{"gene":"S100A9","run_date":"2026-06-10T07:46:28","timeline":{"discoveries":[{"year":2007,"finding":"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.","method":"Surface plasmon resonance, HEK293 transfection with TLR4/CD14/MD2, phagocytes expressing nonfunctional TLR4, Mrp8/Mrp14 knockout mice","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (SPR, cell transfection, genetic KO models), replicated across cell types, in vivo validation in two sepsis models","pmids":["17767165"],"is_preprint":false},{"year":2004,"finding":"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.","method":"Targeted gene disruption (MRP14-/- mice), in vitro tubulin polymerization assays, phosphorylation studies, Rac1/Cdc42 activation assays, wound healing in vivo model","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — genetic KO with defined molecular phenotype, in vitro reconstitution of tubulin polymerization, in vivo validation, multiple orthogonal readouts","pmids":["15331440"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Proteomic analysis of human psoriatic epidermis, chromatin binding assay (S100A9 binding to C3 promoter region), S100A9 genetic knockout mouse models","journal":"Immunity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct chromatin binding demonstrated, genetic KO with phenotypic readout, single lab with two orthogonal methods","pmids":["24332034"],"is_preprint":false},{"year":1996,"finding":"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.","method":"Metabolic labeling with [32P]orthophosphate, 2D electrophoresis, differential centrifugation, 45Ca2+ overlay, isoelectric focusing","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct biochemical fractionation and Ca2+ binding assays, single lab with multiple orthogonal methods","pmids":["8558004"],"is_preprint":false},{"year":2003,"finding":"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.","method":"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","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct protein interaction by multiple methods (co-purification/MS, AFM, cell-free reconstitution, cellular co-transfection), structure-function analysis","pmids":["12719414"],"is_preprint":false},{"year":2015,"finding":"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.","method":"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":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, KO with defined molecular defect in trafficking, colocalization microscopy, in vitro and in vivo validation","pmids":["26385519"],"is_preprint":false},{"year":2017,"finding":"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.","method":"Recombinant S100A9 treatment of AML cell lines, TLR4 blocking/knockout, phospho-kinase assays, in vivo AML mouse model, flow cytometry for differentiation markers","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — TLR4-mediated signaling pathway defined with receptor blocking, pathway activation confirmed by phospho-assays, in vivo validation, single lab","pmids":["28137827"],"is_preprint":false},{"year":2006,"finding":"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.","method":"Purified MRP8/MRP14 treatment of human microvascular endothelial cells, caspase activation assays, Bcl-2 overexpression, DNA fragmentation assay, annexin V staining","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined molecular mechanism with caspase assays and Bcl-2 rescue, single lab with multiple orthogonal methods","pmids":["17095618"],"is_preprint":false},{"year":2022,"finding":"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.","method":"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","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor-specific effects confirmed with inhibitors and distinct quaternary forms, in vitro and in vivo validation, single lab","pmids":["36310133"],"is_preprint":false},{"year":2020,"finding":"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.","method":"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","journal":"Circulation research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined Nur77 mechanistic pathway with both pharmacological inhibitor and genetic KO, in vitro and in vivo, single lab","pmids":["32434457"],"is_preprint":false},{"year":2021,"finding":"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.","method":"ChIP-seq, nuclear extract co-immunoprecipitation with transcription factors, artificial promoter recruitment assay, nuclear-specific expression constructs, breast transformation phenotype assays","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq, co-IP with transcription factors, functional rescue with nuclear-specific expression, single lab with multiple orthogonal methods","pmids":["33523865"],"is_preprint":false},{"year":2023,"finding":"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.","method":"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","journal":"Acta pharmaceutica Sinica. B","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP defining competitive interaction, genetic KO with defined phenotype, rescue by transfusion, single lab","pmids":["37799387"],"is_preprint":false},{"year":2022,"finding":"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.","method":"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","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — unbiased CRISPR screen plus direct ChIP validation, epigenetic mechanism with JMJD3, in vivo KO validation, multiple orthogonal methods","pmids":["35543413"],"is_preprint":false},{"year":1998,"finding":"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.","method":"Co-transfection of MRP14 promoter-CAT constructs with C/EBPα and v-myb expression constructs, Northern blot analysis","journal":"Immunobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter-reporter assay with defined transcription factors, mRNA confirmation by Northern blot, single lab","pmids":["9717674"],"is_preprint":false},{"year":1994,"finding":"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.","method":"Western blot, metabolic labeling, Northern blot, calcium ionophore (A23187) and thapsigargin treatment, actinomycin D and cycloheximide co-treatment experiments","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple pharmacological dissection experiments establishing transcriptional mechanism, Northern blot, single lab","pmids":["8053890"],"is_preprint":false},{"year":1999,"finding":"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.","method":"Chemical cross-linking, density gradient centrifugation, mass spectrometry, yeast two-hybrid, calcium overlays, Western blotting, flow cytometry","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — four independent methods all showing negative interaction between S100A12 and S100A9, rigorous multi-method study","pmids":["10464253"],"is_preprint":false},{"year":2016,"finding":"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.","method":"UPF1 knockdown in monocytic cells, hnRNP E2 binding site analysis, miRNA-328 overexpression/inhibition, qRT-PCR for S100A9 expression, monocytic differentiation assays","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined post-transcriptional mechanism with hnRNP E2 and miRNA-328 competition, functional rescue experiments, single lab","pmids":["27573788"],"is_preprint":false},{"year":1999,"finding":"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.","method":"Recombinant protein expression, ESI/MS, C4 reverse-phase HPLC, oxidative refolding, 65Zn2+ overlay assay on PVDF membrane","journal":"Protein expression and purification","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — direct biochemical characterization of disulfide and Zn2+ binding using recombinant protein and truncation analysis, single lab","pmids":["10049680"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Cell-type specific TLR4 and TSC1 conditional knockout mice, recombinant S100A9 administration, mTORC1 activity assays, hyperketonemia measurement in diabetic mice","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type specific genetic dissection with multiple KO lines, defined TLR4-mTORC1 pathway, pharmacological rescue with recombinant protein, in vivo validation","pmids":["35840613"],"is_preprint":false},{"year":2024,"finding":"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.","method":"ChIP assay demonstrating S100A9 binding to CD274 promoter, T-cell proliferation/cytotoxicity assays, S100A9 inhibitor treatment in vitro and in vivo, scRNA-seq","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter binding by ChIP, functional T-cell suppression assay, in vivo validation, single lab","pmids":["38454445"],"is_preprint":false},{"year":2004,"finding":"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.","method":"Protein purification from carrageenan exudate, amino acid sequence analysis, recombinant S100A9 production, fibroblast proliferation assay, immunoblot quantification","journal":"European journal of biochemistry","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — direct purification and identification, recombinant protein functional validation, single lab","pmids":["15153104"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Human neutrophil stimulation with various agents, ROS inhibitors, K+ channel blockers, ELISA for secreted S100A9, S100A8, and S100A12","journal":"Journal of immunology research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological dissection of secretion mechanism with defined inhibitors, multiple stimuli tested, single lab","pmids":["27057553"],"is_preprint":false},{"year":2024,"finding":"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.","method":"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","journal":"Biomedicine & pharmacotherapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with defined signaling pathway, in vitro and in vivo validation, single lab","pmids":["38308971"],"is_preprint":false},{"year":2024,"finding":"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.","method":"S100A9 conditional KO mice, tMCAO stroke model, transcriptomic analysis, STAT6 phosphorylation inhibitor AS1517499, in vitro macrophage stimulation, paquinimod S100A9 inhibitor","journal":"CNS neuroscience & therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with defined STAT6/PPARγ pathway, pharmacological inhibitor epistasis, in vitro and in vivo, single lab","pmids":["39107960"],"is_preprint":false},{"year":2024,"finding":"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.","method":"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":"Journal for immunotherapy of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined TLR4-dependent mechanism, pharmacological inhibitor blocking, functional T-cell assay, single lab","pmids":["39266214"],"is_preprint":false},{"year":2017,"finding":"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.","method":"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","journal":"Frontiers of medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter binding by ChIP, reporter assay, functional apoptosis readout, single lab","pmids":["28063140"],"is_preprint":false},{"year":2014,"finding":"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.","method":"MALDI-TOF/MS, co-immunoprecipitation of S100A9 with TGFβ1, NF-κB/Akt/mTOR pathway assays, calcium imaging, EMT marker expression","journal":"Cell communication and signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct physical interaction shown by MS and co-IP, functional consequences in signaling, single lab","pmids":["24670043"],"is_preprint":false},{"year":2022,"finding":"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.","method":"In vivo brain metastasis models resistant to WBRT, genetic and pharmacological targeting of S100A9-RAGE-NF-κB-JunB pathway, tumor radiotherapy response assays","journal":"Nature medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined signaling pathway with genetic and pharmacological validation in vivo, single lab, multiple model systems","pmids":["35411077"],"is_preprint":false}],"current_model":"S100A9 (MRP14) is a calcium- and zinc-binding S100-family protein that forms a heterodimer with S100A8 (MRP8); this dimer acts as an endogenous TLR4 ligand (via S100A8) that activates MyD88/IRAK-1/NF-κB and p38 MAPK signaling, while intracellularly S100A9 is phosphorylated by p38 MAPK to regulate MRP8/S100A9-dependent microtubule polymerization and phagocyte transendothelial migration, facilitates TLR3 trafficking from early to late endosomes, can enter the nucleus to modulate gene transcription (C3, PD-L1, and co-activator functions), and engages additional receptors including RAGE and CD69 depending on its oligomeric state, collectively placing it as a multifunctional alarmin that couples innate immune signaling, cytoskeletal dynamics, and transcriptional regulation."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":1994,"claim":"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","pmids":["8053890"],"confidence":"Medium","gaps":["Identity of the calcium-induced repressor protein not determined","Does not address protein-level function"]},{"year":1996,"claim":"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","pmids":["8558004"],"confidence":"Medium","gaps":["Kinase responsible not identified at this stage","Functional consequence of translocation undefined here"]},{"year":1998,"claim":"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","pmids":["9717674"],"confidence":"Medium","gaps":["No demonstration of direct C/EBPα binding to the promoter","In vivo relevance not tested"]},{"year":1999,"claim":"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","pmids":["10049680"],"confidence":"Medium","gaps":["Functional role of disulfide and Zn2+ binding in vivo not established","Murine protein only"]},{"year":1999,"claim":"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","pmids":["10464253"],"confidence":"High","gaps":["Negative result; does not address other S100 partners"]},{"year":2003,"claim":"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","pmids":["12719414"],"confidence":"High","gaps":["Stoichiometry of the oxidase interaction not fully resolved","In vivo contribution to ROS production not quantified here"]},{"year":2004,"claim":"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","pmids":["15331440"],"confidence":"High","gaps":["Direct molecular link between the complex and tubulin not structurally defined","How phosphorylation feeds into Rac1/Cdc42 not mechanistically resolved"]},{"year":2004,"claim":"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","pmids":["15153104"],"confidence":"Medium","gaps":["Receptor mediating proliferation not identified","Physiological significance versus heterodimer unclear"]},{"year":2006,"claim":"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","pmids":["17095618"],"confidence":"Medium","gaps":["Receptor/entry mechanism for cell-death induction unknown","In vivo relevance not tested"]},{"year":2007,"claim":"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","pmids":["17767165"],"confidence":"High","gaps":["Structural basis of S100A8-TLR4 docking not resolved","S100A9's precise contribution beyond complex formation not isolated"]},{"year":2013,"claim":"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","pmids":["24332034"],"confidence":"Medium","gaps":["Sequence specificity and co-factors of chromatin binding undefined","How S100A9 enters/retains in the nucleus unknown"]},{"year":2015,"claim":"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","pmids":["26385519"],"confidence":"High","gaps":["Mechanism by which S100A9 drives endosomal maturation unknown","Whether S100A8 participates not addressed"]},{"year":2015,"claim":"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","pmids":["27057553"],"confidence":"Medium","gaps":["Molecular machinery of unconventional secretion not identified","Single cell type tested"]},{"year":2016,"claim":"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","pmids":["27573788"],"confidence":"Medium","gaps":["Direct demonstration of altered splicing isoforms limited","Generalizability beyond monocytic cells unclear"]},{"year":2017,"claim":"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","pmids":["28137827","28063140"],"confidence":"Medium","gaps":["Reconciliation of pro-differentiation versus pro-apoptotic outcomes across contexts incomplete","Single-lab findings"]},{"year":2020,"claim":"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","pmids":["32434457"],"confidence":"Medium","gaps":["Receptor coupling S100A9 to Nur77 induction not defined","Direct versus indirect regulation of Nur77 unclear"]},{"year":2021,"claim":"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","pmids":["33523865"],"confidence":"Medium","gaps":["Identity of the bridging transcription factors not fully defined","Mechanism of nuclear import unknown"]},{"year":2022,"claim":"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","pmids":["36310133"],"confidence":"Medium","gaps":["Structural details of CD69 engagement not resolved","What governs dimer/tetramer equilibrium in vivo unclear"]},{"year":2022,"claim":"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","pmids":["35840613"],"confidence":"High","gaps":["How non-parenchymal mTORC1 activation restrains hepatocyte ketogenesis mechanistically incomplete","Endogenous source of S100A9 in this setting"]},{"year":2022,"claim":"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","pmids":["35543413"],"confidence":"High","gaps":["Whether C/EBPδ and C/EBPα act redundantly not resolved","Tissue specificity of the JMJD3 mechanism unclear"]},{"year":2022,"claim":"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","pmids":["35411077"],"confidence":"Medium","gaps":["Determinants of RAGE versus TLR4 engagement not defined","Direct S100A9-RAGE binding affinity not characterized"]},{"year":2023,"claim":"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","pmids":["37799387"],"confidence":"Medium","gaps":["Structural basis of MANF-S100A8 competition unresolved","Whether MANF affects S100A9 homodimer/other functions untested"]},{"year":2024,"claim":"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","pmids":["38308971","39266214","38454445"],"confidence":"Medium","gaps":["How a single alarmin balances inflammatory versus immunosuppressive programs unresolved","Link between extracellular signaling and direct promoter binding mechanistically incomplete"]},{"year":2024,"claim":"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","pmids":["39107960"],"confidence":"Medium","gaps":["Whether S100A9 acts directly upstream of STAT6 or indirectly unclear","Receptor coupling in microglia not defined"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Medium","gaps":["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":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[2,10,19]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[2,10,19]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,8,27]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[1,3]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4,11]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[3,4]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2,10]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[1,3]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[5]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[20,21]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,8]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,5,22,24]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,8,18,27]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[2,10,19]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[7,22]}],"complexes":["S100A8/S100A9 (calprotectin) heterodimer","NADPH oxidase cytosolic factor assembly"],"partners":["S100A8","TLR4","MD2","TLR3","CD69","TGFB1","MANF","CYBB"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P06702","full_name":"Protein S100-A9","aliases":["Calgranulin-B","Calprotectin L1H subunit","Leukocyte L1 complex heavy chain","Migration inhibitory factor-related protein 14","MRP-14","p14","S100 calcium-binding protein A9"],"length_aa":114,"mass_kda":13.2,"function":"S100A9 is a calcium- and zinc-binding protein which plays a prominent role in the regulation of inflammatory processes and immune response (PubMed:12626582, PubMed:15331440, PubMed:16258195, PubMed:19122197, PubMed:20103766, PubMed:21325622, PubMed:8423249). It can induce neutrophil chemotaxis, adhesion, can increase the bactericidal activity of neutrophils by promoting phagocytosis via activation of SYK, PI3K/AKT, and ERK1/2 and can induce degranulation of neutrophils by a MAPK-dependent mechanism (PubMed:12626582, PubMed:15331440, PubMed:20103766). Predominantly found as calprotectin (S100A8/A9) which has a wide plethora of intra- and extracellular functions (PubMed:16258195, PubMed:19122197, PubMed:8423249). The intracellular functions include: facilitating leukocyte arachidonic acid trafficking and metabolism, modulation of the tubulin-dependent cytoskeleton during migration of phagocytes and activation of the neutrophilic NADPH-oxidase (PubMed:15331440, PubMed:21325622). Also participates in regulatory T-cell differentiation together with CD69 (PubMed:26296369). Activates NADPH-oxidase by facilitating the enzyme complex assembly at the cell membrane, transferring arachidonic acid, an essential cofactor, to the enzyme complex and S100A8 contributes to the enzyme assembly by directly binding to NCF2/P67PHOX (PubMed:15642721, PubMed:22808130). The extracellular functions involve pro-inflammatory, antimicrobial, oxidant-scavenging and apoptosis-inducing activities (PubMed:19534726, PubMed:8423249). Its pro-inflammatory activity includes recruitment of leukocytes, promotion of cytokine and chemokine production, and regulation of leukocyte adhesion and migration (PubMed:15598812, PubMed:21487906). Acts as an alarmin or a danger associated molecular pattern (DAMP) molecule and stimulates innate immune cells via binding to pattern recognition receptors such as Toll-like receptor 4 (TLR4) and receptor for advanced glycation endproducts (AGER) (PubMed:19402754). Binding to TLR4 and AGER activates the MAP-kinase and NF-kappa-B signaling pathways resulting in the amplification of the pro-inflammatory cascade (PubMed:19402754, PubMed:22804476). Has antimicrobial activity towards bacteria and fungi and exerts its antimicrobial activity probably via chelation of Zn(2+) which is essential for microbial growth (PubMed:19087201). Can induce cell death via autophagy and apoptosis and this occurs through the cross-talk of mitochondria and lysosomes via reactive oxygen species (ROS) and the process involves BNIP3 (PubMed:19935772). Can regulate neutrophil number and apoptosis by an anti-apoptotic effect; regulates cell survival via ITGAM/ITGB and TLR4 and a signaling mechanism involving MEK-ERK (PubMed:22363402). Its role as an oxidant scavenger has a protective role in preventing exaggerated tissue damage by scavenging oxidants (PubMed:21912088, PubMed:22489132). Can act as a potent amplifier of inflammation in autoimmunity as well as in cancer development and tumor spread (PubMed:16258195). Has transnitrosylase activity; in oxidatively-modified low-densitity lipoprotein (LDL(ox))-induced S-nitrosylation of GAPDH on 'Cys-247' proposed to transfer the NO moiety from NOS2/iNOS to GAPDH via its own S-nitrosylated Cys-3 (PubMed:25417112). The iNOS-S100A8/A9 transnitrosylase complex is proposed to also direct selective inflammatory stimulus-dependent S-nitrosylation of multiple targets such as ANXA5, EZR, MSN and VIM by recognizing a [IL]-x-C-x-x-[DE] motif (PubMed:25417112)","subcellular_location":"Secreted; Cytoplasm; Cytoplasm, cytoskeleton; Cell membrane","url":"https://www.uniprot.org/uniprotkb/P06702/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/S100A9","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":true,"resolved_as":"MIF","ensg_id":"ENSG00000240972","cell_line_id":"CID000997","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"nucleoplasm","grade":3}],"interactors":[{"gene":"CSNK2A1;CSNK2A3","stoichiometry":10.0},{"gene":"RBM14","stoichiometry":10.0},{"gene":"RAB2A","stoichiometry":10.0},{"gene":"PSME3","stoichiometry":10.0},{"gene":"DDB1","stoichiometry":4.0},{"gene":"RAB1B;RAB1C","stoichiometry":4.0},{"gene":"TMED10","stoichiometry":4.0},{"gene":"RABAC1","stoichiometry":4.0},{"gene":"CEP85","stoichiometry":0.2},{"gene":"FIGNL1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000997","total_profiled":1310},"omim":[{"mim_id":"621210","title":"PU.1 (SPI1)-INDUCED REGULATOR OF S100A8 AND S100A9 ALARMIN TRANSCRIPTION 1, NONCODING; PIRAT1","url":"https://www.omim.org/entry/621210"},{"mim_id":"620874","title":"ADHESION G PROTEIN-COUPLED RECEPTOR F5; ADGRF5","url":"https://www.omim.org/entry/620874"},{"mim_id":"618190","title":"LUNG CANCER-ASSOCIATED TRANSCRIPT 1, NONCODING; LUCAT1","url":"https://www.omim.org/entry/618190"},{"mim_id":"614995","title":"INTERLEUKIN 17 RECEPTOR E; IL17RE","url":"https://www.omim.org/entry/614995"},{"mim_id":"611775","title":"KAWASAKI DISEASE","url":"https://www.omim.org/entry/611775"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Intermediate filaments","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"bone marrow","ntpm":30401.1},{"tissue":"cervix","ntpm":13503.3},{"tissue":"esophagus","ntpm":30106.4},{"tissue":"vagina","ntpm":13777.0}],"url":"https://www.proteinatlas.org/search/S100A9"},"hgnc":{"alias_symbol":["P14","MIF","NIF","LIAG","MRP14","MAC387","60B8AG","CGLB","MRP-14","S100-A9"],"prev_symbol":["CAGB","CFAG"]},"alphafold":{"accession":"P06702","domains":[{"cath_id":"1.10.238.10","chopping":"26-85","consensus_level":"medium","plddt":97.5957,"start":26,"end":85}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P06702","model_url":"https://alphafold.ebi.ac.uk/files/AF-P06702-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P06702-F1-predicted_aligned_error_v6.png","plddt_mean":94.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=S100A9","jax_strain_url":"https://www.jax.org/strain/search?query=S100A9"},"sequence":{"accession":"P06702","fasta_url":"https://rest.uniprot.org/uniprotkb/P06702.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P06702/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P06702"}},"corpus_meta":[{"pmid":"17767165","id":"PMC_17767165","title":"Mrp8 and Mrp14 are endogenous activators of Toll-like receptor 4, promoting lethal, endotoxin-induced shock.","date":"2007","source":"Nature medicine","url":"https://pubmed.ncbi.nlm.nih.gov/17767165","citation_count":1153,"is_preprint":false},{"pmid":"16846592","id":"PMC_16846592","title":"S100A8 and S100A9 in inflammation and cancer.","date":"2006","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/16846592","citation_count":588,"is_preprint":false},{"pmid":"15331440","id":"PMC_15331440","title":"MRP8 and MRP14 control microtubule reorganization during transendothelial migration of phagocytes.","date":"2004","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/15331440","citation_count":298,"is_preprint":false},{"pmid":"2644218","id":"PMC_2644218","title":"Physical and genetic map of the major nif gene cluster from Azotobacter vinelandii.","date":"1989","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/2644218","citation_count":268,"is_preprint":false},{"pmid":"9920411","id":"PMC_9920411","title":"Novel insights into structure and function of MRP8 (S100A8) and MRP14 (S100A9).","date":"1998","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/9920411","citation_count":233,"is_preprint":false},{"pmid":"24453429","id":"PMC_24453429","title":"S100A8 and S100A9: DAMPs at the crossroads between innate immunity, traditional risk factors, and cardiovascular disease.","date":"2013","source":"Mediators of inflammation","url":"https://pubmed.ncbi.nlm.nih.gov/24453429","citation_count":222,"is_preprint":false},{"pmid":"24332034","id":"PMC_24332034","title":"S100A8-S100A9 protein complex mediates psoriasis by regulating the expression of complement factor C3.","date":"2013","source":"Immunity","url":"https://pubmed.ncbi.nlm.nih.gov/24332034","citation_count":216,"is_preprint":false},{"pmid":"30083975","id":"PMC_30083975","title":"Calprotectin (S100A8/S100A9): a key protein between inflammation and cancer.","date":"2018","source":"Inflammation research : official journal of the European Histamine Research Society ... [et al.]","url":"https://pubmed.ncbi.nlm.nih.gov/30083975","citation_count":202,"is_preprint":false},{"pmid":"32434457","id":"PMC_32434457","title":"S100A9 Links Inflammation and Repair in Myocardial Infarction.","date":"2020","source":"Circulation research","url":"https://pubmed.ncbi.nlm.nih.gov/32434457","citation_count":184,"is_preprint":false},{"pmid":"22095980","id":"PMC_22095980","title":"S100A8 and S100A9 in cardiovascular biology and disease.","date":"2011","source":"Arteriosclerosis, thrombosis, and vascular biology","url":"https://pubmed.ncbi.nlm.nih.gov/22095980","citation_count":181,"is_preprint":false},{"pmid":"10464253","id":"PMC_10464253","title":"S100A12 is expressed exclusively by granulocytes and acts independently from MRP8 and MRP14.","date":"1999","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10464253","citation_count":177,"is_preprint":false},{"pmid":"22489132","id":"PMC_22489132","title":"Pro-inflammatory S100A8 and S100A9 proteins: self-assembly into multifunctional native and amyloid complexes.","date":"2012","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/22489132","citation_count":175,"is_preprint":false},{"pmid":"23123827","id":"PMC_23123827","title":"Review of S100A9 biology and its role in cancer.","date":"2012","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/23123827","citation_count":155,"is_preprint":false},{"pmid":"17095618","id":"PMC_17095618","title":"MRP8/MRP14 impairs endothelial integrity and induces a caspase-dependent and -independent cell death program.","date":"2006","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/17095618","citation_count":126,"is_preprint":false},{"pmid":"28137827","id":"PMC_28137827","title":"S100A9 induces differentiation of acute myeloid leukemia cells through TLR4.","date":"2017","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/28137827","citation_count":117,"is_preprint":false},{"pmid":"38013255","id":"PMC_38013255","title":"Roles of S100A8, S100A9 and S100A12 in infection, inflammation and immunity.","date":"2023","source":"Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/38013255","citation_count":115,"is_preprint":false},{"pmid":"23386971","id":"PMC_23386971","title":"Robust shifts in S100a9 expression with aging: a novel mechanism for chronic inflammation.","date":"2013","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/23386971","citation_count":108,"is_preprint":false},{"pmid":"30586702","id":"PMC_30586702","title":"Antiangiogenic VEGF165b Regulates Macrophage Polarization via S100A8/S100A9 in Peripheral Artery Disease.","date":"2019","source":"Circulation","url":"https://pubmed.ncbi.nlm.nih.gov/30586702","citation_count":107,"is_preprint":false},{"pmid":"36405711","id":"PMC_36405711","title":"From bench to bedside: Calprotectin (S100A8/S100A9) as a biomarker in rheumatoid arthritis.","date":"2022","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/36405711","citation_count":89,"is_preprint":false},{"pmid":"35411077","id":"PMC_35411077","title":"Stratification of radiosensitive brain metastases based on an actionable S100A9/RAGE resistance mechanism.","date":"2022","source":"Nature medicine","url":"https://pubmed.ncbi.nlm.nih.gov/35411077","citation_count":82,"is_preprint":false},{"pmid":"8558004","id":"PMC_8558004","title":"Phosphorylation of MRP14, an S100 protein expressed during monocytic differentiation, modulates Ca(2+)-dependent translocation from cytoplasm to membranes and cytoskeleton.","date":"1996","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/8558004","citation_count":81,"is_preprint":false},{"pmid":"27057553","id":"PMC_27057553","title":"Secretion of S100A8, S100A9, and S100A12 by Neutrophils Involves Reactive Oxygen Species and Potassium Efflux.","date":"2015","source":"Journal of immunology research","url":"https://pubmed.ncbi.nlm.nih.gov/27057553","citation_count":80,"is_preprint":false},{"pmid":"7519798","id":"PMC_7519798","title":"Expression and complex formation of S100-like proteins MRP8 and MRP14 by macrophages during renal allograft rejection.","date":"1994","source":"Transplantation","url":"https://pubmed.ncbi.nlm.nih.gov/7519798","citation_count":77,"is_preprint":false},{"pmid":"12937135","id":"PMC_12937135","title":"Expression of calcium-binding proteins MRP8 and MRP14 in inflammatory muscle diseases.","date":"2003","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/12937135","citation_count":71,"is_preprint":false},{"pmid":"25017168","id":"PMC_25017168","title":"Challenges to develop nitrogen-fixing cereals by direct nif-gene transfer.","date":"2014","source":"Plant science : an international journal of experimental plant biology","url":"https://pubmed.ncbi.nlm.nih.gov/25017168","citation_count":71,"is_preprint":false},{"pmid":"30728384","id":"PMC_30728384","title":"S100A8 & S100A9: Alarmin mediated inflammation in tendinopathy.","date":"2019","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/30728384","citation_count":71,"is_preprint":false},{"pmid":"12719414","id":"PMC_12719414","title":"Changing the conformation state of cytochrome b558 initiates NADPH oxidase activation: MRP8/MRP14 regulation.","date":"2003","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12719414","citation_count":70,"is_preprint":false},{"pmid":"20105291","id":"PMC_20105291","title":"S100A8 and S100A9 in experimental osteoarthritis.","date":"2010","source":"Arthritis research & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/20105291","citation_count":68,"is_preprint":false},{"pmid":"9845287","id":"PMC_9845287","title":"Widespread expression of MRP8 and MRP14 in human cerebral malaria by microglial cells.","date":"1998","source":"Acta neuropathologica","url":"https://pubmed.ncbi.nlm.nih.gov/9845287","citation_count":68,"is_preprint":false},{"pmid":"23223301","id":"PMC_23223301","title":"Mrp14 deficiency ameliorates amyloid β burden by increasing microglial phagocytosis and modulation of amyloid precursor protein processing.","date":"2012","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/23223301","citation_count":68,"is_preprint":false},{"pmid":"15740587","id":"PMC_15740587","title":"Expression patterns of S100A7 (psoriasin) and S100A9 (calgranulin-B) in keratinocyte differentiation.","date":"2005","source":"Experimental dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/15740587","citation_count":66,"is_preprint":false},{"pmid":"11295086","id":"PMC_11295086","title":"Immunohistochemical investigation of S100A9 expression in pulmonary adenocarcinoma: S100A9 expression is associated with tumor differentiation.","date":"2001","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/11295086","citation_count":65,"is_preprint":false},{"pmid":"22505354","id":"PMC_22505354","title":"Hypoxia and HIF-1 increase S100A8 and S100A9 expression in prostate cancer.","date":"2012","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/22505354","citation_count":62,"is_preprint":false},{"pmid":"10400597","id":"PMC_10400597","title":"Genetic and molecular analysis of cglB, a gene essential for single-cell gliding in Myxococcus xanthus.","date":"1999","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/10400597","citation_count":61,"is_preprint":false},{"pmid":"33643287","id":"PMC_33643287","title":"Interleukin 17 Promotes Expression of Alarmins S100A8 and S100A9 During the Inflammatory Response of Keratinocytes.","date":"2021","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/33643287","citation_count":61,"is_preprint":false},{"pmid":"7678846","id":"PMC_7678846","title":"Expression and complex assembly of calcium-binding proteins MRP8 and MRP14 during differentiation of murine myelomonocytic cells.","date":"1993","source":"Journal of leukocyte biology","url":"https://pubmed.ncbi.nlm.nih.gov/7678846","citation_count":60,"is_preprint":false},{"pmid":"14597726","id":"PMC_14597726","title":"Expression of MRP8 and MRP14 by macrophages is a marker for severe forms of glomerulonephritis.","date":"2003","source":"Journal of leukocyte biology","url":"https://pubmed.ncbi.nlm.nih.gov/14597726","citation_count":57,"is_preprint":false},{"pmid":"17636430","id":"PMC_17636430","title":"S100A8/S100A9 and their association with cartilage and bone.","date":"2007","source":"Journal of molecular histology","url":"https://pubmed.ncbi.nlm.nih.gov/17636430","citation_count":54,"is_preprint":false},{"pmid":"32582175","id":"PMC_32582175","title":"Epigenetic Regulation of S100A9 and S100A12 Expression in Monocyte-Macrophage System in Hyperglycemic Conditions.","date":"2020","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/32582175","citation_count":53,"is_preprint":false},{"pmid":"38308971","id":"PMC_38308971","title":"S100A9-/- alleviates LPS-induced acute lung injury by regulating M1 macrophage polarization and inhibiting pyroptosis via the TLR4/MyD88/NFκB signaling axis.","date":"2024","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/38308971","citation_count":52,"is_preprint":false},{"pmid":"10725790","id":"PMC_10725790","title":"The regulatory role of MRP8 (S100A8) and MRP14 (S100A9) in the transendothelial migration of human leukocytes.","date":"1999","source":"Pathobiology : journal of immunopathology, molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/10725790","citation_count":52,"is_preprint":false},{"pmid":"25342131","id":"PMC_25342131","title":"Injury-induced MRP8/MRP14 stimulates IP-10/CXCL10 in monocytes/macrophages.","date":"2014","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/25342131","citation_count":52,"is_preprint":false},{"pmid":"17090475","id":"PMC_17090475","title":"Up-regulation of S100A8 and S100A9 protein in bronchial epithelial cells by lipopolysaccharide.","date":"2006","source":"Experimental lung research","url":"https://pubmed.ncbi.nlm.nih.gov/17090475","citation_count":52,"is_preprint":false},{"pmid":"7507970","id":"PMC_7507970","title":"The monoclonal antibody MAC387 detects an epitope on the calcium-binding protein MRP14.","date":"1994","source":"Journal of leukocyte biology","url":"https://pubmed.ncbi.nlm.nih.gov/7507970","citation_count":51,"is_preprint":false},{"pmid":"8053890","id":"PMC_8053890","title":"Expression of the calcium-binding proteins MRP8 and MRP14 in monocytes is regulated by a calcium-induced suppressor mechanism.","date":"1994","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/8053890","citation_count":48,"is_preprint":false},{"pmid":"1524561","id":"PMC_1524561","title":"The calcium binding proteins MRP8 and MRP14 in acute and chronic inflammation.","date":"1992","source":"Behring Institute Mitteilungen","url":"https://pubmed.ncbi.nlm.nih.gov/1524561","citation_count":47,"is_preprint":false},{"pmid":"28074060","id":"PMC_28074060","title":"S100A8/A9 and S100A9 reduce acute lung injury.","date":"2017","source":"Immunology and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/28074060","citation_count":46,"is_preprint":false},{"pmid":"22301734","id":"PMC_22301734","title":"The role of S100a9 in the pathogenesis of Alzheimer's disease: the therapeutic effects of S100a9 knockdown or knockout.","date":"2012","source":"Neuro-degenerative diseases","url":"https://pubmed.ncbi.nlm.nih.gov/22301734","citation_count":46,"is_preprint":false},{"pmid":"33523865","id":"PMC_33523865","title":"S100A8/S100A9 cytokine acts as a transcriptional coactivator during breast cellular transformation.","date":"2021","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/33523865","citation_count":45,"is_preprint":false},{"pmid":"33549095","id":"PMC_33549095","title":"S100A9 blockade prevents lipopolysaccharide-induced lung injury via suppressing the NLRP3 pathway.","date":"2021","source":"Respiratory research","url":"https://pubmed.ncbi.nlm.nih.gov/33549095","citation_count":45,"is_preprint":false},{"pmid":"34285336","id":"PMC_34285336","title":"S100A9 in adult asthmatic patients: a biomarker for neutrophilic asthma.","date":"2021","source":"Experimental & molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34285336","citation_count":44,"is_preprint":false},{"pmid":"9693055","id":"PMC_9693055","title":"Copurification of P6, MRP8, and MRP14 from human granulocytes and separation of individual proteins.","date":"1998","source":"Protein expression and purification","url":"https://pubmed.ncbi.nlm.nih.gov/9693055","citation_count":42,"is_preprint":false},{"pmid":"37799387","id":"PMC_37799387","title":"MANF brakes TLR4 signaling by competitively binding S100A8 with S100A9 to regulate macrophage phenotypes in hepatic fibrosis.","date":"2023","source":"Acta pharmaceutica Sinica. B","url":"https://pubmed.ncbi.nlm.nih.gov/37799387","citation_count":41,"is_preprint":false},{"pmid":"39266214","id":"PMC_39266214","title":"S100A9 and HMGB1 orchestrate MDSC-mediated immunosuppression in melanoma through TLR4 signaling.","date":"2024","source":"Journal for immunotherapy of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/39266214","citation_count":36,"is_preprint":false},{"pmid":"36310133","id":"PMC_36310133","title":"Alarming and Calming: Opposing Roles of S100A8/S100A9 Dimers and Tetramers on Monocytes.","date":"2022","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/36310133","citation_count":36,"is_preprint":false},{"pmid":"28609200","id":"PMC_28609200","title":"Significance of S100A8, S100A9 and calprotectin levels in bladder cancer.","date":"2017","source":"Scandinavian journal of clinical and laboratory investigation","url":"https://pubmed.ncbi.nlm.nih.gov/28609200","citation_count":36,"is_preprint":false},{"pmid":"33361205","id":"PMC_33361205","title":"Deletion of S100a8 and S100a9 Enhances Skin Hyperplasia and Promotes the Th17 Response in Imiquimod-Induced Psoriasis.","date":"2020","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/33361205","citation_count":35,"is_preprint":false},{"pmid":"26385519","id":"PMC_26385519","title":"Regulation of TLR3 Activation by S100A9.","date":"2015","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/26385519","citation_count":34,"is_preprint":false},{"pmid":"15153104","id":"PMC_15153104","title":"Fibroblast growth-stimulating activity of S100A9 (MRP-14).","date":"2004","source":"European journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15153104","citation_count":34,"is_preprint":false},{"pmid":"15040889","id":"PMC_15040889","title":"Expression of MRP14 gene is frequently down-regulated in Chinese human esophageal cancer.","date":"2004","source":"Cell research","url":"https://pubmed.ncbi.nlm.nih.gov/15040889","citation_count":31,"is_preprint":false},{"pmid":"20422274","id":"PMC_20422274","title":"Calgranulin B (S100A9/MRP14): a key molecule in idiopathic pulmonary fibrosis?","date":"2011","source":"Inflammation","url":"https://pubmed.ncbi.nlm.nih.gov/20422274","citation_count":31,"is_preprint":false},{"pmid":"35543413","id":"PMC_35543413","title":"C/EBPδ-induced epigenetic changes control the dynamic gene transcription of S100a8 and S100a9.","date":"2022","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/35543413","citation_count":29,"is_preprint":false},{"pmid":"24670043","id":"PMC_24670043","title":"Inflammation and pancreatic cancer: molecular and functional interactions between S100A8, S100A9, NT-S100A8 and TGFβ1.","date":"2014","source":"Cell communication and signaling : CCS","url":"https://pubmed.ncbi.nlm.nih.gov/24670043","citation_count":29,"is_preprint":false},{"pmid":"32903598","id":"PMC_32903598","title":"S100A8 and S100A9 Promote Apoptosis of Chronic Eosinophilic Leukemia Cells.","date":"2020","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/32903598","citation_count":28,"is_preprint":false},{"pmid":"14555857","id":"PMC_14555857","title":"Interleukin-10 influences the expression of MRP8 and MRP14 in human dendritic cells.","date":"2003","source":"International archives of allergy and immunology","url":"https://pubmed.ncbi.nlm.nih.gov/14555857","citation_count":28,"is_preprint":false},{"pmid":"31262951","id":"PMC_31262951","title":"Galectin-3 and S100A9: Novel Diabetogenic Factors Mediating Pancreatic Cancer-Associated Diabetes.","date":"2019","source":"Diabetes care","url":"https://pubmed.ncbi.nlm.nih.gov/31262951","citation_count":26,"is_preprint":false},{"pmid":"39107960","id":"PMC_39107960","title":"S100A9 deletion in microglia/macrophages ameliorates brain injury through the STAT6/PPARγ pathway in ischemic stroke.","date":"2024","source":"CNS neuroscience & therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/39107960","citation_count":25,"is_preprint":false},{"pmid":"37844250","id":"PMC_37844250","title":"Viral nanoparticle vaccines against S100A9 reduce lung tumor seeding and metastasis.","date":"2023","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/37844250","citation_count":24,"is_preprint":false},{"pmid":"29296934","id":"PMC_29296934","title":"Neutrophils and the S100A9 protein critically regulate granuloma formation.","date":"2016","source":"Blood advances","url":"https://pubmed.ncbi.nlm.nih.gov/29296934","citation_count":24,"is_preprint":false},{"pmid":"22957762","id":"PMC_22957762","title":"The distribution and expression of S100A8 and S100A9 in gingival epithelium of mice.","date":"2012","source":"Journal of periodontal research","url":"https://pubmed.ncbi.nlm.nih.gov/22957762","citation_count":24,"is_preprint":false},{"pmid":"32009294","id":"PMC_32009294","title":"Transfer of Nitrogen Fixation (nif) Genes to Non-diazotrophic Hosts.","date":"2020","source":"Chembiochem : a European journal of chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/32009294","citation_count":23,"is_preprint":false},{"pmid":"25772177","id":"PMC_25772177","title":"S100A9 as a Pharmacological Target Molecule in Inflammation and Cancer.","date":"2015","source":"Endocrine, metabolic & immune disorders drug targets","url":"https://pubmed.ncbi.nlm.nih.gov/25772177","citation_count":22,"is_preprint":false},{"pmid":"28157385","id":"PMC_28157385","title":"Enhanced S100A9 and S100A12 expression in acute coronary syndrome.","date":"2017","source":"Biomarkers in medicine","url":"https://pubmed.ncbi.nlm.nih.gov/28157385","citation_count":22,"is_preprint":false},{"pmid":"10722871","id":"PMC_10722871","title":"MRP8/MRP14, CD11b and HLA-DR expression of alveolar macrophages in pneumonia.","date":"2000","source":"Immunology letters","url":"https://pubmed.ncbi.nlm.nih.gov/10722871","citation_count":22,"is_preprint":false},{"pmid":"9717674","id":"PMC_9717674","title":"The transcription factors c-myb and C/EBP alpha regulate the monocytic/myeloic gene MRP14.","date":"1998","source":"Immunobiology","url":"https://pubmed.ncbi.nlm.nih.gov/9717674","citation_count":22,"is_preprint":false},{"pmid":"32854769","id":"PMC_32854769","title":"The alarmins S100A8 and S100A9 mediate acute pain in experimental synovitis.","date":"2020","source":"Arthritis research & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/32854769","citation_count":22,"is_preprint":false},{"pmid":"10617929","id":"PMC_10617929","title":"Accumulation of MAC387+ macrophages in paracortical areas of lymph nodes in rhesus monkeys acutely infected with simian immunodeficiency virus.","date":"1999","source":"Microbes and infection","url":"https://pubmed.ncbi.nlm.nih.gov/10617929","citation_count":21,"is_preprint":false},{"pmid":"37686186","id":"PMC_37686186","title":"S100A8 and S100A9 in Hematologic Malignancies: From Development to Therapy.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/37686186","citation_count":20,"is_preprint":false},{"pmid":"34360737","id":"PMC_34360737","title":"S100A9 Alters the Pathway of Alpha-Synuclein Amyloid Aggregation.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/34360737","citation_count":20,"is_preprint":false},{"pmid":"23340902","id":"PMC_23340902","title":"Immunohistochemical expression of RAGE and its ligand (S100A9) in cervical lesions.","date":"2013","source":"Cell biochemistry and biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/23340902","citation_count":20,"is_preprint":false},{"pmid":"36652782","id":"PMC_36652782","title":"Emerging targets for cancer treatment: S100A9/RAGE.","date":"2023","source":"ESMO open","url":"https://pubmed.ncbi.nlm.nih.gov/36652782","citation_count":19,"is_preprint":false},{"pmid":"35840613","id":"PMC_35840613","title":"Hepatic non-parenchymal S100A9-TLR4-mTORC1 axis normalizes diabetic ketogenesis.","date":"2022","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/35840613","citation_count":19,"is_preprint":false},{"pmid":"36812310","id":"PMC_36812310","title":"Unmasking of the von Willebrand A-domain surface adhesin CglB at bacterial focal adhesions mediates myxobacterial gliding motility.","date":"2023","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/36812310","citation_count":19,"is_preprint":false},{"pmid":"27573788","id":"PMC_27573788","title":"UPF1 regulates myeloid cell functions and S100A9 expression by the hnRNP E2/miRNA-328 balance.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/27573788","citation_count":18,"is_preprint":false},{"pmid":"12590055","id":"PMC_12590055","title":"The time-dependent expression of fibronectin, MRP8, MRP14 and defensin in surgically treated human skin wounds.","date":"2003","source":"Forensic science international","url":"https://pubmed.ncbi.nlm.nih.gov/12590055","citation_count":17,"is_preprint":false},{"pmid":"21185856","id":"PMC_21185856","title":"Porcine S100A8 and S100A9: molecular characterizations and crucial functions in response to Haemophilus parasuis infection.","date":"2010","source":"Developmental and comparative immunology","url":"https://pubmed.ncbi.nlm.nih.gov/21185856","citation_count":17,"is_preprint":false},{"pmid":"10049680","id":"PMC_10049680","title":"Overexpression, oxidative refolding, and zinc binding of recombinant forms of the murine S100 protein MRP14 (S100A9).","date":"1999","source":"Protein expression and purification","url":"https://pubmed.ncbi.nlm.nih.gov/10049680","citation_count":17,"is_preprint":false},{"pmid":"38454445","id":"PMC_38454445","title":"S100A9+CD14+ monocytes contribute to anti-PD-1 immunotherapy resistance in advanced hepatocellular carcinoma by attenuating T cell-mediated antitumor function.","date":"2024","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/38454445","citation_count":16,"is_preprint":false},{"pmid":"33005006","id":"PMC_33005006","title":"Elevated S100A9 expression in chronic rhinosinusitis coincides with elevated MMP production and proliferation in vitro.","date":"2020","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/33005006","citation_count":16,"is_preprint":false},{"pmid":"23243608","id":"PMC_23243608","title":"S100A9 and tumor growth.","date":"2012","source":"Oncoimmunology","url":"https://pubmed.ncbi.nlm.nih.gov/23243608","citation_count":15,"is_preprint":false},{"pmid":"38504474","id":"PMC_38504474","title":"Advances in the study of S100A9 in cardiovascular diseases.","date":"2024","source":"Cell proliferation","url":"https://pubmed.ncbi.nlm.nih.gov/38504474","citation_count":14,"is_preprint":false},{"pmid":"37949322","id":"PMC_37949322","title":"Inhibition of S100A9 alleviates neurogenic pulmonary edema after subarachnoid hemorrhage.","date":"2023","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/37949322","citation_count":14,"is_preprint":false},{"pmid":"38420589","id":"PMC_38420589","title":"S100A9 aggravates early brain injury after subarachnoid hemorrhage via inducing neuroinflammation and inflammasome activation.","date":"2024","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/38420589","citation_count":14,"is_preprint":false},{"pmid":"35717907","id":"PMC_35717907","title":"S100A9 promotes inflammatory response in diabetic nonalcoholic fatty liver disease.","date":"2022","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/35717907","citation_count":14,"is_preprint":false},{"pmid":"7762618","id":"PMC_7762618","title":"Presence of MRP8 and MRP14 in pancreatic cell lines: differential expression and localization in CFPAC-1 cells.","date":"1995","source":"The American journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/7762618","citation_count":14,"is_preprint":false},{"pmid":"17101129","id":"PMC_17101129","title":"S100A9-positive granulocytes and monocytes in lipopolysaccharide-induced anterior ocular inflammation.","date":"2006","source":"Experimental eye research","url":"https://pubmed.ncbi.nlm.nih.gov/17101129","citation_count":14,"is_preprint":false},{"pmid":"28063140","id":"PMC_28063140","title":"Regulatory mechanism and functional analysis of S100A9 in acute promyelocytic leukemia cells.","date":"2017","source":"Frontiers of medicine","url":"https://pubmed.ncbi.nlm.nih.gov/28063140","citation_count":14,"is_preprint":false},{"pmid":"38170783","id":"PMC_38170783","title":"S100A9 exerts insulin-independent antidiabetic and anti-inflammatory effects.","date":"2024","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/38170783","citation_count":13,"is_preprint":false},{"pmid":"31062027","id":"PMC_31062027","title":"Organization and regulation of cyanobacterial nif gene clusters: implications for nitrogenase expression in plant cells.","date":"2019","source":"FEMS microbiology letters","url":"https://pubmed.ncbi.nlm.nih.gov/31062027","citation_count":13,"is_preprint":false},{"pmid":"31055998","id":"PMC_31055998","title":"Clinical importance of S100A9 in osteosarcoma development and as a diagnostic marker and therapeutic target.","date":"2019","source":"Bioengineered","url":"https://pubmed.ncbi.nlm.nih.gov/31055998","citation_count":13,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":49373,"output_tokens":7779,"usd":0.132402,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":17083,"output_tokens":7266,"usd":0.133532,"stage2_stop_reason":"end_turn"},"total_usd":0.265934,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"Surface plasmon resonance, HEK293 transfection with TLR4/CD14/MD2, phagocytes expressing nonfunctional TLR4, Mrp8/Mrp14 knockout mice\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (SPR, cell transfection, genetic KO models), replicated across cell types, in vivo validation in two sepsis models\",\n      \"pmids\": [\"17767165\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"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.\",\n      \"method\": \"Targeted gene disruption (MRP14-/- mice), in vitro tubulin polymerization assays, phosphorylation studies, Rac1/Cdc42 activation assays, wound healing in vivo model\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — genetic KO with defined molecular phenotype, in vitro reconstitution of tubulin polymerization, in vivo validation, multiple orthogonal readouts\",\n      \"pmids\": [\"15331440\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Proteomic analysis of human psoriatic epidermis, chromatin binding assay (S100A9 binding to C3 promoter region), S100A9 genetic knockout mouse models\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct chromatin binding demonstrated, genetic KO with phenotypic readout, single lab with two orthogonal methods\",\n      \"pmids\": [\"24332034\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"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.\",\n      \"method\": \"Metabolic labeling with [32P]orthophosphate, 2D electrophoresis, differential centrifugation, 45Ca2+ overlay, isoelectric focusing\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct biochemical fractionation and Ca2+ binding assays, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"8558004\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct protein interaction by multiple methods (co-purification/MS, AFM, cell-free reconstitution, cellular co-transfection), structure-function analysis\",\n      \"pmids\": [\"12719414\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, KO with defined molecular defect in trafficking, colocalization microscopy, in vitro and in vivo validation\",\n      \"pmids\": [\"26385519\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Recombinant S100A9 treatment of AML cell lines, TLR4 blocking/knockout, phospho-kinase assays, in vivo AML mouse model, flow cytometry for differentiation markers\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — TLR4-mediated signaling pathway defined with receptor blocking, pathway activation confirmed by phospho-assays, in vivo validation, single lab\",\n      \"pmids\": [\"28137827\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"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.\",\n      \"method\": \"Purified MRP8/MRP14 treatment of human microvascular endothelial cells, caspase activation assays, Bcl-2 overexpression, DNA fragmentation assay, annexin V staining\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined molecular mechanism with caspase assays and Bcl-2 rescue, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"17095618\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor-specific effects confirmed with inhibitors and distinct quaternary forms, in vitro and in vivo validation, single lab\",\n      \"pmids\": [\"36310133\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined Nur77 mechanistic pathway with both pharmacological inhibitor and genetic KO, in vitro and in vivo, single lab\",\n      \"pmids\": [\"32434457\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"ChIP-seq, nuclear extract co-immunoprecipitation with transcription factors, artificial promoter recruitment assay, nuclear-specific expression constructs, breast transformation phenotype assays\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq, co-IP with transcription factors, functional rescue with nuclear-specific expression, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"33523865\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Acta pharmaceutica Sinica. B\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP defining competitive interaction, genetic KO with defined phenotype, rescue by transfusion, single lab\",\n      \"pmids\": [\"37799387\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — unbiased CRISPR screen plus direct ChIP validation, epigenetic mechanism with JMJD3, in vivo KO validation, multiple orthogonal methods\",\n      \"pmids\": [\"35543413\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"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.\",\n      \"method\": \"Co-transfection of MRP14 promoter-CAT constructs with C/EBPα and v-myb expression constructs, Northern blot analysis\",\n      \"journal\": \"Immunobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter-reporter assay with defined transcription factors, mRNA confirmation by Northern blot, single lab\",\n      \"pmids\": [\"9717674\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"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.\",\n      \"method\": \"Western blot, metabolic labeling, Northern blot, calcium ionophore (A23187) and thapsigargin treatment, actinomycin D and cycloheximide co-treatment experiments\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple pharmacological dissection experiments establishing transcriptional mechanism, Northern blot, single lab\",\n      \"pmids\": [\"8053890\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"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.\",\n      \"method\": \"Chemical cross-linking, density gradient centrifugation, mass spectrometry, yeast two-hybrid, calcium overlays, Western blotting, flow cytometry\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — four independent methods all showing negative interaction between S100A12 and S100A9, rigorous multi-method study\",\n      \"pmids\": [\"10464253\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"UPF1 knockdown in monocytic cells, hnRNP E2 binding site analysis, miRNA-328 overexpression/inhibition, qRT-PCR for S100A9 expression, monocytic differentiation assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined post-transcriptional mechanism with hnRNP E2 and miRNA-328 competition, functional rescue experiments, single lab\",\n      \"pmids\": [\"27573788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"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.\",\n      \"method\": \"Recombinant protein expression, ESI/MS, C4 reverse-phase HPLC, oxidative refolding, 65Zn2+ overlay assay on PVDF membrane\",\n      \"journal\": \"Protein expression and purification\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct biochemical characterization of disulfide and Zn2+ binding using recombinant protein and truncation analysis, single lab\",\n      \"pmids\": [\"10049680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Cell-type specific TLR4 and TSC1 conditional knockout mice, recombinant S100A9 administration, mTORC1 activity assays, hyperketonemia measurement in diabetic mice\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type specific genetic dissection with multiple KO lines, defined TLR4-mTORC1 pathway, pharmacological rescue with recombinant protein, in vivo validation\",\n      \"pmids\": [\"35840613\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"ChIP assay demonstrating S100A9 binding to CD274 promoter, T-cell proliferation/cytotoxicity assays, S100A9 inhibitor treatment in vitro and in vivo, scRNA-seq\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter binding by ChIP, functional T-cell suppression assay, in vivo validation, single lab\",\n      \"pmids\": [\"38454445\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"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.\",\n      \"method\": \"Protein purification from carrageenan exudate, amino acid sequence analysis, recombinant S100A9 production, fibroblast proliferation assay, immunoblot quantification\",\n      \"journal\": \"European journal of biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — direct purification and identification, recombinant protein functional validation, single lab\",\n      \"pmids\": [\"15153104\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Human neutrophil stimulation with various agents, ROS inhibitors, K+ channel blockers, ELISA for secreted S100A9, S100A8, and S100A12\",\n      \"journal\": \"Journal of immunology research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological dissection of secretion mechanism with defined inhibitors, multiple stimuli tested, single lab\",\n      \"pmids\": [\"27057553\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Biomedicine & pharmacotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with defined signaling pathway, in vitro and in vivo validation, single lab\",\n      \"pmids\": [\"38308971\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"S100A9 conditional KO mice, tMCAO stroke model, transcriptomic analysis, STAT6 phosphorylation inhibitor AS1517499, in vitro macrophage stimulation, paquinimod S100A9 inhibitor\",\n      \"journal\": \"CNS neuroscience & therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with defined STAT6/PPARγ pathway, pharmacological inhibitor epistasis, in vitro and in vivo, single lab\",\n      \"pmids\": [\"39107960\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro monocyte-to-MDSC conversion assay with recombinant S100A9, TLR4 and RAGE inhibitors, T-cell proliferation inhibition assay, scRNA-seq of patient monocytes\",\n      \"journal\": \"Journal for immunotherapy of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined TLR4-dependent mechanism, pharmacological inhibitor blocking, functional T-cell assay, single lab\",\n      \"pmids\": [\"39266214\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Frontiers of medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter binding by ChIP, reporter assay, functional apoptosis readout, single lab\",\n      \"pmids\": [\"28063140\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"MALDI-TOF/MS, co-immunoprecipitation of S100A9 with TGFβ1, NF-κB/Akt/mTOR pathway assays, calcium imaging, EMT marker expression\",\n      \"journal\": \"Cell communication and signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct physical interaction shown by MS and co-IP, functional consequences in signaling, single lab\",\n      \"pmids\": [\"24670043\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"In vivo brain metastasis models resistant to WBRT, genetic and pharmacological targeting of S100A9-RAGE-NF-κB-JunB pathway, tumor radiotherapy response assays\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined signaling pathway with genetic and pharmacological validation in vivo, single lab, multiple model systems\",\n      \"pmids\": [\"35411077\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"S100A9 (MRP14) is a calcium- and zinc-binding S100-family protein that forms a heterodimer with S100A8 (MRP8); this dimer acts as an endogenous TLR4 ligand (via S100A8) that activates MyD88/IRAK-1/NF-κB and p38 MAPK signaling, while intracellularly S100A9 is phosphorylated by p38 MAPK to regulate MRP8/S100A9-dependent microtubule polymerization and phagocyte transendothelial migration, facilitates TLR3 trafficking from early to late endosomes, can enter the nucleus to modulate gene transcription (C3, PD-L1, and co-activator functions), and engages additional receptors including RAGE and CD69 depending on its oligomeric state, collectively placing it as a multifunctional alarmin that couples innate immune signaling, cytoskeletal dynamics, and transcriptional regulation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#0, #1]. It partners with S100A8 (MRP8) to form a heterodimer that acts as an endogenous TLR4-MD2 ligand, driving MyD88/IRAK-1/NF-\\u03baB activation and pro-inflammatory cytokine production [#0, #22]; this TLR4 engagement underlies a broad spectrum of downstream outcomes including monocyte-to-MDSC conversion, AML cell differentiation, and an extracellular TLR4-NF-\\u03baB-mTORC1 axis in hepatic non-parenchymal cells that restrains ketogenesis [#6, #18, #24]. 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-\\u03baB-JunB signaling [#8, #27]. 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 [#1, #3], and it co-purifies with the NADPH oxidase machinery to enhance superoxide production via cytochrome b558 [#4]. S100A9 also traffics TLR3 from early to late endosomes, a step required for dsRNA responses [#5]. 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 [#2, #10, #19]. Functionally it governs monocyte/macrophage phenotype switching through Nur77 and STAT6/PPAR\\u03b3 pathways, influencing efferocytosis and inflammation resolution [#9, #23], and its own expression is controlled transcriptionally by C/EBP factors with JMJD3-dependent H3K27me3 demethylation and post-transcriptionally via hnRNP E2/miRNA-328 [#12, #13, #16].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Established that MRP8/MRP14 expression is governed transcriptionally and is sensitive to intracellular calcium, defining an early layer of expression control.\",\n      \"evidence\": \"Calcium ionophore/thapsigargin treatment with Northern blot and actinomycin/cycloheximide dissection in monocytes\",\n      \"pmids\": [\"8053890\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of the calcium-induced repressor protein not determined\", \"Does not address protein-level function\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"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.\",\n      \"evidence\": \"Metabolic 32P labeling, 2D electrophoresis, differential centrifugation, and 45Ca2+ overlay in monocytes\",\n      \"pmids\": [\"8558004\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Kinase responsible not identified at this stage\", \"Functional consequence of translocation undefined here\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Defined transcription factor control of MRP14 expression by showing C/EBP\\u03b1 enhances and v-myb represses the MRP14 promoter.\",\n      \"evidence\": \"Promoter-CAT co-transfection with C/EBP\\u03b1 and v-myb plus Northern blot in HL60 and L132 cells\",\n      \"pmids\": [\"9717674\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No demonstration of direct C/EBP\\u03b1 binding to the promoter\", \"In vivo relevance not tested\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Biochemically characterized MRP14 metal-binding and structure, mapping zinc binding to the C-terminus and identifying an intramolecular disulfide bond.\",\n      \"evidence\": \"Recombinant protein, ESI/MS, oxidative refolding, and 65Zn2+ overlay with truncation analysis\",\n      \"pmids\": [\"10049680\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional role of disulfide and Zn2+ binding in vivo not established\", \"Murine protein only\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Clarified specificity within the S100 family by showing S100A12 does not physically interact with S100A8/S100A9 despite shared calcium-dependent translocation.\",\n      \"evidence\": \"Chemical cross-linking, density gradient centrifugation, mass spectrometry, and yeast two-hybrid\",\n      \"pmids\": [\"10464253\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Negative result; does not address other S100 partners\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Linked S100A8/S100A9 to the oxidative burst by demonstrating it enhances NADPH oxidase activity through calcium-dependent interaction with cytochrome b558.\",\n      \"evidence\": \"Co-purification/MS from neutrophils, cell-free oxidase reconstitution, AFM, and B-lymphocyte co-transfection\",\n      \"pmids\": [\"12719414\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of the oxidase interaction not fully resolved\", \"In vivo contribution to ROS production not quantified here\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"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.\",\n      \"evidence\": \"MRP14-/- mice, in vitro tubulin polymerization, phosphorylation studies, Rac1/Cdc42 assays, and in vivo wound healing\",\n      \"pmids\": [\"15331440\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular link between the complex and tubulin not structurally defined\", \"How phosphorylation feeds into Rac1/Cdc42 not mechanistically resolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identified an extracellular growth-promoting activity by purifying S100A9 homodimer as a fibroblast growth-stimulating factor from inflammation exudate.\",\n      \"evidence\": \"Purification from carrageenan exudate, sequencing, and recombinant fibroblast proliferation assay\",\n      \"pmids\": [\"15153104\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor mediating proliferation not identified\", \"Physiological significance versus heterodimer unclear\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Showed the extracellular MRP8/MRP14 complex can trigger endothelial cell death via mitochondrial caspase-dependent and caspase-independent routes.\",\n      \"evidence\": \"Purified complex on microvascular endothelial cells with caspase assays, Bcl-2 overexpression, and DNA fragmentation/annexin V\",\n      \"pmids\": [\"17095618\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor/entry mechanism for cell-death induction unknown\", \"In vivo relevance not tested\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"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.\",\n      \"evidence\": \"SPR, TLR4/CD14/MD2 HEK293 transfection, nonfunctional-TLR4 phagocytes, and Mrp8/Mrp14 KO mice in sepsis models\",\n      \"pmids\": [\"17767165\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of S100A8-TLR4 docking not resolved\", \"S100A9's precise contribution beyond complex formation not isolated\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Revealed an intranuclear function, showing S100A9 acts as a chromatin component binding the C3 promoter to modulate complement expression in skin inflammation.\",\n      \"evidence\": \"Proteomics of psoriatic epidermis, chromatin binding assay, and S100A9 KO psoriasis models\",\n      \"pmids\": [\"24332034\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Sequence specificity and co-factors of chromatin binding undefined\", \"How S100A9 enters/retains in the nucleus unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined an intracellular trafficking role by showing S100A9 is required for TLR3 movement from early to late endosomes for dsRNA sensing.\",\n      \"evidence\": \"S100A9-KO macrophages, reciprocal co-IP, endosomal colocalization microscopy, and in vivo polyIC\",\n      \"pmids\": [\"26385519\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which S100A9 drives endosomal maturation unknown\", \"Whether S100A8 participates not addressed\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"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.\",\n      \"evidence\": \"Human neutrophil stimulation with ROS inhibitors and K+ channel blockers, ELISA for secreted protein\",\n      \"pmids\": [\"27057553\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular machinery of unconventional secretion not identified\", \"Single cell type tested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Uncovered post-transcriptional control via the UPF1\\u2013hnRNP E2\\u2013miRNA-328 axis regulating S100A9 splicing during monocytic differentiation.\",\n      \"evidence\": \"UPF1 knockdown, miRNA-328 gain/loss, hnRNP E2 binding-site analysis, and qRT-PCR\",\n      \"pmids\": [\"27573788\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct demonstration of altered splicing isoforms limited\", \"Generalizability beyond monocytic cells unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated context-dependent S100A9-TLR4 signaling promotes AML cell differentiation through p38/ERK/JNK, and showed PML/RAR\\u03b1-PU.1 drive S100A9 expression with overexpression inducing APL apoptosis.\",\n      \"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\",\n      \"pmids\": [\"28137827\", \"28063140\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reconciliation of pro-differentiation versus pro-apoptotic outcomes across contexts incomplete\", \"Single-lab findings\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Linked S100A9 to reparative macrophage programming by showing it upregulates Nur77 to drive Ly6Chi-to-Ly6Clo monocyte switching and efferocytosis after myocardial infarction.\",\n      \"evidence\": \"S100A9 blocker and S100A9-/- mice, in vitro stimulation, and Nur77 activity/expression assays\",\n      \"pmids\": [\"32434457\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor coupling S100A9 to Nur77 induction not defined\", \"Direct versus indirect regulation of Nur77 unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed nuclear S100A8/S100A9 are recruited genome-wide to promoters/enhancers and act with transcription factors to drive oncogenic transcription in breast transformation.\",\n      \"evidence\": \"ChIP-seq, nuclear-extract co-IP with transcription factors, artificial promoter recruitment, and nuclear-specific expression constructs\",\n      \"pmids\": [\"33523865\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of the bridging transcription factors not fully defined\", \"Mechanism of nuclear import unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established that quaternary structure switches receptor usage: calcium-induced tetramers bind CD69 to limit inflammation while dimers signal through TLR4 to promote it.\",\n      \"evidence\": \"Dimer-versus-tetramer adhesion/migration/traction assays, CD69 binding, TLR4/CD69 inhibitors, and in vivo granuloma/dermatitis models\",\n      \"pmids\": [\"36310133\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural details of CD69 engagement not resolved\", \"What governs dimer/tetramer equilibrium in vivo unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined an extracellular metabolic role, with S100A9 activating a TLR4-NF-\\u03baB-mTORC1 axis in hepatic non-parenchymal cells to suppress diabetic ketogenesis insulin-independently.\",\n      \"evidence\": \"Cell-type-specific TLR4/TSC1 conditional KO mice, recombinant S100A9, mTORC1 assays, and ketone measurement in diabetic mice\",\n      \"pmids\": [\"35840613\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How non-parenchymal mTORC1 activation restrains hepatocyte ketogenesis mechanistically incomplete\", \"Endogenous source of S100A9 in this setting\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established the upstream epigenetic-transcriptional control of S100a8/S100a9 by C/EBP\\u03b4-directed JMJD3-dependent H3K27me3 demethylation, required for neutrophil recruitment.\",\n      \"evidence\": \"Genome-wide CRISPR screen, ChIP for C/EBP\\u03b4 binding, H3K27me3 demethylation assays, and C/EBP\\u03b4 KO lung inflammation model\",\n      \"pmids\": [\"35543413\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether C/EBP\\u03b4 and C/EBP\\u03b1 act redundantly not resolved\", \"Tissue specificity of the JMJD3 mechanism unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed S100A9 signals through RAGE-NF-\\u03baB-JunB in brain metastases to mediate radiotherapy resistance, expanding its receptor repertoire beyond TLR4.\",\n      \"evidence\": \"In vivo WBRT-resistant brain metastasis models with genetic and pharmacological pathway targeting\",\n      \"pmids\": [\"35411077\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Determinants of RAGE versus TLR4 engagement not defined\", \"Direct S100A9-RAGE binding affinity not characterized\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified MANF as a negative regulator that competitively binds S100A8 to block heterodimer formation and TLR4-NF-\\u03baB signaling in hepatic fibrosis.\",\n      \"evidence\": \"Co-IP of MANF with S100A8, heterodimer competition assay, myeloid-specific MANF KO mice, and macrophage transfusion rescue\",\n      \"pmids\": [\"37799387\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of MANF-S100A8 competition unresolved\", \"Whether MANF affects S100A9 homodimer/other functions untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Consolidated S100A9's pro-inflammatory and immunosuppressive roles: driving M1 polarization/NLRP3 via TLR4/MyD88/NF-\\u03baB, converting monocytes to MDSC-like cells via TLR4, and activating PD-L1 transcription by binding the CD274 promoter.\",\n      \"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\",\n      \"pmids\": [\"38308971\", \"39266214\", \"38454445\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How a single alarmin balances inflammatory versus immunosuppressive programs unresolved\", \"Link between extracellular signaling and direct promoter binding mechanistically incomplete\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated that S100A9 restrains anti-inflammatory macrophage switching via STAT6/PPAR\\u03b3 after ischemic stroke, with inhibition promoting efferocytosis and resolution.\",\n      \"evidence\": \"S100A9 conditional KO mice, tMCAO model, transcriptomics, STAT6 inhibitor epistasis, and paquinimod treatment\",\n      \"pmids\": [\"39107960\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether S100A9 acts directly upstream of STAT6 or indirectly unclear\", \"Receptor coupling in microglia not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [2, 10, 19]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [2, 10, 19]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 8, 27]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [1, 3]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 10]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [1, 3]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [20, 21]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 5, 22, 24]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 8, 18, 27]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [2, 10, 19]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [7, 22]}\n    ],\n    \"complexes\": [\n      \"S100A8/S100A9 (calprotectin) heterodimer\",\n      \"NADPH oxidase cytosolic factor assembly\"\n    ],\n    \"partners\": [\n      \"S100A8\",\n      \"TLR4\",\n      \"MD2\",\n      \"TLR3\",\n      \"CD69\",\n      \"TGFB1\",\n      \"MANF\",\n      \"CYBB\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}