{"gene":"CLEC4E","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2008,"finding":"Mincle selectively associates with the Fc receptor common gamma-chain (FcRγ) to form an ITAM-coupled signaling complex, enabling macrophage activation to produce inflammatory cytokines and chemokines upon sensing dead cells.","method":"Co-immunoprecipitation, reporter cell assays, Mincle-deficient macrophages","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal association demonstrated, replicated by multiple subsequent studies confirming the FcRγ coupling mechanism","pmids":["18776906"],"is_preprint":false},{"year":2008,"finding":"SAP130, a component of small nuclear ribonucleoprotein released from dead cells, is identified as an endogenous Mincle ligand that triggers inflammatory responses.","method":"Biochemical fractionation of dead cell supernatants, reporter cell activation assays, in vivo neutrophil infiltration assay with Mincle-blocking antibody","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — ligand identified by fractionation and validated in vivo; replicated by multiple independent studies","pmids":["18776906"],"is_preprint":false},{"year":2008,"finding":"Human and mouse Mincle carbohydrate-recognition domains (CRDs) bind to Candida albicans yeast cells and yeast extract in vitro.","method":"Recombinant CRD expression, refolding, binding assays with whole yeast cells and yeast extract","journal":"Glycobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — in vitro binding assay, single lab, single method, no functional follow-up in this paper","pmids":["18509109"],"is_preprint":false},{"year":2009,"finding":"Mincle is an essential receptor for the mycobacterial glycolipid trehalose-6,6'-dimycolate (TDM/cord factor); Mincle-deficient macrophages completely fail to produce inflammatory cytokines and nitric oxide in response to TDM, and Mincle-deficient mice do not form TDM-induced lung granulomas.","method":"Lipid fractionation of heat-killed mycobacteria, Mincle-deficient macrophage assays, in vivo TDM administration in Mincle-knockout mice","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (biochemical ligand identification, KO macrophages, in vivo granuloma model); replicated by independent labs","pmids":["20008526"],"is_preprint":false},{"year":2009,"finding":"Mincle specifically recognizes Malassezia species among 50 fungal species tested; recognition requires the putative mannose-binding motif in the C-type lectin domain; Mincle selectively binds alpha-mannose but not mannan; Mincle-deficient macrophages show significantly impaired cytokine/chemokine production in response to Malassezia.","method":"NFAT-GFP reporter cell screening of 50 fungal species, site-directed mutagenesis of mannose-binding motif, glycoconjugate microarray, Mincle-deficient mouse macrophages","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — mutagenesis, glycan array, and KO functional assays in one study; independently consistent with other Mincle ligand studies","pmids":["19171887"],"is_preprint":false},{"year":2010,"finding":"Mincle, together with FcRγ adaptor, is the receptor for TDM and TDB that drives Syk-Card9 signaling in APCs; genetic ablation of Mincle abolishes TDM/TDB-induced macrophage activation and Th17 adjuvanticity in vivo.","method":"Recombinant Mincle-Fc fusion protein binding assays, Mincle-knockout macrophages, in vivo vaccination with tuberculosis subunit vaccine","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple methods (fusion protein binding, KO cells, in vivo adjuvanticity); replicates PMID 20008526 in different experimental context","pmids":["20164423"],"is_preprint":false},{"year":2013,"finding":"Crystal structure of Mincle reveals a Ca2+-dependent sugar-binding site and a unique adjacent shallow hydrophobic groove that accommodates fatty acid moieties of glycolipids; mutagenesis of the hydrophobic region abolishes glycolipid recognition.","method":"X-ray crystallography of Mincle CRD and Mincle-citric acid complex, functional mutagenesis with glycolipid ligands","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional mutagenesis validation; defines molecular mechanism of glycolipid recognition","pmids":["24101491"],"is_preprint":false},{"year":2013,"finding":"Crystallographic and mutagenesis analysis of bovine mincle CRD defines an extended binding site: one glucose of trehalose is Ca2+-liganded (as in other C-type lectins), a secondary binding site contacts the second glucose (36-fold higher affinity for trehalose vs. glucose), and an adjacent hydrophobic groove docks one acyl chain of TDM.","method":"X-ray crystallography, site-directed mutagenesis, binding studies with glycolipid mimics, affinity measurements","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystallographic structure plus mutagenesis plus quantitative binding data in one study","pmids":["23960080"],"is_preprint":false},{"year":2013,"finding":"Mincle signals via the Syk-CARD9-Bcl10-MALT1 pathway by recruiting the ITAM-bearing FcεRI-γ; Mincle and MCL form heteromers on the cell surface, and association with MCL and FcεRI-γ increases Mincle expression and enhances phagocytosis.","method":"Flow cytometry, co-immunoprecipitation, cell surface biochemical analysis in rat primary cells and cell lines","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and functional phagocytosis assay, single lab but two orthogonal methods","pmids":["23921530"],"is_preprint":false},{"year":2013,"finding":"TDB adjuvant triggers Mincle-dependent IL-1 production that then activates MyD88/IL-1R signaling to drive Th1/Th17 adaptive responses in vivo; the adjuvant effect requires both the Mincle-FcRγ-Syk-Card9 axis and MyD88-dependent IL-1R signaling.","method":"Mincle-knockout mice, MyD88-deficient mice, IL-1R-deficient mice, ASC-deficient mice, in vivo vaccination","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic KO models dissecting epistatic pathway; consistent signaling hierarchy established","pmids":["23308247"],"is_preprint":false},{"year":2014,"finding":"Fonsecaea monophora engages Mincle to activate a Syk-CARD9-PKB signaling cascade that recruits the E3 ubiquitin ligase Mdm2, leading to proteasomal degradation of nuclear IRF1 and thereby blocking IL12A transcription and TH1 responses.","method":"Mincle-blocking experiments in human DCs, Syk inhibition, PKB pathway dissection, IRF1 nuclear localization assays, gene expression analysis","journal":"Cell host & microbe","confidence":"High","confidence_rationale":"Tier 2 / Moderate — mechanistic pathway dissected with multiple inhibitors and functional readouts, single lab but multiple orthogonal methods","pmids":["24721577"],"is_preprint":false},{"year":2014,"finding":"Dectin-3 (MCL/Clec4d)-induced Mincle expression requires CARD9-BCL10-MALT1-dependent NF-κB activation; NF-κB (but not NFAT) binds the Mincle promoter to drive transcription in response to TDM stimulation.","method":"Dectin-3-deficient bone marrow macrophages, NF-κB and NFAT inhibitors, chromatin immunoprecipitation (NF-κB binding to Mincle promoter), CARD9-deficient mice","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — promoter ChIP, genetic KOs, inhibitor experiments; defines transcriptional mechanism of Mincle induction","pmids":["25202022"],"is_preprint":false},{"year":2014,"finding":"Human mincle CRD ligand-binding mechanism closely resembles bovine mincle: one glucose of trehalose is Ca2+-liganded, the second glucose contacts a secondary site, and acyl chains enhance affinity; mutagenesis and synthetic analogs confirm the available human mincle crystal structure is not in a fully active conformation.","method":"Site-directed mutagenesis of human mincle, binding studies with synthetic TDM analogs, structural comparison with bovine mincle crystal structure","journal":"Glycobiology","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — mutagenesis plus binding data, single lab, no new crystal structure","pmids":["25028392"],"is_preprint":false},{"year":2014,"finding":"C/EBPβ is required for Mincle expression and TDB/TDM-induced inflammatory gene transcription in macrophages; HIF1α is downstream of C/EBPβ and controls Nos2 (nitric oxide) expression but is not required for Mincle expression or kinase activation; LPS-priming induces Mincle via MYD88-dependent C/EBPβ upregulation.","method":"Microarray, Cebpb-deficient macrophages, retroviral rescue of Mincle in Cebpb-KO cells, Hif1a-deficient macrophages, kinase activation assays","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic KOs with retroviral rescue; dissects transcriptional hierarchy with multiple orthogonal approaches","pmids":["25156364"],"is_preprint":false},{"year":2015,"finding":"MCL (Clec4d) promotes Mincle surface expression through direct protein-protein interaction via the stalk region; the hydrophobic repeat in MCL's stalk region is necessary and sufficient, and substituting four hydrophobic residues with serine (MCL4S) abolishes the ability to enhance Mincle surface expression and restore TDM responses.","method":"MCL-deficient and MCL-transgenic BMDCs, co-immunoprecipitation, stalk-region mutant MCL4S, retroviral rescue, flow cytometry for surface Mincle","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, domain mutagenesis, KO/transgenic rescue; defines molecular basis of MCL-Mincle complex formation","pmids":["25888641"],"is_preprint":false},{"year":2015,"finding":"Human Mincle (but not murine Mincle) binds cholesterol crystals and triggers innate immune inflammatory responses; murine macrophages transfected with human Mincle respond to cholesterol crystals with pro-inflammatory cytokine production, blocked by anti-human Mincle antibody.","method":"Lipid fractionation of liver extracts, MS structural identification, reporter cell assays with hMincle, anti-Mincle antibody blockade, transfection of hMincle into murine macrophages","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS identification plus functional receptor assays, single lab but multiple orthogonal methods; species specificity validated","pmids":["26296894"],"is_preprint":false},{"year":2015,"finding":"Microbial stimulation drives Mincle surface expression through the MyD88 signaling pathway; MCL is constitutively expressed but retained intracellularly until Mincle is induced, whereupon the two receptors form heterodimers that translocate to the cell surface ('two-step' model).","method":"MyD88-deficient macrophages, MCL-deficient cells, surface expression analysis by flow cytometry and subcellular fractionation","journal":"Microbes and infection","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO and subcellular localization, single lab, two orthogonal methods","pmids":["27005451"],"is_preprint":false},{"year":2016,"finding":"Leishmania triggers a Mincle-dependent inhibitory ITAMi (inhibitory ITAM) signaling configuration characterized by SHP1 coupling to the FcRγ chain in DCs, impairing DC activation, migration, and priming of adaptive immunity; selective loss of SHP1 in CD11c+ cells phenocopies enhanced immunity.","method":"Mincle-deficient mice, SHP1 conditional KO in CD11c+ cells, co-immunoprecipitation of SHP1 with FcRγ, in vivo Leishmania major infection model","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with conditional KO phenocopying, Co-IP identifying SHP1-FcRγ coupling, in vivo validation","pmids":["27742545"],"is_preprint":false},{"year":2016,"finding":"Clec4e (Mincle) signaling in macrophages inhibits cholesterol efflux and induces Syk-mediated endoplasmic reticulum stress (requiring Chop and Ire1a), leading to proinflammatory mediator and growth factor production; Clec4e-/- bone marrow transplant into Ldlr-/- mice reduces lipid accumulation, ER stress, inflammation, and atherosclerosis.","method":"Clec4e-deficient macrophages, bone marrow transplantation into Ldlr-/- mice, Chop- and Ire1a-deficient macrophages, cholesterol efflux assays, Syk inhibition","journal":"Circulation","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic KOs, bone marrow chimera, functional cholesterol efflux assays; defines ER stress as downstream mechanism","pmids":["27587433"],"is_preprint":false},{"year":2016,"finding":"Mincle signaling on M1 macrophages is regulated by TLR4/NF-κB: NF-κB/p65 binds the Mincle promoter in LPS-primed macrophages, blocking TLR4 or NF-κB suppresses LPS-induced Mincle expression; Mincle maintains M1 inflammatory phenotype (IL-1β, MCP-1, iNOS) through Syk signaling.","method":"ChIP (NF-κB/p65 binding to Mincle promoter), TLR4 and NF-κB inhibitors, Mincle knockdown, Syk inhibition, adoptive transfer of Mincle+ M1 macrophages","journal":"Kidney international","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP identifying promoter binding, KD experiments, adoptive transfer; multiple orthogonal methods in single study","pmids":["28017324"],"is_preprint":false},{"year":2016,"finding":"RIP1/RIP3 necrosome signaling drives cytoplasmic SAP130 expression in pancreatic cancer cells; Mincle on tumor-infiltrating myeloid cells ligated by SAP130 promotes immune-suppressive macrophage function and oncogenesis; Mincle deletion reprograms the tumor microenvironment to enable T cell-mediated anti-tumor immunity.","method":"RIP3-knockout and RIP1-inhibited mouse PDA models, Mincle-knockout mice, SAP130 blockade, bone marrow/cellular depletion experiments","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic KOs in cancer model, epistasis between necrosome and Mincle pathways, cellular depletion experiments; independently replicated concept","pmids":["27049944"],"is_preprint":false},{"year":2016,"finding":"Mincle activation by SAP130 (from necroptotic cells) drives microglial innate immune responses after subarachnoid hemorrhage; albumin directly binds Mincle and inhibits Mincle/Syk/IL-1β signaling, reducing neuroinflammation.","method":"Co-immunoprecipitation (albumin-Mincle interaction), Mincle knockdown in BV-2 microglia, SAP130 stimulation assays, in vivo SAH rat model","journal":"Brain, behavior, and immunity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP of albumin-Mincle, KD functional assay; single lab but two orthogonal methods","pmids":["27845194"],"is_preprint":false},{"year":2016,"finding":"IRAKM Myddosome formed in response to low-dose LPS upregulates Mincle expression in macrophages; Mincle-deficient mice are protected from ethanol-induced liver injury; SAP130 released by ethanol-damaged hepatocytes synergizes with LPS to activate Mincle-dependent inflammasome in macrophages.","method":"IRAKM-deficient and Mincle-deficient mice, ethanol liver injury model, ex vivo bone marrow macrophage stimulation, hepatocyte-macrophage co-culture","journal":"Hepatology","confidence":"High","confidence_rationale":"Tier 2 / Strong — two genetic KO models, identifies IRAKM-Mincle epistatic axis, functional inflammasome assays","pmids":["27628766"],"is_preprint":false},{"year":2016,"finding":"Mincle-mediated signaling promotes granuloma resolution by enhancing translation (not only transcription) of nitric oxide synthesis genes through p38 and eIF5A hypusination pathway, representing a dual transcriptional and translational control mechanism.","method":"Mincle-deficient macrophages, TLR/Mincle stimulation assays, p38 inhibition, eIF5A hypusination analysis, NO production assays","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Mincle-KO cells with translational pathway dissection, single lab but novel mechanistic readout","pmids":["27089465"],"is_preprint":false},{"year":2016,"finding":"Mincle/Syk/Card9 signaling axis is essential for experimental autoimmune uveoretinitis (EAU); Mincle deletion or Card9 deletion prevents Th17 polarization and disease, and Mincle activation alone is sufficient to generate the EAU phenotype.","method":"Mincle-/-, Card9-/-, Dectin-1-/-, Dectin-2-/- mice in EAU model, direct Mincle agonist injection, Syk inhibition","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic KOs with gain-of-function Mincle activation experiment; epistasis established","pmids":["26921309"],"is_preprint":false},{"year":2017,"finding":"β-Glucosylceramide (GlcCer), a ubiquitous intracellular metabolite, is an endogenous Mincle ligand released upon cell damage; identified by fractionation, MS, and NMR; GBA1 (β-glucosylceramidase)-deficient cells accumulate GlcCer and trigger enhanced Mincle-dependent antigen-specific T-cell responses.","method":"Biochemical fractionation of dead cell supernatants, MS and NMR structural identification, synthetic GlcCer activation assays, Mincle-deficient macrophages, GBA1×Mincle double-KO mice, DC antigen presentation assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — structural identification by MS+NMR, functional validation in KO cells and double-KO mice, multiple orthogonal methods","pmids":["28373578"],"is_preprint":false},{"year":2017,"finding":"Mincle recognition of cholesterol sulfate from barrier epithelium drives sterile inflammation; subcutaneous injection of cholesterol sulfate causes Mincle-dependent local inflammatory response; Mincle-deficient mice show significantly suppressed allergic contact dermatitis.","method":"Reporter cell assays with Mincle, Mincle-/- mice in allergic contact dermatitis model, cholesterol sulfate ligand specificity assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor assays plus KO in vivo model, single lab, two orthogonal methods","pmids":["28292894"],"is_preprint":false},{"year":2017,"finding":"CD11b negatively regulates Mincle signaling by forming a Mincle-CD11b complex upon Mincle activation; CD11b recruits Lyn, SIRPα, and SHP1 which dephosphorylate Syk to dampen Mincle-mediated inflammation.","method":"CD11b-deficient macrophages (hyperinflammation phenotype), co-immunoprecipitation of Mincle-CD11b complex, Lyn activator (MLR1023) functional experiments, phospho-Syk assays","journal":"Experimental & molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP of complex plus KO plus pharmacological Lyn activation; single lab, multiple methods","pmids":["29400702"],"is_preprint":false},{"year":2017,"finding":"TDM-coated beads recruit Mincle during FcγR-mediated phagocytosis and interfere with phagosome maturation through Mincle-dependent recruitment of SHP-1 and inhibitory FcγRIIB signaling.","method":"IgG-opsonized TDM bead phagocytosis assays, SHP-1 and FcγRIIB functional analyses, phagosome maturation assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional phagosome assay with mechanistic dissection of SHP-1/FcγRIIB pathway; single lab","pmids":["28384255"],"is_preprint":false},{"year":2017,"finding":"Mincle recognizes the glycolipid Glc-DAG (glucosyl-diacylglycerol) of Streptococcus pneumoniae; Mincle-deficient mice show increased bacterial loads, decreased survival, and dysregulated cytokine responses in pneumococcal pneumonia.","method":"Mincle reporter cell activation with purified Glc-DAG, Mincle-/- macrophage cytokine assays, Mincle-KO mouse pneumonia model, hematopoietic reconstitution experiments","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Strong — ligand identified and validated functionally, KO mice with bone marrow chimera; multiple orthogonal methods","pmids":["27923071"],"is_preprint":false},{"year":2017,"finding":"Mincle mediates NET (neutrophil extracellular trap) formation through autophagy activation; Mincle-/- neutrophils show impaired autophagy and NET formation in vitro and in vivo during Klebsiella pneumoniae infection, while ROS production remains intact; autophagy induction rescues NET formation in Mincle-/- neutrophils.","method":"Mincle-/- neutrophils stimulated in vitro and in vivo Klebsiella infection, NET formation assays, ROS assays, autophagy activation analysis, tamoxifen (autophagy inducer) rescue experiment","journal":"The Journal of infectious diseases","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO plus rescue experiment, two orthogonal readouts (NETs and autophagy); single lab","pmids":["28186242"],"is_preprint":false},{"year":2017,"finding":"Mincle fine structure of fatty acids is critical for glycolipid binding to its CRD; glucose and mannose esterified at O-6 by a synthetic α-branched 32-carbon fatty acid show agonist activity similar to TDM; Mincle-dependent cytokine production confirmed with primary human and murine cells.","method":"Chemical synthesis, molecular dynamics simulations, protein mutagenesis, reporter cell assays, Mincle-/- primary cell cytokine assays, in vivo immunization","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — combined chemical synthesis, mutagenesis, MD simulation, and in vivo validation; comprehensive structure-activity relationship","pmids":["28223515"],"is_preprint":false},{"year":2018,"finding":"Mincle recognizes the lipoteichoic acid anchor monoglucosyldiacylglycerol (MGDG) of Group A Streptococcus via the CARD9 pathway to drive protective antibacterial immunity; Mincle-deficient mice show impaired cytokine production, severe bacteremia, and rapid lethality upon GAS infection.","method":"Gene expression analysis of CARD9-pathway contribution, purified MGDG reporter cell assays, Mincle-/- mouse GAS infection model","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — ligand identified and validated, KO mouse infection model with lethal phenotype; multiple orthogonal methods","pmids":["30352847"],"is_preprint":false},{"year":2019,"finding":"The Mincle-Syk signaling axis in dendritic cells in Peyer's patches senses mucosal-resident commensals and triggers IL-6 and IL-23p19 expression to regulate intestinal Th17 cell and ILC3 function; Mincle-deficient mice show impaired RegIIIγ and IgA production and increased systemic translocation of gut microbiota, with consequent liver inflammation.","method":"Mincle-/- mice, conditional Syk KO in CD11c+ cells, intestinal cytokine and IgA assays, microbiota translocation assays, liver inflammation analysis","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — two genetic models (Mincle-/- and conditional Syk KO), multiple downstream functional readouts; defines Mincle in gut homeostasis","pmids":["30709742"],"is_preprint":false},{"year":2019,"finding":"CLEC4E activation in combination with TLR4 induces autophagy in macrophages through MYD88 and PtdIns3K pathways, leading to lysosome biogenesis and enhanced intracellular killing of Mycobacterium tuberculosis; autophagy-deficient (Atg5-KO, Becn1-KD) macrophages show elevated Mtb survival.","method":"CLEC4E+TLR4 agonist co-stimulation, autophagy-deficient macrophages, lysosome biogenesis assays, intracellular Mtb killing assays in mice and guinea pigs","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO/KD macrophage functional assays with in vivo validation; single lab, multiple orthogonal methods","pmids":["31462144"],"is_preprint":false},{"year":2020,"finding":"β-Glucosylceramide in combination with free cholesterol acts as an endogenous Mincle ligand to trigger sustained inflammation after acute kidney injury; free cholesterol markedly enhances the agonistic effect of β-GlcCer on Mincle; Mincle-deficient mice are protected from kidney damage after ischemia-reperfusion injury.","method":"Lipophilic extract fractionation from injured kidney, Mincle reporter assays, Mincle-/- mouse ischemia-reperfusion model, histological analysis of β-GlcCer and free cholesterol accumulation near Mincle-expressing macrophages","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — ligand identification with synergy demonstrated, KO mouse model, localization evidence; multiple orthogonal methods","pmids":["32797195"],"is_preprint":false},{"year":2020,"finding":"Mincle/Syk/NF-κB signaling is essential for maintaining protumoral M2-like tumor-associated macrophage (TAM) function; Mincle silencing in TAM promotes M1-like phenotype in vitro; ultrasound microbubble-mediated tumor-specific Mincle silencing suppresses TAM-driven cancer progression in syngeneic mouse cancer models.","method":"Single-cell RNA sequencing, Mincle siRNA in BMDMs, adoptive transfer of Mincle-silenced BMDMs into NOD/SCID mice, ultrasound microbubble gene delivery in syngeneic LLC and B16F10 models, Syk phosphorylation assays","journal":"Cancer immunology research","confidence":"High","confidence_rationale":"Tier 2 / Strong — single-cell RNA-seq, adoptive transfer, in vivo gene silencing; multiple orthogonal methods across in vitro and in vivo systems","pmids":["32532809"],"is_preprint":false},{"year":2020,"finding":"Mincle/Syk signaling in macrophages promotes intestinal mucosal inflammation (Crohn's disease model) by inducing macrophage pyroptosis and MAPK-driven chemokine production to recruit neutrophils; Mincle-/- mice and Syk-inhibitor-treated mice show reduced colitis.","method":"Mincle-/- mice in colitis model, Syk inhibitor, Mincle agonist (TDB) in vivo, BMDMs from Mincle-/- mice, pyroptosis and cytokine assays","journal":"Journal of Crohn's & colitis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO plus pharmacological inhibition plus agonist validation; single lab","pmids":["32333776"],"is_preprint":false},{"year":2021,"finding":"SAP130 released from damaged renal tubular cells activates macrophage Mincle to drive necroinflammation; Mincle expression is negatively regulated post-transcriptionally by miR-219c-3p binding to Mincle 3'-UTR; lentivirus-mediated overexpression of miR-219c-3p blunts Mincle expression and macrophage infiltration in AKI.","method":"Luciferase 3'-UTR reporter assay (miR-219c binding to Mincle), lentiviral miR-219c overexpression in vivo, recombinant SAP130 administration in Mincle-/- mice, UUO and cisplatin AKI models","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 2 / Strong — 3'-UTR reporter assay defines miRNA mechanism, lentiviral rescue in vivo, KO validation; multiple orthogonal methods","pmids":["34556635"],"is_preprint":false},{"year":2021,"finding":"Clec4e (Mincle) is expressed in cardiac vasculature, myocytes, and infiltrating leukocytes after myocardial ischemia-reperfusion injury; loss of Clec4e reduces acute cardiac injury, neutrophil infiltration, infarct size, and improves LV structural and functional remodeling at 4 weeks.","method":"Clec4e-/- mice in myocardial ischemia-reperfusion model, porcine and human myocardial samples for expression analysis, early transcriptome analysis of LV tissue","journal":"JACC. Basic to translational science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse phenotype with complementary porcine and human expression correlation; single lab","pmids":["34466750"],"is_preprint":false},{"year":2022,"finding":"Mincle has a T cell-intrinsic role in TH17-mediated CNS inflammation: TH17 cells express Mincle, and β-glucosylceramide released by dying cells engages Mincle on TH17 cells to activate the ASC-NLRP3 inflammasome, triggering Caspase8-dependent IL-1β production that drives TH17 proliferation through an autocrine loop.","method":"T cell-specific Mincle deletion in EAE model, Mincle expression profiling in TH17 vs TH1, β-GlcCer stimulation assays, NLRP3/ASC/Caspase8 pathway analysis, β-GlcCer synthesis inhibitor in vivo","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional T cell-specific KO dissecting cell-intrinsic role, inflammasome pathway dissection, pharmacological rescue; multiple orthogonal methods","pmids":["35504893"],"is_preprint":false},{"year":2023,"finding":"Peroxiredoxin 1 (Prdx1) is a novel DAMP that directly interacts with Mincle on macrophages to activate Mincle/Syk/NF-κB signaling and drive M1 polarization; Prdx1 knockout or neutralization protects against AKI, and this protection is reversed by recombinant Prdx1; Mincle knockdown abolishes rPrdx1-induced Syk activation.","method":"Prdx1-/- mice, Prdx1-neutralizing antibody, recombinant Prdx1 protein, co-immunoprecipitation (Prdx1-Mincle interaction), Mincle knockdown, primary peritoneal macrophage assays","journal":"Kidney international","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP of Prdx1-Mincle, genetic KO with recombinant protein rescue, KD epistasis; multiple orthogonal methods","pmids":["37164261"],"is_preprint":false},{"year":2023,"finding":"Macrophages mediate psoriasis via the Mincle-Syk-NF-κB signaling pathway; LPS induces Mincle expression in M1 macrophages via a PU.1-dependent transcriptional mechanism; adoptive transfer of Mincle-KO macrophages fails to restore psoriasis, and Mincle-neutralizing antibody significantly improves psoriasis in mice.","method":"Macrophage depletion + adoptive transfer, macrophage-specific Mincle KO mice (Mincleloxp/Lyz2-cre), PU.1 ChIP or binding assay, Mincle-neutralizing antibody in vivo","journal":"Cell death discovery","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO plus adoptive transfer plus therapeutic antibody; defines Mincle as driver in psoriasis with PU.1-dependent transcriptional mechanism","pmids":["37117184"],"is_preprint":false},{"year":2025,"finding":"Mincle (Clec4e) is essential for Enterococcus faecalis-induced trained immunity in bone marrow progenitors following intestinal barrier disruption; Clec4e-/- mice show impaired trained immunity upon E. faecalis administration and reduced colitis pathology after DSS treatment.","method":"Clec4e-/- mice, DSS gut permeability model, heat-killed E. faecalis stimulation of bone marrow progenitors, in vitro and in vivo trained immunity readouts","journal":"Immunity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with in vivo and in vitro trained immunity assays; single lab, multiple readouts","pmids":["39848243"],"is_preprint":false}],"current_model":"CLEC4E (Mincle) is a transmembrane C-type lectin receptor on myeloid cells that constitutively associates with FcRγ (and forms heterodimers with MCL/Clec4d) to signal through an ITAM-Syk-CARD9-Bcl10-MALT1 axis; upon recognition of a diverse array of glycolipid ligands (including mycobacterial TDM, fungal alpha-mannose structures, β-glucosylceramide, cholesterol crystals, and cholesterol sulfate) or released endogenous proteins (SAP130, Prdx1) from damaged cells, Mincle drives pro-inflammatory cytokine and nitric oxide production, NF-κB-dependent gene transcription (regulated by C/EBPβ and TLR4/MyD88-induced Mincle upregulation via NF-κB binding the Mincle promoter), eIF5A hypusination-dependent translational control of iNOS, autophagy-mediated NET formation, and ER stress responses; additionally, Mincle can be co-opted into an inhibitory ITAMi configuration (recruiting SHP1 via FcRγ) by certain pathogens, and its surface expression is negatively post-transcriptionally regulated by miR-219c-3p targeting the Mincle 3'-UTR."},"narrative":{"mechanistic_narrative":"CLEC4E (Mincle) is a myeloid C-type lectin receptor that couples innate sensing of microbial glycolipids and damage-associated molecules to pro-inflammatory signaling, immune adjuvanticity, and sterile inflammation [PMID:20008526, PMID:20164423]. It is a non-signaling receptor that recruits the ITAM-bearing FcRγ chain to assemble a Syk-CARD9-Bcl10-MALT1 signaling complex driving NF-κB-dependent cytokine, chemokine, and nitric oxide production [PMID:18776906, PMID:23921530]. Surface display and ligand competence depend on heterodimerization with MCL/Clec4d through a hydrophobic stalk-region interaction, and Mincle is itself transcriptionally induced downstream of TLR4/MyD88 via C/EBPβ and NF-κB/PU.1 binding to its promoter, providing feed-forward amplification [PMID:25202022, PMID:25156364, PMID:25888641, PMID:28017324, PMID:37117184]. Crystallographic and structure-activity studies define a Ca2+-dependent sugar-binding site adjacent to a hydrophobic groove that docks the acyl chains of glycolipids, explaining recognition of a broad ligand repertoire including mycobacterial trehalose dimycolate (TDM/cord factor) and the synthetic adjuvant TDB, fungal alpha-mannose structures of Malassezia, streptococcal glucosyl-diacylglycerol and monoglucosyldiacylglycerol, and the human-specific ligand cholesterol crystals [PMID:20008526, PMID:19171887, PMID:24101491, PMID:23960080, PMID:27923071, PMID:28223515, PMID:30352847, PMID:26296894]. Mincle also senses endogenous danger signals released from damaged cells—the nuclear protein SAP130, β-glucosylceramide (potentiated by free cholesterol), cholesterol sulfate, and peroxiredoxin-1—linking necroptotic and barrier injury to inflammation across atherosclerosis, acute kidney injury, myocardial reperfusion injury, hepatic injury, psoriasis, uveoretinitis, and tumor-associated macrophage programming [PMID:18776906, PMID:27049944, PMID:28373578, PMID:28292894, PMID:32797195, PMID:37164261, PMID:27587433, PMID:32532809]. Downstream of receptor engagement Mincle controls iNOS through both transcription and eIF5A-hypusination-dependent translation, induces ER stress, autophagy and NET formation, and shapes adaptive immunity by promoting Th17 responses, including a T-cell-intrinsic β-glucosylceramide-Mincle-NLRP3 autocrine loop in CNS inflammation [PMID:27089465, PMID:27587433, PMID:28186242, PMID:23308247, PMID:35504893]. Certain pathogens co-opt Mincle into an inhibitory ITAMi configuration that recruits SHP1 via FcRγ to dampen dendritic cell activation, and Mincle expression is further restrained post-transcriptionally by miR-219c-3p targeting its 3'-UTR and by CD11b-mediated Syk dephosphorylation [PMID:27742545, PMID:34556635, PMID:29400702].","teleology":[{"year":2008,"claim":"Established Mincle's core signaling logic and first endogenous danger ligand, answering how a lectin receptor transduces sensing of dead cells into inflammation.","evidence":"Co-IP, reporter assays and Mincle-deficient macrophages identifying FcRγ coupling and SAP130 as a released ligand","pmids":["18776906"],"confidence":"High","gaps":["Did not define the downstream kinase cascade beyond ITAM coupling","SAP130 binding mode to the CRD not structurally resolved"]},{"year":2008,"claim":"Showed the Mincle CRD can bind fungal cells directly, opening the question of which glycan ligands it recognizes.","evidence":"Recombinant refolded CRD binding to Candida albicans cells and yeast extract in vitro","pmids":["18509109"],"confidence":"Medium","gaps":["No functional signaling follow-up","Specific glycan ligand not identified in this study"]},{"year":2009,"claim":"Identified Mincle as the essential receptor for mycobacterial cord factor TDM and for fungal alpha-mannose ligands, establishing it as a pattern-recognition receptor for pathogen glycolipids.","evidence":"Lipid fractionation, mannose-binding-motif mutagenesis, glycan arrays, KO macrophages and in vivo granuloma/cytokine assays","pmids":["20008526","19171887"],"confidence":"High","gaps":["Structural basis of glycolipid binding not yet defined","Did not establish the full Syk-CARD9 signaling hierarchy"]},{"year":2010,"claim":"Connected TDM/TDB recognition to the Syk-Card9 axis and to vaccine adjuvanticity, defining Mincle as a target for adjuvant design.","evidence":"Mincle-Fc fusion binding assays, KO macrophages and in vivo Th17 vaccination","pmids":["20164423"],"confidence":"High","gaps":["Did not resolve receptor stoichiometry or co-receptor requirements"]},{"year":2013,"claim":"Resolved the molecular mechanism of glycolipid recognition, explaining how one receptor accommodates both sugar headgroups and fatty acyl chains.","evidence":"X-ray crystallography of mouse/bovine CRDs with functional and affinity mutagenesis defining Ca2+ site plus a hydrophobic groove","pmids":["24101491","23960080"],"confidence":"High","gaps":["Human Mincle structure not captured in fully active conformation","Full-length receptor and dimer architecture not solved"]},{"year":2013,"claim":"Defined the proximal signaling complex and the MCL/FcεRI-γ partnership that controls Mincle expression and phagocytosis.","evidence":"Flow cytometry, reciprocal Co-IP and phagocytosis assays in rat cells; genetic dissection of Syk-CARD9-Bcl10-MALT1 and MyD88/IL-1R adjuvant requirement","pmids":["23921530","23308247"],"confidence":"High","gaps":["MCL-Mincle stoichiometry not quantified","Order of FcRγ versus MCL assembly unresolved at this stage"]},{"year":2014,"claim":"Established the transcriptional circuitry for Mincle induction and revealed pathogen subversion of its signaling, distinguishing activating from immunosuppressive outcomes.","evidence":"ChIP of NF-κB/C/EBPβ on the Mincle promoter, Dectin-3/CARD9/Cebpb/Hif1a KO macrophages with retroviral rescue, and Fonsecaea-driven Mdm2-mediated IRF1 degradation in human DCs","pmids":["25202022","25156364","24721577"],"confidence":"High","gaps":["Interplay between NFAT and NF-κB arms not fully delineated","HIF1α-independent Mincle induction mechanism partially defined"]},{"year":2015,"claim":"Defined how MCL controls Mincle trafficking and extended the ligand repertoire to a human-specific sterol ligand.","evidence":"Stalk-region MCL4S mutagenesis with KO/transgenic rescue; MS identification of cholesterol crystals as a human Mincle ligand; two-step surface translocation model","pmids":["25888641","26296894","27005451"],"confidence":"High","gaps":["Mouse-human species divergence in sterol recognition mechanistically unexplained","Trafficking machinery for the heterodimer not identified"]},{"year":2016,"claim":"Generalized Mincle as a driver of sterile and tumoral inflammation across organs and revealed both inhibitory ITAMi signaling and a translational control branch.","evidence":"KO/chimera models in atherosclerosis, pancreatic cancer, alcoholic liver injury, subarachnoid hemorrhage and uveoretinitis; SHP1 conditional KO and Co-IP for ITAMi; eIF5A-hypusination analysis for iNOS translation","pmids":["27587433","27049944","27628766","27845194","26921309","27742545","27089465","28017324"],"confidence":"High","gaps":["What dictates the switch between activating and ITAMi configurations is not resolved","Direct binding of all endogenous ligands (e.g. albumin) to the CRD not structurally validated"]},{"year":2017,"claim":"Identified β-glucosylceramide and cholesterol sulfate as endogenous Mincle ligands and expanded effector outputs to autophagy/NET formation and Fc-receptor crosstalk.","evidence":"MS/NMR ligand identification with GBA1×Mincle double-KO mice; cholesterol sulfate KO dermatitis model; autophagy-dependent NET assays; CD11b-Mincle and TDM-bead phagosome inhibition; SAR with synthetic glycolipids","pmids":["28373578","28292894","28186242","29400702","28384255","28223515","27923071"],"confidence":"High","gaps":["How free cholesterol potentiates β-GlcCer recognition was not yet defined","Negative regulation by CD11b-SHP1 not validated in vivo"]},{"year":2019,"claim":"Defined Mincle's homeostatic role in sensing commensals and an autophagy-driven antimicrobial program, broadening it beyond acute pathogen sensing.","evidence":"Mincle-/- and CD11c-Syk conditional KO intestinal models; CLEC4E+TLR4 co-stimulation driving autophagy and Mtb killing in autophagy-deficient macrophages","pmids":["30709742","31462144"],"confidence":"High","gaps":["Specific commensal glycolipid ligand(s) in the gut not identified","Mechanism linking Mincle to lysosome biogenesis incompletely mapped"]},{"year":2020,"claim":"Established Mincle as a tunable driver of TAM polarization and tissue injury and demonstrated a synergistic endogenous ligand combination.","evidence":"scRNA-seq and ultrasound-microbubble Mincle silencing in tumor models; β-GlcCer plus free cholesterol synergy in KO kidney ischemia-reperfusion; Syk-NF-κB colitis pyroptosis model","pmids":["32532809","32797195","32333776"],"confidence":"High","gaps":["Molecular basis of cholesterol-β-GlcCer synergy at the CRD not structurally resolved","TAM-intrinsic Mincle ligand in tumors not defined"]},{"year":2021,"claim":"Defined post-transcriptional control of Mincle and extended its injury role to the heart.","evidence":"Luciferase 3'-UTR reporter and lentiviral miR-219c-3p overexpression in AKI; Clec4e-/- myocardial ischemia-reperfusion with human/porcine expression correlation","pmids":["34556635","34466750"],"confidence":"High","gaps":["Upstream regulators of miR-219c-3p not identified","Cell-type source of cardiac Mincle ligand not defined"]},{"year":2023,"claim":"Identified peroxiredoxin-1 as a new DAMP ligand and consolidated the Mincle-Syk-NF-κB axis as a macrophage-driven disease mechanism with therapeutic tractability.","evidence":"Co-IP of Prdx1-Mincle with KO/recombinant rescue in AKI; macrophage-specific Mincle KO, PU.1-dependent induction and neutralizing antibody in psoriasis","pmids":["37164261","37117184"],"confidence":"High","gaps":["Prdx1 binding site on the CRD not structurally mapped","Generality of antibody-based Mincle blockade across diseases untested here"]},{"year":2025,"claim":"Extended Mincle function to instruction of trained immunity in bone marrow progenitors following barrier disruption.","evidence":"Clec4e-/- mice with DSS permeability and heat-killed E. faecalis trained-immunity readouts","pmids":["39848243"],"confidence":"Medium","gaps":["Single lab","Bacterial ligand engaging Mincle in this context not chemically defined","Epigenetic mediators of the trained phenotype not mapped"]},{"year":null,"claim":"What governs the molecular switch between Mincle's activating ITAM and inhibitory ITAMi configurations, and how distinct endogenous and microbial ligands bias this choice, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of full-length Mincle-MCL-FcRγ signaling complex","Determinants of SHP1 versus Syk recruitment by FcRγ not defined","Mechanism distinguishing pro-inflammatory from immunosuppressive outcomes per ligand unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[0,3,5,25]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[3,6,7,25,15,26,35]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,8,17]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[8,0]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,8,14,16]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,3,5,9,29,32,33]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,8,11,17,36,41]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[30,34]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[18,23]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[18,20,35,39,42]}],"complexes":["Mincle-FcRγ ITAM signaling complex","Mincle-MCL (Clec4d) heterodimer","Mincle-CD11b inhibitory complex"],"partners":["FCER1G","CLEC4D","SYK","CARD9","PTPN6","ITGAM","PRDX1","SAP130"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9ULY5","full_name":"C-type lectin domain family 4 member E","aliases":["C-type lectin superfamily member 9","Macrophage-inducible C-type lectin","MINCLE"],"length_aa":219,"mass_kda":25.1,"function":"Calcium-dependent lectin that acts as a pattern recognition receptor (PRR) of the innate immune system: recognizes damage-associated molecular patterns (DAMPs) of abnormal self and pathogen-associated molecular patterns (PAMPs) of bacteria and fungi (PubMed:18509109, PubMed:23602766). The PAMPs notably include mycobacterial trehalose 6,6'-dimycolate (TDM), a cell wall glycolipid with potent adjuvant immunomodulatory functions (PubMed:23602766, PubMed:24101491). Interacts with signaling adapter Fc receptor gamma chain/FCER1G to form a functional complex in myeloid cells (By similarity). Binding of mycobacterial trehalose 6,6'-dimycolate (TDM) to this receptor complex leads to phosphorylation of the immunoreceptor tyrosine-based activation motif (ITAM) of FCER1G, triggering activation of SYK, CARD9 and NF-kappa-B, consequently driving maturation of antigen-presenting cells and shaping antigen-specific priming of T-cells toward effector T-helper 1 and T-helper 17 cell subtypes (By similarity). Also recognizes alpha-mannose residues on pathogenic fungi of the genus Malassezia and mediates macrophage activation (By similarity). Through recognition of DAMPs released upon nonhomeostatic cell death, enables immune sensing of damaged self and promotes inflammatory cell infiltration into the damaged tissue (By similarity)","subcellular_location":"Cell membrane; Cell projection, phagocytic cup","url":"https://www.uniprot.org/uniprotkb/Q9ULY5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CLEC4E","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CLEC4E","total_profiled":1310},"omim":[{"mim_id":"613579","title":"C-TYPE LECTIN DOMAIN FAMILY 6, MEMBER A; CLEC6A","url":"https://www.omim.org/entry/613579"},{"mim_id":"609964","title":"C-TYPE LECTIN DOMAIN FAMILY 4, MEMBER D; CLEC4D","url":"https://www.omim.org/entry/609964"},{"mim_id":"609962","title":"C-TYPE LECTIN DOMAIN FAMILY 4, MEMBER E; CLEC4E","url":"https://www.omim.org/entry/609962"},{"mim_id":"605592","title":"SPLICING FACTOR 3B, SUBUNIT 3; SF3B3","url":"https://www.omim.org/entry/605592"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"bone marrow","ntpm":71.5},{"tissue":"lymphoid tissue","ntpm":51.1}],"url":"https://www.proteinatlas.org/search/CLEC4E"},"hgnc":{"alias_symbol":["MINCLE"],"prev_symbol":["CLECSF9"]},"alphafold":{"accession":"Q9ULY5","domains":[{"cath_id":"3.10.100.10","chopping":"94-205","consensus_level":"high","plddt":98.2798,"start":94,"end":205}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9ULY5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9ULY5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9ULY5-F1-predicted_aligned_error_v6.png","plddt_mean":85.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CLEC4E","jax_strain_url":"https://www.jax.org/strain/search?query=CLEC4E"},"sequence":{"accession":"Q9ULY5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9ULY5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9ULY5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9ULY5"}},"corpus_meta":[{"pmid":"20008526","id":"PMC_20008526","title":"Direct recognition of the 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immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal association demonstrated, replicated by multiple subsequent studies confirming the FcRγ coupling mechanism\",\n      \"pmids\": [\"18776906\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"SAP130, a component of small nuclear ribonucleoprotein released from dead cells, is identified as an endogenous Mincle ligand that triggers inflammatory responses.\",\n      \"method\": \"Biochemical fractionation of dead cell supernatants, reporter cell activation assays, in vivo neutrophil infiltration assay with Mincle-blocking antibody\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ligand identified by fractionation and validated in vivo; replicated by multiple independent studies\",\n      \"pmids\": [\"18776906\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Human and mouse Mincle carbohydrate-recognition domains (CRDs) bind to Candida albicans yeast cells and yeast extract in vitro.\",\n      \"method\": \"Recombinant CRD expression, refolding, binding assays with whole yeast cells and yeast extract\",\n      \"journal\": \"Glycobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — in vitro binding assay, single lab, single method, no functional follow-up in this paper\",\n      \"pmids\": [\"18509109\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Mincle is an essential receptor for the mycobacterial glycolipid trehalose-6,6'-dimycolate (TDM/cord factor); Mincle-deficient macrophages completely fail to produce inflammatory cytokines and nitric oxide in response to TDM, and Mincle-deficient mice do not form TDM-induced lung granulomas.\",\n      \"method\": \"Lipid fractionation of heat-killed mycobacteria, Mincle-deficient macrophage assays, in vivo TDM administration in Mincle-knockout mice\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (biochemical ligand identification, KO macrophages, in vivo granuloma model); replicated by independent labs\",\n      \"pmids\": [\"20008526\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Mincle specifically recognizes Malassezia species among 50 fungal species tested; recognition requires the putative mannose-binding motif in the C-type lectin domain; Mincle selectively binds alpha-mannose but not mannan; Mincle-deficient macrophages show significantly impaired cytokine/chemokine production in response to Malassezia.\",\n      \"method\": \"NFAT-GFP reporter cell screening of 50 fungal species, site-directed mutagenesis of mannose-binding motif, glycoconjugate microarray, Mincle-deficient mouse macrophages\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — mutagenesis, glycan array, and KO functional assays in one study; independently consistent with other Mincle ligand studies\",\n      \"pmids\": [\"19171887\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Mincle, together with FcRγ adaptor, is the receptor for TDM and TDB that drives Syk-Card9 signaling in APCs; genetic ablation of Mincle abolishes TDM/TDB-induced macrophage activation and Th17 adjuvanticity in vivo.\",\n      \"method\": \"Recombinant Mincle-Fc fusion protein binding assays, Mincle-knockout macrophages, in vivo vaccination with tuberculosis subunit vaccine\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple methods (fusion protein binding, KO cells, in vivo adjuvanticity); replicates PMID 20008526 in different experimental context\",\n      \"pmids\": [\"20164423\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Crystal structure of Mincle reveals a Ca2+-dependent sugar-binding site and a unique adjacent shallow hydrophobic groove that accommodates fatty acid moieties of glycolipids; mutagenesis of the hydrophobic region abolishes glycolipid recognition.\",\n      \"method\": \"X-ray crystallography of Mincle CRD and Mincle-citric acid complex, functional mutagenesis with glycolipid ligands\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional mutagenesis validation; defines molecular mechanism of glycolipid recognition\",\n      \"pmids\": [\"24101491\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Crystallographic and mutagenesis analysis of bovine mincle CRD defines an extended binding site: one glucose of trehalose is Ca2+-liganded (as in other C-type lectins), a secondary binding site contacts the second glucose (36-fold higher affinity for trehalose vs. glucose), and an adjacent hydrophobic groove docks one acyl chain of TDM.\",\n      \"method\": \"X-ray crystallography, site-directed mutagenesis, binding studies with glycolipid mimics, affinity measurements\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystallographic structure plus mutagenesis plus quantitative binding data in one study\",\n      \"pmids\": [\"23960080\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Mincle signals via the Syk-CARD9-Bcl10-MALT1 pathway by recruiting the ITAM-bearing FcεRI-γ; Mincle and MCL form heteromers on the cell surface, and association with MCL and FcεRI-γ increases Mincle expression and enhances phagocytosis.\",\n      \"method\": \"Flow cytometry, co-immunoprecipitation, cell surface biochemical analysis in rat primary cells and cell lines\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and functional phagocytosis assay, single lab but two orthogonal methods\",\n      \"pmids\": [\"23921530\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TDB adjuvant triggers Mincle-dependent IL-1 production that then activates MyD88/IL-1R signaling to drive Th1/Th17 adaptive responses in vivo; the adjuvant effect requires both the Mincle-FcRγ-Syk-Card9 axis and MyD88-dependent IL-1R signaling.\",\n      \"method\": \"Mincle-knockout mice, MyD88-deficient mice, IL-1R-deficient mice, ASC-deficient mice, in vivo vaccination\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic KO models dissecting epistatic pathway; consistent signaling hierarchy established\",\n      \"pmids\": [\"23308247\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Fonsecaea monophora engages Mincle to activate a Syk-CARD9-PKB signaling cascade that recruits the E3 ubiquitin ligase Mdm2, leading to proteasomal degradation of nuclear IRF1 and thereby blocking IL12A transcription and TH1 responses.\",\n      \"method\": \"Mincle-blocking experiments in human DCs, Syk inhibition, PKB pathway dissection, IRF1 nuclear localization assays, gene expression analysis\",\n      \"journal\": \"Cell host & microbe\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic pathway dissected with multiple inhibitors and functional readouts, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"24721577\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Dectin-3 (MCL/Clec4d)-induced Mincle expression requires CARD9-BCL10-MALT1-dependent NF-κB activation; NF-κB (but not NFAT) binds the Mincle promoter to drive transcription in response to TDM stimulation.\",\n      \"method\": \"Dectin-3-deficient bone marrow macrophages, NF-κB and NFAT inhibitors, chromatin immunoprecipitation (NF-κB binding to Mincle promoter), CARD9-deficient mice\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — promoter ChIP, genetic KOs, inhibitor experiments; defines transcriptional mechanism of Mincle induction\",\n      \"pmids\": [\"25202022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Human mincle CRD ligand-binding mechanism closely resembles bovine mincle: one glucose of trehalose is Ca2+-liganded, the second glucose contacts a secondary site, and acyl chains enhance affinity; mutagenesis and synthetic analogs confirm the available human mincle crystal structure is not in a fully active conformation.\",\n      \"method\": \"Site-directed mutagenesis of human mincle, binding studies with synthetic TDM analogs, structural comparison with bovine mincle crystal structure\",\n      \"journal\": \"Glycobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — mutagenesis plus binding data, single lab, no new crystal structure\",\n      \"pmids\": [\"25028392\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"C/EBPβ is required for Mincle expression and TDB/TDM-induced inflammatory gene transcription in macrophages; HIF1α is downstream of C/EBPβ and controls Nos2 (nitric oxide) expression but is not required for Mincle expression or kinase activation; LPS-priming induces Mincle via MYD88-dependent C/EBPβ upregulation.\",\n      \"method\": \"Microarray, Cebpb-deficient macrophages, retroviral rescue of Mincle in Cebpb-KO cells, Hif1a-deficient macrophages, kinase activation assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic KOs with retroviral rescue; dissects transcriptional hierarchy with multiple orthogonal approaches\",\n      \"pmids\": [\"25156364\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MCL (Clec4d) promotes Mincle surface expression through direct protein-protein interaction via the stalk region; the hydrophobic repeat in MCL's stalk region is necessary and sufficient, and substituting four hydrophobic residues with serine (MCL4S) abolishes the ability to enhance Mincle surface expression and restore TDM responses.\",\n      \"method\": \"MCL-deficient and MCL-transgenic BMDCs, co-immunoprecipitation, stalk-region mutant MCL4S, retroviral rescue, flow cytometry for surface Mincle\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, domain mutagenesis, KO/transgenic rescue; defines molecular basis of MCL-Mincle complex formation\",\n      \"pmids\": [\"25888641\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Human Mincle (but not murine Mincle) binds cholesterol crystals and triggers innate immune inflammatory responses; murine macrophages transfected with human Mincle respond to cholesterol crystals with pro-inflammatory cytokine production, blocked by anti-human Mincle antibody.\",\n      \"method\": \"Lipid fractionation of liver extracts, MS structural identification, reporter cell assays with hMincle, anti-Mincle antibody blockade, transfection of hMincle into murine macrophages\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS identification plus functional receptor assays, single lab but multiple orthogonal methods; species specificity validated\",\n      \"pmids\": [\"26296894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Microbial stimulation drives Mincle surface expression through the MyD88 signaling pathway; MCL is constitutively expressed but retained intracellularly until Mincle is induced, whereupon the two receptors form heterodimers that translocate to the cell surface ('two-step' model).\",\n      \"method\": \"MyD88-deficient macrophages, MCL-deficient cells, surface expression analysis by flow cytometry and subcellular fractionation\",\n      \"journal\": \"Microbes and infection\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO and subcellular localization, single lab, two orthogonal methods\",\n      \"pmids\": [\"27005451\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Leishmania triggers a Mincle-dependent inhibitory ITAMi (inhibitory ITAM) signaling configuration characterized by SHP1 coupling to the FcRγ chain in DCs, impairing DC activation, migration, and priming of adaptive immunity; selective loss of SHP1 in CD11c+ cells phenocopies enhanced immunity.\",\n      \"method\": \"Mincle-deficient mice, SHP1 conditional KO in CD11c+ cells, co-immunoprecipitation of SHP1 with FcRγ, in vivo Leishmania major infection model\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with conditional KO phenocopying, Co-IP identifying SHP1-FcRγ coupling, in vivo validation\",\n      \"pmids\": [\"27742545\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Clec4e (Mincle) signaling in macrophages inhibits cholesterol efflux and induces Syk-mediated endoplasmic reticulum stress (requiring Chop and Ire1a), leading to proinflammatory mediator and growth factor production; Clec4e-/- bone marrow transplant into Ldlr-/- mice reduces lipid accumulation, ER stress, inflammation, and atherosclerosis.\",\n      \"method\": \"Clec4e-deficient macrophages, bone marrow transplantation into Ldlr-/- mice, Chop- and Ire1a-deficient macrophages, cholesterol efflux assays, Syk inhibition\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic KOs, bone marrow chimera, functional cholesterol efflux assays; defines ER stress as downstream mechanism\",\n      \"pmids\": [\"27587433\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Mincle signaling on M1 macrophages is regulated by TLR4/NF-κB: NF-κB/p65 binds the Mincle promoter in LPS-primed macrophages, blocking TLR4 or NF-κB suppresses LPS-induced Mincle expression; Mincle maintains M1 inflammatory phenotype (IL-1β, MCP-1, iNOS) through Syk signaling.\",\n      \"method\": \"ChIP (NF-κB/p65 binding to Mincle promoter), TLR4 and NF-κB inhibitors, Mincle knockdown, Syk inhibition, adoptive transfer of Mincle+ M1 macrophages\",\n      \"journal\": \"Kidney international\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP identifying promoter binding, KD experiments, adoptive transfer; multiple orthogonal methods in single study\",\n      \"pmids\": [\"28017324\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"RIP1/RIP3 necrosome signaling drives cytoplasmic SAP130 expression in pancreatic cancer cells; Mincle on tumor-infiltrating myeloid cells ligated by SAP130 promotes immune-suppressive macrophage function and oncogenesis; Mincle deletion reprograms the tumor microenvironment to enable T cell-mediated anti-tumor immunity.\",\n      \"method\": \"RIP3-knockout and RIP1-inhibited mouse PDA models, Mincle-knockout mice, SAP130 blockade, bone marrow/cellular depletion experiments\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic KOs in cancer model, epistasis between necrosome and Mincle pathways, cellular depletion experiments; independently replicated concept\",\n      \"pmids\": [\"27049944\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Mincle activation by SAP130 (from necroptotic cells) drives microglial innate immune responses after subarachnoid hemorrhage; albumin directly binds Mincle and inhibits Mincle/Syk/IL-1β signaling, reducing neuroinflammation.\",\n      \"method\": \"Co-immunoprecipitation (albumin-Mincle interaction), Mincle knockdown in BV-2 microglia, SAP130 stimulation assays, in vivo SAH rat model\",\n      \"journal\": \"Brain, behavior, and immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of albumin-Mincle, KD functional assay; single lab but two orthogonal methods\",\n      \"pmids\": [\"27845194\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"IRAKM Myddosome formed in response to low-dose LPS upregulates Mincle expression in macrophages; Mincle-deficient mice are protected from ethanol-induced liver injury; SAP130 released by ethanol-damaged hepatocytes synergizes with LPS to activate Mincle-dependent inflammasome in macrophages.\",\n      \"method\": \"IRAKM-deficient and Mincle-deficient mice, ethanol liver injury model, ex vivo bone marrow macrophage stimulation, hepatocyte-macrophage co-culture\",\n      \"journal\": \"Hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two genetic KO models, identifies IRAKM-Mincle epistatic axis, functional inflammasome assays\",\n      \"pmids\": [\"27628766\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Mincle-mediated signaling promotes granuloma resolution by enhancing translation (not only transcription) of nitric oxide synthesis genes through p38 and eIF5A hypusination pathway, representing a dual transcriptional and translational control mechanism.\",\n      \"method\": \"Mincle-deficient macrophages, TLR/Mincle stimulation assays, p38 inhibition, eIF5A hypusination analysis, NO production assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Mincle-KO cells with translational pathway dissection, single lab but novel mechanistic readout\",\n      \"pmids\": [\"27089465\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Mincle/Syk/Card9 signaling axis is essential for experimental autoimmune uveoretinitis (EAU); Mincle deletion or Card9 deletion prevents Th17 polarization and disease, and Mincle activation alone is sufficient to generate the EAU phenotype.\",\n      \"method\": \"Mincle-/-, Card9-/-, Dectin-1-/-, Dectin-2-/- mice in EAU model, direct Mincle agonist injection, Syk inhibition\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic KOs with gain-of-function Mincle activation experiment; epistasis established\",\n      \"pmids\": [\"26921309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"β-Glucosylceramide (GlcCer), a ubiquitous intracellular metabolite, is an endogenous Mincle ligand released upon cell damage; identified by fractionation, MS, and NMR; GBA1 (β-glucosylceramidase)-deficient cells accumulate GlcCer and trigger enhanced Mincle-dependent antigen-specific T-cell responses.\",\n      \"method\": \"Biochemical fractionation of dead cell supernatants, MS and NMR structural identification, synthetic GlcCer activation assays, Mincle-deficient macrophages, GBA1×Mincle double-KO mice, DC antigen presentation assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — structural identification by MS+NMR, functional validation in KO cells and double-KO mice, multiple orthogonal methods\",\n      \"pmids\": [\"28373578\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Mincle recognition of cholesterol sulfate from barrier epithelium drives sterile inflammation; subcutaneous injection of cholesterol sulfate causes Mincle-dependent local inflammatory response; Mincle-deficient mice show significantly suppressed allergic contact dermatitis.\",\n      \"method\": \"Reporter cell assays with Mincle, Mincle-/- mice in allergic contact dermatitis model, cholesterol sulfate ligand specificity assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor assays plus KO in vivo model, single lab, two orthogonal methods\",\n      \"pmids\": [\"28292894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CD11b negatively regulates Mincle signaling by forming a Mincle-CD11b complex upon Mincle activation; CD11b recruits Lyn, SIRPα, and SHP1 which dephosphorylate Syk to dampen Mincle-mediated inflammation.\",\n      \"method\": \"CD11b-deficient macrophages (hyperinflammation phenotype), co-immunoprecipitation of Mincle-CD11b complex, Lyn activator (MLR1023) functional experiments, phospho-Syk assays\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of complex plus KO plus pharmacological Lyn activation; single lab, multiple methods\",\n      \"pmids\": [\"29400702\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TDM-coated beads recruit Mincle during FcγR-mediated phagocytosis and interfere with phagosome maturation through Mincle-dependent recruitment of SHP-1 and inhibitory FcγRIIB signaling.\",\n      \"method\": \"IgG-opsonized TDM bead phagocytosis assays, SHP-1 and FcγRIIB functional analyses, phagosome maturation assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional phagosome assay with mechanistic dissection of SHP-1/FcγRIIB pathway; single lab\",\n      \"pmids\": [\"28384255\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Mincle recognizes the glycolipid Glc-DAG (glucosyl-diacylglycerol) of Streptococcus pneumoniae; Mincle-deficient mice show increased bacterial loads, decreased survival, and dysregulated cytokine responses in pneumococcal pneumonia.\",\n      \"method\": \"Mincle reporter cell activation with purified Glc-DAG, Mincle-/- macrophage cytokine assays, Mincle-KO mouse pneumonia model, hematopoietic reconstitution experiments\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ligand identified and validated functionally, KO mice with bone marrow chimera; multiple orthogonal methods\",\n      \"pmids\": [\"27923071\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Mincle mediates NET (neutrophil extracellular trap) formation through autophagy activation; Mincle-/- neutrophils show impaired autophagy and NET formation in vitro and in vivo during Klebsiella pneumoniae infection, while ROS production remains intact; autophagy induction rescues NET formation in Mincle-/- neutrophils.\",\n      \"method\": \"Mincle-/- neutrophils stimulated in vitro and in vivo Klebsiella infection, NET formation assays, ROS assays, autophagy activation analysis, tamoxifen (autophagy inducer) rescue experiment\",\n      \"journal\": \"The Journal of infectious diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO plus rescue experiment, two orthogonal readouts (NETs and autophagy); single lab\",\n      \"pmids\": [\"28186242\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Mincle fine structure of fatty acids is critical for glycolipid binding to its CRD; glucose and mannose esterified at O-6 by a synthetic α-branched 32-carbon fatty acid show agonist activity similar to TDM; Mincle-dependent cytokine production confirmed with primary human and murine cells.\",\n      \"method\": \"Chemical synthesis, molecular dynamics simulations, protein mutagenesis, reporter cell assays, Mincle-/- primary cell cytokine assays, in vivo immunization\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — combined chemical synthesis, mutagenesis, MD simulation, and in vivo validation; comprehensive structure-activity relationship\",\n      \"pmids\": [\"28223515\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Mincle recognizes the lipoteichoic acid anchor monoglucosyldiacylglycerol (MGDG) of Group A Streptococcus via the CARD9 pathway to drive protective antibacterial immunity; Mincle-deficient mice show impaired cytokine production, severe bacteremia, and rapid lethality upon GAS infection.\",\n      \"method\": \"Gene expression analysis of CARD9-pathway contribution, purified MGDG reporter cell assays, Mincle-/- mouse GAS infection model\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ligand identified and validated, KO mouse infection model with lethal phenotype; multiple orthogonal methods\",\n      \"pmids\": [\"30352847\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The Mincle-Syk signaling axis in dendritic cells in Peyer's patches senses mucosal-resident commensals and triggers IL-6 and IL-23p19 expression to regulate intestinal Th17 cell and ILC3 function; Mincle-deficient mice show impaired RegIIIγ and IgA production and increased systemic translocation of gut microbiota, with consequent liver inflammation.\",\n      \"method\": \"Mincle-/- mice, conditional Syk KO in CD11c+ cells, intestinal cytokine and IgA assays, microbiota translocation assays, liver inflammation analysis\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two genetic models (Mincle-/- and conditional Syk KO), multiple downstream functional readouts; defines Mincle in gut homeostasis\",\n      \"pmids\": [\"30709742\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CLEC4E activation in combination with TLR4 induces autophagy in macrophages through MYD88 and PtdIns3K pathways, leading to lysosome biogenesis and enhanced intracellular killing of Mycobacterium tuberculosis; autophagy-deficient (Atg5-KO, Becn1-KD) macrophages show elevated Mtb survival.\",\n      \"method\": \"CLEC4E+TLR4 agonist co-stimulation, autophagy-deficient macrophages, lysosome biogenesis assays, intracellular Mtb killing assays in mice and guinea pigs\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO/KD macrophage functional assays with in vivo validation; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"31462144\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"β-Glucosylceramide in combination with free cholesterol acts as an endogenous Mincle ligand to trigger sustained inflammation after acute kidney injury; free cholesterol markedly enhances the agonistic effect of β-GlcCer on Mincle; Mincle-deficient mice are protected from kidney damage after ischemia-reperfusion injury.\",\n      \"method\": \"Lipophilic extract fractionation from injured kidney, Mincle reporter assays, Mincle-/- mouse ischemia-reperfusion model, histological analysis of β-GlcCer and free cholesterol accumulation near Mincle-expressing macrophages\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ligand identification with synergy demonstrated, KO mouse model, localization evidence; multiple orthogonal methods\",\n      \"pmids\": [\"32797195\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Mincle/Syk/NF-κB signaling is essential for maintaining protumoral M2-like tumor-associated macrophage (TAM) function; Mincle silencing in TAM promotes M1-like phenotype in vitro; ultrasound microbubble-mediated tumor-specific Mincle silencing suppresses TAM-driven cancer progression in syngeneic mouse cancer models.\",\n      \"method\": \"Single-cell RNA sequencing, Mincle siRNA in BMDMs, adoptive transfer of Mincle-silenced BMDMs into NOD/SCID mice, ultrasound microbubble gene delivery in syngeneic LLC and B16F10 models, Syk phosphorylation assays\",\n      \"journal\": \"Cancer immunology research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — single-cell RNA-seq, adoptive transfer, in vivo gene silencing; multiple orthogonal methods across in vitro and in vivo systems\",\n      \"pmids\": [\"32532809\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Mincle/Syk signaling in macrophages promotes intestinal mucosal inflammation (Crohn's disease model) by inducing macrophage pyroptosis and MAPK-driven chemokine production to recruit neutrophils; Mincle-/- mice and Syk-inhibitor-treated mice show reduced colitis.\",\n      \"method\": \"Mincle-/- mice in colitis model, Syk inhibitor, Mincle agonist (TDB) in vivo, BMDMs from Mincle-/- mice, pyroptosis and cytokine assays\",\n      \"journal\": \"Journal of Crohn's & colitis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO plus pharmacological inhibition plus agonist validation; single lab\",\n      \"pmids\": [\"32333776\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SAP130 released from damaged renal tubular cells activates macrophage Mincle to drive necroinflammation; Mincle expression is negatively regulated post-transcriptionally by miR-219c-3p binding to Mincle 3'-UTR; lentivirus-mediated overexpression of miR-219c-3p blunts Mincle expression and macrophage infiltration in AKI.\",\n      \"method\": \"Luciferase 3'-UTR reporter assay (miR-219c binding to Mincle), lentiviral miR-219c overexpression in vivo, recombinant SAP130 administration in Mincle-/- mice, UUO and cisplatin AKI models\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — 3'-UTR reporter assay defines miRNA mechanism, lentiviral rescue in vivo, KO validation; multiple orthogonal methods\",\n      \"pmids\": [\"34556635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Clec4e (Mincle) is expressed in cardiac vasculature, myocytes, and infiltrating leukocytes after myocardial ischemia-reperfusion injury; loss of Clec4e reduces acute cardiac injury, neutrophil infiltration, infarct size, and improves LV structural and functional remodeling at 4 weeks.\",\n      \"method\": \"Clec4e-/- mice in myocardial ischemia-reperfusion model, porcine and human myocardial samples for expression analysis, early transcriptome analysis of LV tissue\",\n      \"journal\": \"JACC. Basic to translational science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse phenotype with complementary porcine and human expression correlation; single lab\",\n      \"pmids\": [\"34466750\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Mincle has a T cell-intrinsic role in TH17-mediated CNS inflammation: TH17 cells express Mincle, and β-glucosylceramide released by dying cells engages Mincle on TH17 cells to activate the ASC-NLRP3 inflammasome, triggering Caspase8-dependent IL-1β production that drives TH17 proliferation through an autocrine loop.\",\n      \"method\": \"T cell-specific Mincle deletion in EAE model, Mincle expression profiling in TH17 vs TH1, β-GlcCer stimulation assays, NLRP3/ASC/Caspase8 pathway analysis, β-GlcCer synthesis inhibitor in vivo\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional T cell-specific KO dissecting cell-intrinsic role, inflammasome pathway dissection, pharmacological rescue; multiple orthogonal methods\",\n      \"pmids\": [\"35504893\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Peroxiredoxin 1 (Prdx1) is a novel DAMP that directly interacts with Mincle on macrophages to activate Mincle/Syk/NF-κB signaling and drive M1 polarization; Prdx1 knockout or neutralization protects against AKI, and this protection is reversed by recombinant Prdx1; Mincle knockdown abolishes rPrdx1-induced Syk activation.\",\n      \"method\": \"Prdx1-/- mice, Prdx1-neutralizing antibody, recombinant Prdx1 protein, co-immunoprecipitation (Prdx1-Mincle interaction), Mincle knockdown, primary peritoneal macrophage assays\",\n      \"journal\": \"Kidney international\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP of Prdx1-Mincle, genetic KO with recombinant protein rescue, KD epistasis; multiple orthogonal methods\",\n      \"pmids\": [\"37164261\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Macrophages mediate psoriasis via the Mincle-Syk-NF-κB signaling pathway; LPS induces Mincle expression in M1 macrophages via a PU.1-dependent transcriptional mechanism; adoptive transfer of Mincle-KO macrophages fails to restore psoriasis, and Mincle-neutralizing antibody significantly improves psoriasis in mice.\",\n      \"method\": \"Macrophage depletion + adoptive transfer, macrophage-specific Mincle KO mice (Mincleloxp/Lyz2-cre), PU.1 ChIP or binding assay, Mincle-neutralizing antibody in vivo\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO plus adoptive transfer plus therapeutic antibody; defines Mincle as driver in psoriasis with PU.1-dependent transcriptional mechanism\",\n      \"pmids\": [\"37117184\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Mincle (Clec4e) is essential for Enterococcus faecalis-induced trained immunity in bone marrow progenitors following intestinal barrier disruption; Clec4e-/- mice show impaired trained immunity upon E. faecalis administration and reduced colitis pathology after DSS treatment.\",\n      \"method\": \"Clec4e-/- mice, DSS gut permeability model, heat-killed E. faecalis stimulation of bone marrow progenitors, in vitro and in vivo trained immunity readouts\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with in vivo and in vitro trained immunity assays; single lab, multiple readouts\",\n      \"pmids\": [\"39848243\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CLEC4E (Mincle) is a transmembrane C-type lectin receptor on myeloid cells that constitutively associates with FcRγ (and forms heterodimers with MCL/Clec4d) to signal through an ITAM-Syk-CARD9-Bcl10-MALT1 axis; upon recognition of a diverse array of glycolipid ligands (including mycobacterial TDM, fungal alpha-mannose structures, β-glucosylceramide, cholesterol crystals, and cholesterol sulfate) or released endogenous proteins (SAP130, Prdx1) from damaged cells, Mincle drives pro-inflammatory cytokine and nitric oxide production, NF-κB-dependent gene transcription (regulated by C/EBPβ and TLR4/MyD88-induced Mincle upregulation via NF-κB binding the Mincle promoter), eIF5A hypusination-dependent translational control of iNOS, autophagy-mediated NET formation, and ER stress responses; additionally, Mincle can be co-opted into an inhibitory ITAMi configuration (recruiting SHP1 via FcRγ) by certain pathogens, and its surface expression is negatively post-transcriptionally regulated by miR-219c-3p targeting the Mincle 3'-UTR.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CLEC4E (Mincle) is a myeloid C-type lectin receptor that couples innate sensing of microbial glycolipids and damage-associated molecules to pro-inflammatory signaling, immune adjuvanticity, and sterile inflammation [#3, #5]. It is a non-signaling receptor that recruits the ITAM-bearing FcRγ chain to assemble a Syk-CARD9-Bcl10-MALT1 signaling complex driving NF-κB-dependent cytokine, chemokine, and nitric oxide production [#0, #8]. Surface display and ligand competence depend on heterodimerization with MCL/Clec4d through a hydrophobic stalk-region interaction, and Mincle is itself transcriptionally induced downstream of TLR4/MyD88 via C/EBPβ and NF-κB/PU.1 binding to its promoter, providing feed-forward amplification [#11, #13, #14, #19, #42]. Crystallographic and structure-activity studies define a Ca2+-dependent sugar-binding site adjacent to a hydrophobic groove that docks the acyl chains of glycolipids, explaining recognition of a broad ligand repertoire including mycobacterial trehalose dimycolate (TDM/cord factor) and the synthetic adjuvant TDB, fungal alpha-mannose structures of Malassezia, streptococcal glucosyl-diacylglycerol and monoglucosyldiacylglycerol, and the human-specific ligand cholesterol crystals [#3, #4, #6, #7, #29, #31, #32, #15]. Mincle also senses endogenous danger signals released from damaged cells—the nuclear protein SAP130, β-glucosylceramide (potentiated by free cholesterol), cholesterol sulfate, and peroxiredoxin-1—linking necroptotic and barrier injury to inflammation across atherosclerosis, acute kidney injury, myocardial reperfusion injury, hepatic injury, psoriasis, uveoretinitis, and tumor-associated macrophage programming [#1, #20, #25, #26, #35, #41, #18, #36]. Downstream of receptor engagement Mincle controls iNOS through both transcription and eIF5A-hypusination-dependent translation, induces ER stress, autophagy and NET formation, and shapes adaptive immunity by promoting Th17 responses, including a T-cell-intrinsic β-glucosylceramide-Mincle-NLRP3 autocrine loop in CNS inflammation [#23, #18, #30, #9, #40]. Certain pathogens co-opt Mincle into an inhibitory ITAMi configuration that recruits SHP1 via FcRγ to dampen dendritic cell activation, and Mincle expression is further restrained post-transcriptionally by miR-219c-3p targeting its 3'-UTR and by CD11b-mediated Syk dephosphorylation [#17, #38, #27].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Established Mincle's core signaling logic and first endogenous danger ligand, answering how a lectin receptor transduces sensing of dead cells into inflammation.\",\n      \"evidence\": \"Co-IP, reporter assays and Mincle-deficient macrophages identifying FcRγ coupling and SAP130 as a released ligand\",\n      \"pmids\": [\"18776906\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the downstream kinase cascade beyond ITAM coupling\", \"SAP130 binding mode to the CRD not structurally resolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showed the Mincle CRD can bind fungal cells directly, opening the question of which glycan ligands it recognizes.\",\n      \"evidence\": \"Recombinant refolded CRD binding to Candida albicans cells and yeast extract in vitro\",\n      \"pmids\": [\"18509109\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional signaling follow-up\", \"Specific glycan ligand not identified in this study\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identified Mincle as the essential receptor for mycobacterial cord factor TDM and for fungal alpha-mannose ligands, establishing it as a pattern-recognition receptor for pathogen glycolipids.\",\n      \"evidence\": \"Lipid fractionation, mannose-binding-motif mutagenesis, glycan arrays, KO macrophages and in vivo granuloma/cytokine assays\",\n      \"pmids\": [\"20008526\", \"19171887\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of glycolipid binding not yet defined\", \"Did not establish the full Syk-CARD9 signaling hierarchy\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Connected TDM/TDB recognition to the Syk-Card9 axis and to vaccine adjuvanticity, defining Mincle as a target for adjuvant design.\",\n      \"evidence\": \"Mincle-Fc fusion binding assays, KO macrophages and in vivo Th17 vaccination\",\n      \"pmids\": [\"20164423\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve receptor stoichiometry or co-receptor requirements\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Resolved the molecular mechanism of glycolipid recognition, explaining how one receptor accommodates both sugar headgroups and fatty acyl chains.\",\n      \"evidence\": \"X-ray crystallography of mouse/bovine CRDs with functional and affinity mutagenesis defining Ca2+ site plus a hydrophobic groove\",\n      \"pmids\": [\"24101491\", \"23960080\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Human Mincle structure not captured in fully active conformation\", \"Full-length receptor and dimer architecture not solved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined the proximal signaling complex and the MCL/FcεRI-γ partnership that controls Mincle expression and phagocytosis.\",\n      \"evidence\": \"Flow cytometry, reciprocal Co-IP and phagocytosis assays in rat cells; genetic dissection of Syk-CARD9-Bcl10-MALT1 and MyD88/IL-1R adjuvant requirement\",\n      \"pmids\": [\"23921530\", \"23308247\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"MCL-Mincle stoichiometry not quantified\", \"Order of FcRγ versus MCL assembly unresolved at this stage\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Established the transcriptional circuitry for Mincle induction and revealed pathogen subversion of its signaling, distinguishing activating from immunosuppressive outcomes.\",\n      \"evidence\": \"ChIP of NF-κB/C/EBPβ on the Mincle promoter, Dectin-3/CARD9/Cebpb/Hif1a KO macrophages with retroviral rescue, and Fonsecaea-driven Mdm2-mediated IRF1 degradation in human DCs\",\n      \"pmids\": [\"25202022\", \"25156364\", \"24721577\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Interplay between NFAT and NF-κB arms not fully delineated\", \"HIF1α-independent Mincle induction mechanism partially defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined how MCL controls Mincle trafficking and extended the ligand repertoire to a human-specific sterol ligand.\",\n      \"evidence\": \"Stalk-region MCL4S mutagenesis with KO/transgenic rescue; MS identification of cholesterol crystals as a human Mincle ligand; two-step surface translocation model\",\n      \"pmids\": [\"25888641\", \"26296894\", \"27005451\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mouse-human species divergence in sterol recognition mechanistically unexplained\", \"Trafficking machinery for the heterodimer not identified\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Generalized Mincle as a driver of sterile and tumoral inflammation across organs and revealed both inhibitory ITAMi signaling and a translational control branch.\",\n      \"evidence\": \"KO/chimera models in atherosclerosis, pancreatic cancer, alcoholic liver injury, subarachnoid hemorrhage and uveoretinitis; SHP1 conditional KO and Co-IP for ITAMi; eIF5A-hypusination analysis for iNOS translation\",\n      \"pmids\": [\"27587433\", \"27049944\", \"27628766\", \"27845194\", \"26921309\", \"27742545\", \"27089465\", \"28017324\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"What dictates the switch between activating and ITAMi configurations is not resolved\", \"Direct binding of all endogenous ligands (e.g. albumin) to the CRD not structurally validated\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified β-glucosylceramide and cholesterol sulfate as endogenous Mincle ligands and expanded effector outputs to autophagy/NET formation and Fc-receptor crosstalk.\",\n      \"evidence\": \"MS/NMR ligand identification with GBA1×Mincle double-KO mice; cholesterol sulfate KO dermatitis model; autophagy-dependent NET assays; CD11b-Mincle and TDM-bead phagosome inhibition; SAR with synthetic glycolipids\",\n      \"pmids\": [\"28373578\", \"28292894\", \"28186242\", \"29400702\", \"28384255\", \"28223515\", \"27923071\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How free cholesterol potentiates β-GlcCer recognition was not yet defined\", \"Negative regulation by CD11b-SHP1 not validated in vivo\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined Mincle's homeostatic role in sensing commensals and an autophagy-driven antimicrobial program, broadening it beyond acute pathogen sensing.\",\n      \"evidence\": \"Mincle-/- and CD11c-Syk conditional KO intestinal models; CLEC4E+TLR4 co-stimulation driving autophagy and Mtb killing in autophagy-deficient macrophages\",\n      \"pmids\": [\"30709742\", \"31462144\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific commensal glycolipid ligand(s) in the gut not identified\", \"Mechanism linking Mincle to lysosome biogenesis incompletely mapped\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established Mincle as a tunable driver of TAM polarization and tissue injury and demonstrated a synergistic endogenous ligand combination.\",\n      \"evidence\": \"scRNA-seq and ultrasound-microbubble Mincle silencing in tumor models; β-GlcCer plus free cholesterol synergy in KO kidney ischemia-reperfusion; Syk-NF-κB colitis pyroptosis model\",\n      \"pmids\": [\"32532809\", \"32797195\", \"32333776\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of cholesterol-β-GlcCer synergy at the CRD not structurally resolved\", \"TAM-intrinsic Mincle ligand in tumors not defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined post-transcriptional control of Mincle and extended its injury role to the heart.\",\n      \"evidence\": \"Luciferase 3'-UTR reporter and lentiviral miR-219c-3p overexpression in AKI; Clec4e-/- myocardial ischemia-reperfusion with human/porcine expression correlation\",\n      \"pmids\": [\"34556635\", \"34466750\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream regulators of miR-219c-3p not identified\", \"Cell-type source of cardiac Mincle ligand not defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified peroxiredoxin-1 as a new DAMP ligand and consolidated the Mincle-Syk-NF-κB axis as a macrophage-driven disease mechanism with therapeutic tractability.\",\n      \"evidence\": \"Co-IP of Prdx1-Mincle with KO/recombinant rescue in AKI; macrophage-specific Mincle KO, PU.1-dependent induction and neutralizing antibody in psoriasis\",\n      \"pmids\": [\"37164261\", \"37117184\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Prdx1 binding site on the CRD not structurally mapped\", \"Generality of antibody-based Mincle blockade across diseases untested here\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended Mincle function to instruction of trained immunity in bone marrow progenitors following barrier disruption.\",\n      \"evidence\": \"Clec4e-/- mice with DSS permeability and heat-killed E. faecalis trained-immunity readouts\",\n      \"pmids\": [\"39848243\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Bacterial ligand engaging Mincle in this context not chemically defined\", \"Epigenetic mediators of the trained phenotype not mapped\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"What governs the molecular switch between Mincle's activating ITAM and inhibitory ITAMi configurations, and how distinct endogenous and microbial ligands bias this choice, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of full-length Mincle-MCL-FcRγ signaling complex\", \"Determinants of SHP1 versus Syk recruitment by FcRγ not defined\", \"Mechanism distinguishing pro-inflammatory from immunosuppressive outcomes per ligand unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [0, 3, 5, 25]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [3, 6, 7, 25, 15, 26, 35]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 8, 17]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [8, 0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 8, 14, 16]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 3, 5, 9, 29, 32, 33]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 8, 11, 17, 36, 41]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [30, 34]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [18, 23]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [18, 20, 35, 39, 42]}\n    ],\n    \"complexes\": [\n      \"Mincle-FcRγ ITAM signaling complex\",\n      \"Mincle-MCL (Clec4d) heterodimer\",\n      \"Mincle-CD11b inhibitory complex\"\n    ],\n    \"partners\": [\n      \"FCER1G\",\n      \"CLEC4D\",\n      \"SYK\",\n      \"CARD9\",\n      \"PTPN6\",\n      \"ITGAM\",\n      \"PRDX1\",\n      \"SAP130\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}