Targeting Neutrophil Extracellular Traps in Neuroinflammation: A Therapeutic Perspective on Neurodegenerative Diseases

Abstract

Highlights What are the main findings? NETs contribute to neuroinflammation by promoting blood–brain barrier disruption and the amplification of inflammatory signaling in several neurodegenerative diseases. Dysregulated NET formation is increasingly recognized as a mechanistic link between innate immune activation and neuronal injury in neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis. What are the implications of the main findings? Targeting the NETosis pathways represents a promising therapeutic strategy to modulate neuroinflammation and reduce neurovascular damage in neurodegenerative disorders. Emerging approaches, including PAD4 inhibition, DNase-mediated NET degradation, and modulation of oxidative signaling pathways, may provide new avenues for therapeutic intervention. Abstract Neuroinflammation is a complex process involved in the pathogenesis of several neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, Huntington’s disease, and amyotrophic lateral sclerosis. Neutrophils, although traditionally considered peripheral immune cells, have emerged as active participants in the immunopathology of the central nervous system (CNS) through the release of neutrophil extracellular traps (NETs), structures composed of decondensed chromatin embedded with pro-inflammatory proteins. Evidence suggests that NETs play a dual role: they are protective against pathogens but can also induce tissue damage when produced in excess. Several pathways are involved in their formation, including vesicle-mediated release (vital NETs), the lytic NADPH oxidase (NOX)-dependent pathway, and the mitochondrial pathway. Targeting NETs therapeutically, through the use of NETosis inhibitors, NET-degrading strategies, or blockade of neutrophil migration, has shown promise in reducing neuroinflammation/neurodegeneration and improving neurological outcomes in experimental models. This review aims to investigate both the protective and deleterious roles of NETs and how this knowledge may reveal new therapeutic strategies to modulate neurodegenerative diseases and preserve neural integrity, offering valuable insights for potential applications in clinical practice.