Inhibition of neutrophil extracellular trap formation ameliorates neuroinflammation and neuronal apoptosis via STING-dependent IRE1α/ASK1/JNK signaling pathway in mice with traumatic brain injury

Journal of Neuroinflammation

Research

Liang Liu¹  Baolong Wang¹  Tuo Li¹  Yuan Zhou¹  Haoran Jia¹  Xiao Liu¹  Jianye Xu¹  Xilei Liu¹  Shenghui Li¹  Quanjun Deng¹  Guili Yang¹  Yanlin Zhu¹  Guihong Shi¹  Liang Mi¹  Jianning Zhang¹  Yanfeng Zhang¹  Yiyao Cao¹  Shu Zhang¹  Guangshuo Ma²  Fanglian Chen³  Xu Zhang⁴ 

[1] Department of Neurosurgery, Tianjin Medical University General Hospital, 300052, Tianjin, People’s Republic of China;Key Laboratory of Post-Trauma Neuro-Repair and Regeneration in Central Nervous System, Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin Neurological Institute, Ministry of Education, 300052, Tianjin, People’s Republic of China;Department of Neurosurgery, Tianjin Medical University General Hospital, 300052, Tianjin, People’s Republic of China;Key Laboratory of Post-Trauma Neuro-Repair and Regeneration in Central Nervous System, Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin Neurological Institute, Ministry of Education, 300052, Tianjin, People’s Republic of China;Department of Neurosurgery, School of Medicine, Tianjin First Central Hospital, Nankai University, 300192, Tianjin, China;Key Laboratory of Post-Trauma Neuro-Repair and Regeneration in Central Nervous System, Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin Neurological Institute, Ministry of Education, 300052, Tianjin, People’s Republic of China;School of Medicine, Nankai University, 300192, Tianjin, China;

关键词: Neutrophil extracellular traps;    Cl-amidine;    Neuroinflammation;    Neuronal apoptosis;    STING;    IRE1α;    Traumatic brain injury;   

DOI  :  10.1186/s12974-023-02903-w

 received in 2023-04-19, accepted in 2023-09-22,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundNeuroinflammation is one of the most important pathogeneses in secondary brain injury after traumatic brain injury (TBI). Neutrophil extracellular traps (NETs) forming neutrophils were found throughout the brain tissue of TBI patients and elevated plasma NET biomarkers correlated with worse outcomes. However, the biological function and underlying mechanisms of NETs in TBI-induced neural damage are not yet fully understood. Here, we used Cl-amidine, a selective inhibitor of NETs to investigate the role of NETs in neural damage after TBI.MethodsControlled cortical impact model was performed to establish TBI. Cl-amidine, 2′3′-cGAMP (an activator of stimulating Interferon genes (STING)), C-176 (a selective STING inhibitor), and Kira6 [a selectively phosphorylated inositol-requiring enzyme-1 alpha [IRE1α] inhibitor] were administrated to explore the mechanism by which NETs promote neuroinflammation and neuronal apoptosis after TBI. Peptidyl arginine deiminase 4 (PAD4), an essential enzyme for neutrophil extracellular trap formation, is overexpressed with adenoviruses in the cortex of mice 1 day before TBI. The short-term neurobehavior tests, magnetic resonance imaging (MRI), laser speckle contrast imaging (LSCI), Evans blue extravasation assay, Fluoro-Jade C (FJC), TUNEL, immunofluorescence, enzyme-linked immunosorbent assay (ELISA), western blotting, and quantitative-PCR were performed in this study.ResultsNeutrophils form NETs presenting in the circulation and brain at 3 days after TBI. NETs inhibitor Cl-amidine treatment improved short-term neurological functions, reduced cerebral lesion volume, reduced brain edema, and restored cerebral blood flow (CBF) after TBI. In addition, Cl-amidine exerted neuroprotective effects by attenuating BBB disruption, inhibiting immune cell infiltration, and alleviating neuronal death after TBI. Moreover, Cl-amidine treatment inhibited microglia/macrophage pro-inflammatory polarization and promoted anti-inflammatory polarization at 3 days after TBI. Mechanistically, STING ligand 2′3′-cGAMP abolished the neuroprotection of Cl-amidine via IRE1α/ASK1/JNK signaling pathway after TBI. Importantly, overexpression of PAD4 promotes neuroinflammation and neuronal death via the IRE1α/ASK1/JNK signaling pathway after TBI. However, STING inhibitor C-176 or IRE1α inhibitor Kira6 effectively abolished the neurodestructive effects of PAD4 overexpression after TBI.ConclusionAltogether, we are the first to demonstrate that NETs inhibition with Cl-amidine ameliorated neuroinflammation, neuronal apoptosis, and neurological deficits via STING-dependent IRE1α/ASK1/JNK signaling pathway after TBI. Thus, Cl-amidine treatment may provide a promising therapeutic approach for the early management of TBI.Graphical Abstract

【 授权许可】

CC BY   
© BioMed Central Ltd., part of Springer Nature 2023

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