Nitric oxide regulates antagonistically phagocytic and neurite outgrowth inhibiting capacities of microglia
Nitric oxide regulates antagonistically phagocytic and neurite outgrowth inhibiting capacities of microglia
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DOI：
10.1002/dneu.22333
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发表时间：
2016-05-01
影响因子：
3
通讯作者：
Bicker, Gerd
中科院分区：
文献类型：
--
作者：
Scheiblich, Hannah;Bicker, Gerd
创伤性损伤或某些神经系统疾病的发病机制伴随有炎症细胞机制，主要由中枢神经系统（CNS）驻留的小胶质细胞的激活引起。在炎症条件下，小胶质细胞上调诱导型NOS（iNOS），导致产生高浓度的自由基分子一氧化氮（NO）。在炎症发作时，高水平的小胶质细胞来源的NO可以作为细胞防御机制，帮助清除受损组织并对抗入侵病原体对CNS的感染。然而，已经表明由活化的小胶质细胞过度产生NO来控制炎症介导的神经元损失，最终导致完全的神经变性。在这里，我们研究了NO如何影响BV-2小胶质细胞的神经元碎片的吞噬作用，以及人NT 2模型神经元的神经突生长如何受到小胶质细胞衍生的NO的影响。NO的存在大大增加了小胶质细胞的吞噬能力，包括脂多糖（LPS）激活的小胶质细胞和凋亡神经元的急性炎症模型。化学操作表明，NO上调吞噬作用独立的sGC/cGMP途径。使用transwell系统，我们发现，反应性小胶质细胞抑制人类神经元的轴突生长，通过产生大量的NO在毫米范围内的有效距离。NOS阻断剂的应用阻止了LPS诱导的NO产生，完全逆转了小胶质细胞对神经突起生长的抑制作用，但减少了神经元碎片的吞噬。我们的结果表明，通过NO合成阻断剂治疗中枢神经系统过度炎症的相当简单的概念必须考虑药物治疗期间功能性拮抗小胶质细胞反应。(c)2015 Wiley Periodicals，Inc.
Traumatic injury or the pathogenesis of some neurological disorders is accompanied by inflammatory cellular mechanisms, mainly resulting from the activation of central nervous system (CNS) resident microglia. Under inflammatory conditions, microglia up-regulate the inducible isoform of NOS (iNOS), leading to the production of high concentrations of the radical molecule nitric oxide (NO). At the onset of inflammation, high levels of microglial-derived NO may serve as a cellular defense mechanism helping to clear the damaged tissue and combat infection of the CNS by invading pathogens. However, the excessive overproduction of NO by activated microglia has been suggested to govern the inflammation-mediated neuronal loss causing eventually complete neurodegeneration. Here, we investigated how NO influences phagocytosis of neuronal debris by BV-2 microglia, and how neurite outgrowth of human NT2 model neurons is affected by microglial-derived NO. The presence of NO greatly increased microglial phagocytic capacity in a model of acute inflammation comprising lipopolysaccharide (LPS)-activated microglia and apoptotic neurons. Chemical manipulations suggested that NO up-regulates phagocytosis independently of the sGC/cGMP pathway. Using a transwell system, we showed that reactive microglia inhibit neurite outgrowth of human neurons via the generation of large amounts of NO over effective distances in the millimeter range. Application of a NOS blocker prevented the LPS-induced NO production, totally reversed the inhibitory effect of microglia on neurite outgrowth, but reduced the engulfment of neuronal debris. Our results indicate that a rather simple notion of treating excessive inflammation in the CNS by NO synthesis blocking agents has to consider functionally antagonistic microglial cell responses during pharmaceutic therapy. (c) 2015 Wiley Periodicals, Inc.