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Tumor necrosis factor alpha mediates lipopolysaccharide-induced microglial toxicity to developing oligodendrocytes when astrocytes are present.
- Source :
-
The Journal of neuroscience : the official journal of the Society for Neuroscience [J Neurosci] 2008 May 14; Vol. 28 (20), pp. 5321-30. - Publication Year :
- 2008
-
Abstract
- 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.
- Subjects :
- Animals
Astrocytes metabolism
Cell Communication drug effects
Cell Death drug effects
Cell Death immunology
Cell Differentiation drug effects
Cell Differentiation immunology
Cells, Cultured
Coculture Techniques
Demyelinating Diseases immunology
Demyelinating Diseases metabolism
Demyelinating Diseases physiopathology
Encephalitis chemically induced
Encephalitis immunology
Gliosis immunology
Gliosis metabolism
Gliosis physiopathology
Inflammation Mediators
Lipopolysaccharides
Mice
Mice, Knockout
Microglia metabolism
NADPH Oxidases chemistry
NADPH Oxidases metabolism
Oligodendroglia metabolism
Peroxynitrous Acid antagonists & inhibitors
Peroxynitrous Acid biosynthesis
Rats
Signal Transduction immunology
Tumor Necrosis Factor-alpha metabolism
Astrocytes immunology
Cell Communication immunology
Encephalitis physiopathology
Microglia immunology
Oligodendroglia immunology
Tumor Necrosis Factor-alpha immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1529-2401
- Volume :
- 28
- Issue :
- 20
- Database :
- MEDLINE
- Journal :
- The Journal of neuroscience : the official journal of the Society for Neuroscience
- Publication Type :
- Academic Journal
- Accession number :
- 18480288
- Full Text :
- https://doi.org/10.1523/JNEUROSCI.3995-07.2008