A new review published in Burns & Trauma highlights the critical role of neutrophil extracellular traps (NETs) in ischemia–reperfusion injury (IRI), a paradoxical condition where restoring blood flow to oxygen-deprived tissues causes further damage. The review, led by researchers from Chongqing University Central Hospital, University Hospital Essen, and Ludwig-Maximilians-University Munich, synthesizes evidence showing that NETs—web-like structures released by neutrophils—can intensify inflammation, block microvessels, and spread injury across organs such as the heart, brain, kidney, liver, and lung.
IRI is a common pathological process in myocardial infarction, ischemic stroke, acute kidney injury, and graft dysfunction after transplantation. While rapid reperfusion is essential for tissue survival, the sudden return of oxygen can activate sterile inflammation, reactive oxygen species (ROS) production, endothelial dysfunction, and immunothrombosis. Neutrophils are among the first immune cells to arrive at injured sites, and they release NETs composed of decondensed DNA, histones, myeloperoxidase (MPO), neutrophil elastase (NE), and other granular proteins. Although NETs are designed to trap microbes during infection, excessive NET formation in sterile injury can damage endothelial cells, promote microthrombus formation, and sustain inflammatory feedback loops.
The review provides a cross-organ perspective on NET-mediated damage. In the heart, NETs worsen cardiomyocyte injury and post-reperfusion inflammation. In the brain, NET accumulation obstructs cerebral microvessels and disrupts the blood–brain barrier, contributing to poor neurological recovery despite successful vessel reopening. 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, potentially leading to multiple organ dysfunction syndrome (MODS).
Biomarkers such as cell-free DNA (cfDNA), citrullinated histone H3 (CitH3), and MPO–DNA complexes may help monitor disease severity and therapeutic response. 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. Therapeutic strategies should aim to control excessive NET formation without eliminating neutrophil function entirely. Potential approaches include limiting harmful neutrophil recruitment, blocking peptidyl arginine deiminase 4 (PAD4)-dependent NET formation, reducing ROS-driven activation, modulating complement pathways, and accelerating NET clearance with deoxyribonuclease I (DNase I)-based therapies.
The findings have implications for reducing reperfusion-related injury in cardiovascular disease, stroke, transplantation, and critical care. However, clinical translation will require organ-specific biomarkers, careful timing, and strong safety evaluation, as NETs also support antimicrobial defense. The review was published in Burns & Trauma with a DOI of 10.1093/burnst/tkag022 and was supported by funding from the Natural Science Foundation of Chongqing, China and other sources.
