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Showing S100A8 — CAGA is a alias.

S100A8

Protein S100-A8 · UniProt P05109

Length
93 aa
Mass
10.8 kDa
Annotated
2026-06-10
100 papers in source corpus 35 papers cited in narrative 35 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

S100A8 is a calcium- and zinc-binding alarmin whose conformational state — homodimer, S100A9 heterodimer, or Ca2+/Zn2+-induced tetramer — dictates which receptor it engages and therefore whether it drives or dampens inflammation (PMID:27251136, PMID:22489132, PMID:36310133). Crystallographic analysis shows that S100A8 binds two zinc ions per homodimer through all-His tetrahedral sites, with zinc and calcium tightening the dimer-dimer interface to favor tetramerization (PMID:27251136). This quaternary switch is functionally decisive: S100A8/A9 dimers activate TLR4, whereas Ca2+-induced tetramers cannot bind TLR4 and instead engage CD69 on monocytes to suppress adhesion, migration, and recruitment (PMID:36310133). Through TLR4, secreted S100A8/A9 acts as an endogenous agonist that primes the NLRP3 inflammasome and IL-1β secretion, driving granulopoiesis after myocardial infarction, neuroinflammation after cerebral ischemia, and myeloid-cell-mediated cardiac dysfunction (PMID:31941367, PMID:19835955, PMID:36625265). Beyond TLR4, S100A8 signals through a panel of receptors with cell-type-specific outputs: RAGE to activate ERK/p38/JNK in tumor cells and IFN-γ in NK cells (PMID:25911757, PMID:25423568), neuroplastin-β (partnered with EMMPRIN) to recruit GRB2 and activate ERK or TRAF2/RAS for keratinocyte and cancer-cell proliferation (PMID:27388991, PMID:30720226), GPIbα to drive procoagulant platelet formation (PMID:36026606), and CD147 to activate RhoA-ROCK signaling in cancer-associated fibroblasts (PMID:38776909). S100A8 also has redox-dependent roles, scavenging reactive oxygen species including hypochlorite (PMID:16216873) and undergoing S-nitrosylation at its single cysteine to acquire NO-transport, mast-cell-suppressing, and anti-inflammatory activity that requires this Cys residue (PMID:18832721, PMID:21142608, PMID:24532576). Intracellularly, S100A8/A9 can localize to the nucleus, bind transcription factors, and act as a transcriptional co-activator that promotes oncogenic transformation (PMID:33523865). Its transcription is controlled by C/EBPδ-directed JMJD3-mediated H3K27me3 demethylation at the S100a8/a9 promoters and by inflammatory and hormonal inputs including IL-10/LPS, glucocorticoids, FGF-2/IL-1β, IL-17A/F, and HIF-1α acting through defined promoter elements (PMID:35543413, PMID:11342660, PMID:15699168, PMID:15943814, PMID:23800059, PMID:22505354).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2008 High

    Established that S100A8 carries a redox-active single cysteine that can be S-nitrosylated, converting it into an NO transporter and anti-inflammatory mediator, defining a post-translational switch on alarmin function.

    Evidence HPLC/MS, biotin-switch assay, Cys-to-Ala mutagenesis, and intravital microscopy in vivo

    PMID:18832721

    Open questions at the time
    • Did not define which receptors mediate the anti-inflammatory effects of S100A8-SNO
    • Physiological source of NO for in vivo S-nitrosylation not established
  2. 2011 High

    Showed the cysteine residue is mechanistically required for S100A8 to suppress mast cell degranulation via ROS inhibition, linking the redox-active Cys to an intracellular signaling output.

    Evidence In vitro mast cell assays, Cys-to-Ala mutagenesis, phosphorylation analysis, and murine acute asthma model

    PMID:21142608

    Open questions at the time
    • Mechanism by which extracellular S100A8 accesses intracellular ROS not defined
    • Receptor mediating mast cell entry/signaling unidentified
  3. 2014 High

    Extended the Cys-dependent anti-inflammatory program to airway epithelium, where S100A8 induces IL-10 and suppresses NF-κB via IkBα/Akt.

    Evidence Intranasal administration in mice, Cys-to-Ala mutagenesis, and LPS-induced acute lung injury model

    PMID:24532576

    Open questions at the time
    • Receptor transducing the IL-10-inducing signal not identified
    • Reconciliation with TLR4-driven proinflammatory roles not addressed
  4. 2016 High

    Resolved the structural basis for metal-dependent oligomerization, showing zinc binds via all-His sites to stabilize the tetramer interface and calcium induces tetramer formation — the structural foundation for state-dependent function.

    Evidence X-ray crystallography of Ca2+/Zn2+-loaded S100A8 in two crystal forms

    PMID:27251136

    Open questions at the time
    • Structures do not show receptor-bound complexes
    • Did not directly link a given oligomer to a specific receptor
  5. 2016 High

    Identified neuroplastin-β as an S100A8 receptor that, with EMMPRIN, forms a heterodimeric receptor recruiting GRB2 to drive ERK and keratinocyte proliferation, defining a non-TLR4 signaling axis.

    Evidence Receptor identification, co-immunoprecipitation, knockdown, and transgenic mouse model

    PMID:27388991

    Open questions at the time
    • Which oligomeric state binds neuroplastin-β not defined
    • Stoichiometry of the NPTNβ/EMMPRIN receptor complex unresolved
  6. 2020 High

    Defined a sequential TLR4-NLRP3-IL-1β cascade by which neutrophil-released S100A8/A9 amplifies emergency granulopoiesis after myocardial infarction.

    Evidence Mouse MI model, S100A8/A9 knockout, pharmacological disruption, and transcriptome analysis

    PMID:31941367

    Open questions at the time
    • Did not address oligomeric state required for TLR4 priming
    • Contribution of S100A8 homodimer versus heterodimer not separated
  7. 2022 High

    Demonstrated that quaternary structure determines receptor selectivity — Ca2+-induced tetramers lose TLR4 binding and instead engage CD69 to suppress monocytes — unifying the opposing pro- and anti-inflammatory roles under one structural switch.

    Evidence Monocyte functional assays, anti-CD69 blocking, and in vivo granuloma and contact dermatitis models

    PMID:36310133

    Open questions at the time
    • Did not co-resolve tetramer-CD69 structure
    • In vivo balance between dimer and tetramer pools under physiological Ca2+ not quantified
  8. 2022 High

    Identified the GPIbα receptor on platelets as an S100A8/A9 target driving procoagulant platelet formation, extending alarmin signaling into hemostasis.

    Evidence Recombinant GPIbα blocking, Bernard-Soulier patient platelets, and GPIbα-knockout mouse platelets

    PMID:36026606

    Open questions at the time
    • Precise S100A8/A9 binding site on GPIbα not mapped
    • Role of CD36 cofactor mechanistically incomplete
  9. 2022 High

    Placed C/EBPδ as a central transcriptional driver of S100a8/a9, acting through JMJD3-mediated H3K27me3 demethylation, revealing an epigenetic mechanism controlling alarmin expression.

    Evidence Genome-wide CRISPR/Cas9 screen, C/EBPδ knockout mouse, and ChIP/chromatin accessibility analysis

    PMID:35543413

    Open questions at the time
    • Stimulus-specific recruitment of C/EBPδ to the locus not fully resolved
    • Integration with other inducers (glucocorticoids, IL-17) not addressed
  10. 2021 High

    Revealed an intracellular nuclear role in which S100A8/A9 are recruited to promoters/enhancers and act as transcriptional co-activators promoting oncogenic transformation, distinct from extracellular receptor signaling.

    Evidence ChIP-seq, nuclear extract co-IP, artificial tethering, and breast transformation assays

    PMID:33523865

    Open questions at the time
    • Direct DNA-binding versus transcription-factor-tethered recruitment not fully distinguished
    • Mechanism of nuclear import not defined
  11. 2024 Medium

    Defined CD147 on cancer-associated fibroblasts as a further S100A8 receptor driving RhoA-ROCK signaling and chemoresistance, broadening the receptor repertoire into the tumor stroma.

    Evidence Patient-derived xenografts, receptor identification, and RhoA-ROCK-MLC2-MRTF-A pathway analysis

    PMID:38776909

    Open questions at the time
    • Single lab; reciprocal validation of CD147 binding limited
    • Oligomeric state binding CD147 not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple receptors (TLR4, CD69, RAGE, neuroplastin-β, GPIbα, CD147) are selected by S100A8's metal-dependent oligomeric and redox states in any given tissue context remains unresolved.
  • No unified map linking specific oligomers/PTMs to each receptor in vivo
  • Relative contributions of homodimer, heterodimer, and tetramer pools in physiological versus disease settings unquantified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 5 GO:0016209 antioxidant activity 2 GO:0098772 molecular function regulator activity 1 GO:0140096 catalytic activity, acting on a protein 1 GO:0140110 transcription regulator activity 1
Localization
GO:0005576 extracellular region 2 GO:0005829 cytosol 2 GO:0005634 nucleus 1
Pathway
R-HSA-1643685 Disease 5 R-HSA-162582 Signal Transduction 4 R-HSA-168256 Immune System 4 R-HSA-74160 Gene expression (Transcription) 2 R-HSA-109582 Hemostasis 1
Partners
CD147CD69GP1BAMANFNPTN (NEUROPLASTIN-Β)RAGES100A9TLR4
Complex memberships
S100A8/S100A9 heterodimer/tetramer

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2016 Crystal structures of calcium- and zinc-loaded human S100A8 reveal that S100A8 binds two zinc ions per homodimer through symmetrical all-His tetrahedral coordination sites (His4 motif), and that zinc stabilizes S100A8 tetramerization by tightening the dimer-dimer interface; calcium induces the S100A8 tetramer. X-ray crystallography (two crystal forms), structural analysis BMC structural biology High 27251136
2012 Ca2+ and Zn2+-binding properties of S100A8 regulate its conformational state and oligomerization, including self-assembly into homodimers, heterodimers with S100A9, tetramers, and higher oligomers including amyloid fibrils; these transitions are linked to distinct functional states. Biophysical characterization, in vitro assembly assays, structural analysis International journal of molecular sciences Medium 22489132
2008 S100A8 undergoes S-nitrosylation at its single Cys residue (Cys34 in human); S-nitrosylated S100A8 (S100A8-SNO) transnitrosylates hemoglobin (acting as an NO transporter), suppresses mast cell activation, and inhibits leukocyte adhesion and extravasation in vivo; the Cys→Ala mutant is not S-nitrosylated, confirming the Cys residue is required. HPLC/mass spectrometry, biotin-switch assay, site-directed mutagenesis (Cys-to-Ala), intravital microscopy, in vitro mast cell assay Journal of immunology High 18832721
2011 S100A8 suppresses IgE-crosslinking-induced mast cell degranulation and cytokine production (IL-6, IL-4, GM-CSF) via inhibition of intracellular ROS, reducing downstream LAT and ERK/MAPK phosphorylation; this activity requires the Cys41 residue, as the Cys41-Ala mutant lacks this anti-inflammatory activity. In vivo, S100A8 reduced eosinophil chemoattractant production and eosinophil infiltration in acute murine asthma. In vitro mast cell assay, site-directed mutagenesis, phosphorylation analysis, murine acute asthma model Antioxidants & redox signaling High 21142608
2014 S100A8 induces IL-10 expression specifically in airway epithelial cells in vivo; this requires the Cys42 residue (Cys42-Ala mutant fails to induce IL-10 and is less immunosuppressive). S100A8 suppresses LPS-induced acute lung injury by reducing NF-κB activation via an IκBα/Akt pathway and downmodulating oxidative stress pathways. Intranasal administration in BALB/c mice, Cys-to-Ala mutagenesis, gene expression time-course, LPS-induced ALI model Journal of immunology High 24532576
2016 Neuroplastin-β (NPTN-β) was identified as a novel receptor for S100A8. Upon S100A8 binding, neuroplastin-β recruits GRB2 and activates ERK, resulting in keratinocyte proliferation. Neuroplastin-β and EMMPRIN (an S100A9 receptor) form a functional heterodimeric receptor complex on keratinocyte surfaces, and knockdown of both receptors suppressed cell proliferation and proinflammatory cytokine induction. Receptor identification, co-immunoprecipitation, knockdown experiments, transgenic mouse model, signaling pathway analysis The Journal of investigative dermatology High 27388991
2019 S100A8/A9 binding to neuroplastin-β (NPTNβ) in lung cancer cells activates TRAF2/RAS signaling, leading to downstream activation of NFIA, NFIB, and SPDEF transcription factors, promoting anchorage-independent growth, motility, and invasiveness. In vitro cancer cell assays, in vivo xenograft model, mechanistic signaling pathway analysis Molecular carcinogenesis Medium 30720226
2022 S100A8/A9 binds GPIbα on platelets to drive formation of procoagulant (phosphatidylserine-positive) platelets, with a supporting role for CD36. This was established using recombinant GPIbα ectodomain as a blocking agent, platelets from a Bernard-Soulier syndrome patient lacking GPIb-IX-V, and platelets from mice deficient in the extracellular domain of GPIbα. Platelet functional assays, recombinant receptor blocking, patient platelets (Bernard-Soulier), GPIbα-knockout mouse platelets, flow cytometry, perfusion assays Blood High 36026606
2022 S100A8/S100A9 dimers activate TLR4, but extracellular calcium induces tetramer formation that prevents TLR4 binding. S100A8/A9 tetramers instead interact with CD69 on monocytes to dampen monocyte adhesion, migration, traction force generation, and immigration in vivo; thus the quaternary structure determines receptor selectivity and opposing inflammatory effects. In vitro monocyte functional assays (adhesion, migration, traction force), in vivo cutaneous granuloma model and contact dermatitis model, receptor blocking with anti-CD69 Advanced science High 36310133
2020 Neutrophil-released S100A8 and S100A9 bind TLR4 on naïve neutrophils, priming the NLRP3 inflammasome and promoting IL-1β secretion, which then stimulates IL-1R1 on hematopoietic stem and progenitor cells in bone marrow to drive granulopoiesis after myocardial infarction. Mouse LAD-ligation MI model, flow cytometry, genetic knockout (S100A8/A9-deficient), pharmacological disruption, transcriptome analysis Circulation High 31941367
2015 S100A8/A9 interacts with RAGE on NK cells to enhance NKG2D ligand-mediated IFN-γ production; RAGE antagonistic peptide and anti-RAGE antibody blocked S100A8/A9-induced NK cell IFN-γ production, and RAGE inhibitor FPS-ZM1 enhanced tumor growth in vivo. Co-culture assays, RAGE inhibitors/blocking antibodies, in vivo tumor model with pharmacological RAGE inhibition Journal of immunology Medium 25911757
2005 S100A8 acts as an avid scavenger of reactive oxygen species including hypochlorite; in neutrophils and monocytes it is more sensitive to hypochlorite oxidation than albumin or LDL. S100A8-S100A9 complexes in atherosclerotic plaque undergo hypochlorite-mediated cross-linking. S100A8 in macrophages regulates NADPH-oxidase activity and fatty acid transport as part of the S100A8-S100A9 heterodimer. Oxidation sensitivity assays, immunoaffinity, redox biochemistry, human plaque characterization The Journal of biological chemistry Medium 16216873
2001 IL-10 synergizes with LPS and IFN-γ to increase S100A8 mRNA (≥9-fold) and secreted S100A8 protein (~4-fold) in macrophages via increased gene transcription; the effect is dependent on de novo protein synthesis and maps to a 178-bp promoter region containing CCAAT-enhancing binding protein motifs. IL-10 induction is mechanistically distinct from STAT-pathway-dependent IL-10 target genes. Luciferase promoter reporter assay, blocking antibodies (endogenous IL-10), mRNA stability analysis, pharmacological pathway dissection Journal of immunology Medium 11342660
2000 IFN-γ and TNF regulate S100A8 mRNA induction in murine macrophages through distinct kinetics; S100A8 gene induction is modulated by intracellular Ca2+ mobilization, protein kinase C, and MAPK pathways. Luciferase reporter assays confirmed LPS and IFN induce S100A8 gene transcription. Luciferase reporter assay, mRNA stability analysis, pharmacological inhibitors of signaling pathways (PKC, MAPK, Ca2+) Journal of immunology Medium 10779802
2005 Glucocorticoids amplify LPS-induced S100A8 expression in macrophages, fibroblasts, and endothelial cells by increasing both gene transcription and mRNA half-life; this requires new protein synthesis, IL-10, cyclooxygenase-2 pathway products, and both ERK1/2 and p38 MAPK. Protein kinase A positively and PKC negatively regulate glucocorticoid enhancement. A NF1 motif at -58 bp is a candidate mediator. GCs also increase constitutive S100A8/A9 in human monocytes. Luciferase promoter reporter assay, gel shift/EMSA, pharmacological pathway inhibitors, mRNA stability assays Journal of immunology Medium 15699168
2005 FGF-2 (enhanced by heparin) and IL-1β are distinct inducers of S100A8 in fibroblasts acting through different promoter elements; induction is partially dependent on the MAPK pathway and requires new protein synthesis. TGF-β suppresses FGF-2/heparin-induced S100A8, possibly via decreased mRNA stability. S100A9 is not co-induced with S100A8 in fibroblasts under any tested condition. Real-time RT-PCR, promoter analysis, pharmacological MAPK inhibition, TGF-β suppression assay The FEBS journal Medium 15943814
2013 TNFα and IL-17A synergistically induce S100A8 mRNA and protein in human keratinocytes via a p38 MAPK-dependent mechanism; this was demonstrated by promoter luciferase reporter assay and p38 MAPK inhibitor blocking studies. qRT-PCR, luciferase reporter assay, p38 MAPK inhibitor Experimental dermatology Medium 23800059
2022 The transcription factor C/EBPδ is a central regulator of S100a8 (and S100a9) expression; C/EBPδ-dependent JMJD3-mediated demethylation of H3K27me3 at S100a8/S100a9 promoters is required for their expression. C/EBPδ KO mice show decreased S100A8/A9 and reduced neutrophil recruitment in acute lung inflammation. Genome-wide CRISPR/Cas9 KO screen, C/EBPδ KO mouse model, ChIP, chromatin accessibility analysis, promoter binding assays eLife High 35543413
2012 Hypoxia and HIF-1α increase S100A8 expression in prostate epithelial cells; functional hypoxia response elements (HREs) within the S100A8 promoter were identified by luciferase reporter assays, and direct HIF-1α binding to the S100A8 promoter was confirmed by chromatin immunoprecipitation. Promoter luciferase reporter assay, chromatin immunoprecipitation (ChIP), HIF-1α overexpression International journal of cancer Medium 22505354
2021 S100A8 and S100A9 are recruited to promoters and enhancers in a model of breast cellular transformation and interact with transcription factors in nuclear extracts, activating transcription when artificially recruited to a target promoter; nuclear-specific expression of S100A8/A9 promotes oncogenic transcription and enhances breast transformation. ChIP-seq, nuclear extract co-immunoprecipitation, artificial recruitment (tethering) to target promoter, nuclear-specific expression constructs Science advances High 33523865
2015 S100A8 promotes anaplastic thyroid carcinoma (ATC) cell proliferation through interaction with RAGE, which activates p38, ERK1/2, and JNK signaling pathways in tumor cells; S100A8 knockdown in ATC cells reduced tumor growth and lung metastasis in orthotopic mouse models. RNAi-mediated stable knockdown, bioluminescent in vivo imaging, orthotopic mouse models, signaling pathway analysis The Journal of clinical endocrinology and metabolism Medium 25423568
2015 S100A8 promotes colorectal tumorigenesis by activating Id3 (inhibitor of differentiation 3) downstream; S100A8 regulates colon cancer cell cycle and proliferation by inducing Id3 expression while inhibiting p21. Id3 expression is regulated by Smad5, which is directly phosphorylated by Akt1, establishing an S100A8→Akt1→Smad5→Id3 axis. Gene expression profiling, immunohistochemistry, proliferation/invasion assays, in vivo nude mouse metastasis model, signaling pathway analysis International journal of cancer Medium 26135667
2020 S100A8 significantly induces PD-L1 expression in monocytes/macrophages (but not tumor cells) through TLR4 receptor engagement and multiple inflammation-related signaling pathways; S100A8 modulates histone modification of the PD-L1 promoter in monocytes/macrophages. S100A8-pretreated macrophages had immunosuppressive function and attenuated anti-tumor CTL activity. TLR4 blocking, pharmacological inhibitors, promoter chromatin analysis (histone modification), co-culture CTL assays, in vivo tumor model Journal of immunology Medium 32198140
2023 MANF (mesencephalic astrocyte-derived neurotrophic factor) binds S100A8 to competitively block S100A8/A9 heterodimer formation, thereby inhibiting S100A8/A9-mediated TLR4-NF-κB signaling activation in macrophages. This was demonstrated by co-immunoprecipitation of MANF with S100A8. Co-immunoprecipitation (CO-IP), S100A8/A9 heterodimer formation assay, TLR4-NF-κB pathway analysis, genetic knockout mouse model Acta pharmaceutica Sinica. B Medium 37799387
2022 S100A8 deficiency promotes epithelial-to-mesenchymal transition (EMT) in renal tubular epithelial cells during diabetic nephropathy through the TLR4/NF-κB signaling pathway; high S100A8/A9 expression activates TLR4/NF-κB to promote EMT and renal interstitial fibrosis. CO-IP assay confirmed that compound AB38b inhibits EMT by interfering with S100A8/A9 expression/interaction. RNA silencing, overexpression lentiviral constructs, TLR4/NF-κB pathway analysis, CO-IP, in vivo diabetic mouse model Metabolism: clinical and experimental Medium 36521551
2019 S100A8 facilitates cholangiocarcinoma metastasis by activating the TLR4/NF-κB signaling pathway, which upregulates VEGF expression in CCA cells; this promotes vascular endothelial cell migration. Both in vitro and in vivo experiments confirmed that S100A8 overexpression enhanced, while knockdown attenuated, migration and metastasis. In vitro migration assays, in vivo xenograft model, TLR4/NF-κB pathway analysis, VEGF expression assays International journal of oncology Medium 31746424
2009 Mrp8 (S100A8) and Mrp14 (S100A9) are endogenous TLR4 agonists that contribute to neuroinflammation after focal cerebral ischemia; Mrp14-deficient mice (which also lack Mrp8 protein) showed significantly reduced lesion volumes, less brain swelling, and reduced macrophage/microglia infiltration after transient focal ischemia. Mrp14 knockout mouse model, focal cerebral ischemia/reperfusion (1 h LAD ligation), lesion volume measurement, immunohistochemistry Biochimica et biophysica acta Medium 19835955
2015 S100A8/A9 deficiency results in impaired upregulation of CD11b on neutrophils during chronic tuberculosis infection, which mediates neutrophil accumulation; S100A8/A9-deficient mice show improved Mycobacterium tuberculosis control specifically during chronic (not acute) TB. S100A8/A9-deficient mouse model, CD11b expression analysis, neutrophil depletion, flow cytometry The Journal of clinical investigation Medium 32134742
2015 S100A8 is rapidly and significantly increased in mature adipocytes during high-fat/high-sucrose diet, and acts as a chemoattractant for macrophages; recombinant S100A8 stimulated chemotactic migration of macrophages in vitro and in vivo and induced proinflammatory molecules (TNF-α and CCL2) in both macrophages and adipocytes. Anti-S100A8 antibody suppressed early macrophage mobilization in adipose tissue and ameliorated diet-induced insulin resistance. Intravital multiphoton imaging (LysM-EGFP transgenic mice), recombinant S100A8 chemotaxis assays, antibody neutralization in vivo Proceedings of the National Academy of Sciences Medium 25848057
2015 Secretion of S100A8/A9 from neutrophils is dependent on production of reactive oxygen species (ROS) and requires K+ efflux through ATP-sensitive K+ channels; particulate stimuli (MSU crystals, nanoparticles) and microbe-derived molecules (zymosan, HKCA) trigger secretion, while chemotactic fMLP does not induce S100A8/A9 secretion. Human neutrophil stimulation assays, ROS inhibitors, K+ channel blockers, ELISA for secreted S100 proteins Journal of immunology research Medium 27057553
2011 IL-1 receptor (IL-1R) signaling in oral keratinocytes, triggered by IL-1α released from Listeria-infected cells, increases S100A8/A9 gene expression in a paracrine manner; S100A8/A9 expression is required for IL-1α-mediated resistance to Listeria invasion, as shRNA knockdown of S100A8/A9 abrogated this protection. Conditioned medium transfer, IL-1R antagonist blocking, shRNA knockdown of S100A8/A9, intracellular bacterial invasion assay Mucosal immunology Medium 22031183
2023 Ponatinib (tyrosine kinase inhibitor) activates the S100A8/A9-TLR4-NLRP3-IL-1β signaling pathway in cardiac and systemic myeloid cells, leading to myocardial inflammation and dysfunction; specific inhibitors of S100A9 (paquinimod), NLRP3 (CY-09), or broad immunosuppression with dexamethasone nearly abolished ponatinib-induced cardiac dysfunction. RNA sequencing (unbiased), in vitro and in vivo pharmacological inhibition, multiple mouse models with cardiovascular comorbidities Circulation research Medium 36625265
2014 S100A8 and S100A9 homodimers (but not their heterodimeric complex) significantly upregulate chondrocyte ADAMTS1, ADAMTS4, ADAMTS5, MMP1, MMP3, and MMP13 gene expression, while decreasing collagen II and aggrecan mRNA, suggesting distinct functions of homodimer vs. heterodimer forms. qRT-PCR of primary ovine articular chondrocytes treated with recombinant homodimer vs. heterodimer forms Arthritis research & therapy Medium 20105291
2021 IL-17A and IL-17F strongly induce S100A8 and S100A9 expression during early maturation stages of primary keratinocytes; S100A9-deficient keratinocytes show no significant role for S100A8/A9 in their own maturation or inflammatory response, and keratinocytes are not target cells for the proinflammatory effects of S100A8/A9. Primary S100A9-/- keratinocyte cultures, cytokine stimulation, imiquimod murine psoriasis model, transcriptome analysis Frontiers in immunology Medium 33643287
2024 Cancer-cell-derived S100A8 binds CD147 receptor on cancer-associated fibroblasts (CAFs) and triggers the intracellular RhoA-ROCK-MLC2-MRTF-A signaling pathway, inducing CAF polarization and leading to chemoresistance in esophageal squamous-cell carcinoma; blocking the S100A8-CD147 pathway improved chemotherapy efficiency. Patient-derived xenografts (PDX), receptor identification (CD147), signaling pathway analysis (RhoA-ROCK-MLC2-MRTF-A), CAF co-culture and functional assays Cell reports. Medicine Medium 38776909

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 Oncogenic mechanisms of the Helicobacter pylori CagA protein. Nature reviews. Cancer 608 15343275
2006 S100A8 and S100A9 in inflammation and cancer. Biochemical pharmacology 588 16846592
2008 Transgenic expression of Helicobacter pylori CagA induces gastrointestinal and hematopoietic neoplasms in mouse. Proceedings of the National Academy of Sciences of the United States of America 459 18192401
2007 Helicobacter pylori CagA targets PAR1/MARK kinase to disrupt epithelial cell polarity. Nature 404 17507984
2016 S100A8/A9: From basic science to clinical application. Pharmacology & therapeutics 361 27492899
2020 Neutrophil-Derived S100A8/A9 Amplify Granulopoiesis After Myocardial Infarction. Circulation 260 31941367
1998 Novel insights into structure and function of MRP8 (S100A8) and MRP14 (S100A9). Biochimica et biophysica acta 233 9920411
2013 S100A8 and S100A9: DAMPs at the crossroads between innate immunity, traditional risk factors, and cardiovascular disease. Mediators of inflammation 222 24453429
2019 Molecular anatomy and pathogenic actions of Helicobacter pylori CagA that underpin gastric carcinogenesis. Cellular & molecular immunology 214 31804619
2018 Calprotectin (S100A8/S100A9): a key protein between inflammation and cancer. Inflammation research : official journal of the European Histamine Research Society ... [et al.] 202 30083975
2005 Helicobacter pylori CagA: a new paradigm for bacterial carcinogenesis. Cancer science 187 16367902
2011 S100A8 and S100A9 in cardiovascular biology and disease. Arteriosclerosis, thrombosis, and vascular biology 181 22095980
2012 Pro-inflammatory S100A8 and S100A9 proteins: self-assembly into multifunctional native and amyloid complexes. International journal of molecular sciences 175 22489132
2005 S100A8 and S100A9 in human arterial wall. Implications for atherogenesis. The Journal of biological chemistry 162 16216873
2020 S100A8/A9 regulates CD11b expression and neutrophil recruitment during chronic tuberculosis. The Journal of clinical investigation 118 32134742
2023 Roles of S100A8, S100A9 and S100A12 in infection, inflammation and immunity. Immunology 115 38013255
2000 IFN-gamma and TNF regulate macrophage expression of the chemotactic S100 protein S100A8. Journal of immunology (Baltimore, Md. : 1950) 107 10779802
1999 S100A8: emerging functions and regulation. Journal of leukocyte biology 104 10534107
2015 Proinflammatory Proteins S100A8/S100A9 Activate NK Cells via Interaction with RAGE. Journal of immunology (Baltimore, Md. : 1950) 100 25911757
2017 Subversion of host kinases: a key network in cellular signaling hijacked by Helicobacter pylori CagA. Molecular microbiology 96 28508421
2005 Regulation of S100A8 by glucocorticoids. Journal of immunology (Baltimore, Md. : 1950) 95 15699168
2008 S-nitrosylated S100A8: novel anti-inflammatory properties. Journal of immunology (Baltimore, Md. : 1950) 91 18832721
2009 S100A8/A9: a Janus-faced molecule in cancer therapy and tumorgenesis. European journal of pharmacology 86 19835859
2022 S100A8/A9 drives the formation of procoagulant platelets through GPIbα. Blood 83 36026606
2016 CagA-mediated pathogenesis of Helicobacter pylori. Microbial pathogenesis 81 26796299
2015 Secretion of S100A8, S100A9, and S100A12 by Neutrophils Involves Reactive Oxygen Species and Potassium Efflux. Journal of immunology research 80 27057553
2006 Helicobacter pylori CagA -- a bacterial intruder conspiring gastric carcinogenesis. International journal of cancer 80 16557568
2011 Oxidative modifications of DAMPs suppress inflammation: the case for S100A8 and S100A9. Antioxidants & redox signaling 75 20919939
2006 CagA protein of Helicobacter pylori: a hijacker of gastric epithelial cell signaling. Biochemical pharmacology 75 17134680
2009 S100A8/A9: a mediator of severe asthma pathogenesis and morbidity? Canadian journal of physiology and pharmacology 73 19898558
2019 S100A8 & S100A9: Alarmin mediated inflammation in tendinopathy. Scientific reports 71 30728384
2016 Platelet-Derived S100A8/A9 and Cardiovascular Disease in Systemic Lupus Erythematosus. Arthritis & rheumatology (Hoboken, N.J.) 71 26946461
2001 Il-10 up-regulates macrophage expression of the S100 protein S100A8. Journal of immunology (Baltimore, Md. : 1950) 71 11342660
2010 S100A8 and S100A9 in experimental osteoarthritis. Arthritis research & therapy 68 20105291
2012 Hypoxia and HIF-1 increase S100A8 and S100A9 expression in prostate cancer. International journal of cancer 62 22505354
2021 Interleukin 17 Promotes Expression of Alarmins S100A8 and S100A9 During the Inflammatory Response of Keratinocytes. Frontiers in immunology 61 33643287
2005 FGF-2, IL-1beta and TGF-beta regulate fibroblast expression of S100A8. The FEBS journal 61 15943814
2018 GIP regulates inflammation and body weight by restraining myeloid-cell-derived S100A8/A9. Nature metabolism 60 32694806
2022 Inhibition of S100A8/A9 ameliorates renal interstitial fibrosis in diabetic nephropathy. Metabolism: clinical and experimental 57 36521551
2011 S100A8 modulates mast cell function and suppresses eosinophil migration in acute asthma. Antioxidants & redox signaling 57 21142608
2014 Bacterial CagA protein induces degradation of p53 protein in a p14ARF-dependent manner. Gut 55 25080447
2023 Ponatinib Drives Cardiotoxicity by S100A8/A9-NLRP3-IL-1β Mediated Inflammation. Circulation research 54 36625265
2016 Identification of an S100A8 Receptor Neuroplastin-β and its Heterodimer Formation with EMMPRIN. The Journal of investigative dermatology 54 27388991
2014 S100A8 induces IL-10 and protects against acute lung injury. Journal of immunology (Baltimore, Md. : 1950) 54 24532576
2009 Mrp-8 and -14 mediate CNS injury in focal cerebral ischemia. Biochimica et biophysica acta 54 19835955
2007 S100A8/S100A9 and their association with cartilage and bone. Journal of molecular histology 54 17636430
2018 S100A8/A9 promotes parenchymal damage and renal fibrosis in obstructive nephropathy. Clinical and experimental immunology 53 29746703
2015 Inflammation-induced S100A8 activates Id3 and promotes colorectal tumorigenesis. International journal of cancer 52 26135667
2006 Up-regulation of S100A8 and S100A9 protein in bronchial epithelial cells by lipopolysaccharide. Experimental lung research 52 17090475
2020 Bacterial CagA protein compromises tumor suppressor mechanisms in gastric epithelial cells. The Journal of clinical investigation 49 32250340
2018 S100A8/A9 Drives Neuroinflammatory Priming and Protects against Anxiety-like Behavior after Sepsis. Journal of immunology (Baltimore, Md. : 1950) 49 29563178
2017 S100A8/A9 and S100A9 reduce acute lung injury. Immunology and cell biology 46 28074060
2021 S100A8/S100A9 cytokine acts as a transcriptional coactivator during breast cellular transformation. Science advances 45 33523865
2015 Visualized macrophage dynamics and significance of S100A8 in obese fat. Proceedings of the National Academy of Sciences of the United States of America 45 25848057
2010 The CagA protein of Helicobacter pylori suppresses the functions of dendritic cell in mice. Archives of biochemistry and biophysics 45 20363211
2006 The role of Helicobacter pylori CagA in gastric carcinogenesis. International journal of hematology 45 17118755
2015 Helicobacter pylori cagA Promoter Region Sequences Influence CagA Expression and Interleukin 8 Secretion. The Journal of infectious diseases 43 26401027
2010 Helicobacter pylori CagA protein polymorphisms and their lack of association with pathogenesis. World journal of gastroenterology 43 20712055
2019 Effect of S100A8 and S100A9 on expressions of cytokine and skin barrier protein in human keratinocytes. Molecular medicine reports 42 31322196
2007 Helicobacter pylori and CagA seropositivity and its association with gastric and oesophageal carcinoma. Scandinavian journal of gastroenterology 42 17613922
2023 MANF brakes TLR4 signaling by competitively binding S100A8 with S100A9 to regulate macrophage phenotypes in hepatic fibrosis. Acta pharmaceutica Sinica. B 41 37799387
2023 The functions and regulatory pathways of S100A8/A9 and its receptors in cancers. Frontiers in pharmacology 40 37701037
2013 TNFα- and IL-17A-mediated S100A8 expression is regulated by p38 MAPK. Experimental dermatology 39 23800059
2023 A review of signal pathway induced by virulent protein CagA of Helicobacter pylori. Frontiers in cellular and infection microbiology 38 37124036
2020 Proinflammatory S100A8 Induces PD-L1 Expression in Macrophages, Mediating Tumor Immune Escape. Journal of immunology (Baltimore, Md. : 1950) 38 32198140
2011 IL-1 receptor regulates S100A8/A9-dependent keratinocyte resistance to bacterial invasion. Mucosal immunology 38 22031183
2001 Assessment of Helicobacter pylori vacA and cagA genotypes and host serological response. Journal of clinical microbiology 38 11283053
2021 Hypoxia-Induced S100A8 Expression Activates Microglial Inflammation and Promotes Neuronal Apoptosis. International journal of molecular sciences 37 33530496
2022 S100A8 regulates autophagy-dependent ferroptosis in microglia after experimental subarachnoid hemorrhage. Experimental neurology 36 35870523
2022 Alarming and Calming: Opposing Roles of S100A8/S100A9 Dimers and Tetramers on Monocytes. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 36 36310133
2017 Significance of S100A8, S100A9 and calprotectin levels in bladder cancer. Scandinavian journal of clinical and laboratory investigation 36 28609200
2020 Deletion of S100a8 and S100a9 Enhances Skin Hyperplasia and Promotes the Th17 Response in Imiquimod-Induced Psoriasis. Journal of immunology (Baltimore, Md. : 1950) 35 33361205
2019 Neuroplastin-β mediates S100A8/A9-induced lung cancer disseminative progression. Molecular carcinogenesis 35 30720226
2014 S100A8 is a novel therapeutic target for anaplastic thyroid carcinoma. The Journal of clinical endocrinology and metabolism 34 25423568
2019 S100A8 facilitates cholangiocarcinoma metastasis via upregulation of VEGF through TLR4/NF‑κB pathway activation. International journal of oncology 33 31746424
2019 RETRACTED: CDX1 Expression Induced by CagA-Expressing Helicobacter pylori Promotes Gastric Tumorigenesis. Molecular cancer research : MCR 30 31416838
2016 Involvement of calprotectin (S100A8/A9) in molecular pathways associated with HNSCC. Oncotarget 30 26883112
2016 S100A8/A9 is associated with estrogen receptor loss in breast cancer. Oncology letters 30 26998104
2007 cagA gene and protein status among Iranian Helicobacter pylori strains. Digestive diseases and sciences 30 17939043
2022 C/EBPδ-induced epigenetic changes control the dynamic gene transcription of S100a8 and S100a9. eLife 29 35543413
2014 Inflammation and pancreatic cancer: molecular and functional interactions between S100A8, S100A9, NT-S100A8 and TGFβ1. Cell communication and signaling : CCS 29 24670043
2020 S100A8 and S100A9 Promote Apoptosis of Chronic Eosinophilic Leukemia Cells. Frontiers in immunology 28 32903598
2025 Helicobacter pylori CagA promotes gastric cancer immune escape by upregulating SQLE. Cell death & disease 26 39809787
2018 CagA increases DNA methylation and decreases PTEN expression in human gastric cancer. Molecular medicine reports 26 30431097
2011 Potentiation of Helicobacter pylori CagA protein virulence through homodimerization. The Journal of biological chemistry 26 21813645
1996 Mixed infection with cagA-positive and cagA-negative strains of Helicobacter pylori. Helicobacter 26 9398886
2023 S-100 Proteins: Basics and Applications as Biomarkers in Animals with Special Focus on Calgranulins (S100A8, A9, and A12). Biology 25 37372165
2016 Expressions of the CagA protein and CagA-signaling molecules predict Helicobacter pylori dependence of early-stage gastric DLBCL. Blood 24 27864293
2012 The distribution and expression of S100A8 and S100A9 in gingival epithelium of mice. Journal of periodontal research 24 22957762
2024 Alarmin S100A8 imparts chemoresistance of esophageal cancer by reprogramming cancer-associated fibroblasts. Cell reports. Medicine 23 38776909
2023 Deficiency of S100A8/A9 attenuates pulmonary microvascular leakage in septic mice. Respiratory research 23 37978525
2019 Helicobacter pylori inhibits GKN1 expression via the CagA/p-ERK/AUF1 pathway. Helicobacter 23 31657090
2001 Helicobacter pylori CagA: analysis of sequence diversity in relation to phosphorylation motifs and implications for the role of CagA as a virulence factor. Helicobacter 23 11683921
2024 S100A8-enriched microglia populate the brain of tau-seeded and accelerated aging mice. Aging cell 22 38403918
2023 Blockage of S100A8/A9 ameliorates septic nephropathy in mice. Frontiers in pharmacology 22 37547329
2020 The alarmins S100A8 and S100A9 mediate acute pain in experimental synovitis. Arthritis research & therapy 22 32854769
2018 Protein S100-A8: A potential metastasis-associated protein for breast cancer determined via iTRAQ quantitative proteomic and clinicopathological analysis. Oncology letters 21 29552168
2018 CagA and VacA genes of Helicobacter pylori and their clinical relevance. Indian journal of pathology & microbiology 21 29567886
2016 Crystal structure of human S100A8 in complex with zinc and calcium. BMC structural biology 21 27251136
2014 Association of increased S100A8 serum protein with early pregnancy loss. American journal of reproductive immunology (New York, N.Y. : 1989) 21 25252120

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