학술논문
Microglia Protect Neurons against Ischemia by Synthesis of Tumor Necrosis Factor.
Document Type
Article
Author
Lambertsen, Kate Lykke; Clausen, Bettina Hjelm; Babcock, Alicia Anne; Gregersen, Rikke; Fenger, Christina; Nielsen, Helle Hvilsted; Haugaard, Laila Skov; Wirenfeldt, Martin; Nielsen, Marianne; Dagnaes-Hansen, Frederik; Bluethmann, Horst; Færgeman, Nils Joakim; Meldgaard, Michael; Deierborg, Tomas; Finsen, Bente
Source
Subject
*NEUROPROTECTIVE agents
*MICROGLIA
*LEUCOCYTES
*TUMOR necrosis factors
*CEREBRAL ischemia
*ENCEPHALITIS
*DIAGNOSIS
*PHYSIOLOGY
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Language
ISSN
0270-6474
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. [ABSTRACT FROM AUTHOR]