title: Genetic ablation of soluble tumor necrosis factor with preservation of membrane tumor necrosis factor is associated with neuroprotection after focal cerebral ischemia.
abstract: Microglia respond to focal cerebral ischemia by increasing their production of the neuromodulatory cytokine tumor necrosis factor, which exists both as membrane-anchored tumor necrosis factor and as cleaved soluble tumor necrosis factor forms. We previously demonstrated that tumor necrosis factor knockout mice display increased lesion volume after focal cerebral ischemia, suggesting that tumor necrosis factor is neuroprotective in experimental stroke. Here, we extend our studies to show that mice with intact membrane-anchored tumor necrosis factor, but no soluble tumor necrosis factor, display reduced infarct volumes at one and five days after stroke. This was associated with improved functional outcome after experimental stroke. No changes were found in the mRNA levels of tumor necrosis factor and tumor necrosis factor-related genes (TNFR1, TNFR2, TACE), pro-inflammatory cytokines (IL-1β, IL-6) or chemokines (CXCL1, CXCL10, CCL2); however, protein expression of TNF, IL-1β, IL-6 and CXCL1 was reduced in membrane-anchored tumor necrosis factor(Δ/Δ) compared to membrane-anchored tumor necrosis factor(wt/wt) mice one day after experimental stroke. This was paralleled by reduced MHCII expression and a reduction in macrophage infiltration in the ipsilateral cortex of membrane-anchored tumor necrosis factor(Δ/Δ) mice. Collectively, these findings indicate that membrane-anchored tumor necrosis factor mediates the protective effects of tumor necrosis factor signaling in experimental stroke, and therapeutic strategies specifically targeting soluble tumor necrosis factor could be beneficial in clinical stroke therapy.
authors.affiliation: Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, USA.
authors.forename: Pernille M
authors.initials: PM
authors.lastname: Madsen
authors.affiliation: Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
authors.forename: Bettina H
authors.initials: BH
authors.lastname: Clausen
authors.affiliation: Molecular Sleep Lab, Department of Diagnostics, Glostrup Hospital, 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, Odense, Denmark.
authors.forename: Stine
authors.initials: S
authors.lastname: Thyssen
authors.affiliation: Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
authors.forename: Lotte K
authors.initials: LK
authors.lastname: Kristensen
authors.affiliation: Department of Experimental Medical Sciences, Experimental Neuroinflammation Laboratory, Lund University, Lund, Sweden.
authors.forename: Martina
authors.initials: M
authors.lastname: Svensson
authors.affiliation: KMEB, Molecular Endocrinology, Odense University Hospital, Odense, Denmark.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Ditzel
authors.affiliation: Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
authors.forename: Bente
authors.initials: B
authors.lastname: Finsen
authors.affiliation: Department of Experimental Medical Sciences, Experimental Neuroinflammation Laboratory, Lund University, Lund, Sweden.
authors.forename: Tomas
authors.initials: T
authors.lastname: Deierborg
authors.affiliation: The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, USA.
authors.forename: Roberta
authors.initials: R
authors.lastname: Brambilla
authors.affiliation: Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark klambertsen@health.sdu.dk r.brambilla@miami.edu.
authors.forename: Kate L
authors.initials: KL
authors.lastname: Lambertsen
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000503:physiopathology*; D016207:Cytokines / Q000097:blood / Q000235:genetics; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D000066829:Neuroprotection; D012333:RNA, Messenger / Q000097:blood; D012995:Solubility; D020521:Stroke / Q000097:blood* / Q000188:drug therapy; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000235:genetics*
chemical_list: D016207:Cytokines; D008565:Membrane Proteins; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha
keywords: Tumor necrosis factor; behavior; chemokines; cytokines; macrophages; microglia; neuroprotection