title: Genetic Ablation of Soluble TNF Does Not Affect Lesion Size and Functional Recovery after Moderate Spinal Cord Injury in Mice.
abstract: Traumatic spinal cord injury (SCI) is followed by an instant increase in expression of the microglial-derived proinflammatory cytokine tumor necrosis factor (TNF) within the lesioned cord. TNF exists both as membrane-anchored TNF (mTNF) and as cleaved soluble TNF (solTNF). We previously demonstrated that epidural administration of a dominant-negative inhibitor of solTNF, XPro1595, to the contused spinal cord resulted in changes in Iba1 protein expression in microglia/macrophages, decreased lesion volume, and improved locomotor function. Here, we extend our studies using mice expressing mTNF, but no solTNF (mTNFΔ/Δ), to study the effect of genetic ablation of solTNF on SCI. We demonstrate that TNF levels were significantly decreased within the lesioned spinal cord 3 days after SCI in mTNFΔ/Δmice compared to littermates. This decrease did, however, not translate into significant changes in other pro- and anti-inflammatory cytokines (IL-10, IL-1β, IL-6, IL-5, IL-2, CXCL1, CCL2, or CCL5), despite a tendency towards increased IL-10 and decreased IL-1β, TNFR1, and TNFR2 levels in mTNFΔ/Δmice. In addition, microglial and leukocyte infiltration, activation state (Iba1, CD11b, CD11c, CD45, and MHCII), lesion size, and functional outcome after moderate SCI were comparable between genotypes. Collectively, our data demonstrate that genetic ablation of solTNF does not significantly modulate postlesion outcome after SCI.
authors.affiliation: Neurobiology Research, Institute of Molecular Medicine, J.B. Winsloewsvej 21, st, 5000 Odense C, Denmark.
authors.forename: Ditte Gry
authors.initials: DG
authors.lastname: Ellman
authors.affiliation: Department of Diagnostics, Molecular Sleep Lab, Rigshospitalet, Nordre Ringvej 69, 2600 Glostrup, Denmark.
authors.forename: Matilda
authors.initials: M
authors.lastname: Degn
authors.affiliation: Neurobiology Research, Institute of Molecular Medicine, J.B. Winsloewsvej 21, st, 5000 Odense C, Denmark.
authors.forename: Minna Christiansen
authors.initials: MC
authors.lastname: Lund
authors.affiliation: Neurobiology Research, Institute of Molecular Medicine, J.B. Winsloewsvej 21, st, 5000 Odense C, Denmark.
authors.forename: Bettina Hjelm
authors.initials: BH
authors.lastname: Clausen
authors.affiliation: Neurobiology Research, Institute of Molecular Medicine, J.B. Winsloewsvej 21, st, 5000 Odense C, Denmark.
authors.forename: Hans Gram
authors.initials: HG
authors.lastname: Novrup
authors.affiliation: Neurobiology Research, Institute of Molecular Medicine, J.B. Winsloewsvej 21, st, 5000 Odense C, Denmark.
authors.forename: Simon Bertram
authors.initials: SB
authors.lastname: Flæng
authors.affiliation: Department of Pathology, Department of Clinical Research, SDU Muscle Research Cluster, University of Southern Denmark, J.B. Winsloewsvej 15, 5000 Odense C, Denmark.
authors.forename: Louise Helskov
authors.initials: LH
authors.lastname: Jørgensen
authors.affiliation: Neurobiology Research, Institute of Molecular Medicine, J.B. Winsloewsvej 21, st, 5000 Odense C, Denmark.
authors.forename: Lujitha
authors.initials: L
authors.lastname: Suntharalingam
authors.affiliation: Neurobiology Research, Institute of Molecular Medicine, J.B. Winsloewsvej 21, st, 5000 Odense C, Denmark.
authors.forename: Åsa Fex
authors.initials: ÅF
authors.lastname: Svenningsen
authors.affiliation: The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, 1095 NW 14th Terrace, Miami, FL 33136, USA.
authors.forename: Roberta
authors.initials: R
authors.lastname: Brambilla
authors.affiliation: Neurobiology Research, Institute of Molecular Medicine, J.B. Winsloewsvej 21, st, 5000 Odense C, Denmark; Department of Neurology, Odense University Hospital, J.B. Winsloewsvej 4, 5000 Odense C, Denmark; Brain Research-Inter-Disciplinary Guided Excellence (BRIDGE), Department of Clinical Research, 5000 Odense C, Denmark.
authors.forename: Kate Lykke
authors.identifier: 0000-0001-9276-4902
authors.initials: KL
authors.lastname: Lambertsen
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D005260:Female; D005799:Genes, Dominant; D005838:Genotype; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006720:Homozygote; D007249:Inflammation; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D018782:Maze Learning; D051379:Mice; D009000:Monocytes / Q000166:cytology / Q000378:metabolism; D013119:Spinal Cord Injuries / Q000097:blood*; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000097:blood* / Q000235:genetics*
chemical_list: D016207:Cytokines; D005904:Glial Fibrillary Acidic Protein; D014409:Tumor Necrosis Factor-alpha