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Complement C3 Enhances LPS-Elicited Neuroinflammation and Neurodegeneration Via the Mac1/NOX2 Pathway
Ran Zhou, Shih-Heng Chen, Zhan Zhao, Dezhen Tu, Sheng Song, Yubao Wang, Qingshan Wang, Jing Feng et al.. Molecular neurobiology, 2023-06-03
Topic: Inflammation, microglia and astrocytes
Recent studies showed increased expression of complements in various neurodegenerative diseases, including Alzheimer's and Parkinson's diseases. However, the mechanism regulating the expression of complements and their roles in the pathogenesis of neurodegeneration are unclear. We hypothesized that acute neuroinflammation increases the expression and activation of brain complements, which, in turn, participate in chronic neuroinflammation and progressive neurodegeneration. We initially focused on the complement component C3, because C3 can activate microglia by binding to C3 receptors and attaching to damaged neurons destined to be phagocytosed by microglia. We found that complement C3 is upregulated in lipopolysaccharide (LPS)-stimulated neuron/glial cultures. Mechanistic studies revealed that microglia-released proinflammatory factors initiated the enhanced expression of C3 in astroglia during acute neuroinflammation. On the other hand, the sustained C3 expression during chronic neuroinflammation requires releasing damage-associated molecule patterns (DAMPs) from damaged/degenerating brain cells. Our results suggested that DAMPs might act on microglial integrin receptor Mac1 to trigger the activation of NADPH oxidase (NOX2). Activated microglial NOX2 increases the production of extracellular reactive oxygen species (ROS), elevating the levels of intracellular ROS of astroglia and sustaining the astroglial C3 expression. This was supported by the findings showing reduced C3 expression and attenuated neurodegeneration in LPS-treated neuron/glial cultures prepared from mice deficient in Mac1 or NOX2. LPS-induced neurodegeneration and oxidative stress are significantly reduced in C3 KO neuron/glial cultures and mouse brains. Together, this study provides the first evidence demonstrating the role of C3 in regulating chronic neuroinflammation and in driving progressive neurodegeneration.
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APA 7th
Zhou, R., Chen, S.-H., Zhao, Z., Tu, D., Song, S., Wang, Y., et al. (2023). Complement C3 Enhances LPS-Elicited Neuroinflammation and Neurodegeneration Via the Mac1/NOX2 Pathway. Molecular neurobiology. https://doi.org/10.1007/s12035-023-03393-w
Vancouver
Zhou R, Chen S.-H, Zhao Z, Tu D, Song S, Wang Y, et al. Complement C3 Enhances LPS-Elicited Neuroinflammation and Neurodegeneration Via the Mac1/NOX2 Pathway. Molecular neurobiology. 2023. doi:10.1007/s12035-023-03393-w. PMID: 37268807.
BibTeX
@article{zhou2023-37268807,
author = {Zhou, Ran and Chen, Shih-Heng and Zhao, Zhan and Tu, Dezhen and Song, Sheng and Wang, Yubao and Wang, Qingshan and Feng, Jing and others},
title = {{Complement C3 Enhances LPS-Elicited Neuroinflammation and Neurodegeneration Via the Mac1/NOX2 Pathway}},
journal = {Molecular neurobiology},
year = {2023},
doi = {10.1007/s12035-023-03393-w},
pmid = {37268807},
url = {https://doi.org/10.1007/s12035-023-03393-w}
}
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Key findings
- We found that complement C3 is upregulated in lipopolysaccharide (LPS)-stimulated neuron/glial cultures.
- Mechanistic studies revealed that microglia-released proinflammatory factors initiated the enhanced expression of C3 in astroglia during acute neuroinflammation.
- Our results suggested that DAMPs might act on microglial integrin receptor Mac1 to trigger the activation of NADPH oxidase (NOX2).
- LPS-induced neurodegeneration and oxidative stress are significantly reduced in C3 KO neuron/glial cultures and mouse brains.
Study details
- Evidence strengthLow
How this study scored 41/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it. We have no data on journal's citation record, times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record, multi-centre collaboration and free to read, so those were left out: it earned 23 of the 56 points we could judge it on, which is 41 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Molecular neurobiology) |
| Journal's citation record | — / 4 | No journal record from OpenAlex — left out of this score |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 3 / 5 | 2023 — within 6 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multi-centre collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 37268807) |
| Free to read | — / 2 | Access not recorded — left out of this score |
| Points | 23 / 56 | Scored on 10 of 20 parts. We have no data for the rest, so they are left out: 23 of the 56 points we could judge it on is 41 out of 100. |
| Total | 41 / 100 | — |
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