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Microglia Protect Neurons against Ischemia by Synthesis of Tumor Necrosis Factor

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Author

  • Kate Lykke Lambertsen
  • Bettina Hjelm Clausen
  • Alicia Anne Babcock
  • Rikke Gregersen
  • Christina Fenger
  • Helle Hvilsted Nielsen
  • Laila Skov Haugaard
  • Martin Wirenfeldt
  • Marianne Nielsen
  • Frederik Dagnaes-Hansen
  • Horst Bluethmann
  • Nils Joakim Faergeman
  • Michael Meldgaard
  • Tomas Deierborg
  • Bente Finsen
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Summary, in English

Microglia and infiltrating leukocytes are considered major producers of tumor necrosis factor (TNF), which is a crucial player in cerebral ischemia and brain inflammation. We have identified a neuroprotective role for microglial-derived TNF in cerebral ischemia in mice. We show that cortical infarction and behavioral deficit are significantly exacerbated in TNF-knock-out (KO) mice compared with wild-type mice. By using in situ hybridization, immunohistochemistry, and green fluorescent protein bone marrow (BM)-chimeric mice, TNF was shown to be produced by microglia and infiltrating leukocytes. Additional analysis demonstrating that BM-chimeric TNF-KO mice grafted with wild-type BM cells developed larger infarcts than BM-chimeric wild-type mice grafted with TNF-KO BM cells provided evidence that the neuroprotective effect of TNF was attributable to microglial-not leukocyte-derived TNF. In addition, observation of increased infarction in TNF-p55 receptor (TNF-p55R)-KO mice compared with TNF-p75R and wild-type mice suggested that microglial-derived TNF exerts neuroprotective effects through TNF-p55R. We finally report that TNF deficiency is associated with reduced microglial population size and Toll-like receptor 2 expression in unmanipulated brain, which might also influence the neuronal response to injury. Our results identify microglia and microglial-derived TNF as playing a key role in determining the survival of endangered neurons in cerebral ischemia.

Publishing year

2009

Language

English

Pages

1319-1330

Publication/Series

Journal of Neuroscience

Volume

29

Issue

5

Document type

Journal article

Publisher

Society for Neuroscience

Topic

  • Neurosciences

Keywords

  • neuroprotection
  • chimeric mice
  • knock-out mice
  • cytokines
  • neurodegeneration
  • behavior

Status

Published

ISBN/ISSN/Other

  • ISSN: 1529-2401