NADPH oxidase expression in active multiple sclerosis lesions in relation to oxidative tissue damage and mitochondrial injury
Open accessAbstract
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.
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Activated microglia express ROS-generating enzymes such as NADPH oxidase, which are responsible for degeneration of oligodendrocytes and increased BBB permeability by downregulating expression of VE-cadherin, occludin and claudin-5 proteins in microvascular endothelial cells.
“Activated microglia are known to express ROS-generating enzymes, such as NADPH oxidase, which are responsible for degeneration of oligodendrocytes and increased BBB permeability by downregulating the expression of VE-cadherin, occludin and claudin-5 proteins in microvascular ECs (Fischer et al., 2012; Rochfort et al., 2014).”
From The impact of microglial activation on blood-brain barrier in brain diseases (2014) · cites this paper as Fischer et al., 2012
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Lassmann, H. (2014) · Glia · doi:10.1002/glia.22597 · Cited by 191 · see citing works
Self-citationMicroglia in multiple sclerosis: protectors turn destroyers
Yong, V. W. (2022) · Neuron · doi:10.1016/j.neuron.2022.06.023 · Cited by 185 · see citing works
Therapeutic potential of nadph oxidase 1/4 inhibitors
Teixeira, G., Szyndralewiez, C., Molango, S., Carnesecchi, S., Heitz, F., Wiesel, P., & Wood, J. M. (2017) · British Journal of Pharmacology · doi:10.1111/bph.13532 · Cited by 163 · see citing works
Genetic disorders coupled to ROS deficiency
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Immature Dentate Gyrus: An Endophenotype of Neuropsychiatric Disorders
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Defining blood-induced microglia functions in neurodegeneration through multiomic profiling
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Self-citationThe Plasma Membrane: A Platform for Intra- and Intercellular Redox Signaling
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Microglia in multiple sclerosis - pathogenesis and imaging
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Dynamic Responses of Microglia in Animal Models of Multiple Sclerosis
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Self-citation
- Authors
- Fischer, M. T., Sharma, R., Lim, J. L., Haider, L., Frischer, J. M., Drexhage, J., Mahad, D., Bradl, M., van Horssen, J., & Lassmann, H.
- Affiliations
- Medical University of Vienna (AT)
- Amsterdam UMC Location Vrije Universiteit Amsterdam (NL)
- Newcastle University (GB)
- Corresponding author
- Lassmann, Hans
- Venue
- Brain
- Publisher
- Oxford University Press (OUP)
- Published
- 2012-02-24
- Volume
- 135
- Issue
- 3
- Pages
- 886-899
- ISSN
- 0006-8950 (ISSN-L)
- 1460-2156
- PMC
- PMC3286337
- OpenAlex
- W2160427694
- Cited by
- 507
- References
- 69
- Citations by year
- 2026: 27 · 2025: 28 · 2024: 31 · 2023: 27 · 2022: 26 · 2021: 41 · 2020: 46 · 2019: 39 · 2018: 34 · 2017: 48 · 2016: 43 · 2015: 39 · 2014: 36 · 2013: 30 · 2012: 12
- FWCI
- 26.99
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc
- Locations
- Brain (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- Digital Academic REpository of VU University Amsterdam (Vrije Universiteit Amsterdam) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Funders
- National Multiple Sclerosis Society
- Multiple Sclerosis Society
- Austrian Science Fund (P24245, P 19854)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- multiple sclerosis, NADPH oxidase, oxidative stress, mitochondrial injury, reactive oxygen species, reactive nitrogen species, microglia, macrophages, gp91phox, p22phox, p47phox, NOX1, demyelination, neurodegeneration, oligodendrocyte damage, axonal dystrophy, respiratory burst, relapsing-remitting multiple sclerosis
- MeSH terms
- NADPH Oxidase 1, NADPH Oxidase 2, Adult, Aged, Aged, 80 and over, Demyelinating Diseases, DNA, Mitochondrial, Female, Humans, Immunohistochemistry, Macrophages, Male, Membrane Glycoproteins, Middle Aged, Mitochondria, Multiple Sclerosis, Nerve Degeneration, RNA, Blotting, Western, RNA, Antisense, Respiratory Burst, Reactive Oxygen Species, Microglia, Oxidative Stress, NADPH Oxidases, Microarray Analysis, Genome-Wide Association Study
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