IL-1β and TNF-α induce neurotoxicity through glutamate production: a potential role for neuronal glutaminase
Ling Ye,Ling Ye,Ling Ye,Yunlong Huang,Lixia Zhao,Yuju Li,Lijun Sun,You Zhou,Guanxiang Qian,Jialin C. Zheng,Jialin C. Zheng +10 more
Reads0
Chats0
TLDR
Using primary rat and human neuronal cultures, it is confirmed that interleukin‐1β and tumor necrosis factor‐α, two pro‐inflammatory cytokines that are typically elevated in neurodegenerative disease states, induced neuronal death and apoptosis in vitro.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 diseasesread more
Citations
More filters
Journal ArticleDOI
Single-Cell RNA Sequencing of Microglia throughout the Mouse Lifespan and in the Injured Brain Reveals Complex Cell-State Changes.
Timothy R. Hammond,Timothy R. Hammond,Timothy R. Hammond,Connor Dufort,Lasse Dissing-Olesen,Lasse Dissing-Olesen,Lasse Dissing-Olesen,Stefanie Giera,Stefanie Giera,Adam Young,Alec Wysoker,Alec J. Walker,Alec J. Walker,Alec J. Walker,Frederick Gergits,Michael Segel,James Nemesh,Samuel E. Marsh,Samuel E. Marsh,Samuel E. Marsh,Arpiar Saunders,Arpiar Saunders,Evan Z. Macosko,Florent Ginhoux,Jinmiao Chen,Robin J.M. Franklin,Xianhua Piao,Xianhua Piao,Steven A. McCarroll,Steven A. McCarroll,Beth Stevens +30 more
TL;DR: The analysis of RNA expression patterns of more than 76,000 individual microglia in mice during development, in old age, and after brain injury uncovered at least nine transcriptionally distinct microglial states, which expressed unique sets of genes and were localized in the brain using specific markers.
Journal ArticleDOI
Neuronal Cell Death.
TL;DR: Which forms of cell death occur in stroke and Alzheimer's disease are reassess, and why it has been so difficult to pinpoint the type of neuronal death involved is discussed.
Journal ArticleDOI
Obesity and neuroinflammation: a pathway to cognitive impairment.
TL;DR: The evidence that obesity and high fat feeding can lead to cognitive dysfunction is addressed and the idea that obesity-associated systemic inflammation leads to inflammation within the brain, particularly the hypothalamus, and that this is partially responsible for negative cognitive outcomes is examined.
Journal ArticleDOI
Cytokines and Chemokines at the Crossroads of Neuroinflammation, Neurodegeneration, and Neuropathic Pain
TL;DR: This review will focus on how cytokines and chemokines affect neuroinflammation and disease pathogenesis in bacterial meningitis and brain abscesses, Lyme neuroborreliosis, human immunodeficiency virus encephalitis, and neuropathic pain.
Journal ArticleDOI
Apoptosis in Alzheimer's disease: an understanding of the physiology, pathology and therapeutic avenues.
M. Obulesu,M. Jhansi Lakshmi +1 more
TL;DR: This review summarizes the crucial apoptotic mechanisms occurring in both mitochondria and ER and gives substantial summary of the diverse mechanisms studied in vivo and in vitro.
References
More filters
Journal ArticleDOI
Microglia-mediated neurotoxicity: uncovering the molecular mechanisms
TL;DR: Overactivated microglia can be detected using imaging techniques and therefore this knowledge offers an opportunity not only for early diagnosis but, importantly, for the development of targeted anti-inflammatory therapies that might slow or halt the progression of neurodegenerative disease.
Journal ArticleDOI
c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism.
Ping Gao,Irina Tchernyshyov,Tsung Cheng Chang,Yun-Sil Lee,Kayoko Kita,Takafumi Ochi,Karen I. Zeller,Angelo M. De Marzo,Jennifer E. Van Eyk,Joshua T. Mendell,Chi V. Dang +10 more
TL;DR: In this paper, the c-Myc (hereafter referred to as Myc) oncogenic transcription factor, which is known to regulate microRNAs and stimulate cell proliferation, transcriptionally represses miR-23a and miR23b, resulting in greater expression of their target protein, mitochondrial glutaminase, in human P-493 B lymphoma cells and PC3 prostate cancer cells.
Journal ArticleDOI
Glutamate as a Neurotransmitter in the Brain: Review of Physiology and Pathology
TL;DR: Endogenous glutamate, by activating NMDA, AMPA or mGluR1 receptors, may contribute to the brain damage occurring acutely after status epilepticus, cerebral ischemia or traumatic brain injury, and may also contribute to chronic neurodegeneration in such disorders as amyotrophic lateral sclerosis and Huntington's chorea.
Journal Article
Abstract #LB-186: c-Myc suppression of miR-23 enhances mitochondrial glutaminase and glutamine metabolism
Ping Gao,Irina Tchernyshyov,Tsung Cheng Chang,Yun Sil Lee,Kayoko Kita,Takafumi Ochi,Karen I. Zeller,Angelo M. De Marzo,Jennifer E. Van Eyk,Joshua T. Mendell,Chi Dang +10 more
TL;DR: The c-Myc oncogenic transcription factor, which is known to regulate microRNAs and stimulate cell proliferation, transcriptionally represses miR-23a and miB-23b, resulting in greater expression of their target protein, mitochondrial glutaminase, in human P-493 B lymphoma cells and PC3 prostate cancer cells, which leads to upregulation of glutamine catabolism.
Journal ArticleDOI
Role of pro-inflammatory cytokines released from microglia in neurodegenerative diseases.
TL;DR: Current understanding of the involvement of cytokines in neurodegenerative disorders and their potential signaling mechanisms are summarized to suggest that microglial activation and pro-inflammatory cytokines merit interest as targets in the treatment of neurodegnerative disorders.
Related Papers (5)
Resting Microglial Cells Are Highly Dynamic Surveillants of Brain Parenchyma in Vivo
Neurotoxic reactive astrocytes are induced by activated microglia
Shane A. Liddelow,Kevin A. Guttenplan,Laura E. Clarke,Frederick C. Bennett,Christopher J. Bohlen,Lucas Schirmer,Mariko L. Bennett,Alexandra E. Münch,Won-Suk Chung,Todd C. Peterson,Daniel K. Wilton,Arnaud Frouin,Brooke A. Napier,Nikhil Panicker,Manoj Kumar,Marion S. Buckwalter,David H. Rowitch,Valina L. Dawson,Ted M. Dawson,Beth Stevens,Ben A. Barres +20 more