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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-\u03b1 (TNF\u03b1) 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<jats:sup>phox<\/jats:sup>, the catalytic subunit of the superoxide-generating NADPH oxidase, LPS caused a similar degree of preOL death in mixed glial cultures of wild-type,<jats:italic>iNOS<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>, and<jats:italic>gp91<\/jats:italic><jats:sup><jats:italic>phox<\/jats:italic>\u2212\/\u2212<\/jats:sup>mice. TNF\u03b1 neutralizing antibody inhibited LPS toxicity, and addition of TNF\u03b1 induced selective preOL injury in mixed glial cultures. Furthermore, disrupting the genes encoding TNF\u03b1 or its receptors TNFR1\/2 completely abolished the deleterious effect of LPS. Our results reveal that TNF\u03b1 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.<\/jats:p>","DOI":"10.1523\/jneurosci.3995-07.2008","type":"journal-article","created":{"date-parts":[[2008,5,14]],"date-time":"2008-05-14T16:28:25Z","timestamp":1210782505000},"page":"5321-5330","source":"Crossref","is-referenced-by-count":127,"title":["Tumor Necrosis Factor \u03b1 Mediates Lipopolysaccharide-Induced Microglial Toxicity to Developing Oligodendrocytes When Astrocytes Are Present"],"prefix":"10.1523","volume":"28","author":[{"given":"Jianrong","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E. 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