Astrocytes promote TNF-mediated toxicity to oligodendrocyte precursors

Sunja Kim, Andrew J. Steelman, Hisami Koito, Jianrong Li

Research output: Contribution to journalArticlepeer-review

Abstract

Neuroinflammation and increased production of tumor necrosis factor (TNF) in the CNS have been implicated in many neurological diseases including white matter disorders periventricular leukomalacia and multiple sclerosis. However, the exact role of TNF in these diseases and how it mediates oligodendrocyte injury remain unclear. Previously, we demonstrated that lipopolysaccharide (LPS) selectively kills oligodendrocyte precursors (preOLs) in a non-cell autonomous fashion through the induction of TNF in mixed glial cultures. Here, we report that activation of oligodendroglial, but not astroglial and microglial, TNFR1 is required for LPS toxicity, and that astrocytes promote TNF-mediated preOL death through a cell contact-dependent mechanism. Microglia were the sole source for TNF production in LPS-treated mixed glial cultures. Ablation of TNFR1 in mixed glia completely prevented LPS-induced death of preOLs. TNFR1-expressing preOLs were similarly susceptible to LPS treatment when seeded into wildtype and TNFR1-/- mixed glial cultures, demonstrating a requirement for oligodendroglial TNFR1 in the cell death. Although exogenous TNF failed to cause significant cell death in enriched preOL cultures, it became cytotoxic when preOLs were in contact with astrocytes. Collectively, our results demonstrate oligodendroglial TNFR1 in mediating inflammatory destruction of preOLs and suggest a previously unrecognized role for astrocytes in promoting TNF toxicity to preOLs.

Original languageEnglish (US)
Pages (from-to)53-66
Number of pages14
JournalJournal of Neurochemistry
Volume116
Issue number1
DOIs
StatePublished - Jan 2011
Externally publishedYes

Keywords

  • cell death
  • inflammation
  • microglia
  • oligodendrocyte precursors
  • periventricular leukomalacia
  • white matter injury

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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