25-Hydroxycholesterol attenuates tumor necrosis factor alpha-induced blood-brain barrier breakdown in vitro
Year: 2024
Type: article
Abstract: Intracellular cholesterol metabolism is regulated by the SREBP-2 and LXR signaling pathways. The effects of inflammation on these molecular mechanisms remain poorly studied, especially at the blood-brain barrier (BBB) level. Tumor necrosis factor α (TNFα) is a proinflammatory cytokine associated with BBB dysfunction. Therefore, the aim of our study was to investigate the effects of TNFα on BBB cholesterol metabolism, focusing on its underlying signaling pathways. Using a human in vitro BBB model composed of human brain-like endothelial cells (hBLECs) and brain pericytes (HBPs), we observed that TNFα increases BBB permeability by degrading the tight junction protein CLAUDIN-5 and activating stress signaling pathways in both cell types. TNFα also promotes cholesterol release and decreases cholesterol accumulation and APOE secretion. In hBLECs, the expression of SREBP-2 targets (LDLR and HMGCR) is increased, while ABCA1 expression is decreased. In HBPs, only LDLR and ABCA1 expression is increased. TNFα treatment also induces 25-hydroxycholesterol (25-HC) production, a cholesterol metabolite involved in the immune response and intracellular cholesterol metabolism. 25-HC pretreatment attenuates TNFα-induced BBB leakage and partially alleviates the effects of TNFα on ABCA1, LDLR, and HMGCR expression. Overall, our results suggest that TNFα favors cholesterol efflux via an LXR/ABCA1-independent mechanism at the BBB, while it activates the SREBP-2 pathway. Treatment with 25-HC partially reversed the effect of TNFα on the LXR/SREBP-2 pathways. Our study provides novel perspectives for better understanding cerebrovascular signaling events linked to BBB dysfunction and cholesterol metabolism in neuroinflammatory diseases.
Institutions: Université d'Artois, Centre National de la Recherche Scientifique, Université de Picardie Jules Verne, Archéologie et Archéométrie, Oslo University Hospital, University of Oslo, University of Latvia, University of Lübeck, Centre Hospitalier Universitaire Vaudois, University of Lausanne
Language: English
Subfield: Neurology
Field: Neuroscience
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $3,810
Funders: EU Joint Programme – Neurodegenerative Disease Research, European Environment Agency, Deutsche Forschungsgemeinschaft, Agence Nationale de la Recherche, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, Ministerstvo Školství, Mládeže a Tělovýchovy, Bundesministerium für Bildung und Forschung, Österreichische Forschungsförderungsgesellschaft, Norges Forskningsråd, Région Hauts-de-France, Conseil Régional Hauts-de-France, European Regional Development Fund, Stockholm Resilience Centre, Stockholm University
Awards: PET analyses of ABC transporter function for diagnostics and stratification of dementia patients, Extracellular vesicles As potential Trojan horses to cross the Blood-Brain Barrier?, Dissecting the cellular sources and immune functions of Oxysterols during Neuroinflammation, G4409414385, G4690130468, Die Rolle der Blut Hirn Schranke in der Alzheimer Krankheit:
Untersuchung der funktionellen Interaktion von LRP1 mit ABCTransporterproteinen, G5361889845, PET analyses of ABC transporter function for diagnostics and stratification of dementia patients, G5901861748, G7557857086, PETABC - PET-Untersuchungen der ABC-Transporterfunktion zur Diagnostik und Stratifizierung von Demenzpatienten, G8916104452
OpenAlex ID: W4401800495