Proinflammatory effects of S100A8/A9 via TLR4 and RAGE signaling pathways in BV-2 microglial cells
Open accessAbstract
S100A8/A9, a heterodimer of the two calcium-binding proteins S100A8 and S100A9, has emerged as an important proinflammatory mediator in acute and chronic inflammation. However, whether S100A8/A9 is implicated in microglial‑induced neuroinflammatory response remains unclear. Here, we found that S100A8/A9 significantly increased the secretion of proinflammatory cytokines inclu-ding tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in cultured BV-2 microglial cells. Inhibition of the Toll-like receptor 4 (TLR4) and the receptor for advanced glycation end-products (RAGE) with C225 and a RAGE-blocking antibody, respectively significantly reduced the secretion of TNF-α and IL-6 from S100A8/A9-stimulated BV-2 microglial cells. Furthermore, S100A8/A9 markedly enhanced the nuclear translocation of NF-κB p65 and the DNA-binding activities of NF-κB in BV-2 microglial cells, and suppression of ERK and JNK/MAPK signaling pathways by PD98059 or SP600125 significantly inhibited NF-κB activity and the release of TNF-α and IL-6 in the S100A8/A9-treated BV-2 microglial cells. Our data also showed that inhibition of NF-κB with pyrrolidine dithiocarbamate (PDTC) significantly reduced the secretion of TNF-α and IL-6 from BV-2 microglial cells treated with S100A8/A9. Taken together, our data suggest that S100A8/A9 acts directly on BV-2 microglial cells via binding to TLR4 and RAGE on the membrane and then stimulates the secretion of proinflammatory cytokines through ERK and JNK-mediated NF-κB activity in BV-2 microglial cells. Targeting S100A8/A9 may provide a novel therapeutic strategy in microglial-induced neuroinflammatory diseases.
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Tau-dependent microglial activation enhances secretion of pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α.
“Tau-dependent microglial activation can enhance secretion of pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α [421–423].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [422]
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- Authors
- Ma, L., Sun, P., Zhang, J.-C., Zhang, Q., & Yao, S.-L.
- Affiliations
- Wuhan Union Hospital (CN)
- Corresponding author
- Zhang, Qing
- Venue
- International Journal of Molecular Medicine
- Publisher
- Spandidos Publications
- Published
- 2017-05-12
- Volume
- 40
- Issue
- 1
- Pages
- 31-38
- ISSN
- 1107-3756 (ISSN-L)
- 1791-244X
- PMC
- PMC5466387
- OpenAlex
- W2613996502
- Cited by
- 196
- References
- 48
- Citations by year
- 2026: 23 · 2025: 32 · 2024: 30 · 2023: 35 · 2022: 23 · 2021: 11 · 2020: 19 · 2019: 10 · 2018: 10 · 2017: 2
- FWCI
- 4.58
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- International Journal of Molecular Medicine (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (81101401)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › S100 Proteins and Annexins
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Advanced Glycation End Products research
- Keywords
- S100A8/A9, microglia, neuroinflammation, TLR4, RAGE, NF-κB, ERK signaling, JNK signaling, TNF-α, interleukin-6, inflammatory cytokines, pyrrolidine dithiocarbamate, C225, BV-2 cells
- MeSH terms
- Receptor for Advanced Glycation End Products, Animals, Cell Line, Transformed, Inflammation, Signal Transduction, Cytokines, Microglia, Inflammation Mediators, Calgranulin A, Calgranulin B, Toll-Like Receptor 4, Mice
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