IL-1β and TNF-α induce neurotoxicity through glutamate production

A potential role for neuronal glutaminase

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

Research output: Contribution to journalArticle

122 Citations (Scopus)

Abstract

Glutaminase 1 is the main enzyme responsible for glutamate production in mammalian cells. The roles of macrophage and microglia glutaminases in brain injury, infection, and inflammation are well documented. However, little is known about the regulation of neuronal glutaminase, despite neurons being a predominant cell type of glutaminase expression. Using primary rat and human neuronal cultures, we confirmed that interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), two pro-inflammatory cytokines that are typically elevated in neurodegenerative disease states, induced neuronal death and apoptosis in vitro. Furthermore, both intracellular and extracellular glutamate levels were significantly elevated following IL-1β and/or TNF-α treatment. Pre-treatment with N-Methyl-d-aspartate (NMDA) receptor antagonist MK-801 blocked cytokine-induced glutamate production and alleviated the neurotoxicity, indicating that IL-1β and/or TNF-α induce neurotoxicity through glutamate. To determine the potential source of excess glutamate production in the culture during inflammation, we investigated the neuronal glutaminase and found that treatment with IL-1β or TNF-α significantly upregulated the kidney-type glutaminase (KGA), a glutaminase 1 isoform, in primary human neurons. The up-regulation of neuronal glutaminase was also demonstrated in situ in a murine model of HIV-1 encephalitis. In addition, IL-1β or TNF-α treatment increased the levels of KGA in cytosol and TNF-α specifically increased KGA levels in the extracellular fluid, away from its main residence in mitochondria. Together, these findings support neuronal glutaminase as a potential component of neurotoxicity during inflammation and that modulation of glutaminase may provide therapeutic avenues for neurodegenerative diseases. Pro-inflammatory cytokines such as TNF-α and IL-1β increase kidney-type mitochondrial glutaminase in the cytosol of neurons and TNF-α may further release glutaminase to the extracellular space. Consequently, intracellular and extracellular glutamate levels increase in neurons during inflammation. The excess levels of glutamate in the extracellular space may induce neuronal injury and death. Therefore, neuronal glutaminase is a potential component of neurotoxicity during inflammation.

Original languageEnglish (US)
Pages (from-to)897-908
Number of pages12
JournalJournal of Neurochemistry
Volume125
Issue number6
DOIs
StatePublished - Jun 1 2013

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Glutaminase
Interleukin-1
Glutamic Acid
Tumor Necrosis Factor-alpha
Neurons
Neurodegenerative diseases
Inflammation
Kidney
Extracellular Space
Encephalitis
Cytokines
Neurodegenerative Diseases
Cytosol
Mitochondria
Dizocilpine Maleate
Macrophages
Extracellular Fluid
Microglia

Keywords

  • glutamate
  • glutaminase
  • inflammation
  • neurotoxicity

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

IL-1β and TNF-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, Guanxiang; Zheng, Jialin C.

In: Journal of Neurochemistry, Vol. 125, No. 6, 01.06.2013, p. 897-908.

Research output: Contribution to journalArticle

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AU - Zhou, You

AU - Qian, Guanxiang

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