Histones of Neutrophil Extracellular Traps Induce CD11b Expression in Brain Pericytes Via Dectin-1 after Traumatic Brain Injury

Liu, Yang‐Wuyue; Zhang, Jingyu; Bi, Wanda; Zhou, Mi; Li, Jiabo; Xiong, Tiantian; Yang, Nan; Zhao, Li; Chen, Xing; Zhou, Yuanguo; He, Wenhui; Yang, Teng; Wang, Hao; Xu, Lunshan; Dai, Shuang-Shuang

doi:10.1007/s12264-022-00902-0

Cited by 11 publications

(3 citation statements)

References 47 publications

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“…Clinical results have shown that neutrophil circulating levels increase by 4-fold and these neutrophils infiltrate the cortical and subcortical parenchyma over several days after TBI [23,24]. NETs generated from activated neutrophils damage the central nervous system (CNS) through many mechanisms after TBI, such as the disruption of brain cells and vascular endothelial cells [25][26][27]. Considering the terrible role of ER stress activation in the process of secondary brain injury [15] we hypothesized that there was a connection between NETs and ER stress in TBI.…”

Section: Discussionmentioning

confidence: 99%

Neutrophil extracellular traps aggravate neuronal endoplasmic reticulum stress and apoptosis via TLR9 after traumatic brain injury

Min

Shi

et al. 2023

Cell Death Dis

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Endoplasmic reticulum (ER) stress and ER stress-mediated apoptosis play an important role during secondary brain damage after traumatic brain injury (TBI). Increased neutrophil extracellular traps (NETs) formation has been demonstrated to be associated with neurological damage after TBI. However, the correlation between ER stress and NETs remains unclear, and the specific function of NETs in neurons has not been defined. In this study, we found that the levels of NETs circulating biomarkers were remarkably elevated in the plasma of TBI patients. We then inhibited NETs formation by peptidylarginine deiminase 4 (PAD4, a critical enzyme for NETs formation) deficiency and discovered that ER stress activation and ER stress-mediated neuronal apoptosis were reduced. The degradation of NETs via DNase I showed similar outcomes. Furthermore, overexpression of PAD4 aggravated neuronal ER stress and ER stress-associated apoptosis, while TLR9 antagonist administration abrogated the damage caused by NETs. In addition to in vivo experiments, in vitro experiments revealed that treatment with a TLR9 antagonist alleviated NETs-induced ER stress and apoptosis in HT22 cells. Collectively, our results indicated that ER stress as well as the accompanying neuronal apoptosis can be ameliorated by disruption of NETs and that suppression of the TLR9-ER stress signaling pathway may contribute to positive outcomes after TBI.

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Section: Discussionmentioning

confidence: 99%

Neutrophil extracellular traps aggravate neuronal endoplasmic reticulum stress and apoptosis via TLR9 after traumatic brain injury

Min

Shi

et al. 2023

Cell Death Dis

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“…The mouse model of TBI was constructed as described previously using an automatic impact machine (LinTech, Monrovia, CA, USA) and a downstroke (velocity, 2.5 m/s; deformation depth, 3.5 mm; duration, 150 ms) to create a degree of severe TBI [ 19 , 20 ]. This reproducible and consistent model is generally associated with 30% mortality within the first 5 min after injury.…”

Section: Methodsmentioning

confidence: 99%

FOXO1 reshapes neutrophils to aggravate acute brain damage and promote late depression after traumatic brain injury

Zhou,

Liu,

et al. 2024

Military Med Res

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Background Neutrophils are traditionally viewed as first responders but have a short onset of action in response to traumatic brain injury (TBI). However, the heterogeneity, multifunctionality, and time-dependent modulation of brain damage and outcome mediated by neutrophils after TBI remain poorly understood. Methods Using the combined single-cell transcriptomics, metabolomics, and proteomics analysis from TBI patients and the TBI mouse model, we investigate a novel neutrophil phenotype and its associated effects on TBI outcome by neurological deficit scoring and behavioral tests. We also characterized the underlying mechanisms both in vitro and in vivo through molecular simulations, signaling detections, gene expression regulation assessments [including dual-luciferase reporter and chromatin immunoprecipitation (ChIP) assays], primary cultures or co-cultures of neutrophils and oligodendrocytes, intracellular iron, and lipid hydroperoxide concentration measurements, as well as forkhead box protein O1 (FOXO1) conditional knockout mice. Results We identified that high expression of the FOXO1 protein was induced in neutrophils after TBI both in TBI patients and the TBI mouse model. Infiltration of these FOXO1high neutrophils in the brain was detected not only in the acute phase but also in the chronic phase post-TBI, aggravating acute brain inflammatory damage and promoting late TBI-induced depression. In the acute stage, FOXO1 upregulated cytoplasmic Versican (VCAN) to interact with the apoptosis regulator B-cell lymphoma-2 (BCL-2)-associated X protein (BAX), suppressing the mitochondrial translocation of BAX, which mediated the antiapoptotic effect companied with enhancing interleukin-6 (IL-6) production of FOXO1high neutrophils. In the chronic stage, the “FOXO1-transferrin receptor (TFRC)” mechanism contributes to FOXO1high neutrophil ferroptosis, disturbing the iron homeostasis of oligodendrocytes and inducing a reduction in myelin basic protein, which contributes to the progression of late depression after TBI. Conclusions FOXO1high neutrophils represent a novel neutrophil phenotype that emerges in response to acute and chronic TBI, which provides insight into the heterogeneity, reprogramming activity, and versatility of neutrophils in TBI.

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“…Neuroinflammation inducing secondary damage to the brain is heralded by the release of proinflammatory cytokines, chemokines and inflammatory mediators (Ziebell and Morganti-Kossmann, 2010). The resulting inflammatory environment stimulates resident microglia and astrocytes while activated brain endothelial cells cause blood brain barrier (BBB) permeabilization which brings about infiltration of peripheral leukocytes (Acosta et al, 2013;Hernandez-Ontiveros et al, 2013;Liu et al, 2022). Inflammatory mediators are released by these leukocytes, specifically macrophages, neutrophils and lymphocytes, and play a crucial role in neuronal death (Mele et al, 2021).…”

Section: Neuroinflammationmentioning

confidence: 99%

Traumatic brain injury: Mechanisms, manifestations, and visual sequelae

et al. 2023

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Traumatic brain injury (TBI) results when external physical forces impact the head with sufficient intensity to cause damage to the brain. TBI can be mild, moderate, or severe and may have long-term consequences including visual difficulties, cognitive deficits, headache, pain, sleep disturbances, and post-traumatic epilepsy. Disruption of the normal functioning of the brain leads to a cascade of effects with molecular and anatomical changes, persistent neuronal hyperexcitation, neuroinflammation, and neuronal loss. Destructive processes that occur at the cellular and molecular level lead to inflammation, oxidative stress, calcium dysregulation, and apoptosis. Vascular damage, ischemia and loss of blood brain barrier integrity contribute to destruction of brain tissue. This review focuses on the cellular damage incited during TBI and the frequently life-altering lasting effects of this destruction on vision, cognition, balance, and sleep. The wide range of visual complaints associated with TBI are addressed and repair processes where there is potential for intervention and neuronal preservation are highlighted.

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Histones of Neutrophil Extracellular Traps Induce CD11b Expression in Brain Pericytes Via Dectin-1 after Traumatic Brain Injury

Cited by 11 publications

References 47 publications

Neutrophil extracellular traps aggravate neuronal endoplasmic reticulum stress and apoptosis via TLR9 after traumatic brain injury

Neutrophil extracellular traps aggravate neuronal endoplasmic reticulum stress and apoptosis via TLR9 after traumatic brain injury

FOXO1 reshapes neutrophils to aggravate acute brain damage and promote late depression after traumatic brain injury

Traumatic brain injury: Mechanisms, manifestations, and visual sequelae

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