A comprehensive review published in Burns & Trauma on 15 June 2026 consolidates current understanding of how neutrophils and their extracellular traps (NETs) contribute to ischemia–reperfusion injury (IRI) across multiple organs, proposing that these immune structures act not merely as inflammatory debris but as dynamic mediators that can either protect or harm depending on context. The work, led by researchers from Chongqing University Central Hospital, University Hospital Essen, and Ludwig-Maximilians-University Munich, systematically examines IRI in the heart, brain, kidney, liver, lung, and transplanted organs, emphasizing the need for organ-specific biomarkers and precisely timed interventions.
IRI occurs when blood flow is restored to tissue after a period of ischemia, a common scenario in heart attack, stroke, organ transplantation, and severe trauma. While reperfusion is essential for tissue survival, the sudden return of oxygen can trigger sterile inflammation, oxidative stress, endothelial dysfunction, and immunothrombosis. Neutrophils are among the first immune cells to arrive at the injury site, where they release inflammatory mediators, proteases, and NETs—web-like structures composed of decondensed DNA, histones, myeloperoxidase (MPO), and neutrophil elastase (NE). Under normal conditions, NETs trap and kill pathogens, but in sterile injury, excessive NET formation can damage endothelial cells, obstruct microvessels, and amplify inflammation.
The review highlights that NETs are not uniformly detrimental; their effects vary by organ, disease stage, and local microenvironment. 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 clinical 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, intensifying inflammation and graft dysfunction post-transplantation. The review also introduces the concept of a “NET–organ axis,” whereby NET-driven inflammation and thrombosis extend damage beyond the original injury site and can contribute to multiple organ dysfunction syndrome (MODS).
Potential biomarkers such as cell-free DNA (cfDNA), citrullinated histone H3 (CitH3), and MPO–DNA complexes could help monitor disease severity and therapeutic response, according to the authors. The review underscores that NETs are dynamic immune structures whose effects depend on timing and tissue context. The therapeutic goal, the authors 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 may move NET-targeted treatment from broad immune suppression toward more precise, stage-specific intervention.
Future strategies for reducing reperfusion-related injury could include limiting harmful neutrophil recruitment, blocking peptidyl arginine deiminase 4 (PAD4)-dependent NET formation, reducing reactive oxygen species (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 full review is available at https://doi.org/10.1093/burnst/tkag022.
