Neurotoxic effects of lipopolysaccharide on nigral dopaminergic neurons are mediated by microglial activation, interleukin-1β, and expression of caspase-11 in mice
Neurotoxic effects of lipopolysaccharide on nigral dopaminergic neurons are mediated by microglial activation, interleukin-1β, and expression of caspase-11 in mice
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DOI：
10.1074/jbc.m407328200
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发表时间：
2004-12-03
影响因子：
4.8
通讯作者：
Mochizuki, H
中科院分区：
文献类型：
--
作者：
Arai, H;Furuya, T;Mochizuki, H
内毒素脂多糖（LPS）是革兰氏阴性细菌细胞壁的一种成分，通过激活大鼠和小鼠的小胶质细胞选择性地诱导黑质（SN）多巴胺能神经元变性。Caspase-11在LPS诱导的小鼠感染性休克中起关键作用。我们研究了LPS对C57 BL/6小鼠和caspase-11基因敲除小鼠SN多巴胺能神经元的神经毒性机制。将LPS立体定位注射到小鼠一侧的SN中，并将载体注射到另一侧的SN中。采用免疫组化、Western blotting、酶联免疫吸附试验和逆转录聚合酶链反应检测黑质多巴胺能神经元的损伤和小胶质细胞的活化。在C57 BL/6小鼠中，在注射后第7天和第14天，与注射溶剂的对侧相比，黑质内注射1或3 μ g/穆尔/部位的LPS减少了SN中的酪氨酸羟化酶阳性神经元并增加了小胶质细胞。以3 μ g/穆尔/部位的剂量在黑质内注射LPS，在注射后6、8和12 h诱导腹侧中脑中caspase-11 mRNA的表达，并在注射后8和12 h诱导SN中caspase-11阳性细胞的表达。此外，在注射后12和24小时，3 μ g/穆尔/部位的LPS增加腹侧中脑中的白细胞介素-1 β含量。LPS未能在caspase-11敲除小鼠中引起这些反应。我们的研究结果表明，LPS对黑质多巴胺能神经元的神经毒性作用是通过小胶质细胞活化，白细胞介素-1 β和caspase-11表达介导的。
The endotoxin lipopolysaccharide (LPS), a component of the Gram-negative bacterial cell wall, selectively induces degeneration of substantia nigral (SN) dopaminergic neurons via activation of microglial cells in rats and mice. Caspase-11 plays a crucial role in LPS-induced septic shock in mice. We examined the mechanism of LPS neurotoxicity on SN dopaminergic neurons in C57BL/6 mice and caspase-11 knockout mice. Mice were stereotaxically injected with LPS into the SN on one side and vehicle into the SN of the other side. Immunohistochemistry, Western blotting analysis, enzyme-linked immunosorbent assay, and reverse transcriptase-PCR were performed to evaluate damage of SN dopaminergic neurons and activation of microglial cells. Intranigral injection of LPS at 1 or 3 mug/mul/site decreased tyrosine hydroxylase-positive neurons and increased microglial cells in the SN compared with the contralateral side injected with vehicle at days 7 and 14 post-injection in C57BL/6 mice. Intranigral injection of LPS at 3 mug/mul/ site induced the expression of caspase-11 mRNA in the ventral midbrain at 6, 8, and 12 h postinjection, and the expression of caspase-11-positive cells in the SN at 8 and 12 h post-injection. Moreover, LPS at 3 mug/mul/ site increased interleukin-1beta content in the ventral midbrain at 12 and 24 h post-injection. LPS failed to elicit these responses in caspase-11 knockout mice. Our results indicate that the neurotoxic effects of LPS on nigral dopaminergic neurons are mediated by microglial activation, interleukin-1beta, and caspase-11 expression in mice.