Peroxynitrite generated by inducible nitric oxide synthase and NADPH oxidase mediates microglial toxicity to oligodendrocytes
Peroxynitrite generated by inducible nitric oxide synthase and NADPH oxidase mediates microglial toxicity to oligodendrocytes
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DOI：
10.1073/pnas.0502552102
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发表时间：
2005-07-12
影响因子：
11.1
通讯作者：
Rosenberg, PA
中科院分区：
文献类型：
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作者：
Li, JR;Baud, O;Rosenberg, PA
中枢神经系统反应性小胶质细胞参与了脑室周围白质软化和多发性硬化症等脑白质疾病的发病机制。然而，激活的小胶质细胞杀死少突胶质细胞(OLs)的机制仍然不清楚。在这里，我们证明了脂多糖(LPS)诱导的发育中的OL的死亡是由小胶质细胞衍生的过氧亚硝酸盐引起的，过氧亚硝酸盐是一氧化氮(NO)和超氧阴离子的反应产物。用一氧化氮合酶抑制剂、超氧化物歧化酶模拟物或分解催化剂阻断过氧亚硝酸盐的形成可消除细胞毒性。只有小胶质细胞表达诱导型一氧化氮合酶(MOS)，而OL不表达；MOS基因敲除小鼠的小胶质细胞在激活时不具有细胞毒性。超氧化物的分子来源被确定为超氧化物产生酶NADPH氧化酶。该酶在内毒素暴露时被激活，其抑制作用可阻止小胶质细胞对OL的毒性作用。此外，从缺乏氧化酶催化成分gp91Phox的小鼠中分离出的小胶质细胞未能诱导细胞死亡。我们的结果揭示了NADPH氧化酶在内毒素诱导的OL死亡中的作用，并提示MOS产生的过氧亚硝酸盐和激活的小胶质细胞中的NADPH氧化酶可能在白质疾病的发病机制中发挥重要作用。
Reactive microglia in the CNS have been implicated in the pathogenesis of white matter disorders, such as periventricular leukomalacia and multiple sclerosis. However, the mechanism by which activated microglia kill oligodendrocytes (OLs) remains elusive. Here we show that lipopolysaccharide (LPS)-induced death of developing OLs is caused by microglia-derived peroxynitrite, the reaction product of nitric oxide (NO) and superoxide anion. Blocking peroxynitrite formation with nitric oxide synthase inhibitors, superoxide dismutase mimics, or a decomposition catalyst abrogated the cytotoxicity. Only microglia, but not OLs, expressed inducible NO synthase (MOS) after LPS challenge; microglia from MOS knockout mice were not cytotoxic upon activation. The molecular source for superoxide was identified as the superoxide-generating enzyme NADPH oxidase. The oxidase was activated upon LPS exposure, and its inhibition prevented microglial toxicity toward OLs. Furthermore, microglia isolated from mice deficient in the catalytic component of the oxidase, gp91phox, failed to induce cell death. Our results reveal a role for NADPH oxidase in LPS-induced OL death and suggest that peroxynitrite produced by MOS and NADPH oxidase in activated microglia may play an important role in the pathogenesis of white matter disorders.