期刊
JOURNAL OF NEUROSCIENCE
卷 28, 期 20, 页码 5321-5330出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.3995-07.2008
关键词
oligodendrocyte precursors; cell death; white matter injury; cerebral palsy; glia; nitric oxide
资金
- NICHD NIH HHS [HD18655, P30 HD018655] Funding Source: Medline
- NINDS NIH HHS [P01 NS038475, R01 NS060017, R01 NS060017-03, P01NS38475, R01 NS060017-04, R56 NS060017, R01 NS060017-01A1, P01 NS038475-09, R01 NS060017-02, NS060017] Funding Source: Medline
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 (TNF alpha) 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. TNF alpha neutralizing antibody inhibited LPS toxicity, and addition of TNF alpha induced selective preOL injury in mixed glial cultures. Furthermore, disrupting the genes encoding TNF alpha or its receptors TNFR1/2 completely abolished the deleterious effect of LPS. Our results reveal that TNF alpha 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.
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