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The Journal of Neuroscience, May 14, 2008, 28(20):5321-5330; doi:10.1523/JNEUROSCI.3995-07.2008

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Neurobiology of Disease
Tumor Necrosis Factor Mediates Lipopolysaccharide-Induced Microglial Toxicity to Developing Oligodendrocytes When Astrocytes Are Present

Jianrong Li,¹ E. Radhika Ramenaden,¹ Jie Peng,² Hisami Koito,² Joseph J. Volpe,¹ and Paul A. Rosenberg¹

¹Department of Neurology and the F. M. Kirby Neurobiology Center, Children's Hospital Boston, and the Program in Neuroscience, Harvard Medical School, Boston, Massachusetts 02115, and ²Department of Veterinary Integrative Biosciences, Texas A & M University, College Station, Texas 77843

Correspondence should be addressed to either of the following: Dr. Paul A. Rosenberg, Department of Neurology, Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, Email: paul.rosenberg{at}childrens.havard.edu; or Dr. Jianrong Li at her present address, Department of Veterinary Integrative Biosciences, Texas A & M University, Mail Stop 4458, College Station, TX 77843, Email: jrli{at}cvm.tamu.edu

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- (TNF) 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 neutralizing antibody inhibited LPS toxicity, and addition of TNF induced selective preOL injury in mixed glial cultures. Furthermore, disrupting the genes encoding TNF or its receptors TNFR1/2 completely abolished the deleterious effect of LPS. Our results reveal that TNF 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.

Key words: oligodendrocyte precursors; cell death; white matter injury; cerebral palsy; glia; nitric oxide

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Received Aug. 31, 2007; revised April 2, 2008; accepted April 4, 2008.

Correspondence should be addressed to either of the following: Dr. Paul A. Rosenberg, Department of Neurology, Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, Email: paul.rosenberg{at}childrens.havard.edu; or Dr. Jianrong Li at her present address, Department of Veterinary Integrative Biosciences, Texas A & M University, Mail Stop 4458, College Station, TX 77843, Email: jrli{at}cvm.tamu.edu

This article has been cited by other articles:

				I. Singh, A. K. Singh, and M. A. Contreras Peroxisomal Dysfunction in Inflammatory Childhood White Matter Disorders: An Unexpected Contributor to Neuropathology J Child Neurol, September 1, 2009; 24(9): 1147 - 1157. [Abstract] [PDF]

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