Microglia and neurodegeneration: The role of systemic inflammation
Microglia and neurodegeneration: The role of systemic inflammation
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DOI：
10.1002/glia.22350
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发表时间：
2013-01-01
期刊：
影响因子：
6.2
通讯作者：
Cunningham, Colm
中科院分区：
文献类型：
--
作者：
Cunningham, Colm
CNS炎症在慢性神经退行性疾病的进展中起作用是公认的，尽管其发生的机制仍不清楚。大多数慢性神经退行性疾病期间的炎症反应由小胶质细胞主导，并且这些细胞导致神经元损伤和变性的机制是深入研究的主题。最近发现，全身性炎症在这些疾病的进展中起着重要作用。存在充分描述的适应性通路以将全身性炎症信号传递到大脑，但是如果急性损伤足够强烈（如在严重脓毒症中）或足够长时间（如在用强剂量的炎性原如脂多糖（LPS）反复刺激中），则这些通路的激活似乎对大脑有害。值得注意的是，中等剂量的炎性原在脑中产生新的病理学，并且当叠加在现有病理学上或在遗传易感性的背景下时加重或加速疾病的特征。现在很明显，在多种慢性疾病状态和衰老中，小胶质细胞由先前的病理或遗传倾向引发，以更有力地响应随后的炎症刺激，从而将对全身性炎症的适应性CNS炎症反应转化为对个体具有有害后果的反应。在这篇综述中，将讨论支持全身炎症在慢性神经退行性疾病中发挥重要作用的临床前和临床证据。小胶质细胞可能影响神经元损伤和功能障碍的机制，作为全身刺激的结果，将被强调。(c)2012 Wiley Periodicals，Inc.
It is well accepted that CNS inflammation has a role in the progression of chronic neurodegenerative disease, although the mechanisms through which this occurs are still unclear. The inflammatory response during most chronic neurodegenerative disease is dominated by the microglia and mechanisms by which these cells contribute to neuronal damage and degeneration are the subject of intense study. More recently it has emerged that systemic inflammation has a significant role to play in the progression of these diseases. Well-described adaptive pathways exist to transduce systemic inflammatory signals to the brain, but activation of these pathways appears to be deleterious to the brain if the acute insult is sufficiently robust, as in severe sepsis, or sufficiently prolonged, as in repeated stimulation with robust doses of inflammogens such as lipopolysaccharide (LPS). Significantly, moderate doses of inflammogens produce new pathology in the brain and exacerbate or accelerate features of disease when superimposed upon existing pathology or in the context of genetic predisposition. It is now apparent in multiple chronic disease states, and in ageing, that microglia are primed by prior pathology, or by genetic predisposition, to respond more vigorously to subsequent inflammatory stimulation, thus transforming an adaptive CNS inflammatory response to systemic inflammation, into one that has deleterious consequences for the individual. In this review, the preclinical and clinical evidence supporting a significant role for systemic inflammation in chronic neurodegenerative diseases will be discussed. Mechanisms by which microglia might effect neuronal damage and dysfunction, as a consequence of systemic stimulation, will be highlighted. (c) 2012 Wiley Periodicals, Inc.