Neutrophil Extracellular Traps and Neuroinflammatory Signaling in Brain Ischemic Insults: Mechanisms, Blood-Brain Barrier Dysfunction, and Therapeutic Targeting
Alper Fatih Ardic1, Nurittin Ardic2,*
1 Asklepios Kliniken Schildautal Seesen, Neurology Clinic, Lower Saxony, Germany
2 Med-International UK Health Agency Ltd., Nuneaton, UK
* Corresponding Author: Nurittin Ardic. Email: 
(This article belongs to the Special Issue: Cellular and Molecular Insights into Brain Ischemic Insults)
BIOCELL https://doi.org/10.32604/biocell.2026.082812
Received 23 March 2026; Accepted 21 May 2026; Published online 04 June 2026
Abstract
Neutrophil extracellular traps (NETs) are increasingly recognized as significant contributors to neurovascular damage following ischemic brain injuries. This review examines how NETs link intravascular thrombosis to downstream neuroinflammation via a pathway-centric framework. We synthesize recent preclinical and clinical evidence showing that NET-derived histones, extracellular DNA, and granular enzymes activate convergent inflammatory pathways, including the high mobility group box 1–Toll-like receptor 4 axis, nuclear factor kappa B, Janus kinase 2/signal transducer and transcription activator 3, NOD-like receptor pyrin domain-containing 3 inflammasome, and cyclic GMP–AMP synthase–interferon gene signaling. These mechanisms contribute to disruption of the blood-brain barrier, glial activation, oxidative damage, and amplification of sterile neuroinflammation. We also discuss translational implications, including therapeutic strategies targeting NETs, candidate biomarkers, and current challenges in clinical practice. Overall, NETs appear to be significant enhancers of ischemic brain injury and promising targets for mechanistically directed intervention.
Keywords
Neutrophil extracellular traps; brain ischemic insults; neuroinflammation; blood-brain barrier; nuclear factor kappa B; NOD-like receptor pyrin domain-containing 3 inflammasome; high-mobility group box 1–Toll-like receptor 4; neurovascular unit; sterile inflammation; therapeutic targeting
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