Tumor necrosis factor-α induces neurotoxicity via glutamate release from hemichannels of activated microglia in an autocrine manner

被引:596
作者
Takeuchi, Hideyuki [1 ]
Jin, Shijie [1 ]
Wang, Jinyan [1 ]
Zhang, Guiqin [1 ]
Kawanokuchi, Jun [1 ]
Kuno, Reiko [1 ]
Sonobe, Yoshifumi [1 ]
Mizuno, Tetsuya [1 ]
Suzumura, Akio [1 ]
机构
[1] Nagoya Univ, Environm Med Res Inst, Dept Neuroimmunol, Chikusa Ku, Nagoya, Aichi 4648601, Japan
关键词
D O I
10.1074/jbc.M600504200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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-alpha (TNF-alpha) secreted from activated microglia may elicit neurodegeneration through caspase-dependent cascades and silencing cell survival signals. However, direct neurotoxicity of TNF-alpha is relatively weak, because TNF-alpha also increases production of neuroprotective factors. Accordingly, it is still controversial how TNF-alpha exerts neurotoxicity in neurodegenerative diseases. Here we have shown that TNF-alpha 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.
引用
收藏
页码:21362 / 21368
页数:7
相关论文
共 46 条
[21]   Production and neuroprotective functions of fractalkine in the central nervous system [J].
Mizuno, T ;
Kawanokuchi, J ;
Numata, K ;
Suzumura, A .
BRAIN RESEARCH, 2003, 979 (1-2) :65-70
[22]   EXPRESSION OF CYTOKINES DURING GLIAL DIFFERENTIATION [J].
MIZUNO, T ;
SAWADA, M ;
SUZUMURA, A ;
MARUNOUCHI, T .
BRAIN RESEARCH, 1994, 656 (01) :141-146
[23]   Microglia in diseases of the central nervous system [J].
Nelson, PT ;
Soma, LA ;
Lavi, E .
ANNALS OF MEDICINE, 2002, 34 (7-8) :491-500
[24]   The proposed role of glutamine in some cells of the immune system and speculative consequences for the whole animal [J].
Newsholme, EA ;
Calder, PC .
NUTRITION, 1997, 13 (7-8) :728-730
[25]   RATES OF UTILIZATION OF GLUCOSE, GLUTAMINE AND OLEATE AND FORMATION OF END-PRODUCTS BY MOUSE PERITONEAL-MACROPHAGES IN CULTURE [J].
NEWSHOLME, P ;
NEWSHOLME, EA .
BIOCHEMICAL JOURNAL, 1989, 261 (01) :211-218
[26]   THE RELEASE AND UPTAKE OF EXCITATORY AMINO-ACIDS [J].
NICHOLLS, D ;
ATTWELL, D .
TRENDS IN PHARMACOLOGICAL SCIENCES, 1990, 11 (11) :462-468
[27]   Newer aspects of glutamine/glutamate metabolism: the role of acute pH changes [J].
Nissim, I .
AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY, 1999, 277 (04) :F493-F497
[28]   An inflammatory review of Parkinson's disease [J].
Orr, CF ;
Rowe, DB ;
Halliday, GM .
PROGRESS IN NEUROBIOLOGY, 2002, 68 (05) :325-340
[29]   Memantine is a clinically well tolerated N-methyl-D-aspartate (NMDA) receptor antagonist -: a review of preclinical data [J].
Parsons, CG ;
Danysz, W ;
Quack, G .
NEUROPHARMACOLOGY, 1999, 38 (06) :735-767
[30]  
PIANI D, 1994, J IMMUNOL, V152, P3578