Cited by 196S100 Proteins and AnnexinsNeuroinflammation and Neurodegeneration MechanismsAdvanced Glycation End Products research

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Proinflammatory effects of S100A8/A9 via TLR4 and RAGE signaling pathways in BV-2 microglial cells

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Ma, Li, Sun, Peng, Zhang, Jian-Cheng, Zhang, Qing, Yao, Shang-Long·2017·International Journal of Molecular Medicine

DOI 10.3892/ijmm.2017.2987PMC PMC5466387

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Abstract

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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The endogenous Toll–like receptor 4 agonist S100A8/S100A9 (calprotectin) as innate amplifier of infection, autoimmunity, and cancer
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“As an endogenous ligand of TLR4 and RAGE (14), S100A8/A9 also amplifies the production of proinflammatory cytokines and contributes to CNS injury (2,15).”
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“In addition to their intracellular functions, some S100 proteins, including S100A9, are secreted by unknown mechanisms, which then bind to pattern recognition receptors on the cell membrane resulting in NF-κB activation in the target cell (Chen et al., 2015; Donato, 2003; Ma et al., 2017).”
BackgroundInfluential
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“Mechanistically, extracellular S100A8/A9 acts as a cytokine to activate endothelial cells and platelets and amplify neutrophil adhesion and NETosis, primarily through Toll-like receptor 4 (TLR4) and the receptor for advanced glycation end-products (RAGE) on both neutrophils and platelets [53].”
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Additional file 2 of S100A8/A9 as a risk factor for breast cancer negatively regulated by DACH1
Zhang, X., Niu, M., Li, T., Wu, Y., Gao, J., Yi, M., & Wu, K. (2024) · Figshare · doi:10.6084/m9.figshare.26653612
Additional file 1 of Glycyrrhizic acid inhibits myeloid differentiation of hematopoietic stem cells by binding S100 calcium binding protein A8 to improve cognition in aged mice
Gong, X., Shen, H., Guo, L., Huang, C., Su, T., Wang, H., Feng, S., Yang, S., Huo, F., Liu, H., et al. (2023) · Figshare · doi:10.6084/m9.figshare.22617409
Additional file 3 of Glycyrrhizic acid inhibits myeloid differentiation of hematopoietic stem cells by binding S100 calcium binding protein A8 to improve cognition in aged mice
Gong, X., Shen, H., Guo, L., Huang, C., Su, T., Wang, H., Feng, S., Yang, S., Huo, F., Liu, H., et al. (2023) · Figshare · doi:10.6084/m9.figshare.22617418
Additional file 1 of FGF18 alleviates sepsis-induced acute lung injury by inhibiting the NF-κB pathway
Hu, Z., Dai, J., Xu, T., Chen, H., Shen, G., Zhou, J., Ma, H., Wang, Y., & Jin, L. (2024) · Figshare · doi:10.6084/m9.figshare.25309927
Additional file 4 of Glycyrrhizic acid inhibits myeloid differentiation of hematopoietic stem cells by binding S100 calcium binding protein A8 to improve cognition in aged mice
Gong, X., Shen, H., Guo, L., Huang, C., Su, T., Wang, H., Feng, S., Yang, S., Huo, F., Liu, H., et al. (2023) · Figshare · doi:10.6084/m9.figshare.22617421
Additional file 3 of S100A8/A9 as a risk factor for breast cancer negatively regulated by DACH1
Zhang, X., Niu, M., Li, T., Wu, Y., Gao, J., Yi, M., & Wu, K. (2024) · Figshare · doi:10.6084/m9.figshare.26653615
Additional file 5 of Glycyrrhizic acid inhibits myeloid differentiation of hematopoietic stem cells by binding S100 calcium binding protein A8 to improve cognition in aged mice
Gong, X., Shen, H., Guo, L., Huang, C., Su, T., Wang, H., Feng, S., Yang, S., Huo, F., Liu, H., et al. (2023) · Figshare · doi:10.6084/m9.figshare.22617424
Additional file 1 of S100A8/A9 as a risk factor for breast cancer negatively regulated by DACH1
Zhang, X., Niu, M., Li, T., Wu, Y., Gao, J., Yi, M., & Wu, K. (2024) · Figshare · doi:10.6084/m9.figshare.26653606
Additional file 8 of Glycyrrhizic acid inhibits myeloid differentiation of hematopoietic stem cells by binding S100 calcium binding protein A8 to improve cognition in aged mice
Gong, X., Shen, H., Guo, L., Huang, C., Su, T., Wang, H., Feng, S., Yang, S., Huo, F., Liu, H., et al. (2023) · Figshare · doi:10.6084/m9.figshare.22617433
Additional file 6 of Glycyrrhizic acid inhibits myeloid differentiation of hematopoietic stem cells by binding S100 calcium binding protein A8 to improve cognition in aged mice
Gong, X., Shen, H., Guo, L., Huang, C., Su, T., Wang, H., Feng, S., Yang, S., Huo, F., Liu, H., et al. (2023) · Figshare · doi:10.6084/m9.figshare.22617427
Additional file 2 of Glycyrrhizic acid inhibits myeloid differentiation of hematopoietic stem cells by binding S100 calcium binding protein A8 to improve cognition in aged mice
Gong, X., Shen, H., Guo, L., Huang, C., Su, T., Wang, H., Feng, S., Yang, S., Huo, F., Liu, H., et al. (2023) · Figshare · doi:10.6084/m9.figshare.22617412
Additional file 9 of Glycyrrhizic acid inhibits myeloid differentiation of hematopoietic stem cells by binding S100 calcium binding protein A8 to improve cognition in aged mice
Gong, X., Shen, H., Guo, L., Huang, C., Su, T., Wang, H., Feng, S., Yang, S., Huo, F., Liu, H., et al. (2023) · Figshare · doi:10.6084/m9.figshare.22617436
Additional file 7 of Glycyrrhizic acid inhibits myeloid differentiation of hematopoietic stem cells by binding S100 calcium binding protein A8 to improve cognition in aged mice
Gong, X., Shen, H., Guo, L., Huang, C., Su, T., Wang, H., Feng, S., Yang, S., Huo, F., Liu, H., et al. (2023) · Figshare · doi:10.6084/m9.figshare.22617430
Additional file 2 of FGF18 alleviates sepsis-induced acute lung injury by inhibiting the NF-κB pathway
Hu, Z., Dai, J., Xu, T., Chen, H., Shen, G., Zhou, J., Ma, H., Wang, Y., & Jin, L. (2024) · Figshare · doi:10.6084/m9.figshare.25310271
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“…suggest that TLR2 may play a more prominent role than TLR4 in the thrombo-inflammatory pathways associated with MPNs. Previous studies have demonstrated important roles of TLR4 and RAGE in S100A8/A9-mediated inflammatory responses, but TLR2 signaling was not investigated in those studies [15,16].”
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Ramu, S., Vázquez‐Mera, S., Menzel, M., Cerps, S., Nieto‐Fontarigo, J. J., Hvidtfeldt, M. W., Porsbjerg, C. M., Sverrild, A., & Uller, L. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1911911

Authors: Ma, L., Sun, P., Zhang, J.-C., Zhang, Q., & Yao, S.-L.
Affiliations: Wuhan Union Hospital (CN)
Corresponding author: Zhang, Qing
ORCID: Ma, Li
Sun, Peng
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
DOI: 10.3892/ijmm.2017.2987
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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Proinflammatory effects of S100A8/A9 via TLR4 and RAGE signaling pathways in BV-2 microglial cells

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