A comprehensive review published in Burns & Trauma on June 15, 2026, reveals that neutrophil extracellular traps (NETs) play a central role in ischemia-reperfusion injury (IRI), a common and damaging consequence of restoring blood flow after heart attack, stroke, transplantation, and severe injury. The review, conducted by researchers from Chongqing University Central Hospital, Chongqing University, University Hospital Essen, University of Duisburg-Essen, and Ludwig-Maximilians-University Munich, synthesizes evidence from multiple organ systems to highlight how NETs can intensify inflammation, obstruct microvessels, damage endothelial barriers, and spread injury to distant organs.
IRI occurs when blood flow is restored to tissue after a period of ischemia. While rapid reperfusion is essential for tissue survival, it paradoxically triggers sterile inflammation, reactive oxygen species (ROS) production, endothelial dysfunction, and immunothrombosis. Neutrophils, the immune system's first responders, arrive early at injured sites and release NETs—web-like structures composed of decondensed DNA, histones, myeloperoxidase (MPO), neutrophil elastase (NE), and other granular proteins. These structures are designed to trap microbes during infection, but in sterile injury, excessive NET formation can damage endothelial cells, promote microthrombus formation, and sustain inflammatory feedback loops.
The review provides a cross-organ perspective, detailing how NETs contribute to IRI in the heart, brain, kidney, liver, lung, and transplanted organs. In the heart, NETs worsen cardiomyocyte injury and post-reperfusion inflammation. In the brain, NET accumulation can obstruct cerebral microvessels and disrupt the blood–brain barrier, contributing 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," where NET-driven inflammation and thrombosis extend damage beyond the original injury site, contributing to multiple organ dysfunction syndrome (MODS).
The authors emphasize that NETs are dynamic immune structures whose effects depend on timing, tissue context, and the balance between host defense and tissue damage. They argue that 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. This perspective could shift 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. Biomarkers such as cell-free DNA (cfDNA), citrullinated histone H3 (CitH3), and MPO–DNA complexes may help monitor disease severity and therapeutic response. However, the review cautions that 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 findings may inform future strategies for reducing reperfusion-related injury in cardiovascular disease, stroke, transplantation, and critical care. The review is published with a DOI of 10.1093/burnst/tkag022 and was supported by grants from the Natural Science Foundation of Chongqing, China, among others.
