A comprehensive review published in Burns & Trauma on June 15, 2026, brings together evidence demonstrating that neutrophils and the web-like structures they release, known as neutrophil extracellular traps (NETs), are central players in ischemia-reperfusion injury (IRI). IRI occurs when blood flow is restored to tissue after a period of ischemia, such as during heart attack, stroke, transplantation, or severe injury. While reperfusion is essential for tissue survival, it can paradoxically trigger a damaging second wave of inflammation and tissue damage.
The review, conducted 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 the heart, brain, kidney, liver, lung, and transplanted organs. The authors explain that reperfusion injury often begins at the vascular interface, where damaged tissues and activated endothelial cells release damage-associated molecular patterns (DAMPs), cytokines, and chemokines, recruiting neutrophils into vulnerable microvessels. Activated neutrophils can then release NETs, which are composed of decondensed DNA, histones, myeloperoxidase (MPO), neutrophil elastase (NE), 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. 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, as noted in the study (DOI: 10.1093/burnst/tkag022).
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 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 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. With better patient stratification, NET-targeted therapies may offer a practical route to protecting organs after reperfusion.
The research was supported by the Natural Science Foundation of Chongqing, China (Grant No. CSTB2025NSCQ-GPX1056), the Science and Technology Research Program of Chongqing Municipal Education Commission (Grant No. KJQN202300114), the National Natural Science Foundation of China (Grant No. 82500355), the 2023 Key Disciplines on Public Health Construction in Chongqing, and the National Natural Science Foundation of China (Grant No. 81900381). More information about the publishing journal can be found at Chuanlink Innovations.
