Regulation of oxidative stress in long-lived lipopolysaccharide-activated microglia
Regulation of oxidative stress in long-lived lipopolysaccharide-activated microglia
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DOI：
10.1111/j.1440-1681.2012.05716.x
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发表时间：
2012-07-01
影响因子：
2.9
通讯作者：
Nagatsu, Toshiharu
中科院分区：
文献类型：
--
作者：
Kaneko, Yoko S.;Ota, Akira;Nagatsu, Toshiharu
以前，我们报道了最佳剂量的脂多糖（LPS）显着延长小鼠原代培养的小胶质细胞的寿命，通过抑制凋亡和自噬细胞死亡途径。本研究的目的是评估这些细胞如何保护自己免受LPS处理产生的活性氧（ROS）。该研究是在从小鼠新生儿脑中获得的小胶质细胞中进行的，这些小胶质细胞在普通培养条件下注定会在几天内死亡。LPS（1 ng/mL和100 ng/mL）处理15 h后，细胞内ROS的产生最多。诱导型一氧化氮（NO）合酶蛋白的表达显着增加，由LPS处理的第1天，随后由NO的生产。无论是铜/锌-或锰-超氧化物歧化酶蛋白（SOD）的表达也增加了16小时和LPS处理的第1天。LPS不影响Cu/Zn-和Mn-SOD蛋白的表达，也没有延长具有突变的Toll样受体（TLR）4的小胶质细胞的寿命。本研究的结果表明，SOD功能作为一个有效的屏障，以克服在原代培养的小胶质细胞中产生的ROS LPS处理后，TLR 4可能显着参与诱导这些蛋白质。小胶质细胞可能能够保护自己免受氧化应激，使它们能够存活超过1个月。由于长寿命的小胶质细胞可能在神经退行性疾病的恶化中发挥关键作用，因此将活化的小胶质细胞带回到其静息阶段可能是抑制潜在神经退行性疾病恶化的新的和有前途的策略。
Previously, we reported that an optimal dose of lipopolysaccharide (LPS) markedly extends the life span of mouse primary-cultured microglia by suppressing apoptotic and autophagic cell death pathways. The aim of the present study was to assess how these cells protect themselves against reactive oxygen species (ROS) generated by LPS treatment. The study was conducted in microglia obtained from murine neonate brain, which are destined to die within a few days under ordinary culture conditions. The generation of ROS was maximal after 15h LPS treatment (1ng/mL LPS and 100ng/mL LPS). The expression of inducible nitric oxide (NO) synthase protein was significantly increased by Day 1 of LPS treatment and was followed by the production of NO. The expression of either Cu/Zn- or Mn-superoxide dismutase protein (SOD) was also increased by 16h and Day 1 of LPS treatment. LPS did not affect the expression of Cu/Zn- and Mn-SOD proteins, nor did it extend the life span of microglia that had mutated Toll-like receptor (TLR) 4. The findings of the present study suggest that SODs function as a potent barrier to overcome ROS generated in primary-cultured microglia following LPS treatment and that TLR4 may be significantly involved in inducing these proteins. The microglia may be able to protect themselves against oxidative stress, allowing them to live for more than 1month. Because long-lived microglia may play a critical role in the exacerbation of neurodegeneration, bringing activated microglia back to their resting stage could be a new and promising strategy to inhibit the deterioration underlying neurodegenerative disorders.