NADPH Oxidase Mediates Lipopolysaccharide-induced Neurotoxicity and Proinflammatory Gene Expression in Activated Microglia
Open accessAbstract
Parkinson's disease is characterized by the progressive degeneration of dopaminergic neurons in the substantia nigra. We have previously reported that lipopolysaccharide (LPS)-induced degeneration of dopaminergic neurons is mediated by the release of proinflammatory factors from activated microglia. Here, we report the pivotal role of NADPH oxidase in inflammation-mediated neurotoxicity, where the LPS-induced loss of nigral dopaminergic neurons in vivo was significantly less pronounced in NADPH oxidase-deficient (PHOX-/-) mice when compared with control (PHOX+/+) mice. Dopaminergic neurons in primary mensencephalic neuron-glia cultures from PHOX+/+ mice were significantly more sensitive to LPS-induced neurotoxicity in vitro when compared with PHOX-/- mice. Further, PHOX+/+ neuron-glia cultures chemically depleted of microglia failed to show dopaminergic neurotoxicity with the addition of LPS. Neuron-enriched cultures from both PHOX+/+ mice and PHOX-/- mice also failed to show any direct LPS-induced dopaminergic neurotoxicity. However, the addition of PHOX+/+ microglia to neuron-enriched cultures from either strain resulted in reinstatement of LPS-induced dopaminergic neurotoxicity, supporting the role of microglia as the primary source of NADPH oxidase-generated insult and neurotoxicity. Immunostaining for F4/80 in mensencephalic neuron-glia cultures revealed that PHOX-/- microglia failed to show activated morphology at 10 h, suggesting an important role of reactive oxygen species (ROS) generated from NADPH oxidase in the early activation of microglia. LPS also failed to elicit extracellular superoxide and produced low levels of intracellular ROS in microglia-enriched cultures from PHOX-/- mice. Gene expression and release of tumor necrosis factor alpha was much lower in PHOX-/- mice than in control PHOX+/+ mice. Together, these results demonstrate the dual neurotoxic functions of microglial NADPH oxidase: 1) the production of extracellular ROS that is toxic to dopamine neurons and 2) the amplification of proinflammatory gene expression and associated neurotoxicity.
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Activation of microglia with LPS and injection of LPS in the brain induce IL-1β and NO production via Nox1.
“activation of microglia with lipopolysaccharide (LPS), a component of Gram-negative bacteria commonly used to model proinflammatory and neurotoxic activation of microglia (Lehnardt et al., 2003;Qin et al., 2004), and injection of LPS in the brain induce IL-1 and NO⅐ production via Nox1”
From Neurotoxic Activation of Microglia Is Promoted by a Nox1-Dependent NADPH Oxidase (2008) · cites this paper as Qin et al., 2004
Formation of extracellular O2− was not detected in LPS-stimulated microglial cultures from Nox2-KO mice.
“Accordingly, formation of extracellular O 2 ⅐Ϫ was not detected in LPS-stimulated microglial cultures from Nox2-KO mice (Qin et al., 2004).”
From Neurotoxic Activation of Microglia Is Promoted by a Nox1-Dependent NADPH Oxidase (2008) · cites this paper as Qin et al., 2004
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- Authors
- Qin, L., Liu, Y., Wang, T., Wei, S.-J., Block, M. L., Wilson, B., Liu, B., & Hong, J.-S.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Qin, Liya
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2004-01
- Volume
- 279
- Issue
- 2
- Pages
- 1415-1421
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2039190334
- Cited by
- 574
- References
- 4
- Citations by year
- 2026: 8 · 2025: 14 · 2024: 8 · 2023: 17 · 2022: 14 · 2021: 29 · 2020: 25 · 2019: 18 · 2018: 22 · 2017: 23 · 2016: 24 · 2015: 29 · 2014: 36 · 2013: 30 · 2012: 40
- FWCI
- 20.77
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Keywords
- NADPH oxidase, lipopolysaccharide, neurotoxicity, microglia, Parkinson's disease, dopaminergic neurons, substantia nigra, reactive oxygen species, superoxide, pro-inflammatory gene expression, TNF-α, neuroinflammation, neuron-glia co-culture
- MeSH terms
- Animals, Cells, Cultured, Dopamine, Dose-Response Relationship, Drug, Female, Gene Expression Regulation, Immunohistochemistry, Inflammation, Lipopolysaccharides, Male, Mice, Inbred C57BL, Mice, Transgenic, Neuroglia, Neurons, Substantia Nigra, Superoxides, Time Factors, Tumor Necrosis Factor-alpha, Reactive Oxygen Species, Microglia, Transgenes, NADPH Oxidases, Reverse Transcriptase Polymerase Chain Reaction, Mice
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