title: Tracking CNS and systemic sources of oxidative stress during the course of chronic neuroinflammation.
abstract: The functional dynamics and cellular sources of oxidative stress are central to understanding MS pathogenesis but remain elusive, due to the lack of appropriate detection methods. Here we employ NAD(P)H fluorescence lifetime imaging to detect functional NADPH oxidases (NOX enzymes) in vivo to identify inflammatory monocytes, activated microglia, and astrocytes expressing NOX1 as major cellular sources of oxidative stress in the central nervous system of mice affected by experimental autoimmune encephalomyelitis (EAE). This directly affects neuronal function in vivo, indicated by sustained elevated neuronal calcium. The systemic involvement of oxidative stress is mirrored by overactivation of NOX enzymes in peripheral CD11b(+) cells in later phases of both MS and EAE. This effect is antagonized by systemic intake of the NOX inhibitor and anti-oxidant epigallocatechin-3-gallate. Together, this persistent hyper-activation of oxidative enzymes suggests an "oxidative stress memory" both in the periphery and CNS compartments, in chronic neuroinflammation.
authors.affiliation: German Rheumatism Research Center, Berlin, Germany.|Department of Neurology, NeuroCure Clinical Research Center, Clinical and Experimental Multiple Sclerosis Research Center, Charité-Universitätsmedizin Berlin, Berlin, Germany.|Institut für Neuropathologie, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Agata A
authors.initials: AA
authors.lastname: Mossakowski
authors.affiliation: German Rheumatism Research Center, Berlin, Germany.|Institut für Neuropathologie, Charité-Universitätsmedizin Berlin, Berlin, Germany.|Intravital Imaging and Immune Dynamics, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Julian
authors.initials: J
authors.lastname: Pohlan
authors.affiliation: German Rheumatism Research Center, Berlin, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Bremer
authors.affiliation: German Rheumatism Research Center, Berlin, Germany.
authors.forename: Randall
authors.initials: R
authors.lastname: Lindquist
authors.affiliation: Institute for Medical Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Millward
authors.affiliation: Experimental and Clinical Research Center, Max Delbrueck Center for Molecular Medicine and Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Bock
authors.affiliation: Institut für Neuropathologie, Charité-Universitätsmedizin Berlin, Berlin, Germany.|Intravital Imaging and Immune Dynamics, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Karolin
authors.initials: K
authors.lastname: Pollok
authors.affiliation: Institut für Neuropathologie, Charité-Universitätsmedizin Berlin, Berlin, Germany.|Intravital Imaging and Immune Dynamics, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Ronja
authors.initials: R
authors.lastname: Mothes
authors.affiliation: Institut für Neuropathologie, Charité-Universitätsmedizin Berlin, Berlin, Germany.|Intravital Imaging and Immune Dynamics, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Leonard
authors.initials: L
authors.lastname: Viohl
authors.affiliation: German Rheumatism Research Center, Berlin, Germany.|Institut für Neuropathologie, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Moritz
authors.initials: M
authors.lastname: Radbruch
authors.affiliation: German Rheumatism Research Center, Berlin, Germany.
authors.forename: Jenny
authors.initials: J
authors.lastname: Gerhard
authors.affiliation: Department of Neurology, NeuroCure Clinical Research Center, Clinical and Experimental Multiple Sclerosis Research Center, Charité-Universitätsmedizin Berlin, Berlin, Germany.|Experimental and Clinical Research Center, Max Delbrueck Center for Molecular Medicine and Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Judith
authors.initials: J
authors.lastname: Bellmann-Strobl
authors.affiliation: Department of Neurology, NeuroCure Clinical Research Center, Clinical and Experimental Multiple Sclerosis Research Center, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Janina
authors.initials: J
authors.lastname: Behrens
authors.affiliation: Institute for Medical Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Carmen
authors.initials: C
authors.lastname: Infante-Duarte
authors.affiliation: Experimental and Clinical Research Center, Max Delbrueck Center for Molecular Medicine and Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Mähler
authors.affiliation: Experimental and Clinical Research Center, Max Delbrueck Center for Molecular Medicine and Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Boschmann
authors.affiliation: Institut für Neuropathologie, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Jan Leo
authors.initials: JL
authors.lastname: Rinnenthal
authors.affiliation: DZNE-German Center for Neurodegenerative Diseases, Berlin, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Füchtemeier
authors.affiliation: Department of Paediatrics I, Neonatology, University Hospital Essen, Essen, 45122, Germany.
authors.forename: Josephine
authors.initials: J
authors.lastname: Herz
authors.affiliation: German Rheumatism Research Center, Berlin, Germany.|Department of Neurology, NeuroCure Clinical Research Center, Clinical and Experimental Multiple Sclerosis Research Center, Charité-Universitätsmedizin Berlin, Berlin, Germany.|Intravital Imaging and Immune Dynamics, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Florence C
authors.initials: FC
authors.lastname: Pache
authors.affiliation: German Rheumatism Research Center, Berlin, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Bardua
authors.affiliation: Department of Neuropsychiatry and Laboratory of Molecular Psychiatry, Charité-Universitätsmedizin Berlin, Cluster of Excellence NeuroCure and BIH, Berlin, Germany.
authors.forename: Josef
authors.initials: J
authors.lastname: Priller
authors.affiliation: German Rheumatism Research Center, Berlin, Germany.|Intravital Imaging and Immune Dynamics, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Anja E
authors.initials: AE
authors.lastname: Hauser
authors.affiliation: Department of Neurology, NeuroCure Clinical Research Center, Clinical and Experimental Multiple Sclerosis Research Center, Charité-Universitätsmedizin Berlin, Berlin, Germany.|Experimental and Clinical Research Center, Max Delbrueck Center for Molecular Medicine and Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Friedemann
authors.initials: F
authors.lastname: Paul
authors.affiliation: German Rheumatism Research Center, Berlin, Germany. niesner@drfz.de.
authors.forename: Raluca
authors.initials: R
authors.lastname: Niesner
authors.affiliation: Institut für Neuropathologie, Charité-Universitätsmedizin Berlin, Berlin, Germany. helena.radbruch@charite.de.
authors.forename: Helena
authors.initials: H
authors.lastname: Radbruch
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use; D001253:Astrocytes / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D039481:CD11b Antigen / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002392:Catechin / Q000031:analogs & derivatives / Q000627:therapeutic use; D002908:Chronic Disease; D018450:Disease Progression; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D000068717:Glatiramer Acetate / Q000627:therapeutic use; D006801:Humans; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence / Q000379:methods; D009103:Multiple Sclerosis / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*
chemical_list: D000975:Antioxidants; D039481:CD11b Antigen; D004791:Enzyme Inhibitors; D000068717:Glatiramer Acetate; D002392:Catechin; C045651:epigallocatechin gallate; D019255:NADPH Oxidases; D002118:Calcium
keywords: Fluorescence lifetime microscopy; Intravital imaging; Multiple sclerosis; Neuronal dysfunction; Oxidative stress; Oxidative stress memory