title: Microglia protect neurons against ischemia by synthesis of tumor necrosis factor.
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.
authors.affiliation: Medical Biotechnology Center, University of Southern Denmark, 5000 Odense, Denmark.
authors.forename: Kate Lykke
authors.initials: KL
authors.lastname: Lambertsen
authors.forename: Bettina Hjelm
authors.initials: BH
authors.lastname: Clausen
authors.forename: Alicia Anne
authors.initials: AA
authors.lastname: Babcock
authors.forename: Rikke
authors.initials: R
authors.lastname: Gregersen
authors.forename: Christina
authors.initials: C
authors.lastname: Fenger
authors.forename: Helle Hvilsted
authors.initials: HH
authors.lastname: Nielsen
authors.forename: Laila Skov
authors.initials: LS
authors.lastname: Haugaard
authors.forename: Martin
authors.initials: M
authors.lastname: Wirenfeldt
authors.forename: Marianne
authors.initials: M
authors.lastname: Nielsen
authors.forename: Frederik
authors.initials: F
authors.lastname: Dagnaes-Hansen
authors.forename: Horst
authors.initials: H
authors.lastname: Bluethmann
authors.forename: Nils Joakim
authors.initials: NJ
authors.lastname: Faergeman
authors.forename: Michael
authors.initials: M
authors.lastname: Meldgaard
authors.forename: Tomas
authors.initials: T
authors.lastname: Deierborg
authors.forename: Bente
authors.initials: B
authors.lastname: Finsen
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism* / Q000473:pathology / Q000502:physiology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000502:physiology
chemical_list: D014409:Tumor Necrosis Factor-alpha