Li Jianrong, Ramenaden E Radhika, Peng Jie, Koito Hisami, Volpe Joseph J, Rosenberg Paul A
Department of Neurology and the F. M. Kirby Neurobiology Center, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts 02115, USA.
J Neurosci. 2008 May 14;28(20):5321-30. doi: 10.1523/JNEUROSCI.3995-07.2008.
Reactive microglia and astrocytes are present in lesions of white matter disorders, such as periventricular leukomalacia and multiple sclerosis. However, it is not clear whether they are actively involved in the pathogenesis of these disorders. Previous studies demonstrated that microglia, but not astrocytes, are required for lipopolysaccharide (LPS)-induced selective killing of developing oligodendrocytes (preOLs) and that the toxicity is mediated by microglia-derived peroxynitrite. Here we report that, when astrocytes are present, the LPS-induced, microglia-dependent toxicity to preOLs is no longer mediated by peroxynitrite but instead by a mechanism dependent on tumor necrosis factor-alpha (TNFalpha) signaling. Blocking peroxynitrite formation with nitric oxide synthase (NOS) inhibitors or a decomposition catalyst did not prevent LPS-induced loss of preOLs in mixed glial cultures. PreOLs were highly vulnerable to peroxynitrite; however, the presence of astrocytes prevented the toxicity. Whereas LPS failed to kill preOLs in cocultures of microglia and preOLs deficient in inducible NOS (iNOS) or gp91(phox), the catalytic subunit of the superoxide-generating NADPH oxidase, LPS caused a similar degree of preOL death in mixed glial cultures of wild-type, iNOS-/-, and gp91(phox-/-) mice. TNFalpha neutralizing antibody inhibited LPS toxicity, and addition of TNFalpha induced selective preOL injury in mixed glial cultures. Furthermore, disrupting the genes encoding TNFalpha or its receptors TNFR1/2 completely abolished the deleterious effect of LPS. Our results reveal that TNFalpha signaling, rather than peroxynitrite, is essential in LPS-triggered preOL death in an environment containing all major glial cell types and underscore the importance of intercellular communication in determining the mechanism underlying inflammatory preOL death.
反应性小胶质细胞和星形胶质细胞存在于白质疾病的病变中，如脑室周围白质软化症和多发性硬化症。然而，它们是否积极参与这些疾病的发病机制尚不清楚。先前的研究表明，小胶质细胞而非星形胶质细胞是脂多糖（LPS）诱导发育中的少突胶质细胞前体细胞（preOLs）选择性死亡所必需的，并且这种毒性是由小胶质细胞衍生的过氧亚硝酸盐介导的。在此我们报告，当存在星形胶质细胞时，LPS诱导的、小胶质细胞依赖性的对preOLs的毒性不再由过氧亚硝酸盐介导，而是由一种依赖肿瘤坏死因子-α（TNFα）信号传导的机制介导。用一氧化氮合酶（NOS）抑制剂或分解催化剂阻断过氧亚硝酸盐的形成并不能阻止混合胶质细胞培养物中LPS诱导的preOLs丢失。PreOLs对过氧亚硝酸盐高度敏感；然而，星形胶质细胞的存在可防止毒性。虽然LPS在缺乏诱导型NOS（iNOS）或超氧化物生成NADPH氧化酶的催化亚基gp91（phox）的小胶质细胞和preOLs的共培养物中未能杀死preOLs，但在野生型、iNOS-/-和gp91（phox-/-）小鼠的混合胶质细胞培养物中，LPS导致了相似程度的preOLs死亡。TNFα中和抗体抑制了LPS毒性，并且添加TNFα在混合胶质细胞培养物中诱导了选择性preOL损伤。此外，破坏编码TNFα或其受体TNFR1/2的基因完全消除了LPS的有害作用。我们的结果表明，在包含所有主要胶质细胞类型的环境中，TNFα信号传导而非过氧亚硝酸盐对于LPS触发的preOLs死亡至关重要，并强调了细胞间通讯在确定炎症性preOLs死亡潜在机制中的重要性。
