Department of Comparative Biosciences, University of Wisconsin, Madison, Wisconsin, United States of America.
PLoS One. 2013 Dec 4;8(12):e81584. doi: 10.1371/journal.pone.0081584. eCollection 2013.
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.
睡眠期间间歇性低氧（IH）是睡眠呼吸暂停的标志，导致中枢神经系统（CNS）区域内的神经元凋亡显著增加，以及记忆处理和执行功能相关的认知和行为缺陷。IH 诱导的神经炎症被认为是导致 IH 后认知缺陷的原因之一。在本研究中，我们假设 IH 会以 CNS 区域依赖性方式差异诱导小胶质细胞中炎症因子基因表达，并且 IH 的影响会随时间而变化。为了验证这一假设，成年大鼠在各自的睡眠周期中每天接受 8 小时的间歇性低氧（10.5%O2，2 分钟间隔）暴露。然后分离皮质、延髓和脊髓组织，免疫磁珠分离小胶质细胞，并与正常氧相比，比较炎症基因 iNOS、COX-2、TNFα、IL-1β 和 IL-6 以及先天免疫受体 TLR4 的 mRNA 水平。还评估了组织匀浆中的炎症基因表达（包含所有 CNS 细胞）。我们发现，来自不同 CNS 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更长，而脊髓小胶质细胞的基因表达迅速而短暂。我们还观察到，来自同一区域的小胶质细胞和组织匀浆中的炎症基因表达经常不同，这表明除小胶质细胞以外的细胞也参与 IH 诱导的神经炎症。最后，小胶质细胞 TLR4 mRNA 水平在区域和时间依赖性方式被 IH 强烈上调，并且 TLR4 表达的增加似乎与炎症基因表达的峰值时间一致，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 CNS 区域的间歇性低氧影响中发挥不同的作用。
