Journal
SCIENTIFIC REPORTS
Volume 6, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/srep29291
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Funding
- Lundbeck Foundation [R54-A5539, R67-A6383]
- Carlsberg Foundation [2007_01_0176]
- Novo Nordisk Foundation [R153-A-12550, R168-A14120]
- Fonden til Laegevidenskabens Fremme
- NINDS [1R01NS081040-01]
- Russian Science Foundation [14-50-00060]
- Novo Nordisk Fonden [NNF12OC0002215] Funding Source: researchfish
- Russian Science Foundation [14-50-00060] Funding Source: Russian Science Foundation
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Microglia are activated following cerebral ischemia and increase their production of the neuro-and immunomodulatory cytokine tumor necrosis factor (TNF). To address the function of TNF from this cellular source in focal cerebral ischemia we used TNF conditional knock out mice (LysMcreTNF(fl/fl)) in which the TNF gene was deleted in cells of the myeloid lineage, including microglia. The deletion reduced secreted TNF levels in lipopolysaccharide-stimulated cultured primary microglia by similar to 93%. Furthermore, phosphorylated-ERK/ERK ratios were significantly decreased in naive LysMcreTNF(fl/fl) mice demonstrating altered ERK signal transduction. Micro-PET using (18)[F]-fluorodeoxyglucose immediately after focal cerebral ischemia showed increased glucose uptake in LysMcreTNF(fl/fl) mice, representing significant metabolic changes, that translated into increased infarct volumes at 24 hours and 5 days compared to littermates (TNFfl/fl). In naive LysMcreTNF(fl/fl) mice cytokine levels were low and comparable to littermates. At 6 hours, TNF producing microglia were reduced by 56% in the ischemic cortex in LysMcreTNF(fl/fl) mice compared to littermate mice, whereas no TNF+ leukocytes were detected. At 24 hours, pro-inflammatory cytokine (TNF, IL-1 beta, IL-6, IL-5 and CXCL1) levels were significantly lower in LysMcreTNF(fl/fl) mice, despite comparable infiltrating leukocyte populations. Our results identify microglial TNF as beneficial and neuroprotective in the acute phase and as a modulator of neuroinflammation at later time points after experimental ischemia, which may contribute to regenerative recovery.
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