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

Authors

  • Ling Ye,

    1. Department of Biochemistry and Molecular Biology, Shanghai Jiaotong University School of Medicine, Shanghai, China
    2. Center for Translational Neurodegeneration and Regenerative Therapy, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
    3. Laboratory of Neuroimmunology and Regenerative Therapy, Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska, USA
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  • Yunlong Huang,

    Corresponding author
    1. Laboratory of Neuroimmunology and Regenerative Therapy, Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska, USA
    • Department of Biochemistry and Molecular Biology, Shanghai Jiaotong University School of Medicine, Shanghai, China
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  • Lixia Zhao,

    1. Laboratory of Neuroimmunology and Regenerative Therapy, Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska, USA
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  • Yuju Li,

    1. Laboratory of Neuroimmunology and Regenerative Therapy, Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska, USA
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  • Lijun Sun,

    1. Laboratory of Neuroimmunology and Regenerative Therapy, Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska, USA
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  • You Zhou,

    1. Center for Biotechnology, University of Nebraska Lincoln, Lincoln, Nebraska, USA
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  • Guanxiang Qian,

    1. Department of Biochemistry and Molecular Biology, Shanghai Jiaotong University School of Medicine, Shanghai, China
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  • Jialin C. Zheng

    Corresponding author
    1. Center for Translational Neurodegeneration and Regenerative Therapy, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
    2. Laboratory of Neuroimmunology and Regenerative Therapy, Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska, USA
    3. Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska, USA
    • Department of Biochemistry and Molecular Biology, Shanghai Jiaotong University School of Medicine, Shanghai, China
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Address correspondence and reprint requests to Dr Jialin C. Zheng or Dr. Yunlong Huang, Laboratory of Neuroimmunology and Regenerative Therapy, Departments of Pharmacology and Experimental Neuroscience and Pathology and Microbiology, 985930 Nebraska Medical Center, Omaha, NE 68198-5930, USA. E-mail: jzheng@unmc.edu or yhuan1@unmc.edu ; Dr. Guanxiang Qian, Department of Biochemistry and Molecular Biology, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China. E-mail: qiangx@shsmu.edu.cn

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.

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