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

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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.

Original languageEnglish (US)
Article number29291
JournalScientific Reports
Volume6
DOIs
StatePublished - Jul 7 2016

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Tumor Necrosis Factor-alpha
Stroke
Microglia
Brain Ischemia
Cytokines
Leukocytes
Interleukin-5
Fluorodeoxyglucose F18
Cell Lineage
Interleukin-1
Knockout Mice
Lipopolysaccharides
Interleukin-6
Signal Transduction
Ischemia
Glucose
Population
Genes

ASJC Scopus subject areas

  • General

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Clausen, B. H., Degn, M., Sivasaravanaparan, M., Fogtmann, T., Andersen, M. G., Trojanowsky, M. D., ... Lambertsen, K. L. (2016). Conditional ablation of myeloid TNF increases lesion volume after experimental stroke in mice, possibly via altered ERK1/2 signaling. Scientific Reports, 6, [29291]. https://doi.org/10.1038/srep29291

Conditional ablation of myeloid TNF increases lesion volume after experimental stroke in mice, possibly via altered ERK1/2 signaling. / Clausen, Bettina Hjelm; Degn, Matilda; Sivasaravanaparan, Mithula; Fogtmann, Torben; Andersen, Maria Gammelstrup; Trojanowsky, Michelle D.; Gao, Han; Hvidsten, Svend; Baun, Christina; Deierborg, Tomas; Finsen, Bente; Kristensen, Bjarne Winther; Bak, Sara Thornby; Meyer, Morten; Lee, Jae; Nedospasov, Sergei A.; Brambilla, Roberta; Lambertsen, Kate Lykke.

In: Scientific Reports, Vol. 6, 29291, 07.07.2016.

Research output: Contribution to journalArticle

Clausen, BH, Degn, M, Sivasaravanaparan, M, Fogtmann, T, Andersen, MG, Trojanowsky, MD, Gao, H, Hvidsten, S, Baun, C, Deierborg, T, Finsen, B, Kristensen, BW, Bak, ST, Meyer, M, Lee, J, Nedospasov, SA, Brambilla, R & Lambertsen, KL 2016, 'Conditional ablation of myeloid TNF increases lesion volume after experimental stroke in mice, possibly via altered ERK1/2 signaling', Scientific Reports, vol. 6, 29291. https://doi.org/10.1038/srep29291
Clausen, Bettina Hjelm ; Degn, Matilda ; Sivasaravanaparan, Mithula ; Fogtmann, Torben ; Andersen, Maria Gammelstrup ; Trojanowsky, Michelle D. ; Gao, Han ; Hvidsten, Svend ; Baun, Christina ; Deierborg, Tomas ; Finsen, Bente ; Kristensen, Bjarne Winther ; Bak, Sara Thornby ; Meyer, Morten ; Lee, Jae ; Nedospasov, Sergei A. ; Brambilla, Roberta ; Lambertsen, Kate Lykke. / Conditional ablation of myeloid TNF increases lesion volume after experimental stroke in mice, possibly via altered ERK1/2 signaling. In: Scientific Reports. 2016 ; Vol. 6.
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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 na{\"i}ve 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 na{\"i}ve 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.",
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AU - Clausen, Bettina Hjelm

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AU - Fogtmann, Torben

AU - Andersen, Maria Gammelstrup

AU - Trojanowsky, Michelle D.

AU - Gao, Han

AU - Hvidsten, Svend

AU - Baun, Christina

AU - Deierborg, Tomas

AU - Finsen, Bente

AU - Kristensen, Bjarne Winther

AU - Bak, Sara Thornby

AU - Meyer, Morten

AU - Lee, Jae

AU - Nedospasov, Sergei A.

AU - Brambilla, Roberta

AU - Lambertsen, Kate Lykke

PY - 2016/7/7

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N2 - 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.

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