title: TNF receptor I sensitizes neurons to erythropoietin- and VEGF-mediated neuroprotection after ischemic and excitotoxic injury.
abstract: CNS neurons use robust cytoprotective mechanisms to ensure survival and functioning under conditions of injury. These involve pathways induced by endogenous neuroprotective cytokines such as erythropoietin (EPO). Recently, in contrast to its well known deleterious roles, TNF has also been shown to exhibit neuroprotective properties. In the present study, we investigated the molecular mechanisms by which TNF receptor (TNFR)I mediates neuroprotection by comparing the gene expression profiles of lesioned cortex from WT and TNFRI KO mice after permanent middle cerebral artery occlusion. Several known neuroprotective molecules were identified as TNFRI targets, notably members of the Bcl-2 family, DNA repair machinery and cell cycle, developmental, and differentiation factors, neurotransmitters and growth factors, as well as their receptors, including EPO receptor (EPOR), VEGF, colony-stimulating factor receptor 1, insulin-like growth factor (IGF), and nerve growth factor (NGF). Further analysis showed that induction of EPOR and VEGF expression in primary cortical neurons after glucose deprivation (GD) largely depended on TNFRI and was further up-regulated by TNF. Also, EPO- and VEGF-induced neuroprotection against GD, oxygen-glucose deprivation, and NMDA excitotoxicity depended significantly on TNFRI presence. Finally, EPO prevented neuronal damage induced by kainic acid in WT but not TNFRI KO mice. Our results identify cross-talk between tissue protective cytokines, specifically that TNFRI is necessary for constitutive and GD-induced expression of EPOR and VEGF and for EPO-mediated neuroprotection.
authors.affiliation: Laboratory of Molecular Genetics, Hellenic Pasteur Institute, 11521 Athens, Greece.
authors.forename: Era
authors.initials: E
authors.lastname: Taoufik
authors.forename: Edwige
authors.initials: E
authors.lastname: Petit
authors.forename: Didier
authors.initials: D
authors.lastname: Divoux
authors.forename: Vivian
authors.initials: V
authors.lastname: Tseveleki
authors.forename: Manuela
authors.initials: M
authors.lastname: Mengozzi
authors.forename: Michael L
authors.initials: ML
authors.lastname: Roberts
authors.forename: Samuel
authors.initials: S
authors.lastname: Valable
authors.forename: Pietro
authors.initials: P
authors.lastname: Ghezzi
authors.forename: John
authors.initials: J
authors.lastname: Quackenbush
authors.forename: Michael
authors.initials: M
authors.lastname: Brines
authors.forename: Anthony
authors.initials: A
authors.lastname: Cerami
authors.forename: Lesley
authors.initials: L
authors.lastname: Probert
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000235:genetics* / Q000473:pathology; D016923:Cell Death / Q000235:genetics; D019610:Cytoprotection / Q000235:genetics*; D004921:Erythropoietin / Q000235:genetics*; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity*; D020869:Gene Expression Profiling; D007608:Kainic Acid / Q000633:toxicity; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016202:N-Methylaspartate / Q000633:toxicity; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D017467:Receptors, Erythropoietin / Q000235:genetics; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*
chemical_list: D018690:Excitatory Amino Acid Agonists; D017467:Receptors, Erythropoietin; D047888:Receptors, Tumor Necrosis Factor, Type I; C506236:Tnfrsf1a protein, mouse; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; D004921:Erythropoietin; D016202:N-Methylaspartate; D007608:Kainic Acid