TY - JOUR
T1 - IL-1β and TNF-α induce neurotoxicity through glutamate production
T2 - A potential role for neuronal glutaminase
AU - Ye, Ling
AU - Huang, Yunlong
AU - Zhao, Lixia
AU - Li, Yuju
AU - Sun, Lijun
AU - Zhou, You
AU - Qian, Guanxiang
AU - Zheng, Jialin C.
PY - 2013/6
Y1 - 2013/6
N2 - 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.
AB - 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.
KW - glutamate
KW - glutaminase
KW - inflammation
KW - neurotoxicity
UR - http://www.scopus.com/inward/record.url?scp=84878767675&partnerID=8YFLogxK
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U2 - 10.1111/jnc.12263
DO - 10.1111/jnc.12263
M3 - Article
C2 - 23578284
AN - SCOPUS:84878767675
VL - 125
SP - 897
EP - 908
JO - Journal of Neurochemistry
JF - Journal of Neurochemistry
SN - 0022-3042
IS - 6
ER -