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首页> 外文期刊>Nitric oxide: Biology and chemistry >Nitric oxide signaling inhibits microglia proliferation by activation of protein kinase-G
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Nitric oxide signaling inhibits microglia proliferation by activation of protein kinase-G

机译：一氧化氮信号传导通过激活蛋白激酶-G来抑制小凝血生长化

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摘要

Microglia population is primarily determined by a finely-regulated proliferation process during early development of the central nervous system (CNS). Nitric oxide (NO) is known to inhibit proliferation in numerous cell types. However, how NO signaling regulates microglia proliferation remains elusive. Using wildtype (WT) and inducible nitric oxide synthase knockout (iNOS(-/-)) mice, this study investigated the role and underlying mechanisms of iNOS/NO signaling in microglia proliferation. Here we reported that iNOS(-/-) mice displayed significantly more BrdU-labeled proliferating microglia in the cortex than that in WT mice at postnatal day 10. Compared to microglia isolated from WT mouse cortex, significantly more iNOS(-/-) microglia displayed the specific cell-cycle markers Ki67 and phospho-histone H3 (pH3) in their nuclei. In addition, treating WT microglia with the NOS inhibitor LNAME drastically increased the percentage of cells expressing Ki67 and pH3, whereas treating iNOS(-/-) microglia with NOC18, a slow-release NO-donor, significantly decreased the percentage of microglia expressing the two cell-cycle markers. Moreover, inhibition of protein kinase-G (PKG) in WT microglia increased the proportion of microglia expressing Ki67 and pH3, whereas activation of PKG signaling using 8Br-cGMP in iNOS(-/-) microglia significantly decreased the fraction of microglia displaying Ki67 and pH3. Interestingly, in the presence of a PKG inhibitor, NOC18 increased the quantity of iNOS(-/-) microglia expressing Ki67 and pH3. Together, these results indicate that basal activity of iNOS/NO signaling impedes microglial cell-cycle progression and attenuates proliferation through activation of the cGMP-PKG pathway. However, NO increases microglia cell-cycle progression in the absence of cGMP-PKG signaling.
机译：微胶质细胞群主要由中枢神经系统早期发展（CNS）的精细调节的增殖过程决定。已知一氧化氮（NO）抑制许多细胞类型中的增殖。然而，没有信号调节小胶质细胞增殖如何仍然难以捉摸。本研究研究了粉丝（WT）和诱导型一氧化氮合酶敲除（Inos（ - / - ））小鼠，研究了INOS / NO信号在小胶质细胞增殖中的作用和潜在机制。在这里，我们认为Inos（ - / - ）小鼠在后期的皮层中显示出明显的Brdu标记的增殖小胶质细胞10.与从WT小鼠皮质中分离的小鼠分离的微胶质细胞，显着更多的Inos（ - / - ）微胶质在其核中展示了特定的细胞周期标记Ki67和磷酸型组蛋白H3（pH3）。此外，用NOS抑制剂LNAME治疗WT小胶质细胞大大增加了表达KI67和PH3的细胞百分比，而用NOC18处理INOS（ - / - ）小胶质细胞，一种缓释的无助剂，显着降低了表达微胶质细胞的百分比两个细胞周期标记。此外，WT微胶质细胞中蛋白激酶-G（PKG）的抑制增加了表达KI67和PH3的微胶质细胞比例，而使用8BR-CGMP在INOS（/ - ）微胶质中的PKG信号传导显着降低了显示KI67的微胶质细胞的级分PH3。有趣的是，在PKG抑制剂的存在下，NOC18增加了表达KI67和PH3的InOS（ - / - ）微胶质细胞的量。这些结果表明InOS / No Signing的基础活性阻碍了微胶质细胞周期进展并通过激活CGMP-PKG途径衰减增殖。然而，在没有CGMP-PKG信号传导的情况下，没有增加微胶质细胞周期进展。

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