Differential regulation of trophic and proinflammatory microglial effectors is dependent on severity of neuronal injury
Differential regulation of trophic and proinflammatory microglial effectors is dependent on severity of neuronal injury
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DOI：
10.1002/glia.20610
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发表时间：
2008-02-01
期刊：
影响因子：
6.2
通讯作者：
Todd, Kathryn G.
中科院分区：
文献类型：
--
作者：
Lai, Aaron Y.;Todd, Kathryn G.
据报道，激活小胶质细胞可以促进神经毒性，也可以起到神经保护作用。造成这种二分性反应的一个可能因素可能是近端神经元受损的程度。这项研究的目的是确定不同的神经元损伤程度是否会影响小胶质细胞是具有神经保护作用还是神经毒性。我们将培养的皮层神经元暴露在不同程度的缺氧中，从而产生轻微的损伤(70%死亡，缺氧6小时)。结果显示，经典的小胶质细胞促炎介质包括诱导型一氧化氮合酶、肿瘤坏死因子α和白介素1-β仅在轻度神经元损伤时上调，而营养性小胶质细胞效应因子脑源性神经营养因子和胶质细胞源性神经营养因子在所有程度的神经元损伤时上调。用损伤神经元培养液刺激的小胶质细胞与低氧神经元共培养。在这些共培养中，受到中度损伤而不是轻度或严重损伤的小胶质细胞具有神经保护作用。我们还表明，这种严重程度依赖的现象与自分泌小胶质细胞信号无关，而依赖于神经元损伤后释放的神经递质，即谷氨酸和5‘-三磷酸腺苷。综上所述，我们的结果表明，神经元损伤的严重程度是决定小胶质细胞释放“有毒”和“保护性”效应以及由此产生的神经毒性和神经保护的重要因素。(C)2007年Wiley-Liss，Inc.
Microglial activation has been reported to promote neurotoxicity and also neuroprotective effects. A possible contributor to this dichotomy of responses may be the degree to which proximal neurons are injured. The aim of this study was to determine whether varying the severity of neuronal injury influenced whether microglia were neuroprotective or neurotoxic. We exposed cortical neuronal cultures to varying degrees of hypoxia thereby generating mild (70% death, 6 h hypoxia) injuries. Twenty-four hours after hypoxia, the media from the neuronal cultures was collected and incubated with primary microglial cultures for 24 h. Results showed that the classic microglial proinflammatory mediators including inducible nitric oxide synthase, tumor necrosis factor alpha, and interleukin-1-beta were upregulated only in response to mild neuronal injuries, while the trophic microglial effectors brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor were upregulated in response to all degrees of neuronal injury. Microglia stimulated with media from damaged neurons were co-cultured with hypoxic neurons. Microglia stimulated by moderate, but not mild or severe damage were neuroprotective in these co-cultures. We also showed that the severity-dependent phenomenon was not related to autocrine microglial signaling and was dependent on the neurotransmitters released by neurons after injury, namely glutamate and adenosine 5'-triphosphate. Together our results show that severity of neuronal injury is an important factor in determining microglial release of "toxic" versus "protective" effectors and the resulting neurotoxicity versus neuroprotection. (C) 2007 Wiley-Liss, Inc.