Chronic intermittent hypoxia exerts CNS region-specific effects on rat microglial inflammatory and TLR4 gene expression.
Chronic intermittent hypoxia exerts CNS region-specific effects on rat microglial inflammatory and TLR4 gene expression.
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DOI：
10.1371/journal.pone.0081584
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Watters JJ
中科院分区：
文献类型：
--
作者：
Smith SM;Friedle SA;Watters JJ
睡眠期间间歇性缺氧（IH）是睡眠呼吸暂停的一个标志，可引起显著的神经元凋亡，以及中枢神经系统记忆处理和执行功能基础区域的认知和行为缺陷。IH诱导的神经炎症被认为是IH后认知缺陷的原因之一。在本研究中，我们验证了IH会以中枢神经系统区域依赖的方式诱导小胶质细胞中炎症因子基因表达的差异，并且IH的影响会存在时间上的差异。为了验证这一假设，成年大鼠在各自的睡眠周期中暴露于间歇性缺氧（10.5%氧气间隔2分钟），每天8小时，持续1天，3天或14天。解剖大鼠皮质、髓质和脊髓组织，免疫磁分离小胶质细胞，比较炎症基因iNOS、COX-2、TNFα、IL-1β、IL-6和先天免疫受体TLR4的mRNA水平与常氧环境下的水平。在组织匀浆（包含所有中枢神经系统细胞）中也评估了炎症基因表达。我们发现来自不同中枢神经系统区域的小胶质细胞对IH的反应不同。皮质小胶质细胞的炎症基因表达持续时间较长，而脊髓小胶质细胞的炎症基因表达则是快速而短暂的。我们还观察到，炎症基因在小胶质细胞中的表达与来自同一区域的组织匀浆中的表达经常不同，这表明小胶质细胞以外的细胞也有助于ih诱导的神经炎症。最后，IH以区域和时间依赖的方式强烈上调小胶质细胞TLR4 mRNA水平，TLR4表达的增加似乎与炎症基因表达高峰的时间一致，这表明TLR4可能在IH诱导的神经炎症中发挥作用。总之，这些数据表明，小胶质细胞特异性神经炎症可能在不同中枢神经系统区域间歇性缺氧的影响中发挥不同的作用。
Intermittent hypoxia (IH) during sleep is a hallmark of sleep apnea, causing significant neuronal apoptosis, and cognitive and behavioral deficits in CNS regions underlying memory processing and executive functions. IH-induced neuroinflammation is thought to contribute to cognitive deficits after IH. In the present studies, we tested the hypothesis that IH would differentially induce inflammatory factor gene expression in microglia in a CNS region-dependent manner, and that the effects of IH would differ temporally. To test this hypothesis, adult rats were exposed to intermittent hypoxia (2 min intervals of 10.5% O2) for 8 hours/day during their respective sleep cycles for 1, 3 or 14 days. Cortex, medulla and spinal cord tissues were dissected, microglia were immunomagnetically isolated and mRNA levels of the inflammatory genes iNOS, COX-2, TNFα, IL-1β and IL-6 and the innate immune receptor TLR4 were compared to levels in normoxia. Inflammatory gene expression was also assessed in tissue homogenates (containing all CNS cells). We found that microglia from different CNS regions responded to IH differently. Cortical microglia had longer lasting inflammatory gene expression whereas spinal microglial gene expression was rapid and transient. We also observed that inflammatory gene expression in microglia frequently differed from that in tissue homogenates from the same region, indicating that cells other than microglia also contribute to IH-induced neuroinflammation. Lastly, microglial TLR4 mRNA levels were strongly upregulated by IH in a region- and time-dependent manner, and the increase in TLR4 expression appeared to coincide with timing of peak inflammatory gene expression, suggesting that TLR4 may play a role in IH-induced neuroinflammation. Together, these data indicate that microglial-specific neuroinflammation may play distinct roles in the effects of intermittent hypoxia in different CNS regions.
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影响因子：
3.7
作者：
Hines DJ;Choi HB;Hines RM;Phillips AG;MacVicar BA
通讯作者：
MacVicar BA
影响因子：
4.7
作者：
Gozal, E;Gozal, D;Klein, JB
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影响因子：
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作者：
Bombois, S.;Derambure, P.;Monaca, C.
通讯作者：
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影响因子：
6.4
作者：
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影响因子：
6.1
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Li, RC;Row, BW;Gozal, D
通讯作者：
Gozal, D