Central and systemic endotoxin challenges exacerbate the local inflammatory response and increase neuronal death during chronic neurodegeneration
Central and systemic endotoxin challenges exacerbate the local inflammatory response and increase neuronal death during chronic neurodegeneration
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DOI：
10.1523/jneurosci.2614-05.2005
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发表时间：
2005-10-05
影响因子：
5.3
通讯作者：
Perry, VH
中科院分区：
文献类型：
--
作者：
Cunningham, C;Wilcockson, DC;Perry, VH
炎症对神经退行性疾病如阿尔茨海默病、帕金森病和朊病毒病的进展的贡献知之甚少。在这些疾病的动物模型中，脑炎症主要由慢性小胶质细胞活化和最小的促炎细胞因子表达主导。然而，这些炎性细胞被“引发”以产生对随后的脂多糖（LPS）挑战的过度炎症反应。我们发现，使用ME 7模型的朊病毒疾病，脑内的挑战与LPS的结果在戏剧性的白细胞介素-1 β（IL-1 β）的表达，中性粒细胞浸润，诱导型一氧化氮合酶的表达在朊病毒病小鼠的脑实质相比，在正常小鼠相同的挑战。LPS诱发的全身性炎症也使朊病毒病小鼠中的促炎细胞因子、正五聚蛋白3和诱导型一氧化氮合酶转录比对照小鼠增加更大，并诱导小胶质细胞表达IL-1 β。这些全身性挑战也增加了ME 7动物脑中的神经元凋亡。因此，中枢和外周炎症均可加重局部脑炎症和神经元死亡。单一急性全身性炎症事件可诱导CNS中的神经元死亡的发现对于神经退行性疾病的治疗具有意义。
The contribution of inflammation to the progression of neurodegenerative diseases such as Alzheimer's, Parkinson's, and prion diseases is poorly understood. Brain inflammation in animal models of these diseases is dominated by chronic microglial activation with minimal proinflammatory cytokine expression. However, these inflammatory cells are "primed" to produce exaggerated inflammatory responses to subsequent lipopolysaccharide (LPS) challenges. We show that, using the ME7 model of prion disease, intracerebral challenge with LPS results in dramatic interleukin-1 beta(IL-1 beta) expression, neutrophil infiltration, and inducible nitric oxide synthase expression in the brain parenchyma of prion-diseased mice compared with the same challenge in normal mice. Systemic inflammation evoked by LPS also produced greater increases in proinflammatory cytokines, pentraxin 3, and inducible nitric oxide synthase transcription in prion-diseased mice than in control mice and induced microglial expression of IL-1 beta. These systemic challenges also increased neuronal apoptosis in the brains of ME7 animals. Thus, both central and peripheral inflammation can exacerbate local brain inflammation and neuronal death. The finding that a single acute systemic inflammatory event can induce neuronal death in the CNS has implications for therapy in neurodegenerative diseases.