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Conditional ablatio...
Conditional ablation of myeloid TNF increases lesion volume after experimental stroke in mice, possibly via altered ERK1/2 signaling
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- Clausen, Bettina Hjelm (author)
- University of Southern Denmark
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- Degn, Matilda (author)
- Copenhagen University Hospital
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- Sivasaravanaparan, Mithula (author)
- University of Southern Denmark
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- Fogtmann, Torben (author)
- University of Southern Denmark
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- Andersen, Maria Gammelstrup (author)
- University of Southern Denmark
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- Trojanowsky, Michelle D. (author)
- University of Miami
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- Gao, Han (author)
- University of Miami
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- Hvidsten, Svend (author)
- Odense University Hospital
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- Baun, Christina (author)
- Odense University Hospital
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- Deierborg, Tomas (author)
- Lund University,Lunds universitet,Neuroinflammation,Forskargrupper vid Lunds universitet,Lund University Research Groups
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- Finsen, Bente (author)
- University of Southern Denmark
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- Kristensen, Bjarne Winther (author)
- Odense University Hospital,University of Southern Denmark
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- Bak, Sara Thornby (author)
- University of Southern Denmark
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- Meyer, Morten (author)
- University of Southern Denmark
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- Lee, Jae (author)
- University of Miami
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- Nedospasov, Sergei A. (author)
- P.N. Lebedev Physical Institute of the Russian Academy of Sciences,Lomonosov Moscow State University
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- Brambilla, Roberta (author)
- University of Miami
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- Lambertsen, Kate Lykke (author)
- University of Southern Denmark,Odense University Hospital
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(creator_code:org_t)
- 2016-07-07
- 2016
- English.
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In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6
- Related links:
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http://dx.doi.org/10... (free)
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https://www.nature.c...
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https://doi.org/10.1...
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Abstract
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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 ∼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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Neurologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Neurology (hsv//eng)
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Clausen, Bettina ...
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Degn, Matilda
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Sivasaravanapara ...
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Fogtmann, Torben
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Andersen, Maria ...
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Trojanowsky, Mic ...
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show more...
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Gao, Han
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Hvidsten, Svend
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Baun, Christina
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Deierborg, Tomas
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Finsen, Bente
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Kristensen, Bjar ...
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Bak, Sara Thornb ...
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Meyer, Morten
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Lee, Jae
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Nedospasov, Serg ...
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Brambilla, Rober ...
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Lambertsen, Kate ...
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Neurology
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Scientific Repor ...
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Lund University