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

Abstract

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-␣ (TNF-␣) secreted from activated microglia may elicit neurodegeneration through caspasedependent cascades and silencing cell survival signals. However, direct neurotoxicity of TNF-␣ is relatively weak, because TNF-␣ also increases production of neuroprotective factors. Accordingly, it is still controversial how TNF-␣ exerts neurotoxicity in neurodegenerative diseases. Here we have shown that TNF-␣ 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.

MyD88-Dependent Signals Are Essential for the Host Immune Response in Experimental Brain Abscess

“…This is supported by our histological findings depicting severe edema and necrosis in the brains of MyD88 KO mice at the later time points examined (i.e., 24 and 42 h postinfection) despite similar S. aureus levels between WT and KO mice. Cytokines and chemokines elaborated at high levels can also exert direct neurotoxic effects as demonstrated by others (56,57), and this remains another potential mechanism of necrotic cell death in the brain abscess model. In addition, a reduction in NF-B signaling, presumably through the loss of MyD88, might lead to a reduction in prosurvival signals (58), culminating in increased cell death.…”

Microglial Activation in Stroke: Therapeutic Targets

“…52 This release can produce neuronal death in culture and in ex vivo slice preparations. 52,53 Glutamate release from microglia might thus contribute to ischemic brain injury, 54 but the effect of glutamate release from microglia is likely to be small relative to the effects of neuronal glutamate release and failure of astrocyte glutamate reuptake that occur during brain ischemia. Nonetheless, glutamate release from chronically activated microglia in the postischemic period could contribute to delayed neuronal death at infarct margins or after transient ischemia.…”

Dual effects of TNFα on nerve fiber formation from ventral mesencephalic organotypic tissue cultures

“…Antibodies against TNFα receptor 1 (TNFR1; 2.5 µg/ml; n=7 and 5.0 µg/ml; n=16; goat polyclonal antibody; Santa Cruz Biotechnology, Inc., Santa Cruz, CA) or TNFα receptor 2 (TNFR2; 2.5 µg/ml; n=6 and 5.0 µg/ml; n=15; rabbit polyclonal antibody; Santa Cruz Biotechnology, Inc., Santa Cruz, CA, (Clarke and Branton 2002;Tacheuchi et al 2006)) were added together with TNFα to the medium between 4-7 DIV and evaluated at 7 DIV. In addition, antibodies against TNFR1 and TNFR2 (2.5 µg/ml; TNFR1 n=4, TNFR2 n=5, or 5.0 µg/ml; TNFR1 n=7, TNFR2 n=6) were added without TNFα to test for specific effects of the antibodies per se.…”