Toll-like receptor 4 participates in the myelin disruptions associated with chronic alcohol abuse
Toll-like receptor 4 participates in the myelin disruptions associated with chronic alcohol abuse
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DOI：
10.1002/glia.22327
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发表时间：
2012-05-01
期刊：
影响因子：
6.2
通讯作者：
Guerri, Consuelo
中科院分区：
文献类型：
--
作者：
Alfonso-Loeches, Silvia;Pascual, Maria;Guerri, Consuelo
酒精滥用和酒精中毒可导致脑损伤、白色物质丢失、髓鞘纤维破坏，甚至神经元损伤。这些改变的潜在机制仍然难以捉摸。我们已经证明，慢性乙醇摄入，通过激活胶质细胞Toll样受体4（TLR 4）受体，触发炎症介质的产生，并可能导致脑损伤。由于神经炎症可能与脱髓鞘和神经元损伤有关，我们评估乙醇诱导的TLR 4依赖性促炎环境是否可能参与酗酒者中观察到的髓鞘破坏。使用来自野生型（WT）和TLR 4敲除的脑（KO，TLR 4-/-）小鼠，我们证明慢性乙醇处理下调参与髓鞘形成的蛋白质[蛋白脂质蛋白（PLP）、髓鞘碱性蛋白（MBP）、髓鞘-少突胶质细胞糖蛋白、2，3-环核苷酸-3-磷酸二酯酶和髓鞘相关糖蛋白]，而在乙醇处理的WT小鼠的几个脑区域中硫酸软骨素蛋白聚糖NG 2（NG 2）-蛋白聚糖增加。免疫组织化学分析还显示，乙醇处理改变髓鞘形态减少MBP阳性纤维的数量，并导致少突胶质细胞死亡，如caspase-3阳性少突胶质细胞的增加所示。体内成像系统进一步证实，长期乙醇摄入显著降低WT小鼠的PLP。在乙醇处理的TLR 4-/-小鼠的脑中未观察到大多数髓鞘改变。电子显微镜研究显示，尽管WT乙醇处理小鼠的大脑皮层和胼胝体中分别有4147%的轴突显示髓鞘紊乱，但在乙醇处理的TLR 4-/-小鼠的这些脑区中观察到小的局灶性纤维中断。总之，目前的结果表明，乙醇诱导的神经炎症可能参与髓鞘破坏和白色物质的损失，观察人类酗酒。(c)2012 Wiley Periodicals，Inc.
Alcohol abuse and alcoholism can cause brain damage, loss of white matter, myelin fiber disruption, and even neuronal injury. The underlying mechanisms of these alterations remain elusive. We have shown that chronic ethanol intake, by activating glial toll-like receptor 4 (TLR4) receptors, triggers the production of inflammatory mediators and can cause brain damage. Because neuroinflammation may be associated with demyelination and neuronal damage, we evaluate whether the ethanol-induced TLR4-dependent proinflammatory environment in the brain could be involved in the myelin disruptions observed in alcoholics. Using brains from wild-type (WT) and TLR4 knockout (KO, TLR4-/-) mice, we demonstrate that chronic ethanol treatment downregulated proteins involved in myelination [proteolipid protein (PLP), myelin basic protein (MBP), myelin-oligodendrocyte glycoprotein, 2,3-cyclic-nucleotide-3-phosphodiesterase, and myelin-associated glycoprotein], while increased chondroitin sulfate proteoglycan NG2 (NG2)-proteoglycan in several brain regions of ethanol-treated WT mice. The immunohistochemistry analysis also revealed that ethanol-treatment-altered myelin morphology reduced the number of MBP-positive fibers and caused oligodendrocyte death, as demonstrated by an increase in caspase-3-positive oligodendrocytes. The in vivo imaging system further confirmed that chronic ethanol intake markedly reduced the PLP in WT mice. Most myelin alterations were not observed in brains from ethanol-treated TLR4-/- mice. Electron microscopy studies revealed that although 4147% of axons showed myelin sheath disarrangements in the cerebral cortex and corpus callosum of WT ethanol-treated mice, respectively, small focal fiber disruptions were noticed in these brain areas of ethanol-treated TLR4-/- mice. In summary, the present results suggest that ethanol-induced neuroinflammation might be involved in myelin disruptions and white matter loss observed in human alcoholics. (c) 2012 Wiley Periodicals, Inc.