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Microglia Protect Neurons against Ischemia by Synthesis of Tumor Necrosis Factor

Lambertsen, Kate Lykke; Clausen, Bettina Hjelm; Babcock, Alicia Anne; Gregersen, Rikke; Fenger, Christina; Nielsen, Helle Hvilsted; Haugaard, Laila Skov; Wirenfeldt, Martin; Nielsen, Marianne and Dagnaes-Hansen, Frederik, et al. (2009) In Journal of Neuroscience 29(5). p.1319-1330
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... (More)
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. (Less)
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published
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keywords
neuroprotection, chimeric mice, knock-out mice, cytokines, neurodegeneration, behavior
in
Journal of Neuroscience
volume
29
issue
5
pages
1319 - 1330
publisher
Society for Neuroscience
external identifiers
  • wos:000263072400008
  • scopus:59649117102
ISSN
1529-2401
DOI
10.1523/JNEUROSCI.5505-08.2009
language
English
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yes
id
4a2dff72-b6a9-4c9d-9ec6-00ce456c6b9a (old id 1311381)
date added to LUP
2009-03-17 10:40:21
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2017-11-19 03:56:20
@article{4a2dff72-b6a9-4c9d-9ec6-00ce456c6b9a,
  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.},
  author       = {Lambertsen, Kate Lykke and Clausen, Bettina Hjelm and Babcock, Alicia Anne and Gregersen, Rikke and Fenger, Christina and Nielsen, Helle Hvilsted and Haugaard, Laila Skov and Wirenfeldt, Martin and Nielsen, Marianne and Dagnaes-Hansen, Frederik and Bluethmann, Horst and Faergeman, Nils Joakim and Meldgaard, Michael and Deierborg, Tomas and Finsen, Bente},
  issn         = {1529-2401},
  keyword      = {neuroprotection,chimeric mice,knock-out mice,cytokines,neurodegeneration,behavior},
  language     = {eng},
  number       = {5},
  pages        = {1319--1330},
  publisher    = {Society for Neuroscience},
  series       = {Journal of Neuroscience},
  title        = {Microglia Protect Neurons against Ischemia by Synthesis of Tumor Necrosis Factor},
  url          = {http://dx.doi.org/10.1523/JNEUROSCI.5505-08.2009},
  volume       = {29},
  year         = {2009},
}