How microglia kill neurons
How microglia kill neurons
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DOI：
10.1016/j.brainres.2015.08.031
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发表时间：
2015-12-02
期刊：
影响因子：
2.9
通讯作者：
Vilalta, Anna
中科院分区：
文献类型：
--
作者：
Brown, Guy C.;Vilalta, Anna
小胶质细胞是在大多数脑病理中变得炎性激活的常驻脑巨噬细胞。小胶质细胞通常保护神经元，但在试图限制感染或损伤时可能会意外杀死神经元，这可能在退行性疾病中更常见，因为过去对老年大脑没有明显的选择压力。已经确定了激活的小胶质细胞杀死神经元的许多机制，包括：（i）刺激吞噬细胞NADPH氧化酶（PHOX）以产生超氧化物和衍生氧化剂，（ii）表达产生NO和衍生氧化剂的诱导型一氧化氮合酶（iNOS），（iii）释放谷氨酸和谷氨酰胺酶，（iv）释放TNF α，（v）释放组织蛋白酶B，（vi）应激神经元的吞噬作用，和（vii）减少营养性BDNF和IGF-1的释放。PHOX刺激有助于小胶质细胞活化，但不直接神经毒性，除非NO存在。NO通常具有神经保护作用，但可与超氧化物反应产生神经毒性的过氧亚硝酸盐，或在缺氧的情况下抑制线粒体呼吸。谷氨酸可以由神经胶质或神经元释放，但只有当神经元去极化时才具有神经毒性，例如由于线粒体抑制。TNF α通常具有神经保护作用，但如果caspase-8或NF-κ B活化受到抑制，则可能具有毒性。如果上述机制不杀死神经元，它们仍然可能对神经元施加足够的应力，使它们易于被激活的小胶质细胞吞噬。我们在这里审查是否小胶质细胞杀死神经元是一个人工制品，使进化的意义，或在共同的神经病理学和什么机制的贡献。这篇文章是题为SI：神经保护的特刊的一部分。(C)2015 Elsevier B. V.版权所有。
Microglia are resident brain macrophages that become inflammatory activated in most brain pathologies. Microglia normally protect neurons, but may accidentally kill neurons when attempting to limit infections or damage, and this may be more common with degenerative disease as there was no significant selection pressure on the aged brain in the past. A number of mechanisms by which activated microglia kill neurons have been identified, including: (i) stimulation of the phagocyte NADPH oxidase (PHOX) to produce superoxide and derivative oxidants, (ii) expression of inducible nitric oxide synthase (iNOS) producing NO and derivative oxidants, (iii) release of glutamate and glutaminase, (iv) release of TNF alpha, (v) release of cathepsin B, (vi) phagocytosis of stressed neurons, and (vii) decreased release of nutritive BDNF and IGF-1. PHOX stimulation contributes to microglial activation, but is not directly neurotoxic unless NO is present. NO is normally neuroprotective, but can react with superoxide to produce neurotoxic peroxynitrite, or in the presence of hypoxia inhibit mitochondrial respiration. Glutamate can be released by glia or neurons, but is neurotoxic only if the neurons are depolarised, for example as a result of mitochondrial inhibition. TNF alpha is normally neuroprotective, but can become toxic if caspase-8 or NF-kappa B activation are inhibited. If the above mechanisms do not kill neurons, they may still stress the neurons sufficiently to make them susceptible to phagocytosis by activated microglia. We review here whether microglial killing of neurons is an artefact, makes evolutionary sense or contributes in common neuropathologies and by what mechanisms. This article is part of a Special Issue entitled SI: Neuroprotection. (C) 2015 Elsevier B.V. All rights reserved.