{"gene":"CD300LF","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":2004,"finding":"CD300LF (IREM-1) was identified as a novel inhibitory receptor that interacts with the SH2 domains of SHP-1 via a three-hybrid strategy. Western blot confirmed SHP-1 recruitment to IREM-1, with phosphotyrosine Y205 identified as the main docking site. Cross-linking of IREM-1 inhibits FcεR-induced activation in myeloid cells. The receptor contains two ITIM motifs and is expressed on monocytes and granulocytes.","method":"Three-hybrid screen, Western blot, immunoprecipitation, FACS, cross-linking functional assay","journal":"European journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP confirmed SHP-1 recruitment, specific tyrosine residue identified, functional inhibition assay performed, replicated across transfected cells and endogenous U937 cells","pmids":["15549731"],"is_preprint":false},{"year":2007,"finding":"CD300LF (IREM-1) cytoplasmic domain recruits both SHP-1 and the p85α subunit of PI3K. Y205 and Y249 (ITIM residues) are critical for IREM-1-mediated inhibition of FcεRI-induced degranulation. Mutation of Y205, Y249, Y284 (which abolishes SHP-1 binding) creates an activating receptor that promotes degranulation via PI3K through Y236 and Y263; this activation is blocked by wortmannin and LY-294002.","method":"Immunoprecipitation, site-directed mutagenesis of IREM-1 cytoplasmic tyrosines, functional beta-hexosaminidase secretion assay in RBL cells, PI3K inhibitor studies","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis of specific residues combined with functional assays and pharmacological inhibitors, multiple orthogonal methods in one study","pmids":["17202342"],"is_preprint":false},{"year":2007,"finding":"Crystal structure of the extracellular Ig-V-like domain of IREM-1 (CD300LF) was determined at 2.6 Å resolution. The fold resembles a V-type immunoglobulin domain with close homology to CLM-1, TREM-1, TLT-1, and NKp44. Structural analysis identified a hydrophobic groove on the surface and a structurally variable CDR3-equivalent loop proposed as the main determinant for ligand discrimination.","method":"X-ray crystallography at 2.6 Å resolution","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure determined at 2.6 Å in single study, structural analysis is rigorous but functional validation of ligand-binding sites not performed in same paper","pmids":["17275839"],"is_preprint":false},{"year":2008,"finding":"Cross-linking of CD300LF (MAIR-V) with anti-CD300LF mAb induces caspase-independent, ER stress-independent cell death in peritoneal macrophages and transfectants. This cell death requires the cytoplasmic region but not ITIM or ITSM motifs. Morphologically the dead cells resemble apoptotic cells (loss of blebs) but are resistant to caspase inhibitor Z-VAD-FMK and autophagy inhibitors.","method":"Anti-CD300LF cross-linking, scanning electron microscopy, pharmacological inhibition (Z-VAD-FMK, 3-methyladenine, N-acetyl-L-cysteine), Western blot for XBP-1 splicing, cytoplasmic domain deletion constructs","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean loss-of-function domain mapping with pharmacological controls, single lab, multiple inhibitor experiments","pmids":["18097021"],"is_preprint":false},{"year":2009,"finding":"CLM-1 (CD300LF) acts as a negative regulator of myeloid cells in autoimmune demyelination (EAE model). CLM-1-deficient mice showed increased nitric oxide and proinflammatory cytokine production by myeloid cells in demyelinating spinal cord, increased demyelination, and worse clinical scores, without affecting T cell responses in the periphery or spinal cord.","method":"CLM-1 knockout mouse model, EAE induction, histological scoring, cytokine measurement, flow cytometry of T cells","journal":"The Journal of experimental medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with specific cellular phenotype (myeloid effector regulation) established by epistasis, single lab","pmids":["20038601"],"is_preprint":false},{"year":2011,"finding":"CD300f (mouse) binds phosphatidylserine (PS) exposed on the outer membrane of apoptotic cells; this binding requires a metal ion. CD300f/Fc chimeric protein specifically binds apoptotic cells in a manner inhibitable by Annexin V. Binding was demonstrated by ELISA, cosedimentation, and surface plasmon resonance using phospholipid-containing liposomes. Ectopic expression of CD300f in cell lines enhances phagocytosis of apoptotic cells.","method":"CD300f/Fc chimeric protein binding assays, ELISA, cosedimentation, surface plasmon resonance with liposomes, Annexin V competition, ectopic expression phagocytosis assay","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal biochemical methods (SPR, ELISA, cosedimentation) confirming PS binding, functional phagocytosis assay, metal-ion requirement established","pmids":["21865548"],"is_preprint":false},{"year":2011,"finding":"CD300F blocks both MyD88 and TRIF-mediated TLR signaling in monocytic cells through recruitment of SHP-1. CD300F stimulation (mAb cross-linking or ITIM synthetic peptides) suppressed TLR2, 3, 4, and 9-mediated expression of IL-8 and MMP-9, inhibited IKK activation, IκB phosphorylation/degradation, and NF-κB activation. Immunoprecipitation confirmed SHP-1 association.","method":"mAb cross-linking, synthetic ITIM peptides, luciferase reporter assays, Western blot, immunoprecipitation, pharmacological inhibitors","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple TLR ligands tested, luciferase reporter + Western blot + IP, mechanistic pathway placement via signaling node (SHP-1/NF-κB), single lab with orthogonal methods","pmids":["21536801"],"is_preprint":false},{"year":2012,"finding":"CD300f blocks both MyD88 and TRIF-mediated TLR signaling through combined activation of SHP-1 and SHP-2, whereas CD300a only blocks MyD88-mediated signaling via SHP-1. Differential inhibition is recapitulated by synthetic ITIM peptides of CD300a versus CD300f. This distinction maps to the ability of CD300f (but not CD300a) to activate SHP-2 for TRIF pathway inhibition.","method":"TLR stimulation in THP-1/U937 cells, NF-κB luciferase reporter, synthetic ITIM peptides, signaling inhibitors, Western blot","journal":"Immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter + inhibitor studies + ITIM peptide mimicry, single lab, two orthogonal methods","pmids":["22043923"],"is_preprint":false},{"year":2013,"finding":"CLM-1 (CD300f) negatively regulates eotaxin-induced eosinophil chemotaxis, actin polymerization, calcium influx, and ERK1/2 (but not p38) phosphorylation. Addition of CLM-1 ligand phosphatidylserine rendered wild-type eosinophils hypochemotactic in vitro; blockade of CLM-1/ligand interactions caused hyperchemotaxis in vitro and in an allergic airway model in vivo. CLM-1 regulation was specific to eotaxin/CCR3 and not LTB4 or MIP-1α.","method":"Clm1-/- mouse eosinophils, in vitro chemotaxis assay, calcium flux, ERK/p38 phosphorylation, in vivo allergic airway model, phosphatidylserine ligand addition","journal":"Mucosal immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse combined with ligand addition experiments, multiple signaling readouts, specificity control (LTB4/MIP-1α negative), in vitro and in vivo validation","pmids":["23820751"],"is_preprint":false},{"year":2014,"finding":"CD300f (CLM-1) accumulates in phagocytic cups at apoptotic cell contact sites. Phosphorylation of Y276 in the cytoplasmic tail recruits the p85α subunit of PI3K, which activates downstream Rac/Cdc42 GTPase and drives F-actin remodeling to promote apoptotic cell engulfment. Y276 phosphorylation is required for enhanced phagocytosis. Distinct tyrosine motifs positively (Y276/PI3K) or negatively regulate phagocytosis. Primary CD300f-deficient macrophages show impaired apoptotic cell phagocytosis. CD300f deficiency in FcγRIIB-null mice accelerates lupus-like disease.","method":"Site-directed mutagenesis of CD300f cytoplasmic tyrosines, confocal microscopy, PI3K co-immunoprecipitation, Rac/Cdc42 activation assays, F-actin imaging, CD300f-/- macrophage phagocytosis, autoimmune disease model","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis of specific residues, co-IP of p85α, downstream GTPase and F-actin assays, KO macrophage functional validation, in vivo disease model; multiple orthogonal methods in single study","pmids":["24477292"],"is_preprint":false},{"year":2015,"finding":"CD300f binds ceramide as a ligand and this interaction suppresses IgE-dependent and mast cell-dependent allergic responses. In the DSS colitis model, ceramide-CD300f (LMIR3) binding inhibited ATP-stimulated mast cell activation. CD300f deficiency exacerbated DSS-induced colitis; mast cell-specific CD300f deficiency was responsible. Administration of ceramide liposomes suppressed colitis; disruption of ceramide-LMIR3 interaction aggravated it.","method":"CD300f-/- mice, mast cell-deficient Kit(W-sh) mice, BMMC reconstitution, ATP-stimulated BMMC in vitro activation, ELISA, ceramide liposome treatment, DSS colitis model","journal":"Gut","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO + mast cell-specific reconstitution + in vitro ceramide-CD300f functional assay + in vivo ceramide liposome rescue; multiple orthogonal approaches, single lab","pmids":["25673319"],"is_preprint":false},{"year":2015,"finding":"CD300f is colocalized and physically associated with IL-4Rα in macrophages. CD300f amplifies IL-4Rα-induced signaling, mediator release, and priming. Cd300f-/- cells and mice show decreased IL-4/IL-13-induced responses, IgE production, chemokine expression, and inflammatory cell recruitment in allergen challenge, while IL-4/IL-13 levels are increased (consistent with decreased cytokine consumption).","method":"Co-localization microscopy, physical association assay, Cd300f-/- cells and mice, IL-4Rα cross-linking, allergen challenge model, cytokine ELISA","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — physical association demonstrated, KO cells and mice with defined signaling phenotype, in vitro and in vivo experiments, multiple readouts","pmids":["26124135"],"is_preprint":false},{"year":2016,"finding":"CD300lf and CD300ld are functional cell-surface receptors for murine norovirus (MNV). Identified by genome-wide CRISPR/Cas9 screen. Anti-CD300lf polyclonal antibody significantly reduces viral progeny. Ectopic expression of CD300lf in non-susceptible cell lines from other species enables MNV infection and progeny production, demonstrating CD300lf is sufficient to confer permissivity and can dictate host tropism.","method":"Genome-wide CRISPR/Cas9 loss-of-function screen, antibody blocking, ectopic expression in heterologous cell lines, viral progeny quantification","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — unbiased CRISPR screen identification confirmed by antibody blocking and ectopic expression gain-of-function, multiple lines of evidence","pmids":["27681626"],"is_preprint":false},{"year":2016,"finding":"CD300f expression in dendritic cells (DCs) inhibits efferocytosis (in contrast to its function in macrophages where it promotes phagocytosis). CD300f deficiency in DCs leads to hyperactive phagocytosis of apoptotic cells, enhanced antigen processing and T-cell priming, expansion of memory T cells, and increased ANA levels. This contributes to autoimmune disease predisposition.","method":"Cd300f-/- mouse DCs, efferocytosis assays, antigen presentation assays, T cell priming, ANA measurement, apoptotic cell overload model","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse with cell-type-specific functional readouts, single lab, two orthogonal cell biological approaches","pmids":["26768664"],"is_preprint":false},{"year":2017,"finding":"Ceramide-CD300f binding inhibits LPS-induced skin inflammation. CD300f deficiency enhanced LPS-induced skin edema and neutrophil recruitment. CD300f suppresses release of chemical mediators (vascular permeability factors, neutrophil chemoattractants) from mast cells and neutrophils in response to LPS. Adoptive transfer experiments demonstrated mast cell and neutrophil contributions. Ceramide antibody enhanced and ceramide-containing vesicles suppressed LPS-induced skin inflammation.","method":"CD300f-/- mice, skin pouch model, LPS injection, adoptive mast cell transfer, ceramide antibody/vesicle administration, flow cytometry, mediator ELISA","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO + adoptive transfer + ceramide ligand manipulation in vivo, mechanistic pathway (TLR4 negative regulation via ceramide-CD300f), multiple orthogonal approaches","pmids":["28073916"],"is_preprint":false},{"year":2017,"finding":"CD300f-expressing DCs play a crucial role in resolving gut inflammation. CD300f-deficient DCs show hyperactive phagocytosis of apoptotic cells, stimulating excessive TNF-α secretion predominantly from DCs, which induces secondary IFN-γ overproduction by colonic T cells, leading to prolonged gut inflammation. Abnormal apoptotic cell accumulation in the gut of CD300f-deficient mice was observed.","method":"CD300f-/- mouse colitis model (DSS), DC-specific functional assays, apoptotic cell accumulation imaging, cytokine measurement (TNF-α, IFN-γ), T cell analysis","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse with defined cellular mechanism (DC-mediated TNF-α → T cell IFN-γ cascade), apoptotic cell accumulation demonstrated, multiple readouts","pmids":["28414292"],"is_preprint":false},{"year":2017,"finding":"Ceramide-CD300f interaction suppresses neutrophil chemoattractant production from mast cells and neutrophils in the context of septic peritonitis (CLP model). CD300f-/- mice are protected from CLP-induced death; CD300f deficiency enhances neutrophil accumulation and bacterial clearance. Extracellular ceramide concentrations increase in the peritoneal cavity after CLP, suggesting a negative-feedback role for ceramide-CD300f in innate immunity.","method":"CD300f-/- mice, CLP model, mast cell-deficient mouse reconstitution with WT/CD300f-/- mast cells and neutrophils, in vitro E. coli stimulation of MCs/neutrophils, ceramide vesicle/antibody administration, bacterial burden quantification","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO + adoptive transfer + in vitro ceramide-CD300f functional assay + in vivo ceramide manipulation, multiple orthogonal experiments","pmids":["28655892"],"is_preprint":false},{"year":2018,"finding":"X-ray crystal structure of the MNoV VP1 protruding (P) domain in complex with CD300lf was determined. CD300lf binds the P domain with 2:2 stoichiometry at a cleft between AB and DE loops of the P2 subdomain overlapping neutralizing antibody epitopes. Two bile acid binding sites were identified at the P domain dimer interface distant from receptor binding sites. CD300lf engages MNoV in a manner mimicking host ligand (phosphocholine) binding including similar metal coordination. Monomeric affinity of CD300lf for P domain is low and divalent cation dependent.","method":"X-ray crystallography (CD300lf–P domain complex, CD300lf–phosphocholine complex, CD300lf–bile acid complexes), biophysical assays (SPR, ITC), interface residue mutagenesis, cryo-EM docking","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple crystal structures with mutagenesis validation and biophysical assays, highly rigorous multi-method study","pmids":["30194229"],"is_preprint":false},{"year":2018,"finding":"Crystal structure of soluble CD300lf in complex with the MNoV capsid protruding domain was determined at 2.05 Å resolution. The CD300lf binding site is on the topside of the P domain, involving hydrophilic and hydrophobic interactions, with CD300lf fitting into a complementary cavity stabilized by complementary surface charges. Five of six P domain residues interacting with CD300lf are conserved across MNoV strains. CD300lf-interacting residues are partially conserved in CD300ld but variable in other CD300 family members, consistent with observed infection selectivity.","method":"X-ray crystallography at 2.05 Å resolution, sequence alignment analysis","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — high-resolution crystal structure of receptor-capsid complex, structural basis for selectivity explained, single study but rigorous method","pmids":["29563286"],"is_preprint":false},{"year":2018,"finding":"LMIR3/CD300f deficiency augments antimicrobial activity of mouse neutrophils. LMIR3-KO neutrophils show significantly increased hypochlorous acid production, elastase release, and cytotoxic activity against P. aeruginosa and C. albicans. LMIR3 surface expression increases on bone marrow neutrophils in response to P. aeruginosa infection in a TLR4/MyD88-dependent manner. Elastase and myeloperoxidase inhibitors offset the enhanced antimicrobial activity of KO neutrophils.","method":"LMIR3-KO mice, hypochlorous acid production assay, elastase release assay, cytotoxicity assay, P. aeruginosa/C. albicans infection models, TLR4/MyD88 dependency via inhibitors","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse neutrophil phenotype with pharmacological pathway identification, single lab, multiple readouts","pmids":["30479367"],"is_preprint":false},{"year":2020,"finding":"CD300lf is the sole physiologic receptor for MNoV in vivo. CD300lf is required for both oral and parenteral MNoV infection and for anti-MNoV humoral responses. In STAT1-deficient mice, CD300lf is required for MNoV-induced lethality. Human CD300lf (huCD300lf) is not an entry receptor for human norovirus (HNoV) and does not inhibit HNoV virus-like particle binding to glycans.","method":"CD300lf-/- mice, oral and parenteral MNoV infection, anti-MNoV antibody ELISA, STAT1-/- x CD300lf-/- double KO lethality model, HNoV VLP binding assay with huCD300lf","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO establishes in vivo requirement, multiple infection routes tested, lethality model, negative result for HNoV clearly controlled","pmids":["32251490"],"is_preprint":false},{"year":2020,"finding":"A non-synonymous SNP (rs2034310, C/T) in the CD300f cytoplasmic tail inhibits protein kinase C phosphorylation of a threonine residue and is associated with protection against major depressive disorder, mainly in women. CD300f-/- mice display augmented microglial numbers, increased IL-6 and IL-1Ra mRNA, synaptic strength alterations, and noradrenaline-dependent depressive-like behaviors in females. RNA sequencing and biochemical studies indicate impaired microglial metabolic fitness in CD300f-/- mice.","method":"Human genetic association (SNP analysis), CD300f-/- mouse behavioral phenotyping, RNA sequencing, biochemical metabolic studies, immunohistochemistry","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — PKC phosphorylation site identified with SNP functional consequence, KO mouse phenotype with transcriptomic and biochemical validation, single lab","pmids":["32152116"],"is_preprint":false},{"year":2020,"finding":"CD300LF polymorphisms in inbred mouse strains (I/LnJ vs C57BL/6J) confer resistance to MNV infection in a cell type-dependent manner. A 4-amino-acid difference in the CC' loop of CD300LF determines functional receptor activity. I/LnJ CD300LF does not function as MNV entry factor in macrophage-like cells but does in other cell types. I/LnJ CD300LF binds MNV virions in permissive but not non-permissive cells, indicating a cell type-specific modifier of CD300LF-dependent MNV entry.","method":"Bone marrow-derived macrophage infection assays, lentiviral transduction with C57BL/6J vs I/LnJ CD300LF swap constructs, chimeric receptor mutagenesis, virion binding assay","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reciprocal domain-swap mutagenesis identifies specific residues in CC' loop required for receptor function, virion binding assay confirms mechanism, multiple cell types tested","pmids":["32581099"],"is_preprint":false},{"year":2021,"finding":"CD300lf expression on intestinal epithelial tuft cells is essential for transmission of persistent MNoV strain CR6, demonstrated using a conditional CD300lf knockout mouse. The non-persistent MNoV strain CW3 does not require CD300lf on IECs but utilizes myelomonocytic cells (LysM+ cells) as a major target. CD300lf on B cells, neutrophils, and dendritic cells is not critical for CW3 infection. STAT1 signaling partially restricts CW3 tropism to LysM+ cells.","method":"Conditional Cd300lf knockout mice (IEC-specific, LysM-Cre, CD19-Cre, Mrp8-Cre, CD11c-Cre), MNoV infection, viral RNA quantification, STAT1-/- genetic crosses","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO mouse system with multiple Cre drivers establishes cell-type-specific requirements, two distinct MNV strains compared, epistasis with STAT1","pmids":["33177207"],"is_preprint":false},{"year":2022,"finding":"CD300lf-ceramide interaction inhibits osteoclast differentiation. CD300lf expression is downregulated during osteoclastogenesis. CD300lf ablation increases osteoclast numbers and exacerbates alveolar bone loss in a ligature-induced periodontitis model. Application of ceramide (CD300lf ligand) suppresses osteoclastogenesis in vitro and inhibits alveolar bone loss in vivo.","method":"CD300lf-/- mice, ligature-induced periodontitis model, osteoclast counting, ceramide application in vitro and in vivo, bone resorption quantification","journal":"Journal of clinical periodontology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse + ceramide ligand rescue in vitro and in vivo, single lab, two orthogonal approaches","pmids":["36089906"],"is_preprint":false},{"year":2023,"finding":"CD300f signaling in human monocytes via anti-CD300f mAb cross-linking (DCR-2) suppresses monocytes by upregulating CD274 (PD-L1) and inhibiting T cell proliferation. In macrophages, CD300f signaling drives M2-type polarization with CD274 upregulation further enhanced by IL-4. CD300f signaling activates the PI3K/Akt pathway in monocytes; PI3K/Akt inhibition reduces CD274 expression.","method":"Anti-CD300f mAb cross-linking, T cell proliferation assay, M1/M2 polarization marker flow cytometry, PI3K/Akt pharmacological inhibition, Western blot","journal":"Cellular immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional cross-linking with pathway inhibitor study, two cell types, single lab","pmids":["37302321"],"is_preprint":false},{"year":2024,"finding":"CD300LF-deficient microglia fail to extend processes toward laser-induced cortical lesions (intravital two-photon microscopy), indicating CD300LF is required for microglial detection of damage-associated cues. CD300LF-/- microglia show reduced recognition and clearance of apoptotic cells after mTBI and intracortical apoptotic cell injection, with apoptotic cell remnants retained intracellularly suggesting defective phagolysosomal processing. Proteomic analysis after CCI reveals dysregulation of autophagy-related and metabolic pathways. CD300LF deficiency alters the UDP-P2RY6 axis with upregulation of ENTPD6 and downregulation of P2ry6, implicating impaired purinergic damage sensing.","method":"Intravital two-photon microscopy, CD300LF-/- mice, mTBI and CCI models, intracortical apoptotic cell injection, flow cytometry, proteomics, ENTPD6/P2RY6 mRNA/protein quantification","journal":"Brain, behavior, and immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — intravital live imaging directly demonstrates impaired damage sensing, KO mouse with multiple in vivo models, proteomics + targeted molecular pathway analysis, multiple orthogonal methods","pmids":["40935207"],"is_preprint":false},{"year":2024,"finding":"CD300LF-deficient mice show increased glial proliferation, neuronal loss, and worse neurological function after TBI. Transcriptomic comparison of CD300LF+ vs CD300LF- microglia reveals that CD300LF's neuroprotective role is principally mediated by inhibition of the STING signaling pathway. The STING pathway inhibitor C-176 augments the protective effect.","method":"CD300LF-/- mice, TBI model, transcriptomics (RNA-seq of sorted microglia populations), STING inhibitor C-176 treatment, histological and neurological function scoring","journal":"CNS neuroscience & therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse + transcriptomics identifies STING pathway, pharmacological validation with inhibitor, single lab","pmids":["38965803"],"is_preprint":false},{"year":2025,"finding":"CD300f mediates engulfment of pathogenic Rickettsia species (R. typhi, R. rickettsii) and non-pathogenic R. montanensis by macrophages, using rickettsial phosphatidylserine (PS) as the ligand. CD300f-/- BMDMs show significantly reduced rickettsial engulfment. CD300f-/- mice are protected from fatal rickettsiosis (R. typhi, R. rickettsii) with reduced bacterial burden. Adoptive transfer of CD300f-expressing macrophages restores susceptibility to rickettsiosis in vivo.","method":"CD300f-/- bone marrow-derived macrophages, infection assays with multiple Rickettsia species, in vivo infection model, bacterial burden quantification (spleen), adoptive macrophage transfer","journal":"Infection and immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO macrophage engulfment assay + in vivo KO infection model + adoptive transfer rescue, mechanistic link to rickettsial PS as ligand, multiple pathogens tested","pmids":["40310290"],"is_preprint":false},{"year":2025,"finding":"CD300lf and CD300a colocalize with phosphatidylserine externalized to the outer leaflet of the plasma membrane in a polar formation upon mast cell activation, and cooperate to inhibit mast cell activation. CD300lf also colocalizes with extracellular ceramide on the cell surface, and CD300lf binding to ceramide produces stronger inhibition of mast cell activation than binding to PS alone. Double-KO (Cd300a-/-Cd300lf-/-) mice show exacerbated passive systemic anaphylaxis compared to single KOs.","method":"Imaging and flow cytometry of BMMCs from WT, Cd300a-/-, Cd300lf-/-, Cd300a-/-Cd300lf-/- mice, PS/ceramide colocalization, passive systemic anaphylaxis model","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic double-KO epistasis with single KOs, live cell imaging of receptor-ligand colocalization, in vivo anaphylaxis model, multiple ligand comparisons","pmids":["40073110"],"is_preprint":false}],"current_model":"CD300LF is a type I transmembrane inhibitory immunoreceptor on myeloid cells that binds phosphatidylserine (and ceramide) exposed on apoptotic cells and activated membranes through its extracellular Ig-V-like domain (requiring metal ion coordination); ligand binding triggers cytoplasmic tail tyrosine phosphorylation that recruits SHP-1 (via ITIM Y205/Y249), SHP-2, and the PI3K p85α subunit (via Y276/Y236/Y263) to bidirectionally regulate downstream Rac/Cdc42-F-actin-driven efferocytosis, NF-κB/TLR signaling, and mast cell activation—while its extracellular domain also serves as the primary physiologic entry receptor for murine norovirus (engaging the viral capsid P domain in a metal-dependent, bile-acid-modulated interaction), and in the brain, CD300LF functions as a microglial damage-sensing receptor that integrates purinergic (UDP-P2RY6) signaling, phagolysosomal metabolization of apoptotic debris, and STING pathway inhibition to coordinate neuroinflammatory responses."},"narrative":{"mechanistic_narrative":"CD300LF (IREM-1/CLM-1/MAIR-V/LMIR3/CD300f) is a myeloid immunoreceptor that senses lipids displayed on apoptotic cells and activated membranes and converts that recognition into bidirectional control of phagocytosis and inflammatory signaling [PMID:21865548, PMID:24477292, PMID:21536801]. Its extracellular Ig-V-like domain binds phosphatidylserine in a metal ion-dependent manner inhibitable by Annexin V, and also binds ceramide, enabling recognition of apoptotic cells, microbes, and activated cell surfaces [PMID:21865548, PMID:25673319, PMID:40073110]. Ligand engagement is read out through the cytoplasmic tail: phosphorylated ITIM tyrosines Y205 and Y249 dock SHP-1 (and, distinctively from CD300a, also SHP-2) to suppress FcεRI degranulation and both MyD88- and TRIF-dependent TLR/NF-κB signaling, while Y276 recruits the PI3K p85α subunit to activate Rac/Cdc42-driven F-actin remodeling at phagocytic cups and promote efferocytosis [PMID:15549731, PMID:17202342, PMID:22043923, PMID:24477292]. This dual output makes the receptor a positive driver of apoptotic-cell engulfment in macrophages but an inhibitor in dendritic cells, where its loss causes hyperactive efferocytosis, excess TNF-α, and downstream T-cell-driven autoimmunity and colitis [PMID:24477292, PMID:26768664, PMID:28414292]. Across mast cells, eosinophils, and neutrophils, ceramide- or PS-CD300LF engagement restrains mediator release and chemotaxis, dampening allergic, anaphylactic, septic, and inflammatory bone-loss responses [PMID:23820751, PMID:25673319, PMID:28073916, PMID:28655892, PMID:40073110, PMID:36089906]. Independently of its inhibitory signaling, the CD300LF ectodomain is the physiologic entry receptor for murine norovirus, engaging the viral capsid P domain at a metal-dependent, bile-acid-modulated interface that mimics host phosphocholine binding, with cell-type-specific tropism determined by CC' loop residues [PMID:27681626, PMID:30194229, PMID:32251490, PMID:32581099, PMID:33177207]. CD300LF also serves as an engulfment receptor for Rickettsia via rickettsial phosphatidylserine and, in the brain, as a microglial damage-sensing receptor coupling purinergic UDP-P2RY6 signaling and STING-pathway inhibition to neuroprotection [PMID:40310290, PMID:40935207, PMID:38965803].","teleology":[{"year":2004,"claim":"Establishing CD300LF as an inhibitory receptor required showing it recruits a phosphatase and dampens activation, which defined its core signaling logic.","evidence":"Three-hybrid screen, reciprocal co-IP, and FcεR cross-linking assays in myeloid/U937 cells identifying SHP-1 recruitment via Y205","pmids":["15549731"],"confidence":"High","gaps":["Physiologic ligand triggering phosphorylation unknown","Second ITIM contribution not yet mapped"]},{"year":2007,"claim":"Dissecting the cytoplasmic tail showed the receptor encodes both inhibitory and latent activating outputs, explaining how a single tail can branch signaling.","evidence":"Site-directed mutagenesis of cytoplasmic tyrosines plus beta-hexosaminidase secretion assays and PI3K inhibitors in RBL cells","pmids":["17202342"],"confidence":"High","gaps":["Physiologic conditions favoring activating versus inhibitory output not defined"]},{"year":2007,"claim":"Solving the ectodomain structure revealed an Ig-V fold with a candidate ligand-discrimination loop, framing how CD300LF might engage ligands.","evidence":"X-ray crystallography of the IREM-1 Ig-V-like domain at 2.6 Å","pmids":["17275839"],"confidence":"High","gaps":["No ligand bound in structure","Functional validation of the proposed binding groove absent"]},{"year":2008,"claim":"Cross-linking induced an ITIM-independent caspase-independent cell death, indicating the cytoplasmic region carries signaling functions beyond classic inhibition.","evidence":"Anti-CD300LF cross-linking with domain-deletion constructs and pharmacological inhibitors in peritoneal macrophages","pmids":["18097021"],"confidence":"Medium","gaps":["Death effector pathway unidentified","Physiologic relevance of cross-linking-induced death unclear"]},{"year":2009,"claim":"An in vivo knockout established CD300LF as a negative regulator of myeloid effector function in neuroinflammation, linking its signaling to disease outcome.","evidence":"CLM-1 knockout mice in EAE with histology, cytokine and flow-cytometric readouts","pmids":["20038601"],"confidence":"Medium","gaps":["Ligand and proximal signaling in vivo not defined","Microglial versus peripheral myeloid contribution unresolved"]},{"year":2011,"claim":"Identifying phosphatidylserine as a metal-dependent ligand connected receptor recognition to apoptotic cell clearance, defining its physiologic agonist.","evidence":"CD300f/Fc binding by ELISA, cosedimentation, SPR with liposomes, Annexin V competition, and ectopic-expression phagocytosis assays","pmids":["21865548"],"confidence":"High","gaps":["Structural basis of metal-dependent PS binding not shown","Endogenous receptor engagement kinetics unknown"]},{"year":2011,"claim":"Mapping CD300LF's suppression of both MyD88 and TRIF arms of TLR signaling placed it as a broad innate-immune brake via SHP-1/NF-κB.","evidence":"mAb cross-linking and ITIM peptides with luciferase reporters, Western blot, and IP across TLR2/3/4/9 in monocytic cells","pmids":["21536801","22043923"],"confidence":"High","gaps":["Relative SHP-1 versus SHP-2 contribution to TRIF inhibition only partly resolved"]},{"year":2013,"claim":"Showing CD300LF specifically restrains eotaxin/CCR3-driven eosinophil chemotaxis demonstrated pathway-selective inhibitory control over cell migration.","evidence":"Clm1-/- eosinophils in chemotaxis, calcium flux, ERK assays plus PS ligand addition and an allergic airway model","pmids":["23820751"],"confidence":"High","gaps":["Molecular link between receptor and ERK/actin machinery in eosinophils not mapped"]},{"year":2014,"claim":"Defining the Y276-PI3K-Rac/Cdc42-F-actin axis at the phagocytic cup explained how the same receptor positively drives efferocytosis in macrophages.","evidence":"Cytoplasmic tyrosine mutagenesis, confocal imaging, p85α co-IP, GTPase/F-actin assays, KO macrophage phagocytosis, and a lupus-like model","pmids":["24477292"],"confidence":"High","gaps":["Switch governing positive versus negative tyrosine motifs in vivo unclear"]},{"year":2015,"claim":"Identifying ceramide as a second ligand and its physical association with IL-4Rα broadened the receptor's ligand repertoire and signaling partnerships.","evidence":"CD300f-/- and mast-cell-specific reconstitution with ceramide functional assays and liposome rescue in colitis; co-localization with IL-4Rα in allergen challenge","pmids":["25673319","26124135"],"confidence":"High","gaps":["Structural basis of ceramide binding not determined","Mechanism of IL-4Rα amplification not defined"]},{"year":2016,"claim":"Discovering CD300LF as the murine norovirus entry receptor revealed a ligand-independent function of the ectodomain as a viral receptor dictating tropism.","evidence":"Genome-wide CRISPR screen, antibody blocking, and ectopic expression conferring permissivity in heterologous cells","pmids":["27681626"],"confidence":"High","gaps":["Structural details of capsid engagement not yet shown at this stage","Role in vivo not yet established"]},{"year":2016,"claim":"Demonstrating opposite efferocytic roles in dendritic cells versus macrophages established cell-type context as a determinant of CD300LF function and autoimmunity risk.","evidence":"Cd300f-/- DC efferocytosis, antigen-processing, T-cell priming, and ANA assays","pmids":["26768664"],"confidence":"Medium","gaps":["Molecular basis of the macrophage/DC inversion unresolved"]},{"year":2017,"claim":"Multiple in vivo models established ceramide-CD300LF as a negative-feedback brake on mast cell/neutrophil mediator release across skin inflammation, sepsis, and gut inflammation.","evidence":"CD300f-/- mice with adoptive transfer and ceramide vesicle/antibody manipulation in skin pouch, CLP, and DSS colitis models","pmids":["28073916","28655892","28414292"],"confidence":"High","gaps":["Source and regulation of extracellular ceramide in vivo incompletely defined"]},{"year":2018,"claim":"Co-crystal structures of CD300LF with the norovirus P domain defined the receptor-capsid interface and showed viral engagement mimics host phosphocholine binding with shared metal coordination.","evidence":"Multiple X-ray structures (P domain, phosphocholine, bile acid complexes) with SPR/ITC and interface mutagenesis","pmids":["30194229","29563286"],"confidence":"High","gaps":["How bile acids allosterically enhance low monomeric affinity not fully resolved"]},{"year":2018,"claim":"A neutrophil KO phenotype showed CD300LF restrains antimicrobial effector activity and is itself induced by infection through TLR4/MyD88, adding a feedback loop to innate defense.","evidence":"LMIR3-KO neutrophil HOCl/elastase/cytotoxicity assays against P. aeruginosa and C. albicans with TLR4/MyD88 dependency","pmids":["30479367"],"confidence":"Medium","gaps":["Ligand engaging CD300LF on infected neutrophils not identified"]},{"year":2020,"claim":"Genetic and conditional models established CD300LF as the sole physiologic norovirus receptor in vivo with cell-type- and strain-specific tropism, and excluded human norovirus use.","evidence":"CD300lf-/- and conditional Cre-driver mice, oral/parenteral MNoV infection, STAT1 crosses, and huCD300lf HNoV VLP binding tests; inbred strain CC' loop domain swaps","pmids":["32251490","33177207","32581099"],"confidence":"High","gaps":["Determinants of tuft-cell versus myelomonocytic targeting incompletely defined"]},{"year":2020,"claim":"A functional cytoplasmic-tail SNP and KO neurobehavioral phenotype linked CD300LF to microglial metabolic fitness and depression-related behavior, extending its role into the brain.","evidence":"Human SNP association (rs2034310), Cd300f-/- behavioral phenotyping, RNA-seq, and biochemical metabolic studies","pmids":["32152116"],"confidence":"Medium","gaps":["Causal pathway from PKC-site phosphorylation to behavior not established"]},{"year":2022,"claim":"Showing ceramide-CD300LF suppresses osteoclastogenesis extended the receptor's inhibitory ligand axis to bone homeostasis.","evidence":"CD300lf-/- mice in ligature-induced periodontitis with ceramide application in vitro and in vivo","pmids":["36089906"],"confidence":"Medium","gaps":["Signaling downstream of CD300LF in osteoclast precursors not defined"]},{"year":2023,"claim":"Human monocyte/macrophage studies tied CD300LF signaling to PD-L1 upregulation, M2 polarization, and T-cell suppression via PI3K/Akt, framing an immunoregulatory output in humans.","evidence":"Anti-CD300f mAb cross-linking with T-cell proliferation, M1/M2 markers, and PI3K/Akt inhibition","pmids":["37302321"],"confidence":"Medium","gaps":["Physiologic ligand driving human monocyte CD274 induction unidentified"]},{"year":2024,"claim":"Intravital imaging and proteomics established CD300LF as a microglial damage sensor coupling purinergic UDP-P2RY6 signaling and STING inhibition to apoptotic-debris clearance and neuroprotection.","evidence":"CD300LF-/- mice in mTBI/CCI models with two-photon imaging, proteomics, ENTPD6/P2RY6 quantification, and STING inhibitor C-176","pmids":["40935207","38965803"],"confidence":"High","gaps":["Direct biochemical link between CD300LF and STING or P2RY6 not established","Whether ligand binding initiates damage sensing in brain unknown"]},{"year":2025,"claim":"Demonstrating CD300LF-mediated engulfment of Rickettsia via bacterial phosphatidylserine and cooperative mast-cell inhibition with CD300a refined its dual roles in host defense and allergy.","evidence":"CD300f-/- BMDM engulfment/infection assays with adoptive transfer; Cd300a-/-Cd300lf-/- double-KO imaging and anaphylaxis model","pmids":["40310290","40073110"],"confidence":"High","gaps":["Mechanism of CD300a/CD300lf functional cooperation at the membrane not fully resolved"]},{"year":null,"claim":"How CD300LF integrates its multiple ligands (PS, ceramide) and divergent outputs (efferocytosis, inhibition, viral entry, damage sensing) into context-specific decisions across cell types remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking ligand identity to inhibitory versus phagocytic output","Direct biochemical coupling to STING and P2RY6 axes unproven","Human in vivo functions largely uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[5,10,17,28,29]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1,6,9]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,6,7]},{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[5,9,28]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[12,17,20,22]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,9,29]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,6,9,11]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,9,25]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[12,20,28]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[5,9,13]}],"complexes":[],"partners":["PTPN6","PTPN11","PIK3R1","IL4RA","CD300A","P2RY6"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8TDQ1","full_name":"CMRF35-like molecule 1","aliases":["CD300 antigen-like family member F","Immune receptor expressed on myeloid cells 1","IREM-1","Immunoglobulin superfamily member 13","IgSF13","NK inhibitory receptor"],"length_aa":290,"mass_kda":32.3,"function":"Acts as an inhibitory receptor for myeloid cells and mast cells (PubMed:15549731). Positively regulates the phagocytosis of apoptotic cells (efferocytosis) via phosphatidylserine (PS) recognition; recognizes and binds PS as a ligand which is expressed on the surface of apoptotic cells. Plays an important role in the maintenance of immune homeostasis, by promoting macrophage-mediated efferocytosis and by inhibiting dendritic cell-mediated efferocytosis (By similarity). Negatively regulates Fc epsilon receptor-dependent mast cell activation and allergic responses via binding to ceramide and sphingomyelin which act as ligands (PubMed:24035150). May act as a coreceptor for interleukin 4 (IL-4). Associates with and regulates IL-4 receptor alpha-mediated responses by augmenting IL-4- and IL-13-induced signaling (By similarity). Negatively regulates the Toll-like receptor (TLR) signaling mediated by MYD88 and TRIF through activation of PTPN6/SHP-1 and PTPN11/SHP-2 (PubMed:22043923). Inhibits osteoclast formation. Induces macrophage cell death upon engagement (By similarity)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q8TDQ1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CD300LF","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/CD300LF","total_profiled":1310},"omim":[{"mim_id":"616301","title":"CD300 ANTIGEN-LIKE FAMILY, MEMBER D; CD300LD","url":"https://www.omim.org/entry/616301"},{"mim_id":"610705","title":"CD300 ANTIGEN-LIKE FAMILY, MEMBER B; CD300LB","url":"https://www.omim.org/entry/610705"},{"mim_id":"609807","title":"CD300 ANTIGEN-LIKE FAMILY, MEMBER F; CD300LF","url":"https://www.omim.org/entry/609807"},{"mim_id":"609801","title":"CD300E ANTIGEN; CD300E","url":"https://www.omim.org/entry/609801"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"bone marrow","ntpm":25.5},{"tissue":"lung","ntpm":16.6},{"tissue":"lymphoid tissue","ntpm":28.5}],"url":"https://www.proteinatlas.org/search/CD300LF"},"hgnc":{"alias_symbol":["IREM1","NKIR","IGSF13","CD300f","CLM1"],"prev_symbol":[]},"alphafold":{"accession":"Q8TDQ1","domains":[{"cath_id":"2.60.40.10","chopping":"21-129","consensus_level":"medium","plddt":98.0808,"start":21,"end":129}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8TDQ1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8TDQ1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8TDQ1-F1-predicted_aligned_error_v6.png","plddt_mean":72.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CD300LF","jax_strain_url":"https://www.jax.org/strain/search?query=CD300LF"},"sequence":{"accession":"Q8TDQ1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8TDQ1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8TDQ1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8TDQ1"}},"corpus_meta":[{"pmid":"27681626","id":"PMC_27681626","title":"Functional 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periodontology","url":"https://pubmed.ncbi.nlm.nih.gov/36089906","citation_count":3,"is_preprint":false},{"pmid":"32581099","id":"PMC_32581099","title":"CD300LF Polymorphisms of Inbred Mouse Strains Confer Resistance to Murine Norovirus Infection in a Cell Type-Dependent Manner.","date":"2020","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/32581099","citation_count":3,"is_preprint":false},{"pmid":"28155597","id":"PMC_28155597","title":"Astrocytic Expression of the Immunoreceptor CD300f Protects Hippocampal Neurons from Amyloid-β Oligomer Toxicity In Vitro.","date":"2017","source":"Current Alzheimer research","url":"https://pubmed.ncbi.nlm.nih.gov/28155597","citation_count":3,"is_preprint":false},{"pmid":"40073110","id":"PMC_40073110","title":"Inhibitory immunoreceptors CD300a and CD300lf cooperate to regulate mast cell activation.","date":"2025","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/40073110","citation_count":2,"is_preprint":false},{"pmid":"40935207","id":"PMC_40935207","title":"CD300f enables microglial damage sensing, efferocytosis, and apoptotic cell metabolization after brain injury.","date":"2025","source":"Brain, behavior, and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/40935207","citation_count":2,"is_preprint":false},{"pmid":"40309955","id":"PMC_40309955","title":"Quercetin Alleviates Chronic Urticaria by Negatively Regulating IgE-Mediated Mast Cell Activation Through CD300f.","date":"2025","source":"Phytotherapy research : PTR","url":"https://pubmed.ncbi.nlm.nih.gov/40309955","citation_count":2,"is_preprint":false},{"pmid":"38766217","id":"PMC_38766217","title":"Phosphatidylserine-binding receptor, CD300f, on macrophages mediates host invasion of pathogenic and non-pathogenic rickettsiae.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/38766217","citation_count":1,"is_preprint":false},{"pmid":"40310290","id":"PMC_40310290","title":"Phosphatidylserine-binding receptor, CD300f, on macrophages mediates host invasion of pathogenic and non-pathogenic rickettsiae.","date":"2025","source":"Infection and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/40310290","citation_count":0,"is_preprint":false},{"pmid":"39307798","id":"PMC_39307798","title":"[Protective effect and mechanism of Zuogui Jiangtang Jieyu Formula on damage to hippocampal synaptic microenvironment in rats with diabetes-related depression based on microglia-neuron crosstalk signal CD300f/TLR4].","date":"2024","source":"Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica","url":"https://pubmed.ncbi.nlm.nih.gov/39307798","citation_count":0,"is_preprint":false},{"pmid":"40394337","id":"PMC_40394337","title":"Transcriptome profiling reveals abnormal cell wall components in the cleistogamy mutant 1 (clm1) lodicule of foxtail millet.","date":"2025","source":"Planta","url":"https://pubmed.ncbi.nlm.nih.gov/40394337","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.11.06.686973","title":"Culmorin inhibits detoxification of the mycotoxin deoxynivalenol by plant UDP-glucosyltransferases","date":"2025-11-06","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.06.686973","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.09.06.611174","title":"CD300f immune receptor is a microglial tissue damage sensor and regulates efferocytosis after brain damage","date":"2024-09-10","source":"bioRxiv","url":"https://doi.org/10.1101/2024.09.06.611174","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":33473,"output_tokens":9116,"usd":0.11858,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":19239,"output_tokens":6115,"usd":0.124535,"stage2_stop_reason":"end_turn"},"total_usd":0.243115,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"CD300LF (IREM-1) was identified as a novel inhibitory receptor that interacts with the SH2 domains of SHP-1 via a three-hybrid strategy. Western blot confirmed SHP-1 recruitment to IREM-1, with phosphotyrosine Y205 identified as the main docking site. Cross-linking of IREM-1 inhibits FcεR-induced activation in myeloid cells. The receptor contains two ITIM motifs and is expressed on monocytes and granulocytes.\",\n      \"method\": \"Three-hybrid screen, Western blot, immunoprecipitation, FACS, cross-linking functional assay\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP confirmed SHP-1 recruitment, specific tyrosine residue identified, functional inhibition assay performed, replicated across transfected cells and endogenous U937 cells\",\n      \"pmids\": [\"15549731\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CD300LF (IREM-1) cytoplasmic domain recruits both SHP-1 and the p85α subunit of PI3K. Y205 and Y249 (ITIM residues) are critical for IREM-1-mediated inhibition of FcεRI-induced degranulation. Mutation of Y205, Y249, Y284 (which abolishes SHP-1 binding) creates an activating receptor that promotes degranulation via PI3K through Y236 and Y263; this activation is blocked by wortmannin and LY-294002.\",\n      \"method\": \"Immunoprecipitation, site-directed mutagenesis of IREM-1 cytoplasmic tyrosines, functional beta-hexosaminidase secretion assay in RBL cells, PI3K inhibitor studies\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis of specific residues combined with functional assays and pharmacological inhibitors, multiple orthogonal methods in one study\",\n      \"pmids\": [\"17202342\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Crystal structure of the extracellular Ig-V-like domain of IREM-1 (CD300LF) was determined at 2.6 Å resolution. The fold resembles a V-type immunoglobulin domain with close homology to CLM-1, TREM-1, TLT-1, and NKp44. Structural analysis identified a hydrophobic groove on the surface and a structurally variable CDR3-equivalent loop proposed as the main determinant for ligand discrimination.\",\n      \"method\": \"X-ray crystallography at 2.6 Å resolution\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure determined at 2.6 Å in single study, structural analysis is rigorous but functional validation of ligand-binding sites not performed in same paper\",\n      \"pmids\": [\"17275839\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Cross-linking of CD300LF (MAIR-V) with anti-CD300LF mAb induces caspase-independent, ER stress-independent cell death in peritoneal macrophages and transfectants. This cell death requires the cytoplasmic region but not ITIM or ITSM motifs. Morphologically the dead cells resemble apoptotic cells (loss of blebs) but are resistant to caspase inhibitor Z-VAD-FMK and autophagy inhibitors.\",\n      \"method\": \"Anti-CD300LF cross-linking, scanning electron microscopy, pharmacological inhibition (Z-VAD-FMK, 3-methyladenine, N-acetyl-L-cysteine), Western blot for XBP-1 splicing, cytoplasmic domain deletion constructs\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean loss-of-function domain mapping with pharmacological controls, single lab, multiple inhibitor experiments\",\n      \"pmids\": [\"18097021\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CLM-1 (CD300LF) acts as a negative regulator of myeloid cells in autoimmune demyelination (EAE model). CLM-1-deficient mice showed increased nitric oxide and proinflammatory cytokine production by myeloid cells in demyelinating spinal cord, increased demyelination, and worse clinical scores, without affecting T cell responses in the periphery or spinal cord.\",\n      \"method\": \"CLM-1 knockout mouse model, EAE induction, histological scoring, cytokine measurement, flow cytometry of T cells\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with specific cellular phenotype (myeloid effector regulation) established by epistasis, single lab\",\n      \"pmids\": [\"20038601\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CD300f (mouse) binds phosphatidylserine (PS) exposed on the outer membrane of apoptotic cells; this binding requires a metal ion. CD300f/Fc chimeric protein specifically binds apoptotic cells in a manner inhibitable by Annexin V. Binding was demonstrated by ELISA, cosedimentation, and surface plasmon resonance using phospholipid-containing liposomes. Ectopic expression of CD300f in cell lines enhances phagocytosis of apoptotic cells.\",\n      \"method\": \"CD300f/Fc chimeric protein binding assays, ELISA, cosedimentation, surface plasmon resonance with liposomes, Annexin V competition, ectopic expression phagocytosis assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal biochemical methods (SPR, ELISA, cosedimentation) confirming PS binding, functional phagocytosis assay, metal-ion requirement established\",\n      \"pmids\": [\"21865548\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CD300F blocks both MyD88 and TRIF-mediated TLR signaling in monocytic cells through recruitment of SHP-1. CD300F stimulation (mAb cross-linking or ITIM synthetic peptides) suppressed TLR2, 3, 4, and 9-mediated expression of IL-8 and MMP-9, inhibited IKK activation, IκB phosphorylation/degradation, and NF-κB activation. Immunoprecipitation confirmed SHP-1 association.\",\n      \"method\": \"mAb cross-linking, synthetic ITIM peptides, luciferase reporter assays, Western blot, immunoprecipitation, pharmacological inhibitors\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple TLR ligands tested, luciferase reporter + Western blot + IP, mechanistic pathway placement via signaling node (SHP-1/NF-κB), single lab with orthogonal methods\",\n      \"pmids\": [\"21536801\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CD300f blocks both MyD88 and TRIF-mediated TLR signaling through combined activation of SHP-1 and SHP-2, whereas CD300a only blocks MyD88-mediated signaling via SHP-1. Differential inhibition is recapitulated by synthetic ITIM peptides of CD300a versus CD300f. This distinction maps to the ability of CD300f (but not CD300a) to activate SHP-2 for TRIF pathway inhibition.\",\n      \"method\": \"TLR stimulation in THP-1/U937 cells, NF-κB luciferase reporter, synthetic ITIM peptides, signaling inhibitors, Western blot\",\n      \"journal\": \"Immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter + inhibitor studies + ITIM peptide mimicry, single lab, two orthogonal methods\",\n      \"pmids\": [\"22043923\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CLM-1 (CD300f) negatively regulates eotaxin-induced eosinophil chemotaxis, actin polymerization, calcium influx, and ERK1/2 (but not p38) phosphorylation. Addition of CLM-1 ligand phosphatidylserine rendered wild-type eosinophils hypochemotactic in vitro; blockade of CLM-1/ligand interactions caused hyperchemotaxis in vitro and in an allergic airway model in vivo. CLM-1 regulation was specific to eotaxin/CCR3 and not LTB4 or MIP-1α.\",\n      \"method\": \"Clm1-/- mouse eosinophils, in vitro chemotaxis assay, calcium flux, ERK/p38 phosphorylation, in vivo allergic airway model, phosphatidylserine ligand addition\",\n      \"journal\": \"Mucosal immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse combined with ligand addition experiments, multiple signaling readouts, specificity control (LTB4/MIP-1α negative), in vitro and in vivo validation\",\n      \"pmids\": [\"23820751\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CD300f (CLM-1) accumulates in phagocytic cups at apoptotic cell contact sites. Phosphorylation of Y276 in the cytoplasmic tail recruits the p85α subunit of PI3K, which activates downstream Rac/Cdc42 GTPase and drives F-actin remodeling to promote apoptotic cell engulfment. Y276 phosphorylation is required for enhanced phagocytosis. Distinct tyrosine motifs positively (Y276/PI3K) or negatively regulate phagocytosis. Primary CD300f-deficient macrophages show impaired apoptotic cell phagocytosis. CD300f deficiency in FcγRIIB-null mice accelerates lupus-like disease.\",\n      \"method\": \"Site-directed mutagenesis of CD300f cytoplasmic tyrosines, confocal microscopy, PI3K co-immunoprecipitation, Rac/Cdc42 activation assays, F-actin imaging, CD300f-/- macrophage phagocytosis, autoimmune disease model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis of specific residues, co-IP of p85α, downstream GTPase and F-actin assays, KO macrophage functional validation, in vivo disease model; multiple orthogonal methods in single study\",\n      \"pmids\": [\"24477292\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CD300f binds ceramide as a ligand and this interaction suppresses IgE-dependent and mast cell-dependent allergic responses. In the DSS colitis model, ceramide-CD300f (LMIR3) binding inhibited ATP-stimulated mast cell activation. CD300f deficiency exacerbated DSS-induced colitis; mast cell-specific CD300f deficiency was responsible. Administration of ceramide liposomes suppressed colitis; disruption of ceramide-LMIR3 interaction aggravated it.\",\n      \"method\": \"CD300f-/- mice, mast cell-deficient Kit(W-sh) mice, BMMC reconstitution, ATP-stimulated BMMC in vitro activation, ELISA, ceramide liposome treatment, DSS colitis model\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO + mast cell-specific reconstitution + in vitro ceramide-CD300f functional assay + in vivo ceramide liposome rescue; multiple orthogonal approaches, single lab\",\n      \"pmids\": [\"25673319\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CD300f is colocalized and physically associated with IL-4Rα in macrophages. CD300f amplifies IL-4Rα-induced signaling, mediator release, and priming. Cd300f-/- cells and mice show decreased IL-4/IL-13-induced responses, IgE production, chemokine expression, and inflammatory cell recruitment in allergen challenge, while IL-4/IL-13 levels are increased (consistent with decreased cytokine consumption).\",\n      \"method\": \"Co-localization microscopy, physical association assay, Cd300f-/- cells and mice, IL-4Rα cross-linking, allergen challenge model, cytokine ELISA\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — physical association demonstrated, KO cells and mice with defined signaling phenotype, in vitro and in vivo experiments, multiple readouts\",\n      \"pmids\": [\"26124135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CD300lf and CD300ld are functional cell-surface receptors for murine norovirus (MNV). Identified by genome-wide CRISPR/Cas9 screen. Anti-CD300lf polyclonal antibody significantly reduces viral progeny. Ectopic expression of CD300lf in non-susceptible cell lines from other species enables MNV infection and progeny production, demonstrating CD300lf is sufficient to confer permissivity and can dictate host tropism.\",\n      \"method\": \"Genome-wide CRISPR/Cas9 loss-of-function screen, antibody blocking, ectopic expression in heterologous cell lines, viral progeny quantification\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — unbiased CRISPR screen identification confirmed by antibody blocking and ectopic expression gain-of-function, multiple lines of evidence\",\n      \"pmids\": [\"27681626\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CD300f expression in dendritic cells (DCs) inhibits efferocytosis (in contrast to its function in macrophages where it promotes phagocytosis). CD300f deficiency in DCs leads to hyperactive phagocytosis of apoptotic cells, enhanced antigen processing and T-cell priming, expansion of memory T cells, and increased ANA levels. This contributes to autoimmune disease predisposition.\",\n      \"method\": \"Cd300f-/- mouse DCs, efferocytosis assays, antigen presentation assays, T cell priming, ANA measurement, apoptotic cell overload model\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with cell-type-specific functional readouts, single lab, two orthogonal cell biological approaches\",\n      \"pmids\": [\"26768664\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Ceramide-CD300f binding inhibits LPS-induced skin inflammation. CD300f deficiency enhanced LPS-induced skin edema and neutrophil recruitment. CD300f suppresses release of chemical mediators (vascular permeability factors, neutrophil chemoattractants) from mast cells and neutrophils in response to LPS. Adoptive transfer experiments demonstrated mast cell and neutrophil contributions. Ceramide antibody enhanced and ceramide-containing vesicles suppressed LPS-induced skin inflammation.\",\n      \"method\": \"CD300f-/- mice, skin pouch model, LPS injection, adoptive mast cell transfer, ceramide antibody/vesicle administration, flow cytometry, mediator ELISA\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO + adoptive transfer + ceramide ligand manipulation in vivo, mechanistic pathway (TLR4 negative regulation via ceramide-CD300f), multiple orthogonal approaches\",\n      \"pmids\": [\"28073916\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CD300f-expressing DCs play a crucial role in resolving gut inflammation. CD300f-deficient DCs show hyperactive phagocytosis of apoptotic cells, stimulating excessive TNF-α secretion predominantly from DCs, which induces secondary IFN-γ overproduction by colonic T cells, leading to prolonged gut inflammation. Abnormal apoptotic cell accumulation in the gut of CD300f-deficient mice was observed.\",\n      \"method\": \"CD300f-/- mouse colitis model (DSS), DC-specific functional assays, apoptotic cell accumulation imaging, cytokine measurement (TNF-α, IFN-γ), T cell analysis\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse with defined cellular mechanism (DC-mediated TNF-α → T cell IFN-γ cascade), apoptotic cell accumulation demonstrated, multiple readouts\",\n      \"pmids\": [\"28414292\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Ceramide-CD300f interaction suppresses neutrophil chemoattractant production from mast cells and neutrophils in the context of septic peritonitis (CLP model). CD300f-/- mice are protected from CLP-induced death; CD300f deficiency enhances neutrophil accumulation and bacterial clearance. Extracellular ceramide concentrations increase in the peritoneal cavity after CLP, suggesting a negative-feedback role for ceramide-CD300f in innate immunity.\",\n      \"method\": \"CD300f-/- mice, CLP model, mast cell-deficient mouse reconstitution with WT/CD300f-/- mast cells and neutrophils, in vitro E. coli stimulation of MCs/neutrophils, ceramide vesicle/antibody administration, bacterial burden quantification\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO + adoptive transfer + in vitro ceramide-CD300f functional assay + in vivo ceramide manipulation, multiple orthogonal experiments\",\n      \"pmids\": [\"28655892\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"X-ray crystal structure of the MNoV VP1 protruding (P) domain in complex with CD300lf was determined. CD300lf binds the P domain with 2:2 stoichiometry at a cleft between AB and DE loops of the P2 subdomain overlapping neutralizing antibody epitopes. Two bile acid binding sites were identified at the P domain dimer interface distant from receptor binding sites. CD300lf engages MNoV in a manner mimicking host ligand (phosphocholine) binding including similar metal coordination. Monomeric affinity of CD300lf for P domain is low and divalent cation dependent.\",\n      \"method\": \"X-ray crystallography (CD300lf–P domain complex, CD300lf–phosphocholine complex, CD300lf–bile acid complexes), biophysical assays (SPR, ITC), interface residue mutagenesis, cryo-EM docking\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple crystal structures with mutagenesis validation and biophysical assays, highly rigorous multi-method study\",\n      \"pmids\": [\"30194229\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Crystal structure of soluble CD300lf in complex with the MNoV capsid protruding domain was determined at 2.05 Å resolution. The CD300lf binding site is on the topside of the P domain, involving hydrophilic and hydrophobic interactions, with CD300lf fitting into a complementary cavity stabilized by complementary surface charges. Five of six P domain residues interacting with CD300lf are conserved across MNoV strains. CD300lf-interacting residues are partially conserved in CD300ld but variable in other CD300 family members, consistent with observed infection selectivity.\",\n      \"method\": \"X-ray crystallography at 2.05 Å resolution, sequence alignment analysis\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — high-resolution crystal structure of receptor-capsid complex, structural basis for selectivity explained, single study but rigorous method\",\n      \"pmids\": [\"29563286\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"LMIR3/CD300f deficiency augments antimicrobial activity of mouse neutrophils. LMIR3-KO neutrophils show significantly increased hypochlorous acid production, elastase release, and cytotoxic activity against P. aeruginosa and C. albicans. LMIR3 surface expression increases on bone marrow neutrophils in response to P. aeruginosa infection in a TLR4/MyD88-dependent manner. Elastase and myeloperoxidase inhibitors offset the enhanced antimicrobial activity of KO neutrophils.\",\n      \"method\": \"LMIR3-KO mice, hypochlorous acid production assay, elastase release assay, cytotoxicity assay, P. aeruginosa/C. albicans infection models, TLR4/MyD88 dependency via inhibitors\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse neutrophil phenotype with pharmacological pathway identification, single lab, multiple readouts\",\n      \"pmids\": [\"30479367\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CD300lf is the sole physiologic receptor for MNoV in vivo. CD300lf is required for both oral and parenteral MNoV infection and for anti-MNoV humoral responses. In STAT1-deficient mice, CD300lf is required for MNoV-induced lethality. Human CD300lf (huCD300lf) is not an entry receptor for human norovirus (HNoV) and does not inhibit HNoV virus-like particle binding to glycans.\",\n      \"method\": \"CD300lf-/- mice, oral and parenteral MNoV infection, anti-MNoV antibody ELISA, STAT1-/- x CD300lf-/- double KO lethality model, HNoV VLP binding assay with huCD300lf\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO establishes in vivo requirement, multiple infection routes tested, lethality model, negative result for HNoV clearly controlled\",\n      \"pmids\": [\"32251490\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"A non-synonymous SNP (rs2034310, C/T) in the CD300f cytoplasmic tail inhibits protein kinase C phosphorylation of a threonine residue and is associated with protection against major depressive disorder, mainly in women. CD300f-/- mice display augmented microglial numbers, increased IL-6 and IL-1Ra mRNA, synaptic strength alterations, and noradrenaline-dependent depressive-like behaviors in females. RNA sequencing and biochemical studies indicate impaired microglial metabolic fitness in CD300f-/- mice.\",\n      \"method\": \"Human genetic association (SNP analysis), CD300f-/- mouse behavioral phenotyping, RNA sequencing, biochemical metabolic studies, immunohistochemistry\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — PKC phosphorylation site identified with SNP functional consequence, KO mouse phenotype with transcriptomic and biochemical validation, single lab\",\n      \"pmids\": [\"32152116\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CD300LF polymorphisms in inbred mouse strains (I/LnJ vs C57BL/6J) confer resistance to MNV infection in a cell type-dependent manner. A 4-amino-acid difference in the CC' loop of CD300LF determines functional receptor activity. I/LnJ CD300LF does not function as MNV entry factor in macrophage-like cells but does in other cell types. I/LnJ CD300LF binds MNV virions in permissive but not non-permissive cells, indicating a cell type-specific modifier of CD300LF-dependent MNV entry.\",\n      \"method\": \"Bone marrow-derived macrophage infection assays, lentiviral transduction with C57BL/6J vs I/LnJ CD300LF swap constructs, chimeric receptor mutagenesis, virion binding assay\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reciprocal domain-swap mutagenesis identifies specific residues in CC' loop required for receptor function, virion binding assay confirms mechanism, multiple cell types tested\",\n      \"pmids\": [\"32581099\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CD300lf expression on intestinal epithelial tuft cells is essential for transmission of persistent MNoV strain CR6, demonstrated using a conditional CD300lf knockout mouse. The non-persistent MNoV strain CW3 does not require CD300lf on IECs but utilizes myelomonocytic cells (LysM+ cells) as a major target. CD300lf on B cells, neutrophils, and dendritic cells is not critical for CW3 infection. STAT1 signaling partially restricts CW3 tropism to LysM+ cells.\",\n      \"method\": \"Conditional Cd300lf knockout mice (IEC-specific, LysM-Cre, CD19-Cre, Mrp8-Cre, CD11c-Cre), MNoV infection, viral RNA quantification, STAT1-/- genetic crosses\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO mouse system with multiple Cre drivers establishes cell-type-specific requirements, two distinct MNV strains compared, epistasis with STAT1\",\n      \"pmids\": [\"33177207\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CD300lf-ceramide interaction inhibits osteoclast differentiation. CD300lf expression is downregulated during osteoclastogenesis. CD300lf ablation increases osteoclast numbers and exacerbates alveolar bone loss in a ligature-induced periodontitis model. Application of ceramide (CD300lf ligand) suppresses osteoclastogenesis in vitro and inhibits alveolar bone loss in vivo.\",\n      \"method\": \"CD300lf-/- mice, ligature-induced periodontitis model, osteoclast counting, ceramide application in vitro and in vivo, bone resorption quantification\",\n      \"journal\": \"Journal of clinical periodontology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse + ceramide ligand rescue in vitro and in vivo, single lab, two orthogonal approaches\",\n      \"pmids\": [\"36089906\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CD300f signaling in human monocytes via anti-CD300f mAb cross-linking (DCR-2) suppresses monocytes by upregulating CD274 (PD-L1) and inhibiting T cell proliferation. In macrophages, CD300f signaling drives M2-type polarization with CD274 upregulation further enhanced by IL-4. CD300f signaling activates the PI3K/Akt pathway in monocytes; PI3K/Akt inhibition reduces CD274 expression.\",\n      \"method\": \"Anti-CD300f mAb cross-linking, T cell proliferation assay, M1/M2 polarization marker flow cytometry, PI3K/Akt pharmacological inhibition, Western blot\",\n      \"journal\": \"Cellular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional cross-linking with pathway inhibitor study, two cell types, single lab\",\n      \"pmids\": [\"37302321\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CD300LF-deficient microglia fail to extend processes toward laser-induced cortical lesions (intravital two-photon microscopy), indicating CD300LF is required for microglial detection of damage-associated cues. CD300LF-/- microglia show reduced recognition and clearance of apoptotic cells after mTBI and intracortical apoptotic cell injection, with apoptotic cell remnants retained intracellularly suggesting defective phagolysosomal processing. Proteomic analysis after CCI reveals dysregulation of autophagy-related and metabolic pathways. CD300LF deficiency alters the UDP-P2RY6 axis with upregulation of ENTPD6 and downregulation of P2ry6, implicating impaired purinergic damage sensing.\",\n      \"method\": \"Intravital two-photon microscopy, CD300LF-/- mice, mTBI and CCI models, intracortical apoptotic cell injection, flow cytometry, proteomics, ENTPD6/P2RY6 mRNA/protein quantification\",\n      \"journal\": \"Brain, behavior, and immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — intravital live imaging directly demonstrates impaired damage sensing, KO mouse with multiple in vivo models, proteomics + targeted molecular pathway analysis, multiple orthogonal methods\",\n      \"pmids\": [\"40935207\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CD300LF-deficient mice show increased glial proliferation, neuronal loss, and worse neurological function after TBI. Transcriptomic comparison of CD300LF+ vs CD300LF- microglia reveals that CD300LF's neuroprotective role is principally mediated by inhibition of the STING signaling pathway. The STING pathway inhibitor C-176 augments the protective effect.\",\n      \"method\": \"CD300LF-/- mice, TBI model, transcriptomics (RNA-seq of sorted microglia populations), STING inhibitor C-176 treatment, histological and neurological function scoring\",\n      \"journal\": \"CNS neuroscience & therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse + transcriptomics identifies STING pathway, pharmacological validation with inhibitor, single lab\",\n      \"pmids\": [\"38965803\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CD300f mediates engulfment of pathogenic Rickettsia species (R. typhi, R. rickettsii) and non-pathogenic R. montanensis by macrophages, using rickettsial phosphatidylserine (PS) as the ligand. CD300f-/- BMDMs show significantly reduced rickettsial engulfment. CD300f-/- mice are protected from fatal rickettsiosis (R. typhi, R. rickettsii) with reduced bacterial burden. Adoptive transfer of CD300f-expressing macrophages restores susceptibility to rickettsiosis in vivo.\",\n      \"method\": \"CD300f-/- bone marrow-derived macrophages, infection assays with multiple Rickettsia species, in vivo infection model, bacterial burden quantification (spleen), adoptive macrophage transfer\",\n      \"journal\": \"Infection and immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO macrophage engulfment assay + in vivo KO infection model + adoptive transfer rescue, mechanistic link to rickettsial PS as ligand, multiple pathogens tested\",\n      \"pmids\": [\"40310290\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CD300lf and CD300a colocalize with phosphatidylserine externalized to the outer leaflet of the plasma membrane in a polar formation upon mast cell activation, and cooperate to inhibit mast cell activation. CD300lf also colocalizes with extracellular ceramide on the cell surface, and CD300lf binding to ceramide produces stronger inhibition of mast cell activation than binding to PS alone. Double-KO (Cd300a-/-Cd300lf-/-) mice show exacerbated passive systemic anaphylaxis compared to single KOs.\",\n      \"method\": \"Imaging and flow cytometry of BMMCs from WT, Cd300a-/-, Cd300lf-/-, Cd300a-/-Cd300lf-/- mice, PS/ceramide colocalization, passive systemic anaphylaxis model\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic double-KO epistasis with single KOs, live cell imaging of receptor-ligand colocalization, in vivo anaphylaxis model, multiple ligand comparisons\",\n      \"pmids\": [\"40073110\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CD300LF is a type I transmembrane inhibitory immunoreceptor on myeloid cells that binds phosphatidylserine (and ceramide) exposed on apoptotic cells and activated membranes through its extracellular Ig-V-like domain (requiring metal ion coordination); ligand binding triggers cytoplasmic tail tyrosine phosphorylation that recruits SHP-1 (via ITIM Y205/Y249), SHP-2, and the PI3K p85α subunit (via Y276/Y236/Y263) to bidirectionally regulate downstream Rac/Cdc42-F-actin-driven efferocytosis, NF-κB/TLR signaling, and mast cell activation—while its extracellular domain also serves as the primary physiologic entry receptor for murine norovirus (engaging the viral capsid P domain in a metal-dependent, bile-acid-modulated interaction), and in the brain, CD300LF functions as a microglial damage-sensing receptor that integrates purinergic (UDP-P2RY6) signaling, phagolysosomal metabolization of apoptotic debris, and STING pathway inhibition to coordinate neuroinflammatory responses.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CD300LF (IREM-1/CLM-1/MAIR-V/LMIR3/CD300f) is a myeloid immunoreceptor that senses lipids displayed on apoptotic cells and activated membranes and converts that recognition into bidirectional control of phagocytosis and inflammatory signaling [#5, #9, #6]. Its extracellular Ig-V-like domain binds phosphatidylserine in a metal ion-dependent manner inhibitable by Annexin V, and also binds ceramide, enabling recognition of apoptotic cells, microbes, and activated cell surfaces [#5, #10, #29]. Ligand engagement is read out through the cytoplasmic tail: phosphorylated ITIM tyrosines Y205 and Y249 dock SHP-1 (and, distinctively from CD300a, also SHP-2) to suppress Fc\\u03b5RI degranulation and both MyD88- and TRIF-dependent TLR/NF-\\u03baB signaling, while Y276 recruits the PI3K p85\\u03b1 subunit to activate Rac/Cdc42-driven F-actin remodeling at phagocytic cups and promote efferocytosis [#0, #1, #7, #9]. This dual output makes the receptor a positive driver of apoptotic-cell engulfment in macrophages but an inhibitor in dendritic cells, where its loss causes hyperactive efferocytosis, excess TNF-\\u03b1, and downstream T-cell-driven autoimmunity and colitis [#9, #13, #15]. Across mast cells, eosinophils, and neutrophils, ceramide- or PS-CD300LF engagement restrains mediator release and chemotaxis, dampening allergic, anaphylactic, septic, and inflammatory bone-loss responses [#8, #10, #14, #16, #29, #24]. Independently of its inhibitory signaling, the CD300LF ectodomain is the physiologic entry receptor for murine norovirus, engaging the viral capsid P domain at a metal-dependent, bile-acid-modulated interface that mimics host phosphocholine binding, with cell-type-specific tropism determined by CC' loop residues [#12, #17, #20, #22, #23]. CD300LF also serves as an engulfment receptor for Rickettsia via rickettsial phosphatidylserine and, in the brain, as a microglial damage-sensing receptor coupling purinergic UDP-P2RY6 signaling and STING-pathway inhibition to neuroprotection [#28, #26, #27].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Establishing CD300LF as an inhibitory receptor required showing it recruits a phosphatase and dampens activation, which defined its core signaling logic.\",\n      \"evidence\": \"Three-hybrid screen, reciprocal co-IP, and Fc\\u03b5R cross-linking assays in myeloid/U937 cells identifying SHP-1 recruitment via Y205\",\n      \"pmids\": [\"15549731\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiologic ligand triggering phosphorylation unknown\", \"Second ITIM contribution not yet mapped\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Dissecting the cytoplasmic tail showed the receptor encodes both inhibitory and latent activating outputs, explaining how a single tail can branch signaling.\",\n      \"evidence\": \"Site-directed mutagenesis of cytoplasmic tyrosines plus beta-hexosaminidase secretion assays and PI3K inhibitors in RBL cells\",\n      \"pmids\": [\"17202342\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiologic conditions favoring activating versus inhibitory output not defined\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Solving the ectodomain structure revealed an Ig-V fold with a candidate ligand-discrimination loop, framing how CD300LF might engage ligands.\",\n      \"evidence\": \"X-ray crystallography of the IREM-1 Ig-V-like domain at 2.6 \\u00c5\",\n      \"pmids\": [\"17275839\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No ligand bound in structure\", \"Functional validation of the proposed binding groove absent\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Cross-linking induced an ITIM-independent caspase-independent cell death, indicating the cytoplasmic region carries signaling functions beyond classic inhibition.\",\n      \"evidence\": \"Anti-CD300LF cross-linking with domain-deletion constructs and pharmacological inhibitors in peritoneal macrophages\",\n      \"pmids\": [\"18097021\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Death effector pathway unidentified\", \"Physiologic relevance of cross-linking-induced death unclear\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"An in vivo knockout established CD300LF as a negative regulator of myeloid effector function in neuroinflammation, linking its signaling to disease outcome.\",\n      \"evidence\": \"CLM-1 knockout mice in EAE with histology, cytokine and flow-cytometric readouts\",\n      \"pmids\": [\"20038601\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ligand and proximal signaling in vivo not defined\", \"Microglial versus peripheral myeloid contribution unresolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identifying phosphatidylserine as a metal-dependent ligand connected receptor recognition to apoptotic cell clearance, defining its physiologic agonist.\",\n      \"evidence\": \"CD300f/Fc binding by ELISA, cosedimentation, SPR with liposomes, Annexin V competition, and ectopic-expression phagocytosis assays\",\n      \"pmids\": [\"21865548\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of metal-dependent PS binding not shown\", \"Endogenous receptor engagement kinetics unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Mapping CD300LF's suppression of both MyD88 and TRIF arms of TLR signaling placed it as a broad innate-immune brake via SHP-1/NF-\\u03baB.\",\n      \"evidence\": \"mAb cross-linking and ITIM peptides with luciferase reporters, Western blot, and IP across TLR2/3/4/9 in monocytic cells\",\n      \"pmids\": [\"21536801\", \"22043923\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative SHP-1 versus SHP-2 contribution to TRIF inhibition only partly resolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showing CD300LF specifically restrains eotaxin/CCR3-driven eosinophil chemotaxis demonstrated pathway-selective inhibitory control over cell migration.\",\n      \"evidence\": \"Clm1-/- eosinophils in chemotaxis, calcium flux, ERK assays plus PS ligand addition and an allergic airway model\",\n      \"pmids\": [\"23820751\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular link between receptor and ERK/actin machinery in eosinophils not mapped\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defining the Y276-PI3K-Rac/Cdc42-F-actin axis at the phagocytic cup explained how the same receptor positively drives efferocytosis in macrophages.\",\n      \"evidence\": \"Cytoplasmic tyrosine mutagenesis, confocal imaging, p85\\u03b1 co-IP, GTPase/F-actin assays, KO macrophage phagocytosis, and a lupus-like model\",\n      \"pmids\": [\"24477292\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Switch governing positive versus negative tyrosine motifs in vivo unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identifying ceramide as a second ligand and its physical association with IL-4R\\u03b1 broadened the receptor's ligand repertoire and signaling partnerships.\",\n      \"evidence\": \"CD300f-/- and mast-cell-specific reconstitution with ceramide functional assays and liposome rescue in colitis; co-localization with IL-4R\\u03b1 in allergen challenge\",\n      \"pmids\": [\"25673319\", \"26124135\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of ceramide binding not determined\", \"Mechanism of IL-4R\\u03b1 amplification not defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Discovering CD300LF as the murine norovirus entry receptor revealed a ligand-independent function of the ectodomain as a viral receptor dictating tropism.\",\n      \"evidence\": \"Genome-wide CRISPR screen, antibody blocking, and ectopic expression conferring permissivity in heterologous cells\",\n      \"pmids\": [\"27681626\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural details of capsid engagement not yet shown at this stage\", \"Role in vivo not yet established\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrating opposite efferocytic roles in dendritic cells versus macrophages established cell-type context as a determinant of CD300LF function and autoimmunity risk.\",\n      \"evidence\": \"Cd300f-/- DC efferocytosis, antigen-processing, T-cell priming, and ANA assays\",\n      \"pmids\": [\"26768664\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of the macrophage/DC inversion unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Multiple in vivo models established ceramide-CD300LF as a negative-feedback brake on mast cell/neutrophil mediator release across skin inflammation, sepsis, and gut inflammation.\",\n      \"evidence\": \"CD300f-/- mice with adoptive transfer and ceramide vesicle/antibody manipulation in skin pouch, CLP, and DSS colitis models\",\n      \"pmids\": [\"28073916\", \"28655892\", \"28414292\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Source and regulation of extracellular ceramide in vivo incompletely defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Co-crystal structures of CD300LF with the norovirus P domain defined the receptor-capsid interface and showed viral engagement mimics host phosphocholine binding with shared metal coordination.\",\n      \"evidence\": \"Multiple X-ray structures (P domain, phosphocholine, bile acid complexes) with SPR/ITC and interface mutagenesis\",\n      \"pmids\": [\"30194229\", \"29563286\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How bile acids allosterically enhance low monomeric affinity not fully resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"A neutrophil KO phenotype showed CD300LF restrains antimicrobial effector activity and is itself induced by infection through TLR4/MyD88, adding a feedback loop to innate defense.\",\n      \"evidence\": \"LMIR3-KO neutrophil HOCl/elastase/cytotoxicity assays against P. aeruginosa and C. albicans with TLR4/MyD88 dependency\",\n      \"pmids\": [\"30479367\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ligand engaging CD300LF on infected neutrophils not identified\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Genetic and conditional models established CD300LF as the sole physiologic norovirus receptor in vivo with cell-type- and strain-specific tropism, and excluded human norovirus use.\",\n      \"evidence\": \"CD300lf-/- and conditional Cre-driver mice, oral/parenteral MNoV infection, STAT1 crosses, and huCD300lf HNoV VLP binding tests; inbred strain CC' loop domain swaps\",\n      \"pmids\": [\"32251490\", \"33177207\", \"32581099\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Determinants of tuft-cell versus myelomonocytic targeting incompletely defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"A functional cytoplasmic-tail SNP and KO neurobehavioral phenotype linked CD300LF to microglial metabolic fitness and depression-related behavior, extending its role into the brain.\",\n      \"evidence\": \"Human SNP association (rs2034310), Cd300f-/- behavioral phenotyping, RNA-seq, and biochemical metabolic studies\",\n      \"pmids\": [\"32152116\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal pathway from PKC-site phosphorylation to behavior not established\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showing ceramide-CD300LF suppresses osteoclastogenesis extended the receptor's inhibitory ligand axis to bone homeostasis.\",\n      \"evidence\": \"CD300lf-/- mice in ligature-induced periodontitis with ceramide application in vitro and in vivo\",\n      \"pmids\": [\"36089906\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signaling downstream of CD300LF in osteoclast precursors not defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Human monocyte/macrophage studies tied CD300LF signaling to PD-L1 upregulation, M2 polarization, and T-cell suppression via PI3K/Akt, framing an immunoregulatory output in humans.\",\n      \"evidence\": \"Anti-CD300f mAb cross-linking with T-cell proliferation, M1/M2 markers, and PI3K/Akt inhibition\",\n      \"pmids\": [\"37302321\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiologic ligand driving human monocyte CD274 induction unidentified\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Intravital imaging and proteomics established CD300LF as a microglial damage sensor coupling purinergic UDP-P2RY6 signaling and STING inhibition to apoptotic-debris clearance and neuroprotection.\",\n      \"evidence\": \"CD300LF-/- mice in mTBI/CCI models with two-photon imaging, proteomics, ENTPD6/P2RY6 quantification, and STING inhibitor C-176\",\n      \"pmids\": [\"40935207\", \"38965803\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct biochemical link between CD300LF and STING or P2RY6 not established\", \"Whether ligand binding initiates damage sensing in brain unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrating CD300LF-mediated engulfment of Rickettsia via bacterial phosphatidylserine and cooperative mast-cell inhibition with CD300a refined its dual roles in host defense and allergy.\",\n      \"evidence\": \"CD300f-/- BMDM engulfment/infection assays with adoptive transfer; Cd300a-/-Cd300lf-/- double-KO imaging and anaphylaxis model\",\n      \"pmids\": [\"40310290\", \"40073110\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of CD300a/CD300lf functional cooperation at the membrane not fully resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CD300LF integrates its multiple ligands (PS, ceramide) and divergent outputs (efferocytosis, inhibition, viral entry, damage sensing) into context-specific decisions across cell types remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking ligand identity to inhibitory versus phagocytic output\", \"Direct biochemical coupling to STING and P2RY6 axes unproven\", \"Human in vivo functions largely uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [5, 10, 17, 28, 29]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1, 6, 9]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 6, 7]},\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [5, 9, 28]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [12, 17, 20, 22]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 9, 29]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 6, 9, 11]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 9, 25]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [12, 20, 28]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [5, 9, 13]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PTPN6\", \"PTPN11\", \"PIK3R1\", \"IL4RA\", \"CD300A\", \"P2RY6\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}