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Isolation of Cortical Microglia with Preserved Immunophenotype and Functionality From Murine Neonates
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Peroxynitrite generated by inducible nitric oxide synthase and NADPH oxidase mediates microglial toxicity to

Jianrong Li1, Olivier Baud, Timothy Vartanian

  • 1Department of Neurology, Children's Hospital, and Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA.

Proceedings of the National Academy of Sciences of the United States of America
|July 7, 2005
PubMed

Insights

Activated microglia kill developing oligodendrocytes (OLs) via peroxynitrite, a toxic molecule produced by inducible nitric oxide synthase (iNOS) and NADPH oxidase. This finding sheds light on white matter disorder pathogenesis.

Area of Science:

  • Neuroscience
  • Immunology
  • Cell Biology

Background:

  • Reactive microglia are implicated in white matter disorders like multiple sclerosis.
  • The precise mechanism of microglial-induced oligodendrocyte death is not fully understood.

Purpose of the Study:

  • To elucidate the mechanism by which activated microglia induce oligodendrocyte death.
  • To identify the reactive oxygen and nitrogen species involved in this process.

Main Methods:

  • Utilized lipopolysaccharide (LPS) to activate microglia in vitro and in vivo.
  • Investigated the role of nitric oxide (NO), superoxide anion, and peroxynitrite in oligodendrocyte (OL) death.
  • Employed nitric oxide synthase (iNOS) inhibitors, superoxide dismutase mimics, and NADPH oxidase inhibitors.
  • Examined microglia from iNOS and NADPH oxidase knockout mice.

Main Results:

  • LPS-induced OL death is mediated by microglia-derived peroxynitrite.
  • Peroxynitrite formation is dependent on inducible NO synthase (iNOS) in microglia and NADPH oxidase.
  • Inhibition or genetic deficiency of iNOS or NADPH oxidase abrogated microglial cytotoxicity toward OLs.

Conclusions:

  • Peroxynitrite, generated by iNOS and NADPH oxidase in activated microglia, is a key mediator of oligodendrocyte death.
  • These findings reveal a critical role for NADPH oxidase in microglial-induced OL toxicity.
  • Targeting peroxynitrite production may offer therapeutic strategies for white matter disorders.

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