Pivotal Role of TLR4 Receptors in Alcohol-Induced Neuroinflammation and Brain Damage
Pivotal Role of TLR4 Receptors in Alcohol-Induced Neuroinflammation and Brain Damage
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DOI：
10.1523/jneurosci.0976-10.2010
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发表时间：
2010-06-16
影响因子：
5.3
通讯作者：
Guerri, Consuelo
中科院分区：
文献类型：
--
作者：
Alfonso-Loeches, Silvia;Pascual-Lucas, Maya;Guerri, Consuelo
Toll样受体在先天免疫反应中发挥着重要作用，尽管有新的证据表明它们在脑损伤和神经退行性变中发挥了作用。酗酒会导致大脑损伤，有时还会导致神经退化。我们最近发现，乙醇可以通过触发炎症介质的诱导和细胞死亡来促进TLR4信号在神经胶质细胞中的表达，提示TLR4反应可能是乙醇诱导神经炎症的一个重要机制。本研究旨在确定TLR4在乙醇诱导的神经胶质细胞激活和脑损伤中的潜在作用。在此，我们报道了TLR4在酒精诱导的神经胶质细胞炎症信号中的关键作用，因为TLR4被敲除后，通过使用TLR4缺陷小鼠的小干扰RNA或细胞，取消了微管相关蛋白激酶和核因子-kappaB通路的激活，以及星形胶质细胞产生炎症介质。我们的结果首次表明，尽管长期摄入乙醇上调了雌性野生型小鼠大脑皮层CD11b(小胶质细胞标志物)和胶质纤维酸性蛋白(星形胶质细胞标志物)的免疫反应水平，也增加了caspase-3活性和诱导型一氧化氮合酶、COX-2和细胞因子[白介素1β、肿瘤坏死因子α、白介素6]的水平，但TLR4缺乏对乙醇诱导的胶质细胞激活、炎性介质的诱导和细胞凋亡具有保护作用。我们的发现支持TLR4反应在神经炎症、脑损伤以及可能在慢性酒精摄入引起的神经退行性变中的关键作用。
Toll-like receptors play an important role in the innate immune response, although emerging evidence indicates their role in brain injury and neurodegeneration. Alcohol abuse induces brain damage and can sometimes lead to neurodegeneration. We recently found that ethanol can promote TLR4 signaling in glial cells by triggering the induction of inflammatory mediators and causing cell death, suggesting that the TLR4 response could be an important mechanism of ethanol-induced neuroinflammation. This study aims to establish the potential role of TLR4 in both ethanol-induced glial activation and brain damage. Here we report that TLR4 is critical for ethanol-induced inflammatory signaling in glial cells since the knockdown of TLR4, by using both small interfering RNA or cells from TLR4-deficient mice, abolished the activation of microtubule-associated protein kinase and nuclear factor-kappa B pathways and the production of inflammatory mediators by astrocytes. Our results demonstrate, for the first time, that whereas chronic ethanol intake upregulates the immunoreactive levels of CD11b (microglial marker) and glial fibrillary acidic protein (astrocyte marker), and also increases caspase-3 activity and inducible nitric oxide synthase, COX-2, and cytokine levels [interleukin (IL)-1 beta, tumor necrosis factor-alpha, IL-6] in the cerebral cortex of female wild-type mice, TLR4 deficiency protects against ethanol-induced glial activation, induction of inflammatory mediators, and apoptosis. Our findings support the critical role of the TLR4 response in the neuroinflammation, brain injury, and possibly in the neurodegeneration induced by chronic ethanol intake.