Affinage

S100A9

Protein S100-A9 · UniProt P06702

Length
114 aa
Mass
13.2 kDa
Annotated
2026-06-10
100 papers in source corpus 28 papers cited in narrative 28 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

S100A9 (MRP14) is a calcium- and zinc-binding S100-family protein that functions as a multifunctional alarmin coupling innate immune signaling, phagocyte cytoskeletal dynamics, and transcriptional regulation (PMID:17767165, PMID:15331440). It partners with S100A8 (MRP8) to form a heterodimer that acts as an endogenous TLR4-MD2 ligand, driving MyD88/IRAK-1/NF-κB activation and pro-inflammatory cytokine production (PMID:17767165, PMID:38308971); this TLR4 engagement underlies a broad spectrum of downstream outcomes including monocyte-to-MDSC conversion, AML cell differentiation, and an extracellular TLR4-NF-κB-mTORC1 axis in hepatic non-parenchymal cells that restrains ketogenesis (PMID:28137827, PMID:35840613, PMID:39266214). The quaternary state of the complex dictates receptor choice: dimers signal through TLR4 to promote inflammation, whereas calcium-induced tetramers bind CD69 to dampen monocyte adhesion and migration, and the protein additionally engages RAGE to drive NF-κB-JunB signaling (PMID:36310133, PMID:35411077). Intracellularly, S100A9 is phosphorylated by p38 MAPK as the regulatory subunit of the MRP8/MRP14 complex, controlling microtubule polymerization, Rac1/Cdc42 activation, and transendothelial migration of phagocytes (PMID:15331440, PMID:8558004), and it co-purifies with the NADPH oxidase machinery to enhance superoxide production via cytochrome b558 (PMID:12719414). S100A9 also traffics TLR3 from early to late endosomes, a step required for dsRNA responses (PMID:26385519). Beyond the cytosol, S100A9 enters the nucleus to function as a chromatin-associated transcriptional regulator, binding gene promoters including C3 and CD274/PD-L1 and acting with DNA-binding transcription factors to drive oncogenic and immunosuppressive transcription (PMID:24332034, PMID:33523865, PMID:38454445). Functionally it governs monocyte/macrophage phenotype switching through Nur77 and STAT6/PPARγ pathways, influencing efferocytosis and inflammation resolution (PMID:32434457, PMID:39107960), and its own expression is controlled transcriptionally by C/EBP factors with JMJD3-dependent H3K27me3 demethylation and post-transcriptionally via hnRNP E2/miRNA-328 (PMID:35543413, PMID:9717674, PMID:27573788).

Mechanistic history

Synthesis pass · year-by-year structured walk · 24 steps
  1. 1994 Medium

    Established that MRP8/MRP14 expression is governed transcriptionally and is sensitive to intracellular calcium, defining an early layer of expression control.

    Evidence Calcium ionophore/thapsigargin treatment with Northern blot and actinomycin/cycloheximide dissection in monocytes

    PMID:8053890

    Open questions at the time
    • Identity of the calcium-induced repressor protein not determined
    • Does not address protein-level function
  2. 1996 Medium

    Showed that MRP14 is phosphorylated and that phosphorylated isoforms translocate calcium-dependently toward membranes and cytoskeleton, positioning MRP14 as the regulatory subunit of the complex.

    Evidence Metabolic 32P labeling, 2D electrophoresis, differential centrifugation, and 45Ca2+ overlay in monocytes

    PMID:8558004

    Open questions at the time
    • Kinase responsible not identified at this stage
    • Functional consequence of translocation undefined here
  3. 1998 Medium

    Defined transcription factor control of MRP14 expression by showing C/EBPα enhances and v-myb represses the MRP14 promoter.

    Evidence Promoter-CAT co-transfection with C/EBPα and v-myb plus Northern blot in HL60 and L132 cells

    PMID:9717674

    Open questions at the time
    • No demonstration of direct C/EBPα binding to the promoter
    • In vivo relevance not tested
  4. 1999 Medium

    Biochemically characterized MRP14 metal-binding and structure, mapping zinc binding to the C-terminus and identifying an intramolecular disulfide bond.

    Evidence Recombinant protein, ESI/MS, oxidative refolding, and 65Zn2+ overlay with truncation analysis

    PMID:10049680

    Open questions at the time
    • Functional role of disulfide and Zn2+ binding in vivo not established
    • Murine protein only
  5. 1999 High

    Clarified specificity within the S100 family by showing S100A12 does not physically interact with S100A8/S100A9 despite shared calcium-dependent translocation.

    Evidence Chemical cross-linking, density gradient centrifugation, mass spectrometry, and yeast two-hybrid

    PMID:10464253

    Open questions at the time
    • Negative result; does not address other S100 partners
  6. 2003 High

    Linked S100A8/S100A9 to the oxidative burst by demonstrating it enhances NADPH oxidase activity through calcium-dependent interaction with cytochrome b558.

    Evidence Co-purification/MS from neutrophils, cell-free oxidase reconstitution, AFM, and B-lymphocyte co-transfection

    PMID:12719414

    Open questions at the time
    • Stoichiometry of the oxidase interaction not fully resolved
    • In vivo contribution to ROS production not quantified here
  7. 2004 High

    Defined the intracellular cytoskeletal role, showing MRP8/MRP14 promotes microtubule polymerization required for transendothelial migration and that p38-mediated MRP14 phosphorylation inhibits this, antagonized by S100A8/calcium.

    Evidence MRP14-/- mice, in vitro tubulin polymerization, phosphorylation studies, Rac1/Cdc42 assays, and in vivo wound healing

    PMID:15331440

    Open questions at the time
    • Direct molecular link between the complex and tubulin not structurally defined
    • How phosphorylation feeds into Rac1/Cdc42 not mechanistically resolved
  8. 2004 Medium

    Identified an extracellular growth-promoting activity by purifying S100A9 homodimer as a fibroblast growth-stimulating factor from inflammation exudate.

    Evidence Purification from carrageenan exudate, sequencing, and recombinant fibroblast proliferation assay

    PMID:15153104

    Open questions at the time
    • Receptor mediating proliferation not identified
    • Physiological significance versus heterodimer unclear
  9. 2006 Medium

    Showed the extracellular MRP8/MRP14 complex can trigger endothelial cell death via mitochondrial caspase-dependent and caspase-independent routes.

    Evidence Purified complex on microvascular endothelial cells with caspase assays, Bcl-2 overexpression, and DNA fragmentation/annexin V

    PMID:17095618

    Open questions at the time
    • Receptor/entry mechanism for cell-death induction unknown
    • In vivo relevance not tested
  10. 2007 High

    Established the central paradigm that the complex is an endogenous TLR4 ligand, with S100A8 the active component and S100A9 required to amplify endotoxin-driven inflammation.

    Evidence SPR, TLR4/CD14/MD2 HEK293 transfection, nonfunctional-TLR4 phagocytes, and Mrp8/Mrp14 KO mice in sepsis models

    PMID:17767165

    Open questions at the time
    • Structural basis of S100A8-TLR4 docking not resolved
    • S100A9's precise contribution beyond complex formation not isolated
  11. 2013 Medium

    Revealed an intranuclear function, showing S100A9 acts as a chromatin component binding the C3 promoter to modulate complement expression in skin inflammation.

    Evidence Proteomics of psoriatic epidermis, chromatin binding assay, and S100A9 KO psoriasis models

    PMID:24332034

    Open questions at the time
    • Sequence specificity and co-factors of chromatin binding undefined
    • How S100A9 enters/retains in the nucleus unknown
  12. 2015 High

    Defined an intracellular trafficking role by showing S100A9 is required for TLR3 movement from early to late endosomes for dsRNA sensing.

    Evidence S100A9-KO macrophages, reciprocal co-IP, endosomal colocalization microscopy, and in vivo polyIC

    PMID:26385519

    Open questions at the time
    • Mechanism by which S100A9 drives endosomal maturation unknown
    • Whether S100A8 participates not addressed
  13. 2015 Medium

    Characterized the secretion route, showing S100A9 release from neutrophils depends on ROS and ATP-sensitive K+ channels and is triggered by particulate/microbial stimuli but not fMLP.

    Evidence Human neutrophil stimulation with ROS inhibitors and K+ channel blockers, ELISA for secreted protein

    PMID:27057553

    Open questions at the time
    • Molecular machinery of unconventional secretion not identified
    • Single cell type tested
  14. 2016 Medium

    Uncovered post-transcriptional control via the UPF1–hnRNP E2–miRNA-328 axis regulating S100A9 splicing during monocytic differentiation.

    Evidence UPF1 knockdown, miRNA-328 gain/loss, hnRNP E2 binding-site analysis, and qRT-PCR

    PMID:27573788

    Open questions at the time
    • Direct demonstration of altered splicing isoforms limited
    • Generalizability beyond monocytic cells unclear
  15. 2017 Medium

    Demonstrated context-dependent S100A9-TLR4 signaling promotes AML cell differentiation through p38/ERK/JNK, and showed PML/RARα-PU.1 drive S100A9 expression with overexpression inducing APL apoptosis.

    Evidence Recombinant S100A9 on AML lines with TLR4 blockade and in vivo AML model; ChIP/reporter for PU.1 binding and apoptosis flow cytometry in NB4 cells

    PMID:28063140 PMID:28137827

    Open questions at the time
    • Reconciliation of pro-differentiation versus pro-apoptotic outcomes across contexts incomplete
    • Single-lab findings
  16. 2020 Medium

    Linked S100A9 to reparative macrophage programming by showing it upregulates Nur77 to drive Ly6Chi-to-Ly6Clo monocyte switching and efferocytosis after myocardial infarction.

    Evidence S100A9 blocker and S100A9-/- mice, in vitro stimulation, and Nur77 activity/expression assays

    PMID:32434457

    Open questions at the time
    • Receptor coupling S100A9 to Nur77 induction not defined
    • Direct versus indirect regulation of Nur77 unclear
  17. 2021 Medium

    Showed nuclear S100A8/S100A9 are recruited genome-wide to promoters/enhancers and act with transcription factors to drive oncogenic transcription in breast transformation.

    Evidence ChIP-seq, nuclear-extract co-IP with transcription factors, artificial promoter recruitment, and nuclear-specific expression constructs

    PMID:33523865

    Open questions at the time
    • Identity of the bridging transcription factors not fully defined
    • Mechanism of nuclear import unknown
  18. 2022 Medium

    Established that quaternary structure switches receptor usage: calcium-induced tetramers bind CD69 to limit inflammation while dimers signal through TLR4 to promote it.

    Evidence Dimer-versus-tetramer adhesion/migration/traction assays, CD69 binding, TLR4/CD69 inhibitors, and in vivo granuloma/dermatitis models

    PMID:36310133

    Open questions at the time
    • Structural details of CD69 engagement not resolved
    • What governs dimer/tetramer equilibrium in vivo unclear
  19. 2022 High

    Defined an extracellular metabolic role, with S100A9 activating a TLR4-NF-κB-mTORC1 axis in hepatic non-parenchymal cells to suppress diabetic ketogenesis insulin-independently.

    Evidence Cell-type-specific TLR4/TSC1 conditional KO mice, recombinant S100A9, mTORC1 assays, and ketone measurement in diabetic mice

    PMID:35840613

    Open questions at the time
    • How non-parenchymal mTORC1 activation restrains hepatocyte ketogenesis mechanistically incomplete
    • Endogenous source of S100A9 in this setting
  20. 2022 High

    Established the upstream epigenetic-transcriptional control of S100a8/S100a9 by C/EBPδ-directed JMJD3-dependent H3K27me3 demethylation, required for neutrophil recruitment.

    Evidence Genome-wide CRISPR screen, ChIP for C/EBPδ binding, H3K27me3 demethylation assays, and C/EBPδ KO lung inflammation model

    PMID:35543413

    Open questions at the time
    • Whether C/EBPδ and C/EBPα act redundantly not resolved
    • Tissue specificity of the JMJD3 mechanism unclear
  21. 2022 Medium

    Showed S100A9 signals through RAGE-NF-κB-JunB in brain metastases to mediate radiotherapy resistance, expanding its receptor repertoire beyond TLR4.

    Evidence In vivo WBRT-resistant brain metastasis models with genetic and pharmacological pathway targeting

    PMID:35411077

    Open questions at the time
    • Determinants of RAGE versus TLR4 engagement not defined
    • Direct S100A9-RAGE binding affinity not characterized
  22. 2023 Medium

    Identified MANF as a negative regulator that competitively binds S100A8 to block heterodimer formation and TLR4-NF-κB signaling in hepatic fibrosis.

    Evidence Co-IP of MANF with S100A8, heterodimer competition assay, myeloid-specific MANF KO mice, and macrophage transfusion rescue

    PMID:37799387

    Open questions at the time
    • Structural basis of MANF-S100A8 competition unresolved
    • Whether MANF affects S100A9 homodimer/other functions untested
  23. 2024 Medium

    Consolidated S100A9's pro-inflammatory and immunosuppressive roles: driving M1 polarization/NLRP3 via TLR4/MyD88/NF-κB, converting monocytes to MDSC-like cells via TLR4, and activating PD-L1 transcription by binding the CD274 promoter.

    Evidence S100A9-KO mice in ALI, recombinant S100A9 MDSC conversion with TLR4/RAGE inhibitors, and ChIP for CD274 promoter binding with T-cell suppression assays

    PMID:38308971 PMID:38454445 PMID:39266214

    Open questions at the time
    • How a single alarmin balances inflammatory versus immunosuppressive programs unresolved
    • Link between extracellular signaling and direct promoter binding mechanistically incomplete
  24. 2024 Medium

    Demonstrated that S100A9 restrains anti-inflammatory macrophage switching via STAT6/PPARγ after ischemic stroke, with inhibition promoting efferocytosis and resolution.

    Evidence S100A9 conditional KO mice, tMCAO model, transcriptomics, STAT6 inhibitor epistasis, and paquinimod treatment

    PMID:39107960

    Open questions at the time
    • Whether S100A9 acts directly upstream of STAT6 or indirectly unclear
    • Receptor coupling in microglia not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How S100A9 oligomeric state, post-translational modification, subcellular localization, and receptor choice are integrated into a unified decision logic governing its opposing pro- and anti-inflammatory outputs remains unresolved.
  • No structural model linking quaternary state to receptor selection across TLR4/RAGE/CD69
  • Mechanism of nuclear import and chromatin targeting undefined
  • Contradictory pro- versus anti-inflammatory roles not reconciled mechanistically

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 3 GO:0048018 receptor ligand activity 3 GO:0140110 transcription regulator activity 3 GO:0008092 cytoskeletal protein binding 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005576 extracellular region 2 GO:0005634 nucleus 2 GO:0005829 cytosol 2 GO:0005856 cytoskeleton 2 GO:0005886 plasma membrane 2 GO:0005768 endosome 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-168256 Immune System 4 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-5357801 Programmed Cell Death 2
Partners
CD69CYBBMANFMD2S100A8TGFB1TLR3TLR4
Complex memberships
NADPH oxidase cytosolic factor assemblyS100A8/S100A9 (calprotectin) heterodimer

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 Mrp8 (S100A8) is the active component of the Mrp8/Mrp14 (S100A8/S100A9) complex that directly interacts with the TLR4-MD2 complex (demonstrated by surface plasmon resonance and HEK293 cells transfected with TLR4/CD14/MD2), acting as an endogenous TLR4 ligand. This interaction induces intracellular translocation of MyD88 and activation of IRAK-1 and NF-κB, resulting in elevated TNF-α expression. S100A9 is required as part of the heterodimeric complex to amplify endotoxin-triggered inflammatory responses. Surface plasmon resonance, HEK293 transfection with TLR4/CD14/MD2, phagocytes expressing nonfunctional TLR4, Mrp8/Mrp14 knockout mice Nature medicine High 17767165
2004 MRP14 (S100A9), in complex with MRP8 (S100A8), promotes polymerization of microtubules in phagocytes, which is required for transendothelial migration. MRP14 is specifically phosphorylated by p38 MAPK, and this phosphorylation inhibits MRP8/MRP14-induced tubulin polymerization. Phosphorylation of MRP14 is antagonistically regulated by binding of MRP8 and calcium. MRP14-/- granulocytes contain significantly less polymerized tubulin and show reduced activation of Rac1 and Cdc42 after p38 MAPK stimulation, leading to impaired migration. Targeted gene disruption (MRP14-/- mice), in vitro tubulin polymerization assays, phosphorylation studies, Rac1/Cdc42 activation assays, wound healing in vivo model Blood High 15331440
2013 S100A9 functions as a chromatin component that modulates C3 (complement factor) expression by binding to a region upstream of the C3 transcription start site in mouse and human cells. Genetic deletion of S100A9 in mouse models of psoriasis-like skin inflammation reduced C3 levels and attenuated disease. Proteomic analysis of human psoriatic epidermis, chromatin binding assay (S100A9 binding to C3 promoter region), S100A9 genetic knockout mouse models Immunity Medium 24332034
1996 MRP14 (S100A9) exists as phosphorylated isoforms in monocytes. Phosphorylated MRP14 isoforms show preferential Ca2+-dependent translocation from cytosol toward membranes and cytoskeleton compared to non-phosphorylated forms. Phosphorylated MRP14 shows increased Ca2+ binding, suggesting MRP14 is the regulatory subunit of MRP8/MRP14 complexes. Metabolic labeling with [32P]orthophosphate, 2D electrophoresis, differential centrifugation, 45Ca2+ overlay, isoelectric focusing Journal of immunology Medium 8558004
2003 MRP8/MRP14 (S100A8/S100A9) co-purifies with NADPH oxidase cytosolic factors from neutrophils. The heterodimer enhances oxidase activity by increasing the affinity of p67phox for cytochrome b558 synergistically with p47phox, and initiates oxidase activation through a calcium-dependent specific interaction with cytochrome b558, as shown by atomic force microscopy. Co-purification from neutrophils on anti-p47phox matrix with MS identification, semi-recombinant cell-free oxidase assay, atomic force microscopy, co-transfection of EBV-immortalized B lymphocytes The Journal of biological chemistry High 12719414
2015 Intracellular S100A9 is required for TLR3 trafficking from early endosomes (EE) to late endosomes (LE), a step necessary for TLR3 to encounter and respond to dsRNA agonists. S100A9 colocalizes and physically interacts with TLR3 following polyIC treatment. In S100A9-KO macrophages, TLR3 cannot be detected in late endosomes and fails to colocalize with its agonist, resulting in drastically reduced cytokine production in vitro and in vivo. S100A9-KO primary macrophages, co-immunoprecipitation of S100A9 with TLR3, colocalization microscopy of TLR3 in endosomal compartments, polyIC stimulation assays, S100A9-KO mice in vivo Journal of immunology High 26385519
2017 S100A9 binding to TLR4 on AML cells promotes activation of p38 MAPK, ERK1/2, and JNK signaling pathways, leading to myelomonocytic and monocytic AML cell differentiation. This was demonstrated using recombinant S100A9 in vitro and in an AML mouse model in vivo. Recombinant S100A9 treatment of AML cell lines, TLR4 blocking/knockout, phospho-kinase assays, in vivo AML mouse model, flow cytometry for differentiation markers Blood Medium 28137827
2006 MRP8/MRP14 (S100A8/S100A9) complex triggers endothelial cell death via both caspase-dependent and caspase-independent mechanisms. MRP8/MRP14 induces caspase-9 and caspase-3 activation, DNA fragmentation, and phosphatidylserine exposure independent of death receptor signaling, partly controlled by a mitochondrial pathway. Overexpression of Bcl-2 abrogated caspase activation but did not prevent plasma membrane damage or DNA fragmentation. Purified MRP8/MRP14 treatment of human microvascular endothelial cells, caspase activation assays, Bcl-2 overexpression, DNA fragmentation assay, annexin V staining Blood Medium 17095618
2022 S100A8/S100A9 dimers activate TLR4, but extracellular calcium induces formation of S100A8/S100A9 tetramers that prevent TLR4 binding and instead interact with CD69 on monocytes. S100A8/S100A9 tetramers dampen monocyte adhesion, migration, and traction force generation in vitro and limit monocyte immigration in vivo. These opposing effects are mediated by distinct receptors depending on quaternary structure: dimers signal via TLR4 to promote inflammation, tetramers signal via CD69 to limit inflammation. In vitro adhesion/migration/traction force assays with dimers vs. tetramers, CD69 binding studies, TLR4 and CD69 inhibitors, in vivo granuloma and contact dermatitis models Advanced science Medium 36310133
2020 S100A9 upregulates the levels and activity of the transcription factor Nur77 (Nr4a1) in monocytes and macrophages, facilitating the transition from inflammatory Ly6Chi monocytes to reparatory Ly6Clo macrophages. S100A9 blockade antagonizes Nur77 activity and impairs monocyte phenotype switching and efficient efferocytosis after myocardial infarction. S100A9 blocker (ABR-238901) in vivo treatment, S100A9-/- mice, in vitro monocyte/macrophage stimulation with S100A9, Nur77 activity and expression assays, flow cytometry for Ly6C markers Circulation research Medium 32434457
2021 S100A8 and S100A9 are recruited to numerous gene promoters and enhancers in breast cellular transformation. Nuclear S100A8/S100A9 interact with DNA-binding transcription factors in nuclear extracts and activate transcription when artificially recruited to a target promoter. Nuclear-specific expression of S100A8/S100A9 promotes oncogenic transcription and enhances breast transformation phenotype. ChIP-seq, nuclear extract co-immunoprecipitation with transcription factors, artificial promoter recruitment assay, nuclear-specific expression constructs, breast transformation phenotype assays Science advances Medium 33523865
2023 MANF (mesencephalic astrocyte-derived neurotrophic factor) competitively binds S100A8, blocking S100A8/S100A9 heterodimer formation and thereby inhibiting S100A8/S100A9-mediated TLR4-NF-κB signal activation in macrophages. This was demonstrated mechanistically in hepatic fibrosis. Co-immunoprecipitation of MANF with S100A8, competition assay for S100A8/S100A9 heterodimer formation, TLR4-NF-κB pathway assays, myeloid-specific MANF KO mice, macrophage transfusion rescue experiments Acta pharmaceutica Sinica. B Medium 37799387
2022 The transcription factor C/EBPδ is a central regulator of S100a8 and S100a9 expression. C/EBPδ binds specific sites within S100a8 and S100a9 promoter regions and mediates JMJD3-dependent demethylation of H3K27me3, which is required for their expression. C/EBPδ KO mice show decreased S100A8/A9 expression and reduced neutrophil recruitment in acute lung inflammation. Genome-wide CRISPR/Cas9 KO screen, ChIP for C/EBPδ binding sites in S100a8/S100a9 promoters, H3K27me3 demethylation assays, C/EBPδ KO mouse model of acute lung inflammation eLife High 35543413
1998 C/EBPα transcription factor strongly enhances MRP14 (S100A9) promoter activity when co-transfected with MRP14 promoter-CAT constructs in HL60 cells and L132 fibroblasts. v-myb reduces MRP14 promoter activity. Northern blot analysis confirmed C/EBPα is sufficient to enhance MRP14 expression. Co-transfection of MRP14 promoter-CAT constructs with C/EBPα and v-myb expression constructs, Northern blot analysis Immunobiology Medium 9717674
1994 MRP8/MRP14 (S100A8/S100A9) expression in monocytes is regulated at the transcriptional level. Elevation of intracellular calcium by A23187 or thapsigargin leads to specific down-regulation of MRP8/MRP14 mRNA. This suppressive effect is mediated by decreased mRNA synthesis (not increased degradation), and is antagonized by cycloheximide, indicating that a calcium-induced repressor protein mediates the transcriptional suppression. Western blot, metabolic labeling, Northern blot, calcium ionophore (A23187) and thapsigargin treatment, actinomycin D and cycloheximide co-treatment experiments The Biochemical journal Medium 8053890
1999 S100A12 does not directly interact with MRP8 (S100A8) or MRP14 (S100A9), or their heterodimer, as shown by chemical cross-linking, density gradient centrifugation, mass spectrometric measurements, and yeast two-hybrid detection. S100A12, MRP8, and MRP14 translocate simultaneously to cytoskeletal and membrane structures in a calcium-dependent manner, but act as independent proteins. Chemical cross-linking, density gradient centrifugation, mass spectrometry, yeast two-hybrid, calcium overlays, Western blotting, flow cytometry The Journal of biological chemistry High 10464253
2016 UPF1 regulates S100A9 expression in monocytic cells via hnRNP E2. During monocytic differentiation, miRNA-328 is induced and acts as a decoy for hnRNP E2, relieving hnRNP E2-mediated splicing repression of S100A9 mRNA (which contains an hnRNP E2 binding site within a 5' UTR intron), resulting in S100A9 upregulation. UPF1 knockdown in monocytic cells, hnRNP E2 binding site analysis, miRNA-328 overexpression/inhibition, qRT-PCR for S100A9 expression, monocytic differentiation assays Scientific reports Medium 27573788
1999 Murine MRP14 (S100A9) contains an intramolecular disulfide bond between Cys79 and Cys90. Zinc (Zn2+) binding requires the C-terminal domain, as a truncated form lacking the C-terminus (MRP14 1-102) binds substantially less 65Zn2+ compared to full-length MRP14. Recombinant protein expression, ESI/MS, C4 reverse-phase HPLC, oxidative refolding, 65Zn2+ overlay assay on PVDF membrane Protein expression and purification Medium 10049680
2022 S100A9 activates the TLR4-NF-κB-mTORC1 axis in hepatic non-parenchymal cells to suppress diabetic ketogenesis in an insulin-independent manner. Mechanistically, S100A9 acts extracellularly to activate mTORC1 in a TLR4-dependent manner in non-parenchymal liver cells (not hepatocytes). Recombinant S100A9 administration restrains ketogenesis and improves hyperglycemia in diabetic mice. Cell-type specific TLR4 and TSC1 conditional knockout mice, recombinant S100A9 administration, mTORC1 activity assays, hyperketonemia measurement in diabetic mice Nature communications High 35840613
2024 S100A9 activates PD-L1 transcription in monocytes by directly binding to the CD274 (PD-L1) gene promoter. This promotes immunosuppression via the PD-1/PD-L1 axis, suppressing T-cell proliferation and cytotoxicity, contributing to ICB resistance in hepatocellular carcinoma. ChIP assay demonstrating S100A9 binding to CD274 promoter, T-cell proliferation/cytotoxicity assays, S100A9 inhibitor treatment in vitro and in vivo, scRNA-seq Journal of experimental & clinical cancer research Medium 38454445
2004 S100A9 (as a disulfide-linked homodimer) was purified as a fibroblast growth-stimulating factor from carrageenan-induced inflammation exudate in rats. Recombinant S100A9 and its disulfide-linked homodimer stimulate proliferation of fibroblasts at similar concentrations to the purified native protein. Protein purification from carrageenan exudate, amino acid sequence analysis, recombinant S100A9 production, fibroblast proliferation assay, immunoblot quantification European journal of biochemistry Medium 15153104
2015 S100A9 secretion from neutrophils is dependent on production of reactive oxygen species (ROS) and requires K+ exchange through ATP-sensitive K+ channels. Secretion of S100A9 is induced by particulate molecules (MSU crystals, nanoparticles), microbe-derived molecules (zymosan), and PMA/H2O2, but not by chemotactic factor fMLP. Human neutrophil stimulation with various agents, ROS inhibitors, K+ channel blockers, ELISA for secreted S100A9, S100A8, and S100A12 Journal of immunology research Medium 27057553
2024 S100A9-gene deficiency inhibits macrophage M1 polarization and reduces pulmonary macrophage chemotactic factors and inflammatory cytokines by suppressing the TLR4/MyD88/NF-κB signaling pathway and reversing expression of the NLRP3 pyroptosis pathway in LPS-induced acute lung injury. S100A9-KO mice, LPS-induced ALI model, in vitro macrophage stimulation, TLR4/MyD88/NF-κB pathway assays, NLRP3 pathway assays, flow cytometry for M1 markers Biomedicine & pharmacotherapy Medium 38308971
2024 S100A9 deletion in microglia/macrophages promotes anti-inflammatory phenotype switching and efferocytosis after ischemic stroke via the STAT6/PPARγ pathway. STAT6 phosphorylation inhibitor (AS1517499) abrogates the beneficial effects of S100A9 inhibition, placing STAT6/PPARγ as downstream targets of S100A9 in macrophage polarization. S100A9 conditional KO mice, tMCAO stroke model, transcriptomic analysis, STAT6 phosphorylation inhibitor AS1517499, in vitro macrophage stimulation, paquinimod S100A9 inhibitor CNS neuroscience & therapeutics Medium 39107960
2024 S100A9 and HMGB1 convert healthy donor-derived monocytes into MDSC-like cells through TLR4 signaling. S100A9-mediated conversion to immunosuppressive MDSCs is blocked by TLR4 inhibitors. In vitro monocyte-to-MDSC conversion assay with recombinant S100A9, TLR4 and RAGE inhibitors, T-cell proliferation inhibition assay, scRNA-seq of patient monocytes Journal for immunotherapy of cancer Medium 39266214
2017 PML/RARα and PU.1 are required for ATRA-induced expression of S100A9 in APL cells. PU.1 directly binds to the S100A9 promoter (particularly after ATRA treatment in NB4 cells) and promotes its activity. Overexpression of S100A9 induces apoptosis of NB4 APL cells. ChIP-based PCR demonstrating PU.1 binding to S100A9 promoter, dual-luciferase reporter assay for promoter activity, PML/RARα expression/knockdown, S100A9 overexpression with flow cytometry for apoptosis Frontiers of medicine Medium 28063140
2014 S100A9 forms heterodimers with TGFβ1 (demonstrated by MALDI-TOF/MS and co-immunoprecipitation), and this complex formation is the molecular mechanism underlying the reciprocal antagonism of S100A9 and TGFβ1 on PDAC cell signaling, intracellular calcium, and epithelial-to-mesenchymal transition. MALDI-TOF/MS, co-immunoprecipitation of S100A9 with TGFβ1, NF-κB/Akt/mTOR pathway assays, calcium imaging, EMT marker expression Cell communication and signaling Medium 24670043
2022 S100A9 activates the RAGE-NF-κB-JunB pathway in brain metastases, mediating resistance to whole-brain radiotherapy (WBRT). Targeting this pathway genetically or pharmacologically reverted WBRT resistance in vivo. In vivo brain metastasis models resistant to WBRT, genetic and pharmacological targeting of S100A9-RAGE-NF-κB-JunB pathway, tumor radiotherapy response assays Nature medicine Medium 35411077

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 Mrp8 and Mrp14 are endogenous activators of Toll-like receptor 4, promoting lethal, endotoxin-induced shock. Nature medicine 1153 17767165
2006 S100A8 and S100A9 in inflammation and cancer. Biochemical pharmacology 588 16846592
2004 MRP8 and MRP14 control microtubule reorganization during transendothelial migration of phagocytes. Blood 298 15331440
1989 Physical and genetic map of the major nif gene cluster from Azotobacter vinelandii. Journal of bacteriology 268 2644218
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
2013 S100A8-S100A9 protein complex mediates psoriasis by regulating the expression of complement factor C3. Immunity 216 24332034
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
2020 S100A9 Links Inflammation and Repair in Myocardial Infarction. Circulation research 184 32434457
2011 S100A8 and S100A9 in cardiovascular biology and disease. Arteriosclerosis, thrombosis, and vascular biology 181 22095980
1999 S100A12 is expressed exclusively by granulocytes and acts independently from MRP8 and MRP14. The Journal of biological chemistry 177 10464253
2012 Pro-inflammatory S100A8 and S100A9 proteins: self-assembly into multifunctional native and amyloid complexes. International journal of molecular sciences 175 22489132
2012 Review of S100A9 biology and its role in cancer. Biochimica et biophysica acta 155 23123827
2006 MRP8/MRP14 impairs endothelial integrity and induces a caspase-dependent and -independent cell death program. Blood 126 17095618
2017 S100A9 induces differentiation of acute myeloid leukemia cells through TLR4. Blood 117 28137827
2023 Roles of S100A8, S100A9 and S100A12 in infection, inflammation and immunity. Immunology 115 38013255
2013 Robust shifts in S100a9 expression with aging: a novel mechanism for chronic inflammation. Scientific reports 108 23386971
2019 Antiangiogenic VEGF165b Regulates Macrophage Polarization via S100A8/S100A9 in Peripheral Artery Disease. Circulation 107 30586702
2022 From bench to bedside: Calprotectin (S100A8/S100A9) as a biomarker in rheumatoid arthritis. Frontiers in immunology 89 36405711
2022 Stratification of radiosensitive brain metastases based on an actionable S100A9/RAGE resistance mechanism. Nature medicine 82 35411077
1996 Phosphorylation of MRP14, an S100 protein expressed during monocytic differentiation, modulates Ca(2+)-dependent translocation from cytoplasm to membranes and cytoskeleton. Journal of immunology (Baltimore, Md. : 1950) 81 8558004
2015 Secretion of S100A8, S100A9, and S100A12 by Neutrophils Involves Reactive Oxygen Species and Potassium Efflux. Journal of immunology research 80 27057553
1994 Expression and complex formation of S100-like proteins MRP8 and MRP14 by macrophages during renal allograft rejection. Transplantation 77 7519798
2019 S100A8 & S100A9: Alarmin mediated inflammation in tendinopathy. Scientific reports 71 30728384
2014 Challenges to develop nitrogen-fixing cereals by direct nif-gene transfer. Plant science : an international journal of experimental plant biology 71 25017168
2003 Expression of calcium-binding proteins MRP8 and MRP14 in inflammatory muscle diseases. The American journal of pathology 71 12937135
2003 Changing the conformation state of cytochrome b558 initiates NADPH oxidase activation: MRP8/MRP14 regulation. The Journal of biological chemistry 70 12719414
2012 Mrp14 deficiency ameliorates amyloid β burden by increasing microglial phagocytosis and modulation of amyloid precursor protein processing. The Journal of neuroscience : the official journal of the Society for Neuroscience 68 23223301
2010 S100A8 and S100A9 in experimental osteoarthritis. Arthritis research & therapy 68 20105291
1998 Widespread expression of MRP8 and MRP14 in human cerebral malaria by microglial cells. Acta neuropathologica 68 9845287
2005 Expression patterns of S100A7 (psoriasin) and S100A9 (calgranulin-B) in keratinocyte differentiation. Experimental dermatology 66 15740587
2001 Immunohistochemical investigation of S100A9 expression in pulmonary adenocarcinoma: S100A9 expression is associated with tumor differentiation. Oncology reports 65 11295086
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
1999 Genetic and molecular analysis of cglB, a gene essential for single-cell gliding in Myxococcus xanthus. Journal of bacteriology 61 10400597
1993 Expression and complex assembly of calcium-binding proteins MRP8 and MRP14 during differentiation of murine myelomonocytic cells. Journal of leukocyte biology 60 7678846
2003 Expression of MRP8 and MRP14 by macrophages is a marker for severe forms of glomerulonephritis. Journal of leukocyte biology 57 14597726
2007 S100A8/S100A9 and their association with cartilage and bone. Journal of molecular histology 54 17636430
2020 Epigenetic Regulation of S100A9 and S100A12 Expression in Monocyte-Macrophage System in Hyperglycemic Conditions. Frontiers in immunology 53 32582175
2024 S100A9-/- alleviates LPS-induced acute lung injury by regulating M1 macrophage polarization and inhibiting pyroptosis via the TLR4/MyD88/NFκB signaling axis. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 52 38308971
2014 Injury-induced MRP8/MRP14 stimulates IP-10/CXCL10 in monocytes/macrophages. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 52 25342131
2006 Up-regulation of S100A8 and S100A9 protein in bronchial epithelial cells by lipopolysaccharide. Experimental lung research 52 17090475
1999 The regulatory role of MRP8 (S100A8) and MRP14 (S100A9) in the transendothelial migration of human leukocytes. Pathobiology : journal of immunopathology, molecular and cellular biology 52 10725790
1994 The monoclonal antibody MAC387 detects an epitope on the calcium-binding protein MRP14. Journal of leukocyte biology 51 7507970
1994 Expression of the calcium-binding proteins MRP8 and MRP14 in monocytes is regulated by a calcium-induced suppressor mechanism. The Biochemical journal 48 8053890
1992 The calcium binding proteins MRP8 and MRP14 in acute and chronic inflammation. Behring Institute Mitteilungen 47 1524561
2017 S100A8/A9 and S100A9 reduce acute lung injury. Immunology and cell biology 46 28074060
2012 The role of S100a9 in the pathogenesis of Alzheimer's disease: the therapeutic effects of S100a9 knockdown or knockout. Neuro-degenerative diseases 46 22301734
2021 S100A8/S100A9 cytokine acts as a transcriptional coactivator during breast cellular transformation. Science advances 45 33523865
2021 S100A9 blockade prevents lipopolysaccharide-induced lung injury via suppressing the NLRP3 pathway. Respiratory research 45 33549095
2021 S100A9 in adult asthmatic patients: a biomarker for neutrophilic asthma. Experimental & molecular medicine 44 34285336
1998 Copurification of P6, MRP8, and MRP14 from human granulocytes and separation of individual proteins. Protein expression and purification 42 9693055
2023 MANF brakes TLR4 signaling by competitively binding S100A8 with S100A9 to regulate macrophage phenotypes in hepatic fibrosis. Acta pharmaceutica Sinica. B 41 37799387
2024 S100A9 and HMGB1 orchestrate MDSC-mediated immunosuppression in melanoma through TLR4 signaling. Journal for immunotherapy of cancer 36 39266214
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
2015 Regulation of TLR3 Activation by S100A9. Journal of immunology (Baltimore, Md. : 1950) 34 26385519
2004 Fibroblast growth-stimulating activity of S100A9 (MRP-14). European journal of biochemistry 34 15153104
2011 Calgranulin B (S100A9/MRP14): a key molecule in idiopathic pulmonary fibrosis? Inflammation 31 20422274
2004 Expression of MRP14 gene is frequently down-regulated in Chinese human esophageal cancer. Cell research 31 15040889
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
2003 Interleukin-10 influences the expression of MRP8 and MRP14 in human dendritic cells. International archives of allergy and immunology 28 14555857
2019 Galectin-3 and S100A9: Novel Diabetogenic Factors Mediating Pancreatic Cancer-Associated Diabetes. Diabetes care 26 31262951
2024 S100A9 deletion in microglia/macrophages ameliorates brain injury through the STAT6/PPARγ pathway in ischemic stroke. CNS neuroscience & therapeutics 25 39107960
2023 Viral nanoparticle vaccines against S100A9 reduce lung tumor seeding and metastasis. Proceedings of the National Academy of Sciences of the United States of America 24 37844250
2016 Neutrophils and the S100A9 protein critically regulate granuloma formation. Blood advances 24 29296934
2012 The distribution and expression of S100A8 and S100A9 in gingival epithelium of mice. Journal of periodontal research 24 22957762
2020 Transfer of Nitrogen Fixation (nif) Genes to Non-diazotrophic Hosts. Chembiochem : a European journal of chemical biology 23 32009294
2020 The alarmins S100A8 and S100A9 mediate acute pain in experimental synovitis. Arthritis research & therapy 22 32854769
2017 Enhanced S100A9 and S100A12 expression in acute coronary syndrome. Biomarkers in medicine 22 28157385
2015 S100A9 as a Pharmacological Target Molecule in Inflammation and Cancer. Endocrine, metabolic & immune disorders drug targets 22 25772177
2000 MRP8/MRP14, CD11b and HLA-DR expression of alveolar macrophages in pneumonia. Immunology letters 22 10722871
1998 The transcription factors c-myb and C/EBP alpha regulate the monocytic/myeloic gene MRP14. Immunobiology 22 9717674
1999 Accumulation of MAC387+ macrophages in paracortical areas of lymph nodes in rhesus monkeys acutely infected with simian immunodeficiency virus. Microbes and infection 21 10617929
2023 S100A8 and S100A9 in Hematologic Malignancies: From Development to Therapy. International journal of molecular sciences 20 37686186
2021 S100A9 Alters the Pathway of Alpha-Synuclein Amyloid Aggregation. International journal of molecular sciences 20 34360737
2013 Immunohistochemical expression of RAGE and its ligand (S100A9) in cervical lesions. Cell biochemistry and biophysics 20 23340902
2023 Emerging targets for cancer treatment: S100A9/RAGE. ESMO open 19 36652782
2023 Unmasking of the von Willebrand A-domain surface adhesin CglB at bacterial focal adhesions mediates myxobacterial gliding motility. Science advances 19 36812310
2022 Hepatic non-parenchymal S100A9-TLR4-mTORC1 axis normalizes diabetic ketogenesis. Nature communications 19 35840613
2016 UPF1 regulates myeloid cell functions and S100A9 expression by the hnRNP E2/miRNA-328 balance. Scientific reports 18 27573788
2010 Porcine S100A8 and S100A9: molecular characterizations and crucial functions in response to Haemophilus parasuis infection. Developmental and comparative immunology 17 21185856
2003 The time-dependent expression of fibronectin, MRP8, MRP14 and defensin in surgically treated human skin wounds. Forensic science international 17 12590055
1999 Overexpression, oxidative refolding, and zinc binding of recombinant forms of the murine S100 protein MRP14 (S100A9). Protein expression and purification 17 10049680
2024 S100A9+CD14+ monocytes contribute to anti-PD-1 immunotherapy resistance in advanced hepatocellular carcinoma by attenuating T cell-mediated antitumor function. Journal of experimental & clinical cancer research : CR 16 38454445
2020 Elevated S100A9 expression in chronic rhinosinusitis coincides with elevated MMP production and proliferation in vitro. Scientific reports 16 33005006
2012 S100A9 and tumor growth. Oncoimmunology 15 23243608
2024 S100A9 aggravates early brain injury after subarachnoid hemorrhage via inducing neuroinflammation and inflammasome activation. iScience 14 38420589
2024 Advances in the study of S100A9 in cardiovascular diseases. Cell proliferation 14 38504474
2023 Inhibition of S100A9 alleviates neurogenic pulmonary edema after subarachnoid hemorrhage. Biochemical pharmacology 14 37949322
2022 S100A9 promotes inflammatory response in diabetic nonalcoholic fatty liver disease. Biochemical and biophysical research communications 14 35717907
2017 Regulatory mechanism and functional analysis of S100A9 in acute promyelocytic leukemia cells. Frontiers of medicine 14 28063140
2006 S100A9-positive granulocytes and monocytes in lipopolysaccharide-induced anterior ocular inflammation. Experimental eye research 14 17101129
1995 Presence of MRP8 and MRP14 in pancreatic cell lines: differential expression and localization in CFPAC-1 cells. The American journal of physiology 14 7762618
2024 S100A9 exerts insulin-independent antidiabetic and anti-inflammatory effects. Science advances 13 38170783
2019 Clinical importance of S100A9 in osteosarcoma development and as a diagnostic marker and therapeutic target. Bioengineered 13 31055998
2019 Organization and regulation of cyanobacterial nif gene clusters: implications for nitrogenase expression in plant cells. FEMS microbiology letters 13 31062027

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