microvessels. Once activated, neutrophils release NETs, which can then intensify inflammation, block microvessels, damage endothelial barriers, and spread injury across organs. A key strength of the review is its cross-organ perspective. In the heart, NETs can worsen cardiomyocyte injury and post-reperfusion inflammation. In the brain, NET accumulation may obstruct cerebral microvessels, disrupt the blood–brain barrier, and contribute to the mismatch between successful vessel reopening and poor neurological recovery. In the kidney and liver, NETs interact with tubular cells, hepatocytes, Kupffer cells, and sinusoidal endothelial cells, amplifying inflammation and graft dysfunction. The review also discusses the "NET–organ axis," in which 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 authors emphasize that NETs are dynamic immune structures rather than simple inflammatory debris; their effects depend on timing, tissue context, and the balance between host defense and tissue damage. The therapeutic goal, they argue, 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. This perspective could help move NET-targeted treatment from broad immune suppression toward more precise, stage-specific intervention.
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, clinical translation will require organ-specific biomarkers, careful timing, and strong safety evaluation, because NETs also support antimicrobial defense. With better patient stratification, NET-targeted therapies may offer a practical route to protecting organs after reperfusion. The review was supported by funding from the Natural Science Foundation of Chongqing, China, the Science and Technology Research Program of Chongqing Municipal Education Commission, the National Natural Science Foundation of China, and the 2023 Key Disciplines on Public Health Construction in Chongqing.
For further details, the original study is available at https://doi.org/10.1093/burnst/tkag022. Additional information about Chuanlink Innovations, where the work was published, can be found at http://chuanlink-innovations.com.
