NADPH Oxidase Mediates Lipopolysaccharide-induced Neurotoxicity and Proinflammatory Gene Expression in Activated Microglia*

By L. Qin, Yuxin Liu, Tongguang Wang, Sung‐Jen Wei, M. Block, B. Wilson, B. Liu, Jau-Shyong Hong. Journal of Biological Chemistry, 2004

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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 α 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.

Subfields: Cellular and Molecular Neuroscience, Neurology

View Paper: https://www.semanticscholar.org/paper/81ee59b52ef3291882f1d55244bc8b3c36b65c3c

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Citations in the corpus

Microglia in the TBI Brain: The Good, The Bad, And The Dysregulated (2015, background): “…or pathogen has been removed; however, a dysregulated or excessive M1-like activation in the brain can induce neurotoxicity due to release of pro-inflammatory factors and neurotoxic mediators that set off vicious cycles of microglial-mediated neurodegeneration (Gao et al., 2003; Qin et al., 2004).”
Aggregated α‐synuclein activates microglia: a process leading to disease progression in Parkinson's disease (2005, methodology): “Release of TNF- in the mesencephalic neuron-glia cultures was measured after 3, 6, and 24 h of -synuclein treatment with a rat TNF- enzyme-linked immunosorbent assay kit from R&D Systems (Minneapolis, MN, USA), as described (11, 32).”
Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration (2007, methodology): “Brains were fixed in 4% paraformaldehyde and processed for immunostaining as described previously (Qin et al., 2004).”
Microglial Activation & Chronic Neurodegeneration (2010, background): “NADPH oxidase is a multi-subunit enzyme that catalyzes the production of O2 ● from molecular oxygen, and it is the predominant source of extracellular ROS in phagocytes, such as microglia.(129,130) The enzyme complex is dormant in resting phagocytes and can be activated on exposure to specific stimu”
Microglia and inflammation-mediated neurodegeneration: multiple triggers with a common mechanism. (2005, methodology): “Reconstituted cell culture experiments confirmed that microglia were the source of ROS production, as both PHOX and PHOX / neuron-glia cultures chemically depleted of microglia via leucine-methyl ester failed to show DA neurotoxicity with the addition of LPS (Qin et al., 2004).”
The Reactive Oxygen Species in Macrophage Polarization: Reflecting Its Dual Role in Progression and Treatment of Human Diseases (2016, neutral): “TNFα in PHOX mice [96].”
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Role of Microglia in Neurotrauma (2010, neutral): “NF B pathway and proinflammatory gene expression in these cells.(37,39) NADPH oxidase knockout results in at-”
Inflammation as a causative factor in the aetiology of Parkinson's disease (2007, background): “ROS is significant for the activation of microglia and the production of proinflammatory mediators such as TNF-a (Qin et al., 2004) or prostaglandin E2 (PGE2) (Block and Hong, 2005).”
Microglia-mediated neurotoxicity: uncovering the molecular mechanisms (2007, background): “Furthermore, the crucial role of NADPH oxidase in mediating inflammation-related neurotoxicity has been demonstrated in the following toxins: LP”
Inflammatory Cytokines in Depression: Neurobiological Mechanisms and Therapeutic Implications (2013, background): “…KYN (Guillemin et al., 2003), inducible NO synthase (iNOS) (Possel et al., 2000, Lu et al., 2012), reactive oxygen and nitrogen species (ROS/RNS) (Qin et al., 2004, Block et al., 2007), and MCP-1/CCL2 (Kim et al., 2011), a chemokine involved in attracting peripheral immune cells into the brain…”