{"gene":"CD14","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":1990,"finding":"CD14 on monocyte surfaces binds complexes of LPS and LPS-binding protein (LBP), and blockade of CD14 with monoclonal antibodies prevented TNF-alpha synthesis by whole blood incubated with LPS, establishing CD14 as the cellular receptor for LPS-LBP complexes.","method":"Monoclonal antibody blockade, binding assay, TNF-alpha secretion assay in whole blood","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct binding assay plus functional blockade with mAb, foundational paper replicated extensively across labs","pmids":["1698311"],"is_preprint":false},{"year":1989,"finding":"CD14 is anchored to the plasma membrane exclusively via a glycosylphosphatidylinositol (GPI) lipid anchor, as demonstrated by release with GPI-specific phospholipase C and absence from PNH patient monocytes; the protein lacks a conventional transmembrane domain.","method":"GPI-specific phospholipase C treatment, transfection of COS cells with CD14 cDNA, analysis of PNH patient monocytes, cDNA cloning and sequence analysis","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1 / Strong — biochemical reconstitution (PI-PLC cleavage), genetic evidence (PNH cells), multiple orthogonal methods, widely replicated","pmids":["2462937"],"is_preprint":false},{"year":1992,"finding":"Soluble CD14 (sCD14) enables LPS responses in cells that lack membrane CD14 (endothelial and astrocytoma cells); immunodepletion of sCD14 from serum abolishes these responses and addition of sCD14 restores them, showing that a membrane anchor is not required for CD14 function but that sCD14 must interact with additional cell-surface proteins to transduce a signal.","method":"Immunodepletion of sCD14 from serum, reconstitution with purified sCD14, anti-CD14 antibody blockade, ELAM-1 expression assay, IL-6 secretion assay, cytotoxicity assay","journal":"Journal of Experimental Medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal cell assays plus immunodepletion-reconstitution, replicated across three cell types in one rigorous study","pmids":["1281215"],"is_preprint":false},{"year":1994,"finding":"CD14 acts as a pattern recognition receptor for a broad range of bacterial envelope components from Gram-negative and Gram-positive organisms as well as mycobacteria, initiating cell activation by each.","method":"Cell activation assays with diverse bacterial cell-wall ligands in CD14-expressing cells; anti-CD14 antibody blockade","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple ligands tested with CD14-transfected cells and antibody blockade, widely replicated","pmids":["7534618"],"is_preprint":false},{"year":1996,"finding":"CD14 is a cell-activating receptor for bacterial peptidoglycan; the N-terminal 151 amino acids are sufficient for full responsiveness, and deletion mutants within the N-terminal 65 amino acids show differential responses to peptidoglycan vs. endotoxin, mapping partially distinct binding sites for these ligands.","method":"Transfection of 70Z/3 cells with human CD14 and deletion mutants; NF-kappaB activation assay, IkappaB-alpha degradation, surface IgM expression, anti-CD14 mAb blockade","journal":"Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — deletion mutagenesis with defined functional readouts, multiple orthogonal assays in one study","pmids":["8798531"],"is_preprint":false},{"year":1995,"finding":"CD14 does not confer ligand-specific recognition to distinguish between LPS agonists and antagonists (lipid IVA, RSLA); the species-specific pharmacology of these agents is independent of CD14 origin, indicating that a separate lipid A recognition/signaling receptor distinct from CD14 is responsible for discrimination.","method":"CD14 cDNA transfection into human, mouse, and hamster cell lines; NF-kappaB activation and cytokine assays with lipid A analogues","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 1 / Moderate — systematic cross-species transfection experiments with multiple cell lines and ligands in one study","pmids":["7568119"],"is_preprint":false},{"year":1998,"finding":"GPI anchoring of CD14 (which localizes it to glycolipid-rich membrane microdomains) is not required for LPS-mediated NF-kappaB activation, protein tyrosine kinase phosphorylation, or cytokine production; however, GPI-anchored CD14 but not transmembrane CD14 supports antibody cross-linking-induced calcium mobilization, mediated via phospholipase C and protein tyrosine kinases.","method":"THP-1 cells stably expressing GPI-anchored vs. transmembrane CD14; Triton X-100 solubility fractionation, NF-kappaB activation assay, cytokine ELISA, calcium flux measurement, pharmacological inhibitors","journal":"Infection and Immunity","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct comparison of GPI vs. TM forms with multiple functional readouts and pharmacological dissection in one study","pmids":["9488411"],"is_preprint":false},{"year":1998,"finding":"LBP can transfer LPS to CD11/CD18 (as well as CD14), and CD14 and CD11/CD18 share the same lipid A signaling pathway; a cytoplasmic deletion mutant of CD11/CD18 still activates cells, implying both receptors use an associated signal transducer distinct from themselves.","method":"CHO-K1 transfectants expressing CD14 or CD11/CD18; LPS-binding protein enhancement assay, lipid A analogue agonist/antagonist assays, cytoplasmic deletion mutant analysis","journal":"Journal of Immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal transfection experiments with multiple ligands in one lab, consistent with prior work but not independently replicated","pmids":["9820516"],"is_preprint":false},{"year":2000,"finding":"Soluble and membrane forms of CD14 have different structural determinants for LPS receptor function: certain deletions that abolish LPS binding in membrane CD14 have no effect in soluble CD14, while all five tested deletions essentially abolish soluble CD14 receptor function, suggesting conformationally distinct functional requirements.","method":"Deletion mutagenesis of CD14 expressed as soluble or GPI-anchored form; LPS binding assays, cell activation assays, competition assays with wild-type sCD14","journal":"Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — systematic deletion mutagenesis with both binding and functional assays for two forms of the protein in one study","pmids":["10652298"],"is_preprint":false},{"year":2003,"finding":"Surfactant protein C (SP-C) directly interacts with CD14 in a dose-dependent manner; LPS blocks CD14 binding to SP-C-coated wells, and SP-C enhances CD14 binding to LPS-coated wells, suggesting SP-C binds the same region of CD14 as LPS and facilitates LPS presentation to CD14 analogously to LBP.","method":"Radiolabeled CD14 binding assays, LPS-fluorescent binding to CD14-expressing cells in the presence of SP-C, competitive binding experiments","journal":"Infection and Immunity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding assays with native and synthetic SP-C, multiple orthogonal binding experiments in one study","pmids":["12496149"],"is_preprint":false},{"year":2005,"finding":"CD14 directly interacts with amyloid-beta peptide 42 (Abeta42) at the nanometer scale and mediates phagocytosis of Abeta42 by microglia; CD14-deficient cells fail to internalize exogenous Abeta42 at sub-inflammatory concentrations, while CD14-expressing cells efficiently phagocytose it within 30 minutes.","method":"FLIM-FRET microscopy showing direct molecular interaction; flow cytometry and confocal microscopy of phagocytosis; primary microglia from CD14-deficient mice; CD14-transfected CHO cells","journal":"Brain","confidence":"High","confidence_rationale":"Tier 2 / Strong — FRET-based direct interaction measurement plus genetic KO functional rescue, multiple orthogonal approaches in one study","pmids":["15857927"],"is_preprint":false},{"year":2005,"finding":"CD14 influences ligand specificity of the LPS receptor complex: CD14+/+ macrophages show exquisite sensitivity to smooth LPS (up to 150,000-fold more than CD14-/- cells) and discriminate between LPS partial structures; CD14-/- macrophages cannot distinguish between smooth LPS and its partial structures, indicating CD14 itself contributes to ligand recognition specificity.","method":"Comparative cytokine (TNF) assays in CD14+/+ vs. CD14-/- macrophages with a panel of LPS partial structures and bacterial LPS variants","journal":"Journal of Immunology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — systematic comparison in genetic KO vs. WT macrophages across multiple ligands in one rigorous study","pmids":["16148141"],"is_preprint":false},{"year":2004,"finding":"CD14 is an acute-phase protein regulated by IL-6: IL-6 stimulates CD14 mRNA and protein production in HepG2 hepatoma cells and primary human hepatocytes in vitro, and hepatic CD14 mRNA increases in IL-6+/+ but not IL-6-/- mice following turpentine-induced acute-phase response.","method":"Real-time PCR and protein ELISA in HepG2 and primary hepatocytes treated with IL-6; in vivo turpentine model in IL-6 knockout vs. wild-type mice","journal":"Journal of Immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vitro cytokine stimulation confirmed by in vivo genetic KO model, two orthogonal systems","pmids":["15034063"],"is_preprint":false},{"year":1998,"finding":"Hepatocytes express functional CD14 mRNA and protein; hepatocyte CD14 is upregulated transcriptionally by LPS in vivo (up to 20-fold at mRNA level) and by IL-1beta and/or TNF-alpha, and the expressed protein binds fluorescent LPS and activates NF-kappaB in CHO transfectants, identifying hepatocytes as a source of soluble CD14.","method":"Northern blot, in situ hybridization, nuclear run-on assay, Western blot, NF-kappaB activation assay in stably transfected CHO cells, fluorescent LPS binding","journal":"Infection and Immunity","confidence":"High","confidence_rationale":"Tier 1 / Moderate — functional reconstitution in CHO cells, nuclear run-on transcription assay, and in vivo LPS challenge in one comprehensive study","pmids":["9784508"],"is_preprint":false},{"year":2012,"finding":"CD14 and NFAT are required for LPS-induced PGE2 production and tissue edema formation: LPS stimulation of tissue-resident DCs induces microsomal PGE synthase-1 (mPGES-1) expression and PGE2 production via CD14- and NFAT-dependent pathways, controlling interstitial fluid pressure and antigen delivery to draining lymph nodes.","method":"CD14 knockout mice, NFAT inhibition, in vivo LPS skin injection model, mPGES-1 expression assay, PGE2 ELISA, intravital imaging of lymph node antigen arrival","journal":"Journal of Clinical Investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — CD14 KO mice plus NFAT inhibition with defined molecular pathway and functional in vivo phenotype","pmids":["22466648"],"is_preprint":false},{"year":2015,"finding":"In response to LPS, Gαi1 and Gαi3 form a complex containing CD14 and Gab1, which is required for PI3K-Akt activation; Gαi1/3 deficiency decreases LPS-induced TLR4 endocytosis and IRF3 phosphorylation, shifting macrophages to an M2-like phenotype with suppressed TNF-alpha, IL-6, IL-12, and NO production.","method":"Co-immunoprecipitation of CD14-Gαi1/3-Gab1 complex; Gαi1/3 knockdown in BMDMs; TLR4 endocytosis assay; phospho-Akt, phospho-IRF3 western blots; cytokine ELISA; in vivo LPS tolerance model","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP of complex plus KD phenotype plus in vivo model, multiple orthogonal methods in one study","pmids":["25825741"],"is_preprint":false},{"year":2015,"finding":"CD14 induces a clathrin-dependent immobile fraction of TLR4 at the plasma membrane upon LPS stimulation and drives TLR4 clustering into CD14/LPS/clathrin-positive puncta, initiating endocytosis; CD14/LPS but not TRAM localizes to RAB11A-positive endosomes, indicating CD14 and TRAM traffic independently during LPS signaling.","method":"TIRF microscopy, FRAP, live-cell confocal imaging of TLR4-GFP, CD14, clathrin, TRAM, and RAB11A in HEK293 and U373-CD14 cells; pharmacological and dominant-negative endocytosis inhibition","journal":"Traffic","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct live-cell imaging with multiple fluorescent markers and TIRF microscopy, multiple orthogonal localization methods in one study","pmids":["25707286"],"is_preprint":false},{"year":2020,"finding":"P2X7 receptor activation induces release of CD14 in extracellular vesicles, reducing macrophage plasma membrane CD14 levels and functionally attenuating LPS- (but not monophosphoryl lipid A-) induced pro-inflammatory cytokine production; in a murine sepsis model, P2X7 activity maintains elevated circulating CD14 levels and its reduction increases bacterial load and organ damage.","method":"Flow cytometry of extracellular vesicles; P2X7 pharmacological inhibition and genetic KO; cytokine ELISA; murine cecal ligation-puncture sepsis model with bacterial load and organ damage assessment","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vitro mechanism (vesicle release) confirmed by in vivo P2X7 KO model with multiple functional readouts","pmids":["33135636"],"is_preprint":false},{"year":2022,"finding":"Externalized phosphatidylinositides (PIPs) on the surfaces of apoptotic cells are eat-me signals recognized by CD14+ phagocytes; masking exofacial PIPs or knocking out CD14 in phagocytes blocks apoptotic cell phagocytosis, and exofacial PIP+ cells accumulate in tissues of Cd14-/- mice after apoptosis induction.","method":"Unbiased proteomics to identify ligand; anti-PI(3,4,5)P3 antibody and PH-domain probes; CD14 protein binding to PIP+ cells; CD14 knockout phagocytosis assay; in vivo irradiation model in Cd14-/- mice","journal":"Cell Death and Differentiation","confidence":"High","confidence_rationale":"Tier 2 / Strong — unbiased proteomics combined with KO functional assay and in vivo validation, multiple orthogonal methods","pmids":["35017647"],"is_preprint":false},{"year":2011,"finding":"CD14 modulates adipose tissue inflammatory activity and insulin resistance: recombinant soluble CD14 improves insulin action in wild-type, high-fat-fed, and ob/ob mice (but not CD14 KO mice); bone marrow transplantation from CD14 KO donors protects wild-type recipients from high-fat-diet-induced insulin resistance, linked to decreased mesenteric adipose tissue inflammatory gene expression.","method":"Hyperinsulinemic-euglycemic clamp in WT and CD14 KO mice; bone marrow chimera experiments; adipose tissue gene expression (microarray); rh-sCD14 administration","journal":"Diabetes","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO and bone marrow chimera experiments with functional metabolic readouts and gene expression profiling","pmids":["21700881"],"is_preprint":false},{"year":2009,"finding":"Chicken CD14, unlike mammalian CD14, is a transmembrane protein rather than GPI-anchored; PI-PLC cleaves human CD14 but not chicken CD14 from COS-7 cell surfaces, confirming the structural difference; the intracytoplasmic region of chCD14 contains no obvious signaling motifs.","method":"cDNA cloning, sequence analysis, COS-7 cell transfection, PI-PLC cleavage assay, flow cytometry","journal":"Developmental and Comparative Immunology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct biochemical PI-PLC cleavage experiment plus sequence analysis confirming transmembrane domain, single lab but orthogonal methods","pmids":["18761368"],"is_preprint":false},{"year":2013,"finding":"CD14 and TLR4 jointly mediate cytokine release (MCP-1, IL-6, IL-10) induced by electronegative LDL [LDL(-)] in human monocytes; anti-CD14 and anti-TLR4 antibodies each inhibit 70-80% of cytokine release, and LDL(-) and LPS compete for binding to monocytes and to CD14-coated wells, indicating a shared binding site.","method":"Antibody neutralization, gene silencing (siRNA), CD14 overexpression in THP-1 cells, cell-free CD14 binding assay, competitive binding experiments with LPS and LDL(-)","journal":"Atherosclerosis","confidence":"High","confidence_rationale":"Tier 2 / Moderate — antibody blockade confirmed by siRNA gene silencing and CD14 overexpression, plus cell-free binding assay showing direct competition","pmids":["23880187"],"is_preprint":false},{"year":2011,"finding":"Mycobacterial PIM1 and PIM2 analogues inhibit LPS binding to CD14 in TLR4/MD2/CD14-expressing HEK cells, and CD14 is required for PIM-mediated inhibition of LPS-induced TNF (but not IL-12 p40), revealing a CD14-dependent anti-inflammatory mechanism for mycobacterial PIMs.","method":"LPS binding inhibition assay in HEK cells expressing TLR4/MD2/CD14; CD14-deficient macrophages; rough-LPS (CD14-independent TLR4 stimulation) discrimination assay; TNF and IL-12 ELISA","journal":"PloS ONE","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO macrophages plus HEK cell binding assay, single lab with two complementary approaches","pmids":["21949737"],"is_preprint":false},{"year":1996,"finding":"Anti-CD14 monoclonal antibody treatment in primates prevented endotoxin-induced hypotension, reduced plasma cytokine levels (TNF-alpha, IL-1beta, IL-6, IL-8), and inhibited lung epithelial permeability changes, demonstrating that the CD14 pathway is functionally critical in vivo for LPS-induced septic shock.","method":"Primate model of endotoxemia; anti-CD14 mAb pretreatment; hemodynamic monitoring; cytokine ELISA; lung permeability assay","journal":"Journal of Clinical Investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo primate blockade study with multiple physiological and biochemical endpoints, direct causal demonstration","pmids":["8833900"],"is_preprint":false},{"year":2014,"finding":"Glimepiride activates GPI-phospholipase C to shed CD14 from RAW264 and microglial cell surfaces, and this shedding reduces TNF, IL-1, and IL-6 secretion induced by LPS, Abeta42, alpha-synuclein, and PrP82-146; cytokine production in response to all these ligands is CD14-dependent (blocked by anti-CD14 antiserum and absent in CD14 KO microglia), and glimepiride also reduces LPS/ligand-induced TLR-4 translocation into membrane rafts.","method":"ELISA and immunoblot for CD14 shedding; cytokine ELISA; pharmacological GPI-PLC inhibition; CD14 KO mouse microglia; anti-CD14 antiserum neutralization; membrane raft fractionation","journal":"Journal of Neuroinflammation","confidence":"High","confidence_rationale":"Tier 2 / Strong — CD14 KO genetic validation combined with antibody neutralization and pharmacological GPI-PLC inhibition, multiple ligands and orthogonal methods","pmids":["24952384"],"is_preprint":false}],"current_model":"CD14 is a GPI-anchored (in mammals; transmembrane in chickens) glycoprotein that functions as a co-receptor and pattern recognition molecule for LPS-LBP complexes and diverse bacterial envelope components (peptidoglycan, PIMs), binding ligands primarily through its N-terminal leucine-rich domain, concentrating and presenting them to TLR4 for signal transduction; CD14 also directly mediates phagocytosis of apoptotic cells via externalized phosphatidylinositides and of Abeta42, controls TLR4 endocytosis and TRAM-TRIF pathway activation, couples to Gαi1/3-Gab1-PI3K-Akt signaling, drives NFAT-dependent PGE2 production and tissue edema, and can be shed from the membrane via GPI-PLC or P2X7-dependent extracellular vesicle release, with soluble CD14 enabling LPS responses in cells lacking membrane CD14."},"narrative":{"mechanistic_narrative":"CD14 is a glycosylphosphatidylinositol-anchored myeloid glycoprotein that functions as the cellular receptor and concentrating co-receptor for bacterial endotoxin, binding LPS–LBP complexes and presenting them for innate immune signaling [PMID:1698311, PMID:2462937]. It acts as a broad pattern-recognition molecule for diverse bacterial envelope components from Gram-negative, Gram-positive, and mycobacterial organisms, including peptidoglycan, whose recognition maps to partially distinct sites within the N-terminal region from those used for endotoxin [PMID:7534618, PMID:8798531]. Beyond ligand capture, CD14 itself contributes recognition specificity to the LPS receptor complex, conferring exquisite sensitivity to smooth LPS and the ability to discriminate among LPS partial structures [PMID:16148141], while a separate lipid A signaling receptor governs agonist/antagonist discrimination [PMID:7568119]. CD14 controls the trafficking arm of TLR4 signaling: upon LPS engagement it drives clathrin-dependent TLR4 clustering and endocytosis [PMID:25707286] and nucleates a Gαi1/3–CD14–Gab1 complex required for PI3K–Akt activation, TLR4 internalization, and IRF3-driven responses [PMID:25825741]. It also couples LPS sensing to NFAT-dependent mPGES-1 induction and PGE2 production that drives tissue edema and antigen delivery [PMID:22466648]. Membrane anchoring is dispensable for core signaling: soluble CD14 confers LPS responsiveness on cells lacking membrane CD14 by engaging additional surface proteins, and the soluble and membrane forms have conformationally distinct functional requirements [PMID:1281215, PMID:10652298]. CD14 additionally serves phagocytic functions independent of bacterial sensing, directly binding Abeta42 to mediate microglial uptake [PMID:15857927] and recognizing externalized phosphatidylinositides as eat-me signals on apoptotic cells [PMID:35017647]. Surface CD14 is dynamically regulated through GPI-PLC- and P2X7-driven shedding, which attenuates inflammatory responses [PMID:33135636, PMID:24952384], and the in vivo importance of the pathway is established by primate endotoxemia blockade and CD14-knockout metabolic and septic phenotypes [PMID:8833900, PMID:21700881].","teleology":[{"year":1989,"claim":"Establishing how CD14 attaches to the cell membrane defined the structural basis for its later-discovered role as a mobile, sheddable receptor.","evidence":"GPI-PLC cleavage, PNH monocyte analysis, and cDNA cloning showing no transmembrane domain","pmids":["2462937"],"confidence":"High","gaps":["GPI anchoring leaves CD14 lacking a cytoplasmic signaling domain, implying a required signal-transducing partner not identified here"]},{"year":1990,"claim":"Identified CD14 as the cellular receptor for LPS–LBP complexes, answering what surface molecule initiates monocyte responses to endotoxin.","evidence":"mAb blockade and binding assays with TNF-alpha readout in whole blood","pmids":["1698311"],"confidence":"High","gaps":["Did not identify the transmembrane signal transducer downstream of CD14"]},{"year":1992,"claim":"Showed CD14 function does not require a membrane anchor, establishing that soluble CD14 enables LPS responses in non-myeloid cells.","evidence":"Immunodepletion/reconstitution of serum sCD14 with endothelial and astrocytoma activation readouts","pmids":["1281215"],"confidence":"High","gaps":["The additional cell-surface protein sCD14 engages to transduce signal was not identified"]},{"year":1996,"claim":"Demonstrated the in vivo physiological importance of the CD14 pathway in septic shock.","evidence":"Anti-CD14 mAb pretreatment in a primate endotoxemia model with hemodynamic and cytokine endpoints","pmids":["8833900"],"confidence":"High","gaps":["Did not dissect which downstream effectors mediate the protective effect"]},{"year":1996,"claim":"Broadened CD14 from an LPS receptor to a general pattern-recognition receptor and mapped distinct ligand-binding regions in the N-terminus.","evidence":"Diverse bacterial ligand activation assays plus CD14 deletion mutagenesis in transfected cells","pmids":["7534618","8798531"],"confidence":"High","gaps":["High-resolution structural definition of the separate binding sites not resolved"]},{"year":2000,"claim":"Resolved that soluble and membrane CD14 use conformationally distinct functional determinants, clarifying that the two forms are not interchangeable.","evidence":"Deletion mutagenesis with binding and activation assays comparing soluble and GPI-anchored CD14","pmids":["10652298"],"confidence":"High","gaps":["Structural basis for the conformational difference between forms not defined"]},{"year":2005,"claim":"Extended CD14 beyond bacterial sensing to direct binding and microglial phagocytosis of Abeta42, implicating it in neurodegenerative clearance.","evidence":"FLIM-FRET interaction measurement plus phagocytosis assays in CD14-KO and CD14-transfected cells","pmids":["15857927"],"confidence":"High","gaps":["Signal transducer for CD14-mediated Abeta42 internalization not identified"]},{"year":2011,"claim":"Linked CD14 to metabolic disease by showing it modulates adipose inflammation and insulin resistance.","evidence":"Euglycemic clamp, bone marrow chimeras, and rh-sCD14 administration in WT and CD14-KO mice","pmids":["21700881"],"confidence":"High","gaps":["Molecular ligand driving the adipose inflammatory effect in this setting not defined"]},{"year":2012,"claim":"Connected CD14 sensing to a defined downstream effector pathway producing PGE2 and tissue edema.","evidence":"CD14-KO mice plus NFAT inhibition, mPGES-1 and PGE2 readouts, intravital lymph node imaging","pmids":["22466648"],"confidence":"High","gaps":["How CD14 engagement activates NFAT mechanistically not detailed"]},{"year":2015,"claim":"Defined the molecular machinery by which CD14 governs the trafficking and second wave of TLR4 signaling.","evidence":"Co-IP of CD14–Gαi1/3–Gab1, TIRF/FRAP imaging of TLR4 clustering and endocytosis, knockdown phenotypes","pmids":["25825741","25707286"],"confidence":"High","gaps":["How CD14 nucleates clathrin recruitment at the molecular level not fully resolved"]},{"year":2020,"claim":"Established that surface CD14 is dynamically regulated by P2X7-driven extracellular vesicle release, tuning inflammatory output.","evidence":"Flow cytometry of vesicles, P2X7 inhibition/KO, cytokine assays, and cecal ligation-puncture sepsis model","pmids":["33135636"],"confidence":"High","gaps":["Mechanism coupling P2X7 activity to CD14 vesicle loading not defined"]},{"year":2022,"claim":"Identified externalized phosphatidylinositides as a CD14 eat-me ligand, generalizing its phagocytic-receptor role to apoptotic cell clearance.","evidence":"Unbiased proteomics, PIP probes, CD14-KO phagocytosis assays, and in vivo irradiation model","pmids":["35017647"],"confidence":"High","gaps":["Downstream engulfment signaling from CD14–PIP recognition not mapped"]},{"year":null,"claim":"The identity and stoichiometry of the transmembrane signal transducer(s) that couple GPI-anchored or soluble CD14 to intracellular signaling across its bacterial, apoptotic, and amyloid ligands remain incompletely defined.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified structural model of CD14 ligand-presentation across diverse cargoes","Mechanism linking distinct CD14 ligands to convergent or divergent signaling outputs unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[0,3]},{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[10,18]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[0,18]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,16]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[15,16]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,6,16]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[2,17]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[17]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[16]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,3,15]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[15,16]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[16,17]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[18]}],"complexes":["CD14–Gαi1/3–Gab1 complex","TLR4/MD2/CD14 LPS receptor complex"],"partners":["TLR4","LBP","GNAI1","GNAI3","GAB1","ITGAM","SFTPC"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P08571","full_name":"Monocyte differentiation antigen CD14","aliases":["My23 antigen","Myeloid cell-specific leucine-rich glycoprotein"],"length_aa":375,"mass_kda":40.1,"function":"Coreceptor for bacterial lipopolysaccharide (PubMed:1698311, PubMed:23264655). In concert with LBP, binds to monomeric lipopolysaccharide and delivers it to the LY96/TLR4 complex, thereby mediating the innate immune response to bacterial lipopolysaccharide (LPS) (PubMed:20133493, PubMed:22265692, PubMed:23264655). Acts via MyD88, TIRAP and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response (PubMed:8612135). Acts as a coreceptor for TLR2:TLR6 heterodimer in response to diacylated lipopeptides and for TLR2:TLR1 heterodimer in response to triacylated lipopeptides, these clusters trigger signaling from the cell surface and subsequently are targeted to the Golgi in a lipid-raft dependent pathway (PubMed:16880211). Binds electronegative LDL (LDL(-)) and mediates the cytokine release induced by LDL(-) (PubMed:23880187)","subcellular_location":"Cell membrane; Secreted; Membrane raft; Golgi apparatus","url":"https://www.uniprot.org/uniprotkb/P08571/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CD14","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CD14","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":"619990","title":"TRANSMEMBRANE p24 TRAFFICKING PROTEIN 7; 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immunology","url":"https://pubmed.ncbi.nlm.nih.gov/32849510","citation_count":26,"is_preprint":false},{"pmid":"21921097","id":"PMC_21921097","title":"Soluble CD14 and CD14 polymorphisms in rheumatoid arthritis.","date":"2011","source":"The Journal of rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/21921097","citation_count":25,"is_preprint":false},{"pmid":"18299306","id":"PMC_18299306","title":"Role of complement and CD14 in meconium-induced cytokine formation.","date":"2008","source":"Pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/18299306","citation_count":25,"is_preprint":false},{"pmid":"28239800","id":"PMC_28239800","title":"Intermediate CD14++CD16+ monocyte predicts severe coronary stenosis and extensive plaque involvement in asymptomatic individuals.","date":"2017","source":"The international journal of cardiovascular imaging","url":"https://pubmed.ncbi.nlm.nih.gov/28239800","citation_count":25,"is_preprint":false},{"pmid":"12573661","id":"PMC_12573661","title":"RPE CD14 immunohistochemical, genetic, and functional expression.","date":"2003","source":"Experimental eye research","url":"https://pubmed.ncbi.nlm.nih.gov/12573661","citation_count":24,"is_preprint":false},{"pmid":"14499251","id":"PMC_14499251","title":"Histamine downregulates CD14 expression via H2 receptors on human monocytes.","date":"2003","source":"Clinical immunology (Orlando, Fla.)","url":"https://pubmed.ncbi.nlm.nih.gov/14499251","citation_count":24,"is_preprint":false},{"pmid":"15257175","id":"PMC_15257175","title":"CD14 C(-260)T gene polymorphism, circulating soluble CD14 levels and arteriosclerosis.","date":"2004","source":"Journal of hypertension","url":"https://pubmed.ncbi.nlm.nih.gov/15257175","citation_count":24,"is_preprint":false},{"pmid":"18925877","id":"PMC_18925877","title":"Does the relationship between IgE and the CD14 gene depend on ethnicity?","date":"2008","source":"Allergy","url":"https://pubmed.ncbi.nlm.nih.gov/18925877","citation_count":23,"is_preprint":false},{"pmid":"36288286","id":"PMC_36288286","title":"Up-regulation of BTN3A1 on CD14+ cells promotes Vγ9Vδ2 T cell activation in psoriasis.","date":"2022","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/36288286","citation_count":23,"is_preprint":false},{"pmid":"21949737","id":"PMC_21949737","title":"Mycobacterial PIMs inhibit host inflammatory responses through CD14-dependent and CD14-independent mechanisms.","date":"2011","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/21949737","citation_count":23,"is_preprint":false},{"pmid":"30296338","id":"PMC_30296338","title":"JAG2 signaling induces differentiation of CD14+ monocytes into Langerhans cell histiocytosis-like cells.","date":"2018","source":"Journal of leukocyte biology","url":"https://pubmed.ncbi.nlm.nih.gov/30296338","citation_count":22,"is_preprint":false},{"pmid":"23107636","id":"PMC_23107636","title":"Association between the CD14 gene C-159T polymorphism and serum soluble CD14 with pulmonary tuberculosis.","date":"2012","source":"The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease","url":"https://pubmed.ncbi.nlm.nih.gov/23107636","citation_count":22,"is_preprint":false},{"pmid":"31484727","id":"PMC_31484727","title":"Immunoproteasome Inhibition Selectively Kills Human CD14+ Monocytes and as a Result Dampens IL-23 Secretion.","date":"2019","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/31484727","citation_count":22,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50005,"output_tokens":6507,"usd":0.12381,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15426,"output_tokens":3842,"usd":0.08659,"stage2_stop_reason":"end_turn"},"total_usd":0.2104,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1990,\n      \"finding\": \"CD14 on monocyte surfaces binds complexes of LPS and LPS-binding protein (LBP), and blockade of CD14 with monoclonal antibodies prevented TNF-alpha synthesis by whole blood incubated with LPS, establishing CD14 as the cellular receptor for LPS-LBP complexes.\",\n      \"method\": \"Monoclonal antibody blockade, binding assay, TNF-alpha secretion assay in whole blood\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct binding assay plus functional blockade with mAb, foundational paper replicated extensively across labs\",\n      \"pmids\": [\"1698311\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1989,\n      \"finding\": \"CD14 is anchored to the plasma membrane exclusively via a glycosylphosphatidylinositol (GPI) lipid anchor, as demonstrated by release with GPI-specific phospholipase C and absence from PNH patient monocytes; the protein lacks a conventional transmembrane domain.\",\n      \"method\": \"GPI-specific phospholipase C treatment, transfection of COS cells with CD14 cDNA, analysis of PNH patient monocytes, cDNA cloning and sequence analysis\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — biochemical reconstitution (PI-PLC cleavage), genetic evidence (PNH cells), multiple orthogonal methods, widely replicated\",\n      \"pmids\": [\"2462937\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"Soluble CD14 (sCD14) enables LPS responses in cells that lack membrane CD14 (endothelial and astrocytoma cells); immunodepletion of sCD14 from serum abolishes these responses and addition of sCD14 restores them, showing that a membrane anchor is not required for CD14 function but that sCD14 must interact with additional cell-surface proteins to transduce a signal.\",\n      \"method\": \"Immunodepletion of sCD14 from serum, reconstitution with purified sCD14, anti-CD14 antibody blockade, ELAM-1 expression assay, IL-6 secretion assay, cytotoxicity assay\",\n      \"journal\": \"Journal of Experimental Medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal cell assays plus immunodepletion-reconstitution, replicated across three cell types in one rigorous study\",\n      \"pmids\": [\"1281215\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"CD14 acts as a pattern recognition receptor for a broad range of bacterial envelope components from Gram-negative and Gram-positive organisms as well as mycobacteria, initiating cell activation by each.\",\n      \"method\": \"Cell activation assays with diverse bacterial cell-wall ligands in CD14-expressing cells; anti-CD14 antibody blockade\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple ligands tested with CD14-transfected cells and antibody blockade, widely replicated\",\n      \"pmids\": [\"7534618\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"CD14 is a cell-activating receptor for bacterial peptidoglycan; the N-terminal 151 amino acids are sufficient for full responsiveness, and deletion mutants within the N-terminal 65 amino acids show differential responses to peptidoglycan vs. endotoxin, mapping partially distinct binding sites for these ligands.\",\n      \"method\": \"Transfection of 70Z/3 cells with human CD14 and deletion mutants; NF-kappaB activation assay, IkappaB-alpha degradation, surface IgM expression, anti-CD14 mAb blockade\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — deletion mutagenesis with defined functional readouts, multiple orthogonal assays in one study\",\n      \"pmids\": [\"8798531\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"CD14 does not confer ligand-specific recognition to distinguish between LPS agonists and antagonists (lipid IVA, RSLA); the species-specific pharmacology of these agents is independent of CD14 origin, indicating that a separate lipid A recognition/signaling receptor distinct from CD14 is responsible for discrimination.\",\n      \"method\": \"CD14 cDNA transfection into human, mouse, and hamster cell lines; NF-kappaB activation and cytokine assays with lipid A analogues\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — systematic cross-species transfection experiments with multiple cell lines and ligands in one study\",\n      \"pmids\": [\"7568119\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"GPI anchoring of CD14 (which localizes it to glycolipid-rich membrane microdomains) is not required for LPS-mediated NF-kappaB activation, protein tyrosine kinase phosphorylation, or cytokine production; however, GPI-anchored CD14 but not transmembrane CD14 supports antibody cross-linking-induced calcium mobilization, mediated via phospholipase C and protein tyrosine kinases.\",\n      \"method\": \"THP-1 cells stably expressing GPI-anchored vs. transmembrane CD14; Triton X-100 solubility fractionation, NF-kappaB activation assay, cytokine ELISA, calcium flux measurement, pharmacological inhibitors\",\n      \"journal\": \"Infection and Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct comparison of GPI vs. TM forms with multiple functional readouts and pharmacological dissection in one study\",\n      \"pmids\": [\"9488411\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"LBP can transfer LPS to CD11/CD18 (as well as CD14), and CD14 and CD11/CD18 share the same lipid A signaling pathway; a cytoplasmic deletion mutant of CD11/CD18 still activates cells, implying both receptors use an associated signal transducer distinct from themselves.\",\n      \"method\": \"CHO-K1 transfectants expressing CD14 or CD11/CD18; LPS-binding protein enhancement assay, lipid A analogue agonist/antagonist assays, cytoplasmic deletion mutant analysis\",\n      \"journal\": \"Journal of Immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal transfection experiments with multiple ligands in one lab, consistent with prior work but not independently replicated\",\n      \"pmids\": [\"9820516\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Soluble and membrane forms of CD14 have different structural determinants for LPS receptor function: certain deletions that abolish LPS binding in membrane CD14 have no effect in soluble CD14, while all five tested deletions essentially abolish soluble CD14 receptor function, suggesting conformationally distinct functional requirements.\",\n      \"method\": \"Deletion mutagenesis of CD14 expressed as soluble or GPI-anchored form; LPS binding assays, cell activation assays, competition assays with wild-type sCD14\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — systematic deletion mutagenesis with both binding and functional assays for two forms of the protein in one study\",\n      \"pmids\": [\"10652298\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Surfactant protein C (SP-C) directly interacts with CD14 in a dose-dependent manner; LPS blocks CD14 binding to SP-C-coated wells, and SP-C enhances CD14 binding to LPS-coated wells, suggesting SP-C binds the same region of CD14 as LPS and facilitates LPS presentation to CD14 analogously to LBP.\",\n      \"method\": \"Radiolabeled CD14 binding assays, LPS-fluorescent binding to CD14-expressing cells in the presence of SP-C, competitive binding experiments\",\n      \"journal\": \"Infection and Immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding assays with native and synthetic SP-C, multiple orthogonal binding experiments in one study\",\n      \"pmids\": [\"12496149\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"CD14 directly interacts with amyloid-beta peptide 42 (Abeta42) at the nanometer scale and mediates phagocytosis of Abeta42 by microglia; CD14-deficient cells fail to internalize exogenous Abeta42 at sub-inflammatory concentrations, while CD14-expressing cells efficiently phagocytose it within 30 minutes.\",\n      \"method\": \"FLIM-FRET microscopy showing direct molecular interaction; flow cytometry and confocal microscopy of phagocytosis; primary microglia from CD14-deficient mice; CD14-transfected CHO cells\",\n      \"journal\": \"Brain\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — FRET-based direct interaction measurement plus genetic KO functional rescue, multiple orthogonal approaches in one study\",\n      \"pmids\": [\"15857927\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"CD14 influences ligand specificity of the LPS receptor complex: CD14+/+ macrophages show exquisite sensitivity to smooth LPS (up to 150,000-fold more than CD14-/- cells) and discriminate between LPS partial structures; CD14-/- macrophages cannot distinguish between smooth LPS and its partial structures, indicating CD14 itself contributes to ligand recognition specificity.\",\n      \"method\": \"Comparative cytokine (TNF) assays in CD14+/+ vs. CD14-/- macrophages with a panel of LPS partial structures and bacterial LPS variants\",\n      \"journal\": \"Journal of Immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic comparison in genetic KO vs. WT macrophages across multiple ligands in one rigorous study\",\n      \"pmids\": [\"16148141\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CD14 is an acute-phase protein regulated by IL-6: IL-6 stimulates CD14 mRNA and protein production in HepG2 hepatoma cells and primary human hepatocytes in vitro, and hepatic CD14 mRNA increases in IL-6+/+ but not IL-6-/- mice following turpentine-induced acute-phase response.\",\n      \"method\": \"Real-time PCR and protein ELISA in HepG2 and primary hepatocytes treated with IL-6; in vivo turpentine model in IL-6 knockout vs. wild-type mice\",\n      \"journal\": \"Journal of Immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vitro cytokine stimulation confirmed by in vivo genetic KO model, two orthogonal systems\",\n      \"pmids\": [\"15034063\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Hepatocytes express functional CD14 mRNA and protein; hepatocyte CD14 is upregulated transcriptionally by LPS in vivo (up to 20-fold at mRNA level) and by IL-1beta and/or TNF-alpha, and the expressed protein binds fluorescent LPS and activates NF-kappaB in CHO transfectants, identifying hepatocytes as a source of soluble CD14.\",\n      \"method\": \"Northern blot, in situ hybridization, nuclear run-on assay, Western blot, NF-kappaB activation assay in stably transfected CHO cells, fluorescent LPS binding\",\n      \"journal\": \"Infection and Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — functional reconstitution in CHO cells, nuclear run-on transcription assay, and in vivo LPS challenge in one comprehensive study\",\n      \"pmids\": [\"9784508\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CD14 and NFAT are required for LPS-induced PGE2 production and tissue edema formation: LPS stimulation of tissue-resident DCs induces microsomal PGE synthase-1 (mPGES-1) expression and PGE2 production via CD14- and NFAT-dependent pathways, controlling interstitial fluid pressure and antigen delivery to draining lymph nodes.\",\n      \"method\": \"CD14 knockout mice, NFAT inhibition, in vivo LPS skin injection model, mPGES-1 expression assay, PGE2 ELISA, intravital imaging of lymph node antigen arrival\",\n      \"journal\": \"Journal of Clinical Investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CD14 KO mice plus NFAT inhibition with defined molecular pathway and functional in vivo phenotype\",\n      \"pmids\": [\"22466648\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"In response to LPS, Gαi1 and Gαi3 form a complex containing CD14 and Gab1, which is required for PI3K-Akt activation; Gαi1/3 deficiency decreases LPS-induced TLR4 endocytosis and IRF3 phosphorylation, shifting macrophages to an M2-like phenotype with suppressed TNF-alpha, IL-6, IL-12, and NO production.\",\n      \"method\": \"Co-immunoprecipitation of CD14-Gαi1/3-Gab1 complex; Gαi1/3 knockdown in BMDMs; TLR4 endocytosis assay; phospho-Akt, phospho-IRF3 western blots; cytokine ELISA; in vivo LPS tolerance model\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP of complex plus KD phenotype plus in vivo model, multiple orthogonal methods in one study\",\n      \"pmids\": [\"25825741\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CD14 induces a clathrin-dependent immobile fraction of TLR4 at the plasma membrane upon LPS stimulation and drives TLR4 clustering into CD14/LPS/clathrin-positive puncta, initiating endocytosis; CD14/LPS but not TRAM localizes to RAB11A-positive endosomes, indicating CD14 and TRAM traffic independently during LPS signaling.\",\n      \"method\": \"TIRF microscopy, FRAP, live-cell confocal imaging of TLR4-GFP, CD14, clathrin, TRAM, and RAB11A in HEK293 and U373-CD14 cells; pharmacological and dominant-negative endocytosis inhibition\",\n      \"journal\": \"Traffic\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct live-cell imaging with multiple fluorescent markers and TIRF microscopy, multiple orthogonal localization methods in one study\",\n      \"pmids\": [\"25707286\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"P2X7 receptor activation induces release of CD14 in extracellular vesicles, reducing macrophage plasma membrane CD14 levels and functionally attenuating LPS- (but not monophosphoryl lipid A-) induced pro-inflammatory cytokine production; in a murine sepsis model, P2X7 activity maintains elevated circulating CD14 levels and its reduction increases bacterial load and organ damage.\",\n      \"method\": \"Flow cytometry of extracellular vesicles; P2X7 pharmacological inhibition and genetic KO; cytokine ELISA; murine cecal ligation-puncture sepsis model with bacterial load and organ damage assessment\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vitro mechanism (vesicle release) confirmed by in vivo P2X7 KO model with multiple functional readouts\",\n      \"pmids\": [\"33135636\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Externalized phosphatidylinositides (PIPs) on the surfaces of apoptotic cells are eat-me signals recognized by CD14+ phagocytes; masking exofacial PIPs or knocking out CD14 in phagocytes blocks apoptotic cell phagocytosis, and exofacial PIP+ cells accumulate in tissues of Cd14-/- mice after apoptosis induction.\",\n      \"method\": \"Unbiased proteomics to identify ligand; anti-PI(3,4,5)P3 antibody and PH-domain probes; CD14 protein binding to PIP+ cells; CD14 knockout phagocytosis assay; in vivo irradiation model in Cd14-/- mice\",\n      \"journal\": \"Cell Death and Differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — unbiased proteomics combined with KO functional assay and in vivo validation, multiple orthogonal methods\",\n      \"pmids\": [\"35017647\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CD14 modulates adipose tissue inflammatory activity and insulin resistance: recombinant soluble CD14 improves insulin action in wild-type, high-fat-fed, and ob/ob mice (but not CD14 KO mice); bone marrow transplantation from CD14 KO donors protects wild-type recipients from high-fat-diet-induced insulin resistance, linked to decreased mesenteric adipose tissue inflammatory gene expression.\",\n      \"method\": \"Hyperinsulinemic-euglycemic clamp in WT and CD14 KO mice; bone marrow chimera experiments; adipose tissue gene expression (microarray); rh-sCD14 administration\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO and bone marrow chimera experiments with functional metabolic readouts and gene expression profiling\",\n      \"pmids\": [\"21700881\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Chicken CD14, unlike mammalian CD14, is a transmembrane protein rather than GPI-anchored; PI-PLC cleaves human CD14 but not chicken CD14 from COS-7 cell surfaces, confirming the structural difference; the intracytoplasmic region of chCD14 contains no obvious signaling motifs.\",\n      \"method\": \"cDNA cloning, sequence analysis, COS-7 cell transfection, PI-PLC cleavage assay, flow cytometry\",\n      \"journal\": \"Developmental and Comparative Immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct biochemical PI-PLC cleavage experiment plus sequence analysis confirming transmembrane domain, single lab but orthogonal methods\",\n      \"pmids\": [\"18761368\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CD14 and TLR4 jointly mediate cytokine release (MCP-1, IL-6, IL-10) induced by electronegative LDL [LDL(-)] in human monocytes; anti-CD14 and anti-TLR4 antibodies each inhibit 70-80% of cytokine release, and LDL(-) and LPS compete for binding to monocytes and to CD14-coated wells, indicating a shared binding site.\",\n      \"method\": \"Antibody neutralization, gene silencing (siRNA), CD14 overexpression in THP-1 cells, cell-free CD14 binding assay, competitive binding experiments with LPS and LDL(-)\",\n      \"journal\": \"Atherosclerosis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — antibody blockade confirmed by siRNA gene silencing and CD14 overexpression, plus cell-free binding assay showing direct competition\",\n      \"pmids\": [\"23880187\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Mycobacterial PIM1 and PIM2 analogues inhibit LPS binding to CD14 in TLR4/MD2/CD14-expressing HEK cells, and CD14 is required for PIM-mediated inhibition of LPS-induced TNF (but not IL-12 p40), revealing a CD14-dependent anti-inflammatory mechanism for mycobacterial PIMs.\",\n      \"method\": \"LPS binding inhibition assay in HEK cells expressing TLR4/MD2/CD14; CD14-deficient macrophages; rough-LPS (CD14-independent TLR4 stimulation) discrimination assay; TNF and IL-12 ELISA\",\n      \"journal\": \"PloS ONE\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO macrophages plus HEK cell binding assay, single lab with two complementary approaches\",\n      \"pmids\": [\"21949737\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Anti-CD14 monoclonal antibody treatment in primates prevented endotoxin-induced hypotension, reduced plasma cytokine levels (TNF-alpha, IL-1beta, IL-6, IL-8), and inhibited lung epithelial permeability changes, demonstrating that the CD14 pathway is functionally critical in vivo for LPS-induced septic shock.\",\n      \"method\": \"Primate model of endotoxemia; anti-CD14 mAb pretreatment; hemodynamic monitoring; cytokine ELISA; lung permeability assay\",\n      \"journal\": \"Journal of Clinical Investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo primate blockade study with multiple physiological and biochemical endpoints, direct causal demonstration\",\n      \"pmids\": [\"8833900\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Glimepiride activates GPI-phospholipase C to shed CD14 from RAW264 and microglial cell surfaces, and this shedding reduces TNF, IL-1, and IL-6 secretion induced by LPS, Abeta42, alpha-synuclein, and PrP82-146; cytokine production in response to all these ligands is CD14-dependent (blocked by anti-CD14 antiserum and absent in CD14 KO microglia), and glimepiride also reduces LPS/ligand-induced TLR-4 translocation into membrane rafts.\",\n      \"method\": \"ELISA and immunoblot for CD14 shedding; cytokine ELISA; pharmacological GPI-PLC inhibition; CD14 KO mouse microglia; anti-CD14 antiserum neutralization; membrane raft fractionation\",\n      \"journal\": \"Journal of Neuroinflammation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CD14 KO genetic validation combined with antibody neutralization and pharmacological GPI-PLC inhibition, multiple ligands and orthogonal methods\",\n      \"pmids\": [\"24952384\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CD14 is a GPI-anchored (in mammals; transmembrane in chickens) glycoprotein that functions as a co-receptor and pattern recognition molecule for LPS-LBP complexes and diverse bacterial envelope components (peptidoglycan, PIMs), binding ligands primarily through its N-terminal leucine-rich domain, concentrating and presenting them to TLR4 for signal transduction; CD14 also directly mediates phagocytosis of apoptotic cells via externalized phosphatidylinositides and of Abeta42, controls TLR4 endocytosis and TRAM-TRIF pathway activation, couples to Gαi1/3-Gab1-PI3K-Akt signaling, drives NFAT-dependent PGE2 production and tissue edema, and can be shed from the membrane via GPI-PLC or P2X7-dependent extracellular vesicle release, with soluble CD14 enabling LPS responses in cells lacking membrane CD14.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CD14 is a glycosylphosphatidylinositol-anchored myeloid glycoprotein that functions as the cellular receptor and concentrating co-receptor for bacterial endotoxin, binding LPS–LBP complexes and presenting them for innate immune signaling [#0, #1]. It acts as a broad pattern-recognition molecule for diverse bacterial envelope components from Gram-negative, Gram-positive, and mycobacterial organisms, including peptidoglycan, whose recognition maps to partially distinct sites within the N-terminal region from those used for endotoxin [#3, #4]. Beyond ligand capture, CD14 itself contributes recognition specificity to the LPS receptor complex, conferring exquisite sensitivity to smooth LPS and the ability to discriminate among LPS partial structures [#11], while a separate lipid A signaling receptor governs agonist/antagonist discrimination [#5]. CD14 controls the trafficking arm of TLR4 signaling: upon LPS engagement it drives clathrin-dependent TLR4 clustering and endocytosis [#16] and nucleates a Gαi1/3–CD14–Gab1 complex required for PI3K–Akt activation, TLR4 internalization, and IRF3-driven responses [#15]. It also couples LPS sensing to NFAT-dependent mPGES-1 induction and PGE2 production that drives tissue edema and antigen delivery [#14]. Membrane anchoring is dispensable for core signaling: soluble CD14 confers LPS responsiveness on cells lacking membrane CD14 by engaging additional surface proteins, and the soluble and membrane forms have conformationally distinct functional requirements [#2, #8]. CD14 additionally serves phagocytic functions independent of bacterial sensing, directly binding Abeta42 to mediate microglial uptake [#10] and recognizing externalized phosphatidylinositides as eat-me signals on apoptotic cells [#18]. Surface CD14 is dynamically regulated through GPI-PLC- and P2X7-driven shedding, which attenuates inflammatory responses [#17, #24], and the in vivo importance of the pathway is established by primate endotoxemia blockade and CD14-knockout metabolic and septic phenotypes [#23, #19].\",\n  \"teleology\": [\n    {\n      \"year\": 1989,\n      \"claim\": \"Establishing how CD14 attaches to the cell membrane defined the structural basis for its later-discovered role as a mobile, sheddable receptor.\",\n      \"evidence\": \"GPI-PLC cleavage, PNH monocyte analysis, and cDNA cloning showing no transmembrane domain\",\n      \"pmids\": [\"2462937\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"GPI anchoring leaves CD14 lacking a cytoplasmic signaling domain, implying a required signal-transducing partner not identified here\"]\n    },\n    {\n      \"year\": 1990,\n      \"claim\": \"Identified CD14 as the cellular receptor for LPS–LBP complexes, answering what surface molecule initiates monocyte responses to endotoxin.\",\n      \"evidence\": \"mAb blockade and binding assays with TNF-alpha readout in whole blood\",\n      \"pmids\": [\"1698311\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the transmembrane signal transducer downstream of CD14\"]\n    },\n    {\n      \"year\": 1992,\n      \"claim\": \"Showed CD14 function does not require a membrane anchor, establishing that soluble CD14 enables LPS responses in non-myeloid cells.\",\n      \"evidence\": \"Immunodepletion/reconstitution of serum sCD14 with endothelial and astrocytoma activation readouts\",\n      \"pmids\": [\"1281215\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The additional cell-surface protein sCD14 engages to transduce signal was not identified\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Demonstrated the in vivo physiological importance of the CD14 pathway in septic shock.\",\n      \"evidence\": \"Anti-CD14 mAb pretreatment in a primate endotoxemia model with hemodynamic and cytokine endpoints\",\n      \"pmids\": [\"8833900\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not dissect which downstream effectors mediate the protective effect\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Broadened CD14 from an LPS receptor to a general pattern-recognition receptor and mapped distinct ligand-binding regions in the N-terminus.\",\n      \"evidence\": \"Diverse bacterial ligand activation assays plus CD14 deletion mutagenesis in transfected cells\",\n      \"pmids\": [\"7534618\", \"8798531\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"High-resolution structural definition of the separate binding sites not resolved\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Resolved that soluble and membrane CD14 use conformationally distinct functional determinants, clarifying that the two forms are not interchangeable.\",\n      \"evidence\": \"Deletion mutagenesis with binding and activation assays comparing soluble and GPI-anchored CD14\",\n      \"pmids\": [\"10652298\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for the conformational difference between forms not defined\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Extended CD14 beyond bacterial sensing to direct binding and microglial phagocytosis of Abeta42, implicating it in neurodegenerative clearance.\",\n      \"evidence\": \"FLIM-FRET interaction measurement plus phagocytosis assays in CD14-KO and CD14-transfected cells\",\n      \"pmids\": [\"15857927\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signal transducer for CD14-mediated Abeta42 internalization not identified\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Linked CD14 to metabolic disease by showing it modulates adipose inflammation and insulin resistance.\",\n      \"evidence\": \"Euglycemic clamp, bone marrow chimeras, and rh-sCD14 administration in WT and CD14-KO mice\",\n      \"pmids\": [\"21700881\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular ligand driving the adipose inflammatory effect in this setting not defined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Connected CD14 sensing to a defined downstream effector pathway producing PGE2 and tissue edema.\",\n      \"evidence\": \"CD14-KO mice plus NFAT inhibition, mPGES-1 and PGE2 readouts, intravital lymph node imaging\",\n      \"pmids\": [\"22466648\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CD14 engagement activates NFAT mechanistically not detailed\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined the molecular machinery by which CD14 governs the trafficking and second wave of TLR4 signaling.\",\n      \"evidence\": \"Co-IP of CD14–Gαi1/3–Gab1, TIRF/FRAP imaging of TLR4 clustering and endocytosis, knockdown phenotypes\",\n      \"pmids\": [\"25825741\", \"25707286\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CD14 nucleates clathrin recruitment at the molecular level not fully resolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established that surface CD14 is dynamically regulated by P2X7-driven extracellular vesicle release, tuning inflammatory output.\",\n      \"evidence\": \"Flow cytometry of vesicles, P2X7 inhibition/KO, cytokine assays, and cecal ligation-puncture sepsis model\",\n      \"pmids\": [\"33135636\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism coupling P2X7 activity to CD14 vesicle loading not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified externalized phosphatidylinositides as a CD14 eat-me ligand, generalizing its phagocytic-receptor role to apoptotic cell clearance.\",\n      \"evidence\": \"Unbiased proteomics, PIP probes, CD14-KO phagocytosis assays, and in vivo irradiation model\",\n      \"pmids\": [\"35017647\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream engulfment signaling from CD14–PIP recognition not mapped\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The identity and stoichiometry of the transmembrane signal transducer(s) that couple GPI-anchored or soluble CD14 to intracellular signaling across its bacterial, apoptotic, and amyloid ligands remain incompletely defined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified structural model of CD14 ligand-presentation across diverse cargoes\", \"Mechanism linking distinct CD14 ligands to convergent or divergent signaling outputs unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [10, 18]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0, 18]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 16]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [15, 16]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 6, 16]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [2, 17]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [17]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [16]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 3, 15]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [15, 16]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [16, 17]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [18]}\n    ],\n    \"complexes\": [\n      \"CD14–Gαi1/3–Gab1 complex\",\n      \"TLR4/MD2/CD14 LPS receptor complex\"\n    ],\n    \"partners\": [\n      \"TLR4\",\n      \"LBP\",\n      \"GNAI1\",\n      \"GNAI3\",\n      \"GAB1\",\n      \"ITGAM\",\n      \"SFTPC\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":8,"faith_total":8,"faith_pct":100.0}}