title: NADPH oxidase expression in active multiple sclerosis lesions in relation to oxidative tissue damage and mitochondrial injury.
abstract: Multiple sclerosis is a chronic inflammatory disease of the central nervous system, associated with demyelination and neurodegeneration. The mechanisms of tissue injury are poorly understood, but recent data suggest that mitochondrial injury may play an important role in this process. Mitochondrial injury can be triggered by reactive oxygen and nitric oxide species, and we recently provided evidence for oxidative damage of oligodendrocytes and dystrophic axons in early stages of active multiple sclerosis lesions. In this study, we identified potential sources of reactive oxygen and nitrogen species through gene expression in carefully staged and dissected lesion areas and by immunohistochemical analysis of protein expression. Genome-wide microarrays confirmed mitochondrial injury in active multiple sclerosis lesions, which may serve as an important source of reactive oxygen species. In addition, we found differences in the gene expression levels of various nicotinamide adenine dinucleotide phosphate oxidase subunits between initial multiple sclerosis lesions and control white matter. These results were confirmed at the protein level by means of immunohistochemistry, showing upregulation of the subunits gp91phox, p22phox, p47phox, nicotinamide adenine dinucleotide phosphate oxidase 1 and nicotinamide adenine dinucleotide phosphate oxidase organizer 1 in activated microglia in classical active as well as slowly expanding lesions. The subunits gp91phox and p22phox were constitutively expressed in microglia and were upregulated in the initial lesion. In contrast, p47phox, nicotinamide adenine dinucleotide phosphate oxidase 1 and nicotinamide adenine dinucleotide phosphate oxidase organizer 1 expression were more restricted to the zone of initial damage or to lesions from patients with acute or early relapsing/remitting multiple sclerosis. Double labelling showed co-expression of the nicotinamide adenine dinucleotide phosphate oxidase subunits in activated microglia and infiltrated macrophages, suggesting the assembly of functional complexes. Our data suggest that the inflammation-associated oxidative burst in activated microglia and macrophages plays an important role in demyelination and free radical-mediated tissue injury in the pathogenesis of multiple sclerosis.
authors.affiliation: Centre for Brain Research, Medical University of Vienna, A-1090 Wien, Austria.
authors.forename: Marie T
authors.initials: MT
authors.lastname: Fischer
authors.forename: Rakhi
authors.initials: R
authors.lastname: Sharma
authors.forename: Jamie L
authors.initials: JL
authors.lastname: Lim
authors.forename: Lukas
authors.initials: L
authors.lastname: Haider
authors.forename: Josa M
authors.initials: JM
authors.lastname: Frischer
authors.forename: Joost
authors.initials: J
authors.lastname: Drexhage
authors.forename: Don
authors.initials: D
authors.lastname: Mahad
authors.forename: Monika
authors.initials: M
authors.lastname: Bradl
authors.forename: Jack
authors.initials: J
authors.lastname: van Horssen
authors.forename: Hans
authors.initials: H
authors.lastname: Lassmann
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015153:Blotting, Western; D004272:DNA, Mitochondrial / Q000737:chemistry / Q000235:genetics; D003711:Demyelinating Diseases / Q000473:pathology; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D007150:Immunohistochemistry; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics; D046228:Microarray Analysis; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D008928:Mitochondria / Q000473:pathology*; D009103:Multiple Sclerosis / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D000074624:NADPH Oxidase 1; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000096:biosynthesis* / Q000235:genetics*; D009410:Nerve Degeneration / Q000473:pathology; D018384:Oxidative Stress / Q000502:physiology; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D016372:RNA, Antisense / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D016897:Respiratory Burst
chemical_list: D004272:DNA, Mitochondrial; D008562:Membrane Glycoproteins; D016372:RNA, Antisense; D017382:Reactive Oxygen Species; D012313:RNA; C056558:CYBB protein, human; D000074624:NADPH Oxidase 1; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; C402799:NOX1 protein, human