Microglia protect neurons against ischemia by synthesis of tumor necrosis factor: Microglial Neuroprotection in Experimental Stroke

Kate Lykke Lambertsen, Bettina Hjelm Clausen, Alicia Babcock, Rikke Gregersen, Christina Fenger, Helle Hvilsted Nielsen, Laila Skov Haugaard, Martin Wirenfeldt, Marianne Nielsen, Frederik Dagnaes-Hansen, Horst Bluethmann, Nils J. Færgeman, Michael Meldgaard, Tomas Deierborg, Bente Finsen

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

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.
Original languageEnglish
JournalJournal of Neuroscience
Volume29
Issue number5
Pages (from-to)1319-30
Number of pages11
ISSN0270-6474
DOIs
Publication statusPublished - 2009

Keywords

  • Animals
  • Brain Ischemia
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microglia
  • Neurons
  • Tumor Necrosis Factor-alpha

Fingerprint Dive into the research topics of 'Microglia protect neurons against ischemia by synthesis of tumor necrosis factor: Microglial Neuroprotection in Experimental Stroke'. Together they form a unique fingerprint.

Cite this