Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration
Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration
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DOI：
10.1002/glia.20467
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发表时间：
2007-04-01
期刊：
影响因子：
6.2
通讯作者：
Crews, Fulton T.
中科院分区：
文献类型：
--
作者：
Qin, Liya;Wu, Xuefei;Crews, Fulton T.
炎症与神经退行性疾病(如帕金森氏病)的进行性有关，但其机制尚不清楚。单一系统脂多糖(内毒素，5 mg/kg，i.p.)或肿瘤坏死因子α(肿瘤坏死因子α，0.25 mg/kg，i.p.)在成年野生型小鼠和缺乏肿瘤坏死因子受体的小鼠(肿瘤坏死因子受体1/R2(-/-))上注射，以辨别炎症从外周向脑转移的机制和神经变性的后果。全身注射脂多糖后，脑内肿瘤坏死因子α迅速升高，并持续10个月，而外周肿瘤坏死因子α(血清和肝脏)在9h(血清)和1周(肝脏)已经消退。全身注射肿瘤坏死因子α和脂多糖可激活野生型小鼠的小胶质细胞，并增加脑内促炎因子(即肿瘤坏死因子α、单核细胞趋化蛋白1、白介素1β和核因子-kappa B p65)的表达，但在肿瘤坏死因子1/R2(-/-)小鼠中无此作用。此外，治疗后7个月，内毒素使黑质(SN)内酪氨酸羟化酶免疫反应神经元的数量减少了23%，10个月时减少到47%。综上所述，这些数据表明，成年动物的外周炎症可以：(1)激活脑小胶质细胞，产生慢性升高的炎性因子；(2)诱导黑质DA神经元的延迟性和渐进性丢失。这些发现为帕金森氏病的潜在发病机制和自驱性提供了有价值的见解。(C)2007年Wiley-Liss，Inc.
Inflammation is implicated in the progressive nature of neurodegenerative diseases, such as Parkinson's disease, but the mechanisirts are poorly understood. A single systemic lipopolysaccharide (LPS, 5 mg/kg, i.p.) or tumor necrosis factor alpha (TNF alpha, 0.25 mg/kg, i.p.) injection was administered in adult wild-type mice and in mice lacking TNF alpha receptors (TNF R1/R2(-/-)) to discern the mechanisms of inflammation transfer from the periphery to the brain and the neurodegenerative consequences. Systemic LPS administration resulted in rapid brain TNFa increase that remained elevated for 10 months, while peripheral TNF alpha (serum and liver) had subsided by 9 h (serum) and 1 week (liver). Systemic TNF alpha and LPS administration activated microglia and increased expression of brain pro-inflammatory factors (i.e., TNF alpha, MCP-1, IL-1 beta and NF-kappa B p65) in wild-type mice, but not in TNF R1/R2(-/-) mice. Further, LPS reduced the number of tyrosine hydroxylase-immunoreactive neurons in the substantia nigra (SN) by 23% at 7-months post-treatment, which progressed to 47% at 10 months. Together, these data demonstrate that through TNF alpha, peripheral inflammation in adult animals can: (1) activate brain microglia to produce chronically elevate roinflammatory factors; (2) induce delayed and progressive loss of DA neurons in the SN. These findings provide valuable insight into the potential pathogenesis and self-propelling nature of Parkinson's disease. (c) 2007 Wiley-Liss, Inc.