Microglia protect neurons against ischemia by synthesis of tumor necrosis factor.
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.
Lambertsen
Kate Lykke
KL
Medical Biotechnology Center, University of Southern Denmark, 5000 Odense, Denmark.
Clausen
Bettina Hjelm
BH
Babcock
Alicia Anne
AA
Gregersen
Rikke
R
Fenger
Christina
C
Nielsen
Helle Hvilsted
HH
Haugaard
Laila Skov
LS
Wirenfeldt
Martin
M
Nielsen
Marianne
M
Dagnaes-Hansen
Frederik
F
Bluethmann
Horst
H
Faergeman
Nils Joakim
NJ
Meldgaard
Michael
M
Deierborg
Tomas
T
Finsen
Bente
B
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
D014409:Tumor Necrosis Factor-alpha