Endotoxemia prevents the cerebral inflammatory wave induced by Intraparenchymal lipopolysaccharide injection: Role of glucocorticoids and CD14
Endotoxemia prevents the cerebral inflammatory wave induced by Intraparenchymal lipopolysaccharide injection: Role of glucocorticoids and CD14
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DOI：
10.4049/jimmunol.169.6.3370
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发表时间：
2002-09-15
影响因子：
4.4
通讯作者：
Rivest, S
中科院分区：
文献类型：
--
作者：
Nadeau, S;Rivest, S
在内毒素血症期间，脑中存在强烈的和短暂的先天免疫应答，其与NF-κ B信号传导事件的级联和编码TNF-α和LPS受体CD 14的基因的转录激活相关。本研究调查是否循环LPS有能力调节脑先天性免疫反应引起的纹状体内（IS）注射内毒素。我们还测试了CD 14在这些效应中发挥作用的可能性，并且雄性大鼠在IS LIPS给药前接受了侧脑室注射抗CD 14。单个LPS团注到纹状体引起注射部位同侧小胶质细胞中TNF-α、IkappaB α、CD 14和单核细胞趋化蛋白-1 mRNA的强烈和时间依赖性转录激活。令人惊讶的是，这波诱导的转录本基本上消除了全身内毒素预处理。循环LPS的这种抗炎特性是通过血浆皮质酮介导的，因为外源性皮质激素模拟而糖皮质激素受体拮抗剂RU 486阻止全身内毒素攻击的作用。有趣的是，CD 14部分参与LPS诱导的神经炎症;抗CD 14在第3天显著消除了小胶质细胞活性，但在更早的时候没有。急性脑实质内LPS推注引起的炎症反应与令人信服的神经退行性过程无关。这些数据提供了令人信服的证据表明，全身性炎症，通过增加循环糖皮质激素，有能力防止脑先天性免疫反应引发的IS内毒素注射。本研究也进一步证实了脑内存在这种系统，这种系统受到精细调节，其短暂激活对神经元元件无害。
There is a robust and transient innate immune response in the brain during endotoxemia, which is associated with a cascade of NF-kappaB signaling events and transcriptional activation of genes that encode TNF-alpha and the LPS receptor CD14. The present study investigated whether circulating LPS has the ability to modulate the cerebral innate immune response caused by an intrastriatal (IS) injection of the endotoxin. We also tested the possibility that CD14 plays a role in these effects and male rats received an intracerebroventricular injection with an anti-CD14 before the IS LIPS administration. The single LPS bolus into the striatum caused a strong and time-dependent transcriptional activation of TNF-alpha, IkappaBalpha, CD14, and monocyte chemoattractant protein-1 mRNA in microglial cells ipsilateral to the site of injection. Surprisingly, this wave of induced transcripts was essentially abolished by the systemic endotoxin pretreatment. Such anti-inflammatory properties of circulating LPS are mediated via plasma corticosterone, because exogenous corticoids mimicked while glucocorticoid receptor antagonist RU486 prevented the effects of systemic endotoxin challenge. Of interest is the partial involvement of CD14 in LPS-induced neuroinflammation; the anti-CD14 significantly abolished the microglial activity at day 3, but not at times earlier. The inflammatory response provoked by an acute intraparenchymal LPS bolus was not associated with convincing neurodegenerative processes. These data provide compelling evidence that systemic inflammation, through the increase in circulating glucocorticoids, has the ability to prevent the cerebral innate immune reaction triggered by an IS endotoxin injection. This study also further consolidates the existence of such system in the brain, which is finely regulated and its transient activation is not harmful for the neuronal elements.