title: A soluble Fn14-Fc decoy receptor reduces infarct volume in a murine model of cerebral ischemia.
abstract: Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a member of the tumor necrosis factor superfamily. TWEAK acts on responsive cells via binding to a small cell surface receptor named Fn14. Recent studies have demonstrated that TWEAK can stimulate numerous cellular responses including cell proliferation, migration, and proinflammatory molecule production, but the role of this cytokine in cardiovascular disease and stroke has not been established. The present study investigated whether TWEAK or Fn14 expression was regulated in a murine model of cerebral ischemia and whether TWEAK played a role in ischemia-mediated cell death. We found that TWEAK and Fn14 were expressed by primary mouse cerebral cortex-derived astrocytes and neurons cultured in vitro. Also, both the TWEAK and Fn14 proteins were present at elevated levels in the ischemic penumbra region after middle cerebral artery occlusion. Finally, we report that intracerebroventricular injection of a soluble Fn14-Fc decoy receptor immediately after middle cerebral artery occlusion significantly reduced infarct volume and the extent of microglial cell activation and apoptotic cell death in the ischemic penumbra. We conclude that the cytokine TWEAK may play an important role in ischemia-induced brain injury and that inhibition of TWEAK expression or function in the brain may represent a novel neuroprotective strategy to treat ischemic stroke.
authors.affiliation: Department of Surgery, University of Maryland School of Medicine, 15601 Crabbs Branch Way, Rockville, MD 20855, USA.
authors.forename: Manuel
authors.initials: M
authors.lastname: Yepes
authors.forename: Sharron A N
authors.initials: SA
authors.lastname: Brown
authors.forename: Elizabeth G
authors.initials: EG
authors.lastname: Moore
authors.forename: Elizabeth P
authors.initials: EP
authors.lastname: Smith
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Lawrence
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Winkles
mesh_terms: D000818:Animals; D017209:Apoptosis; D001253:Astrocytes / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002545:Brain Ischemia / Q000473:pathology* / Q000628:therapy; D016923:Cell Death; D002460:Cell Line; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000737:chemistry; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007249:Inflammation; D008297:Male; D008565:Membrane Proteins / Q000737:chemistry / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D009474:Neurons / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000737:chemistry / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D020521:Stroke / Q000473:pathology / Q000628:therapy; D000074050:TWEAK Receptor; D013997:Time Factors; D014162:Transfection
chemical_list: D007141:Immunoglobulin Fc Fragments; D008565:Membrane Proteins; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; C000613297:TNFRSF12A protein, human; D000074050:TWEAK Receptor; C000613299:Tnfrsf12a protein, mouse