Tumor necrosis factor alpha mediates lipopolysaccharide-induced microglial toxicity to developing oligodendrocytes when astrocytes are present.
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.
Li
Jianrong
J
Department of Neurology and the F. M. Kirby Neurobiology Center, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts 02115, USA. jrli@cvm.tamu.edu
Ramenaden
E Radhika
ER
Peng
Jie
J
Koito
Hisami
H
Volpe
Joseph J
JJ
Rosenberg
Paul A
PA
D000818:Animals; D001253:Astrocytes / Q000276:immunology* / Q000378:metabolism; D002450:Cell Communication / Q000187:drug effects / Q000276:immunology*; D016923:Cell Death / Q000187:drug effects / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D018920:Coculture Techniques; D003711:Demyelinating Diseases / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D004660:Encephalitis / Q000139:chemically induced / Q000276:immunology / Q000503:physiopathology*; D005911:Gliosis / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000276:immunology* / Q000378:metabolism; D019255:NADPH Oxidases / Q000737:chemistry / Q000378:metabolism; D009836:Oligodendroglia / Q000276:immunology* / Q000378:metabolism; D030421:Peroxynitrous Acid / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D051381:Rats; D015398:Signal Transduction / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology* / Q000378:metabolism
D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D030421:Peroxynitrous Acid; D019255:NADPH Oxidases