Inhibition of PAD4-mediated neutrophil extracellular traps formation attenuates hypoxic–ischemic brain injury in neonatal mice

• Published in: Experimental neurology 2025-02, Vol.384, p.115065, Article 115065
• Main Authors: Yu, Xiaoping, Chen, Zhaoyan, Ruan, Fei, Jiang, Yaqing, Bao, Wei, Wu, Di, Chao, Lishuo, Wu, Rui, Le, Kai
• Format: Article
• Language: English
• Subjects: Animals; Animals, Newborn; Extracellular Traps - drug effects; Extracellular Traps - metabolism; Hypoxia-Ischemia, Brain - metabolism; Hypoxia-Ischemia, Brain - pathology; Hypoxic–ischemic brain injury; Mice; Mice, Inbred C57BL; Neuroinflammation; Neutrophil extracellular traps; Neutrophils - metabolism; PAD4; Protein-Arginine Deiminase Type 4 - metabolism
• ISSN: 0014-4886; 1090-2430; 1090-2430
• DOI: 10.1016/j.expneurol.2024.115065

Neonatal hypoxic–ischemic encephalopathy (HIE) is the primary cause of neonatal mortality and severe neurological sequelae. The interaction of neuroinflammation with the immune system represents a significant pathological mechanism underlying the development of HIE. Neutrophil extracellular traps (NETs) are a recently identified antimicrobial mechanism utilized by neutrophils. NETs can act as damage-associated molecular patterns, thereby amplifying the immune response and exerting proinflammatory effects. However, further research is needed to elucidate their role in the pathogenesis of HIE. In this study, we investigated the role of NETs in a hypoxic–ischemic brain injury (HIBI) model. We first reported that a pharmacological intervention to inhibit peptidylarginine deiminase type IV (PAD4) may constitute an effective strategy for reducing HI insult-induced neuroinflammation, neuronal apoptosis, and brain tissue destruction while also enhancing long-term neurobehavioral function in mice. These results support a pathological role for NETs in HIBI, and targeting PAD4 is a potential direction for the treatment of HIE. [Display omitted] •HI insult induces the formation of NETs in the brain of neonatal mice with HIBI.•NETs promotes increased neuroinflammation level and brain dysfunction in neonatal mice with HIBI.•Inhibition of PAD4-mediated formation of NETs attenuates HI insult-induced neuronal apoptosis, and brain damage in HIBI.