title: Tumor necrosis factor-like weak inducer of apoptosis increases the permeability of the neurovascular unit through nuclear factor-kappa B pathway activation.
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 fibroblast growth factor-inducible-14 (Fn14). TWEAK can stimulate numerous cellular responses including cell proliferation, migration, and proinflammatory molecule production. The present study investigated whether TWEAK plays a role in the regulation of the permeability of the neurovascular unit (NVU). We found that intracerebral injection of TWEAK in wild-type mice induces activation of the nuclear factor-kappaB (NF-kappaB) pathway and matrix metalloproteinase-9 (MMP-9) expression in the brain with resultant disruption in the structure of the NVU and increase in the permeability of the blood-brain barrier (BBB). TWEAK did not increase MMP-9 activity or BBB permeability when injected into mice genetically deficient in the NF-kappaB family member p50. Furthermore, we report that inhibition of TWEAK activity during cerebral ischemia with an Fn14-Fc decoy receptor results in significant preservation of the integrity of the NVU with attenuation of cerebral ischemia-induced increase in the permeability of the BBB. We conclude that the cytokine TWEAK plays a role in the disruption of the structure and permeability of the NVU during physiological and pathological conditions.
authors.affiliation: Department of Neurology, Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Rohini
authors.initials: R
authors.lastname: Polavarapu
authors.forename: Maria Carolina
authors.initials: MC
authors.lastname: Gongora
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Winkles
authors.forename: Manuel
authors.initials: M
authors.lastname: Yepes
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001812:Blood-Brain Barrier / Q000502:physiology; D002199:Capillary Permeability / Q000502:physiology*; D000074049:Cytokine TWEAK; D004730:Endothelium, Vascular / Q000378:metabolism / Q000502:physiology*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism* / Q000502:physiology; D009474:Neurons / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D048069:Tumor Necrosis Factors / Q000502:physiology*
chemical_list: D000074049:Cytokine TWEAK; D016328:NF-kappa B; C491645:Tnfsf12 protein, mouse; D048069:Tumor Necrosis Factors; D020780:Matrix Metalloproteinase 9