A 'Tangled Web' in the CNS: unraveling neutrophil extracellular traps in neurological disorders

Neutrophil Extracellular Traps (NETs) are web-like structures composed of DNA, histones, and antimicrobial proteins released by activated neutrophils, which play a critical role in modulating neutrophil-mediated immune responses. Initially recognized for their role in host defense, NETs function as "molecular traps" that rapidly ensnare pathogens. They then achieve efficient clearance by directly degrading virulence factors through the action of associated antimicrobial proteins. However, the functions of NETs extend beyond immune defense. Dysregulation of NETs in pathological conditions can lead to detrimental effects. Recent studies have highlighted the importance of aberrant NET formation and impaired clearance in the pathogenesis of central nervous system (CNS) diseases, making them a field hotspot. In view of this, we discuss NETs, the structural characteristics and diverse generation patterns of NETs, and clarify how neutrophils cross the blood-brain barrier (BBB) to enter the CNS. We also explore triggers of NETosis within the brain, such as oxidative stress and inflammatory mediators. Furthermore, we analyze the pathological contributions of NETs to a range of CNS disorders, including stroke, traumatic brain injury (TBI), subarachnoid hemorrhage (SAH), Alzheimer's disease (AD), multiple sclerosis (MS), etc. Finally, we summarize emerging neuroprotective strategies that target NETs, highlighting advances in interventions designed to inhibit NET formation or promote their degradation. By synthesizing current evidence, this review aims to uncover the mysterious veil of NETs in neurological diseases and to offer new insights for understanding disease mechanisms and developing targeted therapeutic approaches.