Tumor Necrosis Factor-α Induces Neurotoxicity via Glutamate Release from Hemichannels of Activated Microglia in an Autocrine Manner*

By H. Takeuchi, Shijie Jin, Jinyan Wang, Guiqin Zhang, J. Kawanokuchi, R. Kuno, Yoshifumi Sonobe, T. Mizuno, A. Suzumura. Journal of Biological Chemistry, 2006

747 citations recorded by the source corpus.

Glutamate released by activated microglia induces excitoneurotoxicity and may contribute to neuronal damage in neurodegenerative diseases, including Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, and multiple sclerosis. In addition, tumor necrosis factor-α (TNF-α) secreted from activated microglia may elicit neurodegeneration through caspase-dependent cascades and silencing cell survival signals. However, direct neurotoxicity of TNF-α is relatively weak, because TNF-α also increases production of neuroprotective factors. Accordingly, it is still controversial how TNF-α exerts neurotoxicity in neurodegenerative diseases. Here we have shown that TNF-α is the key cytokine that stimulates extensive microglial glutamate release in an autocrine manner by up-regulating glutaminase to cause excitoneurotoxicity. Further, we have demonstrated that the connexin 32 hemichannel of the gap junction is another main source of glutamate release from microglia besides glutamate transporters. Although pharmacological blockade of glutamate receptors is a promising therapeutic candidate for neurodegenerative diseases, the associated perturbation of physiological glutamate signals has severe adverse side effects. The unique mechanism of microglial glutamate release that we describe here is another potential therapeutic target. We rescued neuronal cell death in vitro by using a glutaminase inhibitor or hemichannel blockers to diminish microglial glutamate release without perturbing the physiological glutamate level. These drugs may give us a new therapeutic strategy against neurodegenerative diseases with minimum adverse side effects.

Subfields: Cellular and Molecular Neuroscience, Molecular Biology, Neurology

View Paper: https://www.semanticscholar.org/paper/15fbc0b92c51642fbbeaf896ba3d7e12d1c100f3

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cellular and Molecular Neuroscience

1. Robin J. M. Franklin
2. J. Lladó
3. Beth Stevens
4. G. Olmos

In Molecular Biology

1. Robin J. M. Franklin
2. Beth Stevens
3. Steven A. McCarroll
4. Alec Wysoker
5. Jinmiao Chen
6. C. Iadecola

In Neurology

1. Robin J. M. Franklin
2. J. Lladó
3. Beth Stevens
4. Florent Ginhoux
5. G. Olmos
6. C. Iadecola

Citations in the corpus

• Tumor Necrosis Factor Alpha: A Link between Neuroinflammation and Excitotoxicity (2014, positive): “In mouse primary microglia it was demonstrated that TNF-α, through the TNFR1 pathway, induces excitotoxicity by promoting microglial glutamate release from hemichannels of gap junctions in an autocrine manner [73].”
• Single cell RNA sequencing of microglia throughout the mouse lifespan and in the injured brain reveals complex cell-state changes (2018, background): “For example, Il1b and Tnf can both cause neurotoxicity (Takeuchi et al., 2006; Ye et al., 2013), and infiltrating immune cells attracted by the chemokines expressed in the Ccl4+ subpopulation can exacerbate pathology (Gadani et al., 2015).”
• Characterization of phenotype markers and neuronotoxic potential of polarised primary microglia in vitro (2013, methodology): “Based on previous reports, the day after plating, microglia were treated with PBS (vehicle; 10 ll/ml of culture media), LPS at 1 lg/ mL (Takeuchi et al., 2006; Kaindl et al., 2012), IL-1b at 50 ng/mL (Street et al., 2003; Hjorth et al., 2010), IL-4 at 20 ng/mL (Butovsky et al., 2006; Kigerl et al.,…”