VEGI attenuates the inflammatory injury and disruption of blood–brain barrier partly by suppressing the TLR4/NF-κB signaling pathway in experimental traumatic brain injury

Gao, Weiwei; Zhao, Ziqi; Yu, Guang; Zhou, Ziwei; Zhou, Yuan; Hu, Tingting; Jiang, Rongcai; Zhang, Jianning

doi:10.1016/j.brainres.2015.04.035

Cited by 77 publications

(56 citation statements)

References 40 publications

(43 reference statements)

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“…For example, Lian et al showed that mice lacking IĸBɑ , an NF-κB inhibitory protein, showed significantly increased neuroinflammation when assessed in a model of TBI (4). Moreover, in another TBI model, suppressing the NF-κB signaling pathway through exogenous VEGI treatment attenuated brain injury (5). Thus, these studies illustrate that unrestricted NF-κB signaling is an important component in the pathophysiology of brain injury.…”

Section: Introductionmentioning

confidence: 99%

Loss of NLRX1 Exacerbates Neural Tissue Damage and NF-κB Signaling following Brain Injury

Theus

Brickler

Meza

et al. 2017

The Journal of Immunology

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Traumatic and non-traumatic brain injury results from severe disruptions in the cellular microenvironment leading to massive loss of neuronal populations and increased neuroinflammation. The progressive cascade of secondary events, including ischemia, inflammation, excitotoxicity and free radical release contribute to neural tissue damage. NLRX1 is a member of the NLR family of pattern recognition receptors and is a potent negative regulator of several pathways that significantly modulate many of these events. Thus, we hypothesized that NLRX1 limits immune system signaling in the brain following trauma. To evaluate this hypothesis, we utilized Nlrx1−/− mice in a controlled cortical impact (CCI) injury murine model of traumatic brain injury (TBI). Here, we show that the Nlrx1−/− mice exhibited significantly larger brain lesions and increased motor deficits following CCI injury. Mechanistically, our data indicate that the NF-κB signaling cascade is significantly up-regulated in the Nlrx1−/− animals. This up-regulation is associated with increased microglia and macrophage populations in the cortical lesion. Utilizing a mouse neuroblastoma cell line (N2A), we also found that NLRX1 significantly reduced apoptosis under hypoxic conditions. In human patients, we identify 15 NLRs that are significantly dysregulated, including significant downregulation of NLRX1 in brain injury following aneurysm. We further demonstrate a concurrent increase in NF-κB signaling that is correlated with aneurysm severity in these human subjects. Together, our data extend the function of NLRX1 beyond its currently characterized role in host-pathogen defense and identify this highly novel NLR as a significant modulator of brain injury progression.

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Section: Introductionmentioning

confidence: 99%

Loss of NLRX1 Exacerbates Neural Tissue Damage and NF-κB Signaling following Brain Injury

Theus

Brickler

Meza

et al. 2017

The Journal of Immunology

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“…It is well documented that tight junctions undergo an array of molecular changes in response to pathological cues 18 with post-translational degradation 19 and redistribution/internalisation of tight junction proteins reported in response to inflammatory mediators, [20][21][22] kinases, 23 and microbiota changes. 24,25 Internalization is described most commonly for ZO-1, as it resides in the cytoplasm adjacent to the plasma membrane of the cell.…”

Section: Discussionmentioning

confidence: 99%

A novelin vitroplatform for the study of SN38-induced mucosal damage and the development of Toll-like receptor 4-targeted therapeutic options

Wardill

Gibson

Sebille

et al. 2016

Exp Biol Med (Maywood)

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Tight junction and epithelial barrier disruption is a common trait of many gastrointestinal pathologies, including chemotherapyinduced gut toxicity. Currently, there are no validated in vitro models suitable for the study of chemotherapy-induced mucosal damage that allow paralleled functional and structural analyses of tight junction integrity. We therefore aimed to determine if a transparent, polyester membrane insert supports a polarized T84 monolayer with the phenotypically normal tight junctions. T84 cells (passage 5-15) were seeded into either 0.6 cm 2 , 0.4 mm pore mixed-cellulose transwell hanging inserts or 1.12 cm 2 , 0.4 mm pore polyester transwell inserts at varying densities. Transepithelial electrical resistance was measured daily to assess barrier formation. Immunofluoresence for key tight junction proteins (occludin, zonular occludens-1, claudin-1) and transmission electron microscopy were performed to assess tight junction integrity, organelle distribution, and polarity. Reverse transcription-polymerase chain reaction was performed to determine expression of toll-like receptor 4 (TLR4). Liquid chromatography was also conducted to assess SN38 degradation in this model. Polyester membrane inserts support a polarized T84 phenotype with functional tight junctions in vitro. Transmission electron microscopy indicated polarity, with apico-laterally located tight junctions. Immunofluorescence showed membranous staining for all tight junction proteins. No internalization was evident. T84 cells expressed TLR4, although this was significantly lower than levels seen in HT29 cells (P ¼ .0377). SN38 underwent more rapid degradation in the presence of cells (À76.04 AE 1.86%) compared to blank membrane (À48.39 AE 4.01%), indicating metabolic processes. Polyester membrane inserts provide a novel platform for paralleled functional and structural analysis of tight junction integrity in T84 monolayers. T84 cells exhibit the unique ability to metabolize SN38 as well as expressing TLR4, making this an excellent platform to study clinically relevant therapeutic interventions for SN38-induced mucosal damage by targeting TLR4.

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“…Traumatic brain injury (TBI) is a major cause of death and persistent disability [1]. In addition, it is reported that over 5 % of patients with moderate injury, and 16 % of patients with severe injury would develop posttraumatic epilepsy [2,3].…”

Section: Introductionmentioning

confidence: 99%

“…In addition, it is reported that over 5 % of patients with moderate injury, and 16 % of patients with severe injury would develop posttraumatic epilepsy [2,3]. The mechanisms underlying secondary brain damage following TBI are complex and involve two main stages: traumatic cerebral edema and delayed neuronal damage [1][2][3]. Delayed neuronal damage leads to irreversible necrosis or apoptosis of neurons, which could affect the long-term prognosis and quality of life in patients [1,2,4,5].…”

Section: Introductionmentioning

confidence: 99%

“…The mechanisms underlying secondary brain damage following TBI are complex and involve two main stages: traumatic cerebral edema and delayed neuronal damage [1][2][3]. Delayed neuronal damage leads to irreversible necrosis or apoptosis of neurons, which could affect the long-term prognosis and quality of life in patients [1,2,4,5]. It is known that NF-kappa B (NF-κB) can result in neuronal damage by apoptosis.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Effect of recombinant human erythropoietin expressions of apoptosis genes in rats following traumatic brain injury

Yuan¹,

Bian²,

Wei³

et al. 2016

Trop. J. Pharm Res

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VEGI attenuates the inflammatory injury and disruption of blood–brain barrier partly by suppressing the TLR4/NF-κB signaling pathway in experimental traumatic brain injury

Cited by 77 publications

References 40 publications

Loss of NLRX1 Exacerbates Neural Tissue Damage and NF-κB Signaling following Brain Injury

Loss of NLRX1 Exacerbates Neural Tissue Damage and NF-κB Signaling following Brain Injury

A novelin vitroplatform for the study of SN38-induced mucosal damage and the development of Toll-like receptor 4-targeted therapeutic options

Effect of recombinant human erythropoietin expressions of apoptosis genes in rats following traumatic brain injury

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