Conditional ablation of myeloid TNF increases lesion volume after experimental stroke in mice, possibly via altered ERK1/2 signaling

Bettina Hjelm Clausen, Matilda Degn, Mithula Sivasaravanaparan, Torben Fogtmann, Maria Gammelstrup Andersen, Michelle D Trojanowsky, Han Gao, Svend Hvidsten, Christina Baun, Tomas Deierborg, Bente Finsen, Bjarne Winther Kristensen, Sara Thornby Bak, Morten Meyer, Jae Lee, Sergei A Nedospasov, Roberta Brambilla, Kate Lykke Lambertsen

32 Citationer (Scopus)

Abstract

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 ~93%. Furthermore, phosphorylated-ERK/ERK ratios were significantly decreased in naïve 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 naïve 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-1β, 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.

OriginalsprogEngelsk
TidsskriftScientific Reports
Vol/bind6
Sider (fra-til)29291
ISSN2045-2322
DOI
StatusUdgivet - 7 jul. 2016

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