School of Biochemistry and Immunology and Trinity College Institute of Neuroscience, Trinity College, Dublin, Ireland.
Glia. 2013 Jan;61(1):71-90. doi: 10.1002/glia.22350. Epub 2012 Jun 6.
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.
人们普遍认为，中枢神经系统炎症在慢性神经退行性疾病的进展中起作用，尽管其发生机制仍不清楚。在大多数慢性神经退行性疾病中，炎症反应主要由小胶质细胞主导，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，人们发现全身炎症在这些疾病的进展中起着重要作用。已经存在描述良好的适应性途径来将全身炎症信号转导到大脑，但如果急性损伤足够强烈，如严重败血症，或足够持久，如反复用强烈剂量的炎症原（如脂多糖（LPS））刺激，这些途径的激活似乎对大脑有害。重要的是，中等剂量的炎症原在大脑中产生新的病理学，并在现有病理学的基础上或在遗传易感性的背景下，加剧或加速疾病的特征。现在在多种慢性疾病状态和衰老中，小胶质细胞以前的病理学或遗传易感性使其对随后的炎症刺激反应更强烈，从而将适应性中枢神经系统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起重要作用的临床前和临床证据。将重点强调小胶质细胞如何通过全身刺激对神经元损伤和功能障碍产生影响的机制。
