title: Cell type-specific Nrf2 expression in multiple sclerosis lesions.
abstract: Oxidative injury appears to play a major role in the propagation of demyelination and neurodegeneration in multiple sclerosis (MS). It has been suggested that endogenous anti-oxidant defense mechanisms within MS lesions are insufficient to prevent spreading of damage. Thus, current therapeutic approaches (e.g., fumarate treatment) target to up-regulate the expression of a key regulator of anti-oxidative defense, the transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2). In this study, we show that Nrf2 is already strongly up-regulated in active MS lesions. Nuclear Nrf2 expression was particularly observed in oligodendrocytes and its functional activity is indicated by the expression of one of its downstream targets (heme oxygenase 1) in the same cells. In contrast, only a minor number of Nrf2-positive neurons were detected, even in highly inflammatory cortical lesions presenting with extensive oxidative injury. Overall, the most pronounced Nrf2 expression was found in degenerating cells, which showed signs of apoptotic or necrotic cell death. Via whole-genome microarray analyses of MS lesions, we observed a differential expression of numerous Nrf2-responsive genes, also involved in the defense against oxidative stress, predominantly in areas of initial myelin destruction within actively demyelinating white matter lesions. Furthermore, the expression patterns of Nrf2-induced genes differed between the white matter and cortical gray matter. Our study shows that in the MS brain, Nrf2 expression varies in different cell types and is associated with active demyelination in the lesions.
authors.affiliation: Department of Neuroimmunology, Center for Brain Research, Medical University of Vienna, Spitalgasse 4, 1090, Vienna, Austria.
authors.forename: Simon
authors.initials: S
authors.lastname: Licht-Mayer
authors.forename: Isabella
authors.initials: I
authors.lastname: Wimmer
authors.forename: Sarah
authors.initials: S
authors.lastname: Traffehn
authors.forename: Imke
authors.initials: I
authors.lastname: Metz
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Brück
authors.forename: Jan
authors.initials: J
authors.lastname: Bauer
authors.forename: Monika
authors.initials: M
authors.lastname: Bradl
authors.forename: Hans
authors.initials: H
authors.lastname: Lassmann
mesh_terms: D000208:Acute Disease; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D016923:Cell Death / Q000502:physiology; D002467:Cell Nucleus / Q000378:metabolism / Q000473:pathology; D015331:Cohort Studies; D005260:Female; D006801:Humans; D008297:Male; D046228:Microarray Analysis; D008875:Middle Aged; D020528:Multiple Sclerosis, Chronic Progressive / Q000378:metabolism* / Q000473:pathology; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D009836:Oligodendroglia / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress / Q000502:physiology; D066127:White Matter / Q000378:metabolism / Q000473:pathology
chemical_list: D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human