<scp>IL</scp>‐1β and <scp>TNF</scp>‐α induce neurotoxicity through glutamate production: a potential role for neuronal glutaminase

Ye, Ling; Huang, Yunlong; Zhao, Lixia; Li, Yuju; Sun, Lijun; Zhou, You; Qian, Guofeng; Zheng, Jialin

doi:10.1111/jnc.12263

Cited by 274 publications

(188 citation statements)

References 47 publications

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“…In particular, it was determined how VPA affects the production of nitric oxide (NO) and interleukin 1β (IL-1β), as well as the transcription levels of inducible NO synthase (iNOS) and IL-1β, using the established mouse microglial cell line BV2. The effect of VPA on NO and IL-1β production was the focus, as high concentrations of NO and IL-1β released by activated microglia following a pathologic insult may lead to neurotoxicity and has been reported in many neurodegenerative diseases (15)(16)(17)(18)(19). Furthermore, as it has been reported that the inducible nuclear factor-κB (NF-κB) serves a critical role in regulating the expression of inflammatory mediators and inflammatory cytokines (20), including iNOS and IL-1β, the effect of VPA on NF-κB nuclear translocation during microglial activation under iron-rich conditions was also determined.…”

Section: Introductionmentioning

confidence: 99%

Valproic acid attenuates nitric oxide and interleukin‑1β production in lipopolysaccharide‑stimulated iron‑rich microglia

Mairuae

Cheepsunthorn

2018

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Abstract. Iron accumulation in activated microglia has been consistently reported in neurodegenerative diseases. Previous results suggest that these cells facilitate neuroinflammation leading to neuronal cell death. Therefore, chemical compounds that alleviate the activation of iron-rich microglia may result in neuroprotection. In the present study, the effect of valproic acid (VPA) on microglial activation under iron-rich conditions was investigated. BV-2 microglial cells were exposed to lipopolysaccharide (LPS; 1 µg/ml) and iron (300 µg/ml) with or without VPA (1.6 mM). The results demonstrated that VPA attenuated the activation of iron-rich BV2 cells induced by LPS by down-regulating the mRNA expression of inducible nitric oxide (NO) synthase and interleukin 1β (IL-1β; P<0.01), to ultimately reduce the production of NO and IL-1β (P<0.01). These events were accompanied by an attenuation in the nuclear translocation of nuclear factor-κB p65 subunit (P<0.01). These findings suggest that VPA may be therapeutically useful for attenuating the activation of iron-rich microglia.

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Section: Introductionmentioning

confidence: 99%

Valproic acid attenuates nitric oxide and interleukin‑1β production in lipopolysaccharide‑stimulated iron‑rich microglia

Mairuae

Cheepsunthorn

2018

biom rep

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“…In contrast to antiviral responses, TNF-␣ expression in the CNS has also been associated with both neurodegenerative and neurodevelopmental diseases. Both direct and indirect neurotoxic effects of TNF-␣ in culture systems have been reported, and TNF-␣ has been proposed to contribute to neurodegeneration observed in HIV-associated dementia (43)(44)(45)(46)(47)(48)(49)(50). Transgenic mice constitutively expressing TNF-␣ in the CNS exhibit severe inflammation and associated histopathological findings, including microgliosis with infiltrating macrophages (51).…”

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confidence: 99%

Tumor Necrosis Factor Alpha-Induced Recruitment of Inflammatory Mononuclear Cells Leads to Inflammation and Altered Brain Development in Murine Cytomegalovirus-Infected Newborn Mice

Seleme

Kosmac

Jonjić³

et al. 2017

J Virol

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Congenital human cytomegalovirus (HCMV) infection is a significant cause of abnormal neurodevelopment and long-term neurological sequelae in infants and children. Resident cell populations of the developing brain have been suggested to be more susceptible to virus-induced cytopathology, a pathway thought to contribute to the clinical outcomes following intrauterine HCMV infection. However, recent findings in a newborn mouse model of the infection in the developing brain have indicated that elevated levels of proinflammatory mediators leading to mononuclear cell activation and recruitment could underlie the abnormal neurodevelopment. In this study, we demonstrate that treatment with tumor necrosis factor alpha (TNF-␣)-neutralizing antibodies decreased the frequency of CD45 ϩ Ly6C hi CD11b ϩ CCR2 ϩ activated myeloid mononuclear cells (MMCs) and the levels of proinflammatory cytokines in the blood and the brains of murine CMVinfected mice. This treatment also normalized neurodevelopment in infected mice without significantly impacting the level of virus replication. These results indicate that TNF-␣ is a major component of the inflammatory response associated with altered neurodevelopment that follows murine CMV infection of the developing brain and that a subset of peripheral blood myeloid mononuclear cells represent a key effector cell population in this model of virus-induced inflammatory disease of the developing brain.IMPORTANCE Congenital human cytomegalovirus (HCMV) infection is the most common viral infection of the developing human fetus and can result in neurodevelopmental sequelae. Mechanisms of disease leading to neurodevelopmental deficits in infected infants remain undefined, but postulated pathways include loss of neuronal progenitor cells, damage to the developing vascular system of the brain, and altered cellular positioning. Direct virus-mediated cytopathic effects cannot explain the phenotypes of brain damage in most infected infants. Using a mouse model that recapitulates characteristics of the brain infection described in human infants, we have shown that TNF-␣ plays a key role in brain inflammation, including recruitment of inflammatory mononuclear cells. Neutralization of TNF-␣ normalized neurodevelopmental abnormalities in infected mice, providing evidence that virus-induced inflammation is a major component of disease in the developing brain. These results suggest that interventions limiting inflammation associated with the infection could potentially improve the neurologic outcome of infants infected in utero with HCMV.

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“…21,22 The increase of S100B at 6 h indicates an early response of brain cells, sustained and pronounced at 24 h. S100B is a multifaceted protein produced mainly by astrocytes with an important role in neuroinflammation by signaling tissue damage and participating in the inflammatory response by activating microglia. 23 The marked increase of S100B observed in our experiments suggests that mediators released from stimulated alveolar cells might include regulators of S100B.…”

Section: Discussionmentioning

confidence: 99%

Endotoxin-induced lung alveolar cell injury causes brain cell damage

Rodríguez-González

Ramos-Nuez

Martin‐Barrasa

et al. 2014

Exp Biol Med (Maywood)

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Sepsis is the most common cause of acute respiratory distress syndrome, a severe lung inflammatory disorder with an elevated morbidity and mortality. Sepsis and acute respiratory distress syndrome involve the release of inflammatory mediators to the systemic circulation, propagating the cellular and molecular response and affecting distal organs, including the brain. Since it has been reported that sepsis and acute respiratory distress syndrome contribute to brain dysfunction, we investigated the brain-lung crosstalk using a combined experimental in vitro airway epithelial and brain cell injury model. Conditioned medium collected from an in vitro lipopolysaccharide-induced airway epithelial cell injury model using human A549 alveolar cells was subsequently added at increasing concentrations (no conditioned, 2%, 5%, 10%, 15%, 25%, and 50%) to a rat mixed brain cell culture containing both astrocytes and neurons. Samples from culture media and cells from mixed brain cultures were collected before treatment, and at 6 and 24 h for analysis. Conditioned medium at 15% significantly increased apoptosis in brain cell cultures 24 h after treatment, whereas 25% and 50% significantly increased both necrosis and apoptosis. Levels of brain damage markers S100 calcium binding protein B and neuron-specific enolase, interleukin-6, macrophage inflammatory protein-2, as well as matrix metalloproteinase-9 increased significantly after treating brain cells with !2% conditioned medium. Our findings demonstrated that human epithelial pulmonary cells stimulated with bacterial lipopolysaccharide release inflammatory mediators that are able to induce a translational clinically relevant and harmful response in brain cells. These results support a brain-lung crosstalk during sepsis and sepsis-induced acute respiratory distress syndrome.

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IL‐1β and TNF‐α induce neurotoxicity through glutamate production: a potential role for neuronal glutaminase

Cited by 274 publications

References 47 publications

Valproic acid attenuates nitric oxide and interleukin‑1β production in lipopolysaccharide‑stimulated iron‑rich microglia

Valproic acid attenuates nitric oxide and interleukin‑1β production in lipopolysaccharide‑stimulated iron‑rich microglia

Tumor Necrosis Factor Alpha-Induced Recruitment of Inflammatory Mononuclear Cells Leads to Inflammation and Altered Brain Development in Murine Cytomegalovirus-Infected Newborn Mice

Endotoxin-induced lung alveolar cell injury causes brain cell damage

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