Fluvoxamine Confers Neuroprotection via Inhibiting Infiltration of Peripheral Leukocytes and M1 Polarization of Microglia/Macrophages in a Mouse Model of Traumatic Brain Injury

Shi, Mingming; Mi, Liang; Li, Fanjian; Liu, Ying; Zhou, Yuan; Chen, Fanglian; Liu, Liang; Chai, Yan; Yang, Weidong; Zhang, Jianning; Chen, Xin

doi:10.1089/neu.2021.0355

Cited by 14 publications

(16 citation statements)

References 35 publications

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“…TBI was induced by a digital electromagnetically controlled cortical impact (CCI) device (CCI-6.3 device, Custom Design & Fabrication, USA) as previously described ( 32 ). Briefly, each mouse was anesthetized with 1–1.5% isoflurane in 30% oxygen and 70% nitrous oxide during the surgical procedure, and the body temperature was maintained at 37 ± 0.5°C using a heating blanket.…”

Section: Methodsmentioning

confidence: 99%

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Inhibition of neutrophil extracellular trap formation attenuates NLRP1-dependent neuronal pyroptosis via STING/IRE1α pathway after traumatic brain injury in mice

et al. 2023

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IntroductionIncreased neutrophil extracellular trap (NET) formation has been reported to be associated with cerebrovascular dysfunction and neurological deficits in traumatic brain injury (TBI). However, the biological function and underlying mechanisms of NETs in TBI-induced neuronal cell death are not yet fully understood.MethodsFirst, brain tissue and peripheral blood samples of TBI patients were collected, and NETs infiltration in TBI patients was detected by immunofluorescence staining and Western blot. Then, a controlled cortical impact device was used to model brain trauma in mice, and Anti-Ly6G, DNase, and CL-amidine were given to reduce the formation of neutrophilic or NETs in TBI mice to evaluate neuronal death and neurological function. Finally, the pathway changes of neuronal pyroptosis induced by NETs after TBI were investigated by administration of peptidylarginine deiminase 4 (a key enzyme of NET formation) adenovirus and inositol-requiring enzyme-1 alpha (IRE1α) inhibitors in TBI mice.ResultsWe detected that both peripheral circulating biomarkers of NETs and local NETs infiltration in the brain tissue were significantly increased and had positive correlations with worse intracranial pressure (ICP) and neurological dysfunction in TBI patients. Furthermore, the depletion of neutrophils effectively reduced the formation of NET in mice subjected to TBI. we found that degradation of NETs or inhibition of NET formation significantly inhibited nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain containing 1 (NLRP1) inflammasome-mediated neuronal pyroptosis after TBI, whereas these inhibitory effects were abolished by cyclic GMP-AMP (cGAMP), an activator of stimulating Interferon genes (STING). Moreover, overexpression of PAD4 in the cortex by adenoviruses could aggravate NLRP1-mediated neuronal pyroptosis and neurological deficits after TBI, whereas these pro-pyroptotic effects were rescued in mice also receiving STING antagonists. Finally, IRE1α activation was significantly upregulated after TBI, and NET formation or STING activation was found to promote this process. Notably, IRE1α inhibitor administration significantly abrogated NETs-induced NLRP1 inflammasome-mediated neuronal pyroptosis in TBI mice.DiscussionOur findings indicated that NETs could contribute to TBI-induced neurological deficits and neuronal death by promoting NLRP1-mediated neuronal pyroptosis. Suppression of the STING/ IRE1α signaling pathway can ameliorate NETs-induced neuronal pyroptotic death after TBI.

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Section: Methodsmentioning

confidence: 99%

“…Nissl staining was performed to evaluate neuronal damage as previously described ( 32 ). The paraffin-embedded 4% paraformaldehyde-fixed brains were sliced into 10um thick sections.…”

Section: Methodsmentioning

confidence: 99%

Inhibition of neutrophil extracellular trap formation attenuates NLRP1-dependent neuronal pyroptosis via STING/IRE1α pathway after traumatic brain injury in mice

et al. 2023

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“…TBI was conducted using a digital electromagnetically controlled cortical impact (CCI) device (eCCI-6.3 device, Custom Design & Fabrication, USA) as we previously described [23]. In brief, mice were anesthetized with 1.5-3% iso urane in 30% oxygen and 70% nitrous oxide, placed on a heating blanket to maintain body temperature at 37 ± 0.5°C, and subsequently mounted in a stereotaxic head frame.…”

Section: Tbi Modelmentioning

confidence: 99%

“…To assess the cerebral blood ow (CBF) changes in the cortex at pre-surgery and at 1 h, 12 h, 1d, and 3 d after CCI, we used a laser speckle contrast imaging (LSCI) system (PeriCam PSI System, Perimed AB, Sweden) as we previously described [23]. Brie y, the mice were anesthetized and placed prone in a stereotaxic head frame.…”

Section: Laser Speckle Contrast Imagingmentioning

confidence: 99%

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

Shi

Liu

Cao

et al. 2023

Preprint

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Background Neuroinflammation 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.Methods Controlled 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 d 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.Results Neutrophils form NETs presenting in the circulation and brain at 3 d 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 d 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.Conclusion Altogether, 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.

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“…The demographics and clinical characteristics of these patients are shown in Table 1. [19]. Brie y, each mouse was anesthetized with 1-1.5% iso urane in 30% oxygen and 70% nitrous oxide and subsequently placed prone in a stereotaxic head frame.…”

Section: Human Brain Tissuesmentioning

confidence: 99%

Neutrophil extracellular traps exacerbate microglia/macrophages-mediated neuroinflammation via cGAS in mice with traumatic brain injury

Shi

Liu

Cao

et al. 2022

Preprint

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Intense neuroinflammatory response with widespread microglia/macrophage activation and leucocyte infiltration occurring during the acute phase of traumatic brain injury (TBI) is an important mediator of secondary neurological injury. Neutrophils, as the most abundant leukocytes in peripheral circulation and the first-line transmigrated immune cells at the contused parenchyma following TBI, are suggested to worsen TBI outcomes and exacerbate TBI-related neuroinflammation, via unclear mechanisms. We hypothesized that neutrophil extracellular trap (NET) formation as a key mechanistic regulator, exacerbate microglia/macrophage-mediated neuroinflammation and acute neurological deficits after TBI. In this study, we observed massive NET formation in contused brain tissue of TBI patients and elevated plasma NET biomarkers correlated with upregulated cGAS-STING pathway. Overexpression of peptidylarginine deiminase 4 (PAD4) induces an increase in the NET formation that is accompanied by upregulation of the cGAS-STING pathway and exacerbation of microglia/macrophages-mediated neuroinflammation and neurological injury. Additionally, degradation of NETs-associated DNA by DNase 1 and inhibition of NET formation by pharmacological inhibition of PAD effectively inhibit cGAS-STING pathway activation and ameliorate microglia/macrophages-mediated neuroinflammatory responses. Collectively, our data highlight that targeting NETs is a promising therapeutic strategy for TBI treatment.

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Fluvoxamine Confers Neuroprotection via Inhibiting Infiltration of Peripheral Leukocytes and M1 Polarization of Microglia/Macrophages in a Mouse Model of Traumatic Brain Injury

Cited by 14 publications

References 35 publications

Inhibition of neutrophil extracellular trap formation attenuates NLRP1-dependent neuronal pyroptosis via STING/IRE1α pathway after traumatic brain injury in mice

Inhibition of neutrophil extracellular trap formation attenuates NLRP1-dependent neuronal pyroptosis via STING/IRE1α pathway after traumatic brain injury in mice

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

Neutrophil extracellular traps exacerbate microglia/macrophages-mediated neuroinflammation via cGAS in mice with traumatic brain injury

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