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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Figure 1 Proinflammatory cytokine production by BV-2 microglial cells after S100A8/A9 stimulation. Effect of lipopolysaccharide (LPS) (1 µg/ml) and S100A8/A9 (0.01–1.0 µM) on the production of (A) tumor necrosis factor-α (TNF-α) and (B) interleukin-6 (IL-6) in BV-2 microglial cells. TNF-α and IL-6 levels were determined by ELISA after 12 h of incubation. (C) Polymyxin B (25 µg/ml) had no inhibitory effect on S100A8/A9-induced TNF-α expression in BV-2 cells, whereas the effects of LPS were efficiently blocked. TNF-α levels were determined after 12 h of stimulation by ELISA. Each value represents the mean ± SEM of three independent experiments. **P<0.01 and ***P<0.001 compared with the control; ##P<0.01 and ###P<0.001 compared with 0.1 nM S100A8/A9.CC BY-NC-ND · PubMed Central

Figure 2 Effects of receptor for advanced glycation endproducts (RAGE) and Toll-like receptor 4 (TLR4) blockade on S100A8/A9 stimulation. (A) Tumor necrosis factor-α (TNF-α) and (B) interleukin-6 (IL-6), as determined by ELISA, in BV-2 cells after preincubation for 1 h with 1 µg/ml TLR4 inhibitor (C225) or 166 µg/ml RAGE-blocking antibody followed by 12 h of stimulation with lipopolysaccharide (LPS) or S100A8/A9 as indicated. Each value represents the mean ± SEM of three independent experiments. ***P<0.001 compared with the control; ##P<0.01 and ###P<0.001 compared with S100A8/A9.CC BY-NC-ND · PubMed Central

Figure 3 Involvement of nuclear factor-κB (NF-κB) activation in S100A8/A9-stimulated secretion of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). (A) BV-2 cells were stimulated with lipopolysaccharide (LPS) (1 µg/ml) or S100A8/A9 (0.1 µM) for 1 h. Nuclear extracts were prepared and used to analyze NF-κB DNA-binding activity by EMSA, as described in Materials and methods. Binding specificity was confirmed by unlabelled probe (100-fold in excess; lane 5) to compete with labelled oligonucleotide. Free-labelled probes are also indicated. (B and C) p65 NF-κB inhibitor PDTC (50 µM) was added 1 h before activation. Results were confirmed by three independent experiments. **P<0.01 compared with the control; ###P<0.001 compared with S100A8/A9.CC BY-NC-ND · PubMed Central

Figure 4 Involvement of mitogen-activated protein kinase (MAPK) signaling pathways in S100A8/A9-stimulated secretion of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). TNF-α levels determined by (B) ELISA and (C) PCR, and (A) IL-6 levels as determined by PCR in BV-2 cells after 12 h of stimulation with lipopolysaccharide (LPS) (1 µg/ml) or S100A8/A9 (0.1 µM) in the absence or presence of protein kinase inhibitors: extracellular signal-regulated kinase (ERK) inhibitor PD98059 (20 µM), p38 inhibitor SB203580 (7 µM), c-Jun N-terminal kinase (JNK) inhibitor SP600125 (10 µM). Each value represents the mean ± SEM of three independent experiments. ##P<0.01 and ###P<0.001 compared with S100A8/A9.CC BY-NC-ND · PubMed Central

Figure 5 Mitogen-activated protein kinase (MAPK) signaling pathway acts upstream of nuclear factor-κB (NF-κB) in S100A8/A9 stimulation. (A) BV-2 cells were stimulated with lipopolysaccharide (LPS) (1 µg/ml) or S100A8/A9 (0.1 µM). Subcellular location of the p65 subunit was assessed using immunofluorescence assay 60 min after activation. (B) BV-2 cells were stimulated with S100A8/A9 (0.1 µM) in the presence of PD98059 (20 µM), SB203580 (7 µM), SP600125 (10 µM) that were added 60 min before activation. Subcellular location of the p65 subunit was assessed using immunofluorescence assay 60 min after activation. (C and D) Western blot analysis and quantitative data for cytoplasmic and nuclear p65 in BV-2 cells stimulated with S100A8/A9 (0.1 µM) in the presence of PD98059 (20 µM), SB203580 (7 µM) and SP600125 (10 µM). Data are presented as mean ± SEM of three independent experiments. #P<0.05 and ##P<0.01 compared with S100A8/A9;. *P<0.05 and ***P<0.001 compared with the control.CC BY-NC-ND · PubMed Central

Figure 6 Proinflammatory response of the S100A8/A9 contribution to microglial activation. S100A8/A9 activated microglia via binding the receptor for advanced glycation endproducts (RAGE) and Toll-like receptor 4 (TLR4) on the membrane and promoted the production of proinflammatory cytokines in microglia through the activation of c-Jun N-terminal kinase (JNK)/nuclear factor-κB (NF-κB) and extracellular signal-regulated kinase (ERK)/NF-κB signaling pathways.CC BY-NC-ND · PubMed Central

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He, G., Zhao, C., Wu, D.-G., Cheng, H., Sun, L., Zhang, D., Yang, X., Fan, X.-R., Di, G., & Jiang, X. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2020.616559 · Cited by 25
Calprotectin (S100A8/S100A9)-induced cytotoxicity and apoptosis in human gastric cancer AGS cells: Alteration in expression levels of Bax, Bcl-2, and ERK2
Shabani, F., Mahdavi, M., Imani, M., Feizi, M. A. H., & Gheibi, N. (2020) · Human & Experimental Toxicology · doi:10.1177/0960327120909530 · Cited by 25
“(TNF-a) and interleukin-6 (IL-6)) in BV-2 microglial cells via ERK/NF-kB and c-Jun N-terminal kinases (JNKs)/NF-kB signaling pathways.(21) Overexpression and activation of ERK have been found in many human malignant tumors and, as such, represented an attractive target for the development of anticancer drugs.”
Background
Novel insight on marker genes and pathogenic peripheral neutrophil subtypes in acute pancreatitis
Zhang, D., Wang, M., Zhang, Y., Xia, C., Peng, L., Li, K., Yin, H., Li, S., Yang, X., Su, X., et al. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.964622 · Cited by 25
“S100A12 is highly abundant in neutrophils and has been identified as an activator of long-term inflammation via the RAGE pathway (37).”
Background
Transcriptomic analysis reveals the key regulators and molecular mechanisms underlying myometrial activation during equine placentitis†
Ali, H. E., Boakari, Y. L., Loux, S. C., Dini, P., Scoggin, K. E. S., Esteller‐Vico, A., Kalbfleisch, T., & Ball, B. A. (2020) · Biology of Reproduction · doi:10.1093/biolre/ioaa020 · Cited by 25
“In addition, ligand–receptor interaction analysis revealed that S100A8 and S100A9 (both upregulated in placentitis) could interact with TLR4 with a subsequent amplification of the proinflammatory cascade [52].”
Background
Liver-Derived S100A6 Propels β-Cell Dysfunction in NAFLD
Dogra, S., Das, D., Maity, S. K., Paul, A., Rawat, P., Daniel, P. V., Das, K., Mitra, S., Chakrabarti, P., & Mondal, P. (2022) · Diabetes · doi:10.2337/db22-0056 · Cited by 25
Pathogenic roles of neutrophil‐derived alarmins (S100A8/A9) in heart failure: From molecular mechanisms to therapeutic insights
Bai, B., Xu, Y., & Chen, H. (2022) · British Journal of Pharmacology · doi:10.1111/bph.15998 · Cited by 20
Nicotinamide Improves Functional Recovery via Regulation of the RAGE/JNK/NF-κB Signaling Pathway after Brain Injury
Alam, S., Réhman, S. U., & Kim, M. O. (2019) · Journal of Clinical Medicine · doi:10.3390/jcm8020271 · Cited by 22
Highly specific interaction of monomeric S100P protein with interferon beta
Kazakov, A. S., Maiorov, S. A., Deryusheva, E. I., Avkhacheva, N. V., Denessiouk, K. A., Denesyuk, A. I., Rastrygina, V. A., Permyakov, E. A., & Permyakov, S. E. (2019) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2019.12.039 · Cited by 22
RAGE–TLR4 Crosstalk Is the Key Mechanism by Which High Glucose Enhances the Lipopolysaccharide-Induced Inflammatory Response in Primary Bovine Alveolar Macrophages
Yan, L., Li, Y., Tan, T., Qi, J., Fang, J. S., Guo, H., Ren, Z., Gou, L., Geng, Y., Cui, H., et al. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24087007 · Cited by 23
“RAGE, another important receptor involved in the inflammatory response, can bind with various ligands, including advanced glycosylation end products (AGEs) [23], high mobility group box 1 (HMGB1) [24], and the S100A8/A9 heterodimer [25].”
Background
Acute Systemic Inflammatory Response Alters Transcription Profile of Genes Related to Immune Response and Ca2+ Homeostasis in Hippocampus; Relevance to Neurodegenerative Disorders
Czapski, G. A., Zhao, Y., Lukiw, W. J., & Strosznajder, J. B. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21217838 · Cited by 20
“Both of these proteins, via a signaling pathway involving TLR4, RAGE and ERK/NF-κB, lead to secretion of TNF-α and IL-6 in microglia cells (BV2) [59].”
Background
Salivary Proteomics Reveals Significant Changes in Relation to Alzheimer’s Disease and Aging
Contini, C., Serrao, S., Manconi, B., Olianas, A., Iavarone, F., Bizzarro, A., Masullo, C., Castagnola, M., Messana, I., Diaz, G., et al. (2022) · Journal of Alzheimer s Disease · doi:10.3233/jad-220246 · Cited by 19
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) · Immunity & Ageing · doi:10.1186/s12979-023-00337-9 · Cited by 20
“S100A8/S100A9 can stimulate TNF-⍺ and IL-6 production in BV-2 microglia through ERK/NF-κB and JNK/NF-κB signaling pathways [29].”
Background
Salivary S100 proteins screen periodontitis among Korean adults
Karna, S., Shin, Y., Kim, S., & Kim, H. (2018) · Journal Of Clinical Periodontology · doi:10.1111/jcpe.13059 · Cited by 20
“S100 A8 and A9 are human proteins which involved in cell cycle progression, signal transduction, cell- type differentiation, morphological differentiation, and inflammatory events (Khammanivong, Wang, Sorenson, Ross, & Herzberg, 2013; Kojima et al., 2000; Ma et al., 2017; Thorey et al., 2001).”
Background
The alarmin tandem: unraveling the complex effect of S100A8/A9 – from atherosclerosis to cardiac arrhythmias
Cozac, D. A., Halațiu, V.-B., & Scridon, A. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1630410 · Cited by 22
Remodeling the Microenvironment before Occurrence and Metastasis of Cancer
Zhang, X., & Xiang, J. (2018) · International Journal of Biological Sciences · doi:10.7150/ijbs.28669 · Cited by 19
“Primary tumor induction of S100A8 and S100A9 expression has also been shown to recruit Mac1+ myeloid cells via TLR4 to premetastatic sites[121, 122].”
Background
Inhibition of S100A9 alleviates neurogenic pulmonary edema after subarachnoid hemorrhage
Wang, G., Hou, G., Tian, Q., Liu, C., Guo, Y., Wei, H., Zhang, Z., & Li, M. (2023) · Biochemical Pharmacology · doi:10.1016/j.bcp.2023.115905 · Cited by 18
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) · Respiratory Research · doi:10.1186/s12931-024-02733-1 · Cited by 18
“This finding is consistent with previous studies that have shown MAPK kinase inhibitors can alleviate p65 phosphorylation [39, 40].”
Result
S100a8 silencing attenuates inflammation, oxidative stress and apoptosis in BV2 cells induced by oxygen‑glucose deprivation and reoxygenation by upregulating GAB1 expression
Hu, W.-G., & Lin, C. (2020) · Molecular Medicine Reports · doi:10.3892/mmr.2020.11702 · Cited by 18
“Notably, S100A8 induces cytokine expression via the roS‐dependent activation of nF‐κB (39).”
Background
Psycho-cardiology therapeutic effects of Shuangxinfang in rats with depression-behavior post acute myocardial infarction: Focus on protein S100A9 from proteomics
Sun, Y., Wang, Z., Wang, C., Tang, Z., & Zhao, H. (2021) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2021.112303 · Cited by 18
Endogenous Ligands of TLR4 in Microglia: Potential Targets for Related Neurological Diseases
Chen, B., & Di, B. (2024) · Current Drug Targets · doi:10.2174/0113894501316051240821060249 · Cited by 16
Staphylococcus aureus metal acquisition in the mastitic mammary gland
Carlson, S. K., Erickson, D. L., & Wilson, E. (2020) · Microbial Pathogenesis · doi:10.1016/j.micpath.2020.104179 · Cited by 18
The Gengnianchun recipe attenuates insulin resistance-induced diminished ovarian reserve through inhibiting the senescence of granulosa cells
Gao, H., Gao, L., Rao, Y., Qian, L., Li, M., & Wang, W. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1133280 · Cited by 17
“AGER was found to be able to activate the NF-kB signaling pathway and ERK signaling pathway (34, 35), which may indicate a potential molecular mechanism of high concentrations of insulin leading to cell senescence.”
Background
A positive feedback cycle between the alarmin S100A8/A9 and NLRP3 inflammasome-GSDMD signalling reinforces the innate immune response in Candida albicans keratitis
Fang, X., Lian, H., Liu, S., Dong, J., Hua, X., Li, W., Liao, C., & Yuan, X. (2023) · Inflammation Research · doi:10.1007/s00011-023-01757-5 · Cited by 17
“Furthermore, RAGE is also believed to be a major receptor for S100A8/A9, and a recent study reported that S100A8/ A9 promoted RAGE and carboxylated glycan-dependent activation of the MAPK and NF-κB signalling pathways in colon tumour cells [12, 60].”
Background
Serial measurement of circulating calprotectin as a prognostic biomarker in COVID-19 patients in intensive care setting
Nevejan, L., Strypens, T., Nieuwenhove, M. V., Boel, A., Cattoir, L., Vaerenbergh, K. V., Meeus, P., Bossuyt, X., Neve, N. D., & Hoovels, L. V. (2022) · Clinical Chemistry and Laboratory Medicine (CCLM) · doi:10.1515/cclm-2022-1165 · Cited by 16
Exploratory Transcriptomic Profiling Reveals the Role of Gut Microbiota in Vascular Dementia
Kaur, N., LaForce, G. R., Mallela, D. P., Saha, P. P., Buffa, J. A., Li, X. S., Sangwan, N., Rothenberg, K. G., & Zhu, W. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24098091 · Cited by 16
“products, stimulating the production of pro-inflammatory cytokines in microglia and causing brain damage via ERK/NF-B and JNK/NF-B signaling pathways [67,68].”
Background
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. (2023) · Biomarker Research · doi:10.1186/s40364-023-00548-8 · Cited by 16
“Neutrophils or macrophages secret S100A8/A9 to magnify infection-induced inflammation by triggering advanced glycation end products (RAGE) and Toll-like receptor 4 (TLR4) signaling [18].”
Background
Avian MRP126 Restricts Microbial Growth through Ca(II)-Dependent Zn(II) Sequestration
Bozzi, A. T., & Nolan, E. M. (2019) · Biochemistry · doi:10.1021/acs.biochem.9b01012 · Cited by 17
Bioinformatics and molecular docking reveal Cryptotanshinone as the active anti-inflammation component of Qu-Shi-Xie-Zhuo decoction by inhibiting S100A8/A9-NLRP3-IL-1β signaling
Liao, X., Xie, R.-X., Zheng, S.-Y., Fan, C.-L., Zuo, M.-Y., Chen, S., Zhu, J., & Li, J. (2024) · Phytomedicine · doi:10.1016/j.phymed.2024.156257 · Cited by 15
Fatty acid-binding protein 4 drives microglia-mediated neuroinflammation through promoting S100A9 expression and lipid droplet accumulation after intracerebral hemorrhage
He, J., Qin, Z., Liu, H., Cai, Y., Wu, H., Wang, T., Hu, Q., Xu, Y., Yang, P., Wu, X., et al. (2025) · Journal of Neuroinflammation · doi:10.1186/s12974-025-03573-6 · Cited by 19
“The proinflammatory protein S100A9, a key component of the alarmin family, has emerged as a critical mediator of microglial activation in neuroinflammatory and neurodegenerative diseases [44, 45].”
S100A8/S100A9 Promote Progression of Multiple Myeloma via Expansion of Megakaryocytes
Lin, C., Garcia-Gerique, L., Bonner, E. E., Mastio, J., Rosenwasser, M. J., Cruz, Z., Lawler, M. E., Bernabei, L. L., Muthumani, K., Liu, Q., et al. (2023) · Cancer Research Communications · doi:10.1158/2767-9764.crc-22-0368 · Cited by 15
Crisaborole Inhibits Itch and Pain by Preventing Neutrophil Infiltration in a Mouse Model of Atopic Dermatitis
Pavlenko, D., Seven, Z. G. T., Bystrom, L. L., Markan, A., Verpile, R., Ishida, H., & Akiyama, T. (2023) · Acta Dermato Venereologica · doi:10.2340/actadv.v103.13382 · Cited by 16
“Experiments were performed under a protocol approved by the University of Miami Institutional Animal Care and Use Committee (21-111).”
BackgroundMethod
S100A8 acts as an autocrine priming signal for heme-induced human Mϕ pro-inflammatory responses in hemolytic inflammation
Silveira, A. A. A., Mahon, O. R., Cunningham, C. C., Corr, E. M., Mendonça, R., Saad, S. T. O., Costa, F. F., Dunne, A., & Conran, N. (2019) · Journal of Leukocyte Biology · doi:10.1002/jlb.3mia1118-418rr · Cited by 14
Retracted: S100A9 gene silencing inhibits the release of pro‐inflammatory cytokines by blocking the IL ‐17 signalling pathway in mice with acute pancreatitis
Wu, D., Wang, S., Shen, M., Wang, Y., Zhang, B., Wu, Z., Lu, J., & Zheng, Y. (2018) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.13532 · Cited by 14
“A previous study indicated that both TLR4 and RAGE proteins were overexpressed in pancreatitis, as well as highlighting the ability of S100A9 to activate the IL-17 signalling pathway and regulate the expression of inflammatory factors by binding to the cell surface receptors TLR4 and RAGE proteins.(44) Once secreted,…”
Background
Retracted
Characterizing the Macrophage Population in Patients With Idiopathic Subglottic Stenosis
Ospino, R., Berges, A. J., Mafla, L. M., Collins, S. L., Chan‐Li, Y., Lina, I. A., Gelbard, A. H., Hillel, A. T., & Motz, K. (2022) · The Laryngoscope · doi:10.1002/lary.30524 · Cited by 14
“Current evidence suggests that inhibition of this signaling transduction pathway can produce anti-fibrotic effects through the reduction of IL 6.(43) Together, our findings suggest that S100A8/9 may impact pathologic tissue fibrosis in iSGS, thus representing a potential therapeutic target for disease modulation.”
Background
The impact of nutritional immunity on Group B streptococcal pathogenesis during wound infection
Akbari, M. S., Keogh, R. A., Radin, J. N., Sanchez-Rosario, Y., Johnson, M. D. L., Horswill, A. R., Kehl‐Fie, T. E., Burcham, L. R., & Doran, K. S. (2023) · mBio · doi:10.1128/mbio.00304-23 · Cited by 14
“Of note, CP can be pro-inflammatory via binding to Toll-like receptor 4 (TLR4) which could impact inflammation, particularly neutrophil recruitment to the site of infection (11).”
Background
Targeting S100A9 attenuates social dysfunction by modulating neuroinflammation and myelination in a mouse model of autism
Gong, H., Yao, L., Deng, S., Lv, K., Luo, J., Luo, Y., Du, Z., Wu, L.-F., Liu, T., Wang, X., et al. (2024) · Pharmacological Research · doi:10.1016/j.phrs.2024.107568 · Cited by 14
Mechanism of action and therapeutic potential of S100A8/A9 in neuroinflammation and cognitive impairment: From molecular target to clinical application (Review)
Guan, X., Zha, L., Zhu, X., Rao, X., Huang, X., Xiong, Y., Guo, Y., Zhang, M., Zhou, D., Tu, Q., et al. (2025) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2025.5588 · Cited by 14
“To harness the thera‑ peutic potential of S100A8/A9, novel compounds or biologics targeting the protein must be developed, and their safety and efficacy must be assessed (71,73,74,125).”
Intranasally Administered S100A9 Amyloids Induced Cellular Stress, Amyloid Seeding, and Behavioral Impairment in Aged Mice
Iashchishyn, I. A., Алексеевна, Г. М., Moskalenko, R., Davydova, T. V., Wang, C., Sewell, R. D. E., & Morozova‐Roche, L. A. (2018) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.7b00512 · Cited by 13
Quantitative proteomic characterization of microvesicles/exosomes from the cerebrospinal fluid of patients with acute bilirubin encephalopathy
Tan, N., Hu, S., Hu, Z., Wu, Z., & Wang, B. (2020) · Molecular Medicine Reports · doi:10.3892/mmr.2020.11194 · Cited by 13
“at high concentrations, extracellular S100a9 exhibited proinflammatory functions and growth-inhibitory activity, induced cell apoptosis, and exerted deleterious effects by stimulating leukocyte migration and recruitment, enhancing leukocyte-endothelial contact and increasing vascular permeability (58-61).”
Background
Regulation of S100As Expression by Inflammatory Cytokines in Chronic Lymphocytic Leukemia
Ajtić, O. M., Subotički, T., Diklić, M., Đikić, D., Vukotić, M., Dragojević, T., Živković, E., Antic, D. A., & Čokić, V. P. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23136952 · Cited by 13
“These suggest potentially increased levels of factor S100A8/9, as a ligand for TLR4, through negative feedback regulation, while S100A8/A9 also increases IL-6 secretion in cultured microglial cells [14].”
Background
Glioma-derived S100A9 polarizes M2 microglia to inhibit CD8+T lymphocytes for immunosuppression via αvβ3 integrin/AKT1/TGFβ1
Huang, N., Tang, J., Yi, X., Zhang, M., Ли, Б., Cheng, Y. Z., & Chen, J. (2023) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2023.119619 · Cited by 12
Unraveling the Mechanisms of S100A8/A9 in Myocardial Injury and Dysfunction
Xu, Y., Wang, Y., Ning, K., & Bao, Y. (2024) · Current Issues in Molecular Biology · doi:10.3390/cimb46090577 · Cited by 13
“…and promoting cytokine and chemokine production; (8) regulating leukocyte adhesion and migration; and (9) acting as an alarm or danger-associated molecular pattern (DAMP) molecule [8,21], stimulating innate immune cells and leading to the amplification of pro-inflammatory cascade reactions [22,23].”
Background
IL6 inhibition of inflammatory S100A8/9 proteins is NF‐κB mediated in essential thrombocythemia
Diklić, M., Ajtić, O. M., Subotički, T., Djikić, D., Kovačić, M. V., Bjelica, S., Beleslin‐Čokić, B. B., Vukotić, M., Leković, D., Gotić, M., et al. (2019) · Cell Biochemistry and Function · doi:10.1002/cbf.3482 · Cited by 11
“We found increased TNFRSF1A and TRADD gene expression in CD34+ cells of MPN. Previous report revealed that S100A8/A9 significantly increased the secretion of proinflammatory cytokines the tumour necrosis factor-α (TNF-α) and IL6, as well as the nuclear translocation and the DNA-binding activities of NF-κB.25 It has be…”
BackgroundInfluential
Prognostic value of circulating calprotectin levels on the clinical course of COVID-19 differs between serum, heparin, EDTA and citrate sample types
Nevejan, L., Strypens, T., Nieuwenhove, M. V., Boel, A., Cattoir, L., Meeus, P., Bossuyt, X., Neve, N. D., & Hoovels, L. V. (2021) · Clinica Chimica Acta · doi:10.1016/j.cca.2021.12.011 · Cited by 11
“CLP acts as an endogenous ligand of Tolllike receptor 4 (TLR4) and receptor for advanced glycation endproducts (RAGE) [4].”
S100A9 amyloid growth and S100A9 fibril-induced impairment of gamma oscillations in area CA3 of mouse hippocampus ex vivo is prevented by Bri2 BRICHOS
Andrade‐Talavera, Y., Chen, G., Pansieri, J., Arroyo‐García, L. E., Toleikis, Z., Smirnovas, V., Johansson, J., Morozova‐Roche, L. A., & Fisahn, A. (2022) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2022.102366 · Cited by 11
Common contributing factors to COVID-19 and inflammatory bowel disease
Kostoff, R. N., Briggs, M. B., Kanduc, D., Shores, D. R., Kovatsi, L., Vardavas, A. I., & Porter, A. L. (2021) · Toxicology Reports · doi:10.1016/j.toxrep.2021.08.007 · Cited by 11
“IBD: “ In sedentary HFD mice a significant increase in the intestinal oxidative stress parameters and mucosal expression of IL-1 β , TNF-α , IL-17, IFN γ , IL-6, and IL-10 protein were observed and these effects were aggravated in mice subjected to forced treadmill exercise.”
Influential
Arylacetamide deacetylase knockout mice are sensitive to ketoconazole-induced hepatotoxicity and adrenal insufficiency
Nagaoka, M., Fukami, T., Kisui, F., Yamada, T., Sakai, Y., Tashiro, K., Ogiso, T., Konishi, K., Honda, S., Hirosawa, K., et al. (2021) · Biochemical Pharmacology · doi:10.1016/j.bcp.2021.114842 · Cited by 10
Молекулярні механізми утворення метастазів. Маркери метастазування при карциномах щитоподібної залози (огляд літератури)
Zinych, P. P., Pushkarev, V. M., Bolgov, М. Y., Guda, B. B., & PUSHKAREV, V. V. (2020) · Endokrynologia · doi:10.31793/1680-1466.2020.25-3.227 · Cited by 11
Role of lymphoid lineage cells aberrantly expressing alarmins S100A8/A9 in determining the severity of COVID-19
Lee, J., Kim, H., Kim, M., Yoon, S., & Lee, S. (2022) · Genes & Genomics · doi:10.1007/s13258-022-01285-2 · Cited by 10
“By engaging with TLR4 or RAGE, S100A8/A9-mediated NF-κB/MAPK activation generates intracellular signaling cascades, activating pro-inflammatory cytokines/ chemokines for the recruitment and activation of inflammatory cells (Leclerc et al. 2009; Ma et al. 2017; Murray 2014; Nishikawa et al. 2017).”
Background
Divalent cations influence the dimerization mode of murine S100A9 protein by modulating its disulfide bond pattern
Signor, L., Paris, T., Mas, C., Picard, A., Lutfalla, G., Erba, E. B., & Yatime, L. (2020) · Journal of Structural Biology · doi:10.1016/j.jsb.2020.107689 · Cited by 12
Staphylococcus aureus thermonuclease NucA is a key virulence factor in septic arthritis
Li, N., Deshmukh, M. V., Sahin, F., Hafza, N., Ammanath, A. V., Ehnert, S., Nussler, A. K., Weber, A. N. R., Jin, T., & Götz, F. (2025) · Communications Biology · doi:10.1038/s42003-025-07920-4 · Cited by 9
Damage-Associated Molecular Patterns in Perioperative Anesthesia Care: A Clinical Perspective
Maisat, W., & Yuki, K. (2025) · Anesthesia Research · doi:10.3390/anesthres3010001 · Cited by 10
Calprotectin serum levels on admission and during follow-up predict severity and outcome of patients with COVID-19: A prospective study
Gatselis, N., Lyberopoulou, A., Lygoura, V., Giannoulis, G., Samakidou, A., Vaiou, A., Antoniou, K. M., Triantafyllou, K., Stefos, A., Georgiadou, S. P., et al. (2023) · European Journal of Internal Medicine · doi:10.1016/j.ejim.2023.11.001 · Cited by 8
Computational Deciphering of the Role of S100A8 and S100A9 Proteins and Their Changes in the Structure Assembly Influences Their Interaction with TLR4, RAGE, and CD36
Paramasivam, S., Selvan, P. S., & Ekambaram, S. P. (2024) · The Protein Journal · doi:10.1007/s10930-024-10186-0 · Cited by 10
“…reports show that there is a signifi - cant interaction between the different structural assemblies of S100A8 and S100A9 proteins against TLR4 [19, 22–25 ], RAGE [ 22 , 26– 28] and CD36 [7, 29 –31 ] towards the dis - ease progression in RA, the highly contributing S100 pro - tein (as a…”
Influential
Pericardial Fluid Accumulates microRNAs That Regulate Heart Fibrosis after Myocardial Infarction
Silva, E. D., Pereira-Sousa, D., Ribeiro-Costa, F., Cerqueira, R. J., Enguita, F. J., Gomes, R. N., Dias-Ferreira, J., Pereira, C., Castanheira, A., Pinto‐do‐Ó, P., et al. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25158329 · Cited by 8
“Following MI, the cessation of blood flow results in cardiac cell death and impaired contractility [5,6].”
BackgroundInfluential
Oxidative stress-driven disease-associated microglia (DAM)-like polarization in human microglia (HMC3) cells exposed to small-size silver nanoparticles in a transwell co-culture system with neurons (cholinergic differentiated SH-SY5Y) cells in vitro
Skóra, B., & Szychowski, K. A. (2025) · Archives of Toxicology · doi:10.1007/s00204-025-04183-0 · Cited by 9
“In addition to bacterial-derived LPS, several other TLR4 ligands have been identified as damage-associated molecular patterns (DAMPs) (Chen et al. 2009; Fang et al. 2011; Ma et al. 2017; Oseni et al. 2023).”
Euchrenone A10 attenuates septic lung injury though S100A8/A9-dependent TLR4/MyD88/NF-κB signaling
Zhou, L., Xiao, Y., He, J., Ren, H., Zhao, C., Zhang, C., Shu, X., Chen, D., Chen, D., He, X., et al. (2025) · Phytomedicine · doi:10.1016/j.phymed.2025.157336 · Cited by 8
Pro-inflammatory protein S100A9 targeted by a natural molecule to prevent neurodegeneration onset
Leri, M., Sun, D., Svedružić, Ž. M., Šulskis, D., Smirnovas, V., Stefani, M., Morozova‐Roche, L. A., & Bucciantini, M. (2024) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2024.133838 · Cited by 8
High levels of plasma S100A9 at admission indicate an increased risk of death in severe tuberculosis patients
Liu, Q., Li, R., Li, Q., Luo, B., Lin, J., & Lyu, L. (2021) · Journal of Clinical Tuberculosis and Other Mycobacterial Diseases · doi:10.1016/j.jctube.2021.100270 · Cited by 8

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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