title: Conditional ablation of myeloid TNF increases lesion volume after experimental stroke in mice, possibly via altered ERK1/2 signaling.
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.
authors.affiliation: Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, J.B. Winsloewsvej 21st, DK-5000 Odense C, Denmark.
authors.forename: Bettina Hjelm
authors.initials: BH
authors.lastname: Clausen
authors.affiliation: Rigshospitalet, Department of Diagnostics, Molecular Sleep Lab, Nordre Ringvej 69, DK-2600 Glostrup, Denmark.
authors.forename: Matilda
authors.initials: M
authors.lastname: Degn
authors.affiliation: Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, J.B. Winsloewsvej 21st, DK-5000 Odense C, Denmark.
authors.forename: Mithula
authors.initials: M
authors.lastname: Sivasaravanaparan
authors.affiliation: Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, J.B. Winsloewsvej 21st, DK-5000 Odense C, Denmark.
authors.forename: Torben
authors.initials: T
authors.lastname: Fogtmann
authors.affiliation: Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, J.B. Winsloewsvej 21st, DK-5000 Odense C, Denmark.
authors.forename: Maria Gammelstrup
authors.initials: MG
authors.lastname: Andersen
authors.affiliation: Miami Project to Cure Paralysis, University os Miami Miller School of Medicine, 1095 NW 14th Terrace, Miami, FL 33136, USA.
authors.forename: Michelle D
authors.initials: MD
authors.lastname: Trojanowsky
authors.affiliation: Miami Project to Cure Paralysis, University os Miami Miller School of Medicine, 1095 NW 14th Terrace, Miami, FL 33136, USA.
authors.forename: Han
authors.initials: H
authors.lastname: Gao
authors.affiliation: Department of Nulcear Medicine, Odense University Hospital, Sdr. Boulevard 29, DK-5000 Odense C, Denmark.
authors.forename: Svend
authors.initials: S
authors.lastname: Hvidsten
authors.affiliation: Department of Nulcear Medicine, Odense University Hospital, Sdr. Boulevard 29, DK-5000 Odense C, Denmark.
authors.forename: Christina
authors.initials: C
authors.lastname: Baun
authors.affiliation: Department of Experimental Medical Sciences, Experimental Neuroinflammation Laboratory, Lund University, Sölveg 19, 22100 Lund, Sweden.
authors.forename: Tomas
authors.initials: T
authors.lastname: Deierborg
authors.affiliation: Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, J.B. Winsloewsvej 21st, DK-5000 Odense C, Denmark.
authors.forename: Bente
authors.initials: B
authors.lastname: Finsen
authors.affiliation: Institute of Clinical Research, University of Southern Denmark, J.B. Winsloewsvej 19, DK-5000 Odense C, Denmark.|Department of Pathology, Odense University Hospital, Sdr. Boulevard 29, DK-5000 Odense C, Denmark.
authors.forename: Bjarne Winther
authors.initials: BW
authors.lastname: Kristensen
authors.affiliation: Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, J.B. Winsloewsvej 21st, DK-5000 Odense C, Denmark.
authors.forename: Sara Thornby
authors.initials: ST
authors.lastname: Bak
authors.affiliation: Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, J.B. Winsloewsvej 21st, DK-5000 Odense C, Denmark.
authors.forename: Morten
authors.initials: M
authors.lastname: Meyer
authors.affiliation: Miami Project to Cure Paralysis, University os Miami Miller School of Medicine, 1095 NW 14th Terrace, Miami, FL 33136, USA.
authors.forename: Jae
authors.initials: J
authors.lastname: Lee
authors.affiliation: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences and Lomonosov Moscow State University, Vavilova Str 32, Moscow, 119991, Russia.
authors.forename: Sergei A
authors.initials: SA
authors.lastname: Nedospasov
authors.affiliation: Miami Project to Cure Paralysis, University os Miami Miller School of Medicine, 1095 NW 14th Terrace, Miami, FL 33136, USA.
authors.forename: Roberta
authors.initials: R
authors.lastname: Brambilla
authors.affiliation: Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, J.B. Winsloewsvej 21st, DK-5000 Odense C, Denmark.|Department of Neurology, Odense University Hospital, Sdr. Boulevard 29, DK-5000 Odense C, Denmark.
authors.forename: Kate Lykke
authors.initials: KL
authors.lastname: Lambertsen
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D007249:Inflammation / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D015848:Interleukin-5 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007962:Leukocytes / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism; D022423:Myeloid Cells / Q000378:metabolism*; D000066829:Neuroprotection / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D020521:Stroke / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D016207:Cytokines; D053583:Interleukin-1beta; D015848:Interleukin-5; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha