title: Inflammation-induced brain endothelial activation leads to uptake of electrostatically stabilized iron oxide nanoparticles via sulfated glycosaminoglycans.
abstract: Based on our previous data on the presence of very small superparamagnetic iron oxide nanoparticles (VSOP) on brain endothelial structures during experimental autoimmune encephalomyelitis (EAE), we investigated the mechanisms of VSOP binding on inflamed brain endothelial cells in vivo and in vitro. After intravenous application, VSOP were detected in brain endothelial cells of EAE animals at peak disease and prior to clinical onset. In vitro, inflammatory stimuli increased VSOP uptake by brain endothelial bEnd.3 cells, which we confirmed in primary endothelial cells and in bEnd.3 cells cultured under shear stress. Transmission electron microscopy and blocking experiments revealed that during inflammation VSOP were endocytosed by bEnd.3. Modified sulfated glycosaminoglycans (GAG) on inflamed brain endothelial cells were the primary binding site for VSOP, as GAG degradation and inhibition of GAG sulfation reduced VSOP uptake. Thus, VSOP-based MRI is sensitive to visualize early neuroinflammatory processes such as GAG modifications on brain endothelial cells.
authors.affiliation: Institute for Medical Immunology, Charité-Universtitätsmedizin Berlin, Berlin, Germany; Cluster of Excellence NeuroCure and Department of Neurology and Experimental and Clinical Research Center, Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Dominique
authors.initials: D
authors.lastname: Berndt
authors.affiliation: Institute for Medical Immunology, Charité-Universtitätsmedizin Berlin, Berlin, Germany; Experimental and clinical Research Center, Max Delbrueck Center for Molecular Medicine and Charité Universitätsmedizin, Berlin.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Millward
authors.affiliation: Department of Radiology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Schnorr
authors.affiliation: Department of Radiology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Taupitz
authors.affiliation: Medizinische Klinik mit Schwerpunkt Kardiologie und Angiologie, Charité, Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Verena
authors.initials: V
authors.lastname: Stangl
authors.affiliation: Experimental and clinical Research Center, Max Delbrueck Center for Molecular Medicine and Charité Universitätsmedizin, Berlin; Cluster of Excellence NeuroCure and Department of Neurology and Experimental and Clinical Research Center, Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Friedemann
authors.initials: F
authors.lastname: Paul
authors.affiliation: Department of Radiology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Wagner
authors.affiliation: Cluster of Excellence NeuroCure and Department of Neurology and Experimental and Clinical Research Center, Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Jens T
authors.initials: JT
authors.lastname: Wuerfel
authors.affiliation: Department of Radiology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Ingolf
authors.initials: I
authors.lastname: Sack
authors.affiliation: Medizinische Klinik mit Schwerpunkt Kardiologie und Angiologie, Charité, Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Antje
authors.initials: A
authors.lastname: Ludwig
authors.affiliation: Institute for Medical Immunology, Charité-Universtitätsmedizin Berlin, Berlin, Germany; Experimental and clinical Research Center, Max Delbrueck Center for Molecular Medicine and Charité Universitätsmedizin, Berlin. Electronic address: carmen.infante@charite.de.
authors.forename: Carmen
authors.initials: C
authors.lastname: Infante-Duarte
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier; D001921:Brain / Q000166:cytology / Q000473:pathology; D002460:Cell Line; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000378:metabolism* / Q000473:pathology; D004705:Endocytosis; D042783:Endothelial Cells / Q000378:metabolism*; D005260:Female; D006025:Glycosaminoglycans / Q000737:chemistry*; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology; D008279:Magnetic Resonance Imaging; D058185:Magnetite Nanoparticles / Q000737:chemistry*; D051379:Mice; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission
chemical_list: D006025:Glycosaminoglycans; D058185:Magnetite Nanoparticles
keywords: Brain endothelial cells; Extracellular matrix; Glycosaminglycans; Nanoparticles; Neuroinflammation; VSOP