Complement receptor 3 mediates NADPH oxidase activation and dopaminergic neurodegeneration through a Src-Erk-dependent pathway
Open accessAbstract
Microglial NADPH oxidase ( Nox2 ) plays a key role in chronic neuroinflammation and related dopaminergic neurodegeneration in Parkinson's disease (PD). However, the mechanisms behind Nox2 activation remain unclear. Here, we revealed the critical role of complement receptor 3 (CR3), a microglia-specific pattern recognition receptor, in Nox2 activation and subsequent dopaminergic neurodegeneration by using paraquat and maneb-induced PD model. Suppression or genetic deletion of CR3 impeded paraquat and maneb-induced activation of microglial Nox2 , which was associated with attenuation of dopaminergic neurodegeneration. Mechanistic inquiry revealed that blocking CR3 reduced paraquat and maneb-induced membrane translocation of Nox2 cytosolic subunit p47 phox , an essential step for Nox2 activation. Src and Erk (extracellular regulated protein kinases) were subsequently recognized as the downstream signals of CR3. Moreover, inhibition of Src or Erk impaired Nox2 activation in response to paraquat and maneb co-exposure. Finally, we found that CR3-deficient mice were more resistant to paraquat and maneb-induced Nox2 activation and nigral dopaminergic neurodegeneration as well as motor dysfunction than the wild type controls. Taken together, our results showed that CR3 regulated Nox2 activation and dopaminergic neurodegeneration through a Src-Erk-dependent pathway in a two pesticide-induced PD model, providing novel insights into the immune pathogenesis of PD.
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CR3 stimulation results in ERK-stimulated translocation of p47phox to the plasma membrane, indicating NOX2 activation.
“CR3 stimulation results in extracellular signal-regulated kinase (ERK)-stimulated translocation of p47phox to the plasma membrane indicating NOX2 activation [86].”
From ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease (2020) · cites this paper as [86]
NOX2 activity in dopaminergic neurodegeneration is mediated by activation of complement receptor 3 (CR3), a pattern recognition receptor comprised of CD11b and CD18 and agonised by DAMPs.
“NOX2 activity in dopaminergic neurodegeneration is mediated by activation of complement receptor 3 (CR3, aka macrophage-1 antigen (MAC1)), which is a pattern recognition receptor (PRR) comprised of CD11b and CD18 and agonised by DAMPs which contributes to phagocytic activation in response to aggregated protein [85,86].”
From ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease (2020) · cites this paper as [86]
DAMP stimulation of PRRs on microglia, such as CR3 and TLR4, mediates activation of pro-inflammatory signalling transducers NLRP3 inflammasome, NFκB and MAPKs, such as ERK.
“DAMP stimulation of PRRs on microglia, such as CR3 and toll-like receptor 4 (TLR4), mediates activation of pro-inflammatory signalling transducers NLRP3 inflammasome, nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) and mitogen-activated protein kinases (MAPKs), such as ERK [86,91,92].”
From ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease (2020) · cites this paper as [86]
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References 59 · Cited by 104
- Authors
- Hou, L., Wang, K., Zhang, C., Sun, F., Che, Y., Zhao, X., Zhang, D., Li, H., & Wang, Q.
- Affiliations
- Dalian Medical University (CN)
- Shandong University (CN)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Corresponding author
- Wang, Ke
- Wang, Qingshan
- Venue
- Redox Biology
- Publisher
- Elsevier BV
- Published
- 2018-04
- Volume
- 14
- Pages
- 250-260
- ISSN
- 2213-2317 (ISSN-L)
- PMC
- PMC5975223
- OpenAlex
- W2758829395
- Cited by
- 104
- References
- 59
- Citations by year
- 2026: 4 · 2025: 14 · 2024: 13 · 2023: 10 · 2022: 11 · 2021: 15 · 2020: 18 · 2019: 15 · 2018: 2 · 2017: 1 · 2016: 1
- FWCI
- 6.85
- Type
- journal article
- Language
- en
- Update notices
- erratum (2024-12-01)
- Open access
- gold
- doi.org
- Licence
- Locations
- Redox Biology (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- National Natural Science Foundation of China (81703264)
- Dalian Medical University (201122)
- Liaoning BaiQianWan Talents Program ([2017]90)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Keywords
- complement receptor 3, NADPH oxidase NOX2, dopaminergic neuron loss, Parkinson's disease, microglia, Src kinase, ERK signaling, p47phox translocation, paraquat, maneb, neuroinflammation, motor impairment, immune pathogenesis
- MeSH terms
- NADPH Oxidase 2, Animals, Cells, Cultured, Enzyme Activation, Mice, Inbred C57BL, Paraquat, Parkinson Disease, Secondary, Pesticides, Signal Transduction, Macrophage-1 Antigen, Rats, Sprague-Dawley, src-Family Kinases, MAP Kinase Signaling System, Dopaminergic Neurons
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