{"gene":"ITGAX","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":1995,"finding":"CD11c/CD18 functions as a transmembrane signaling receptor for lipopolysaccharide (LPS), capable of initiating signal transduction (NF-κB translocation) independently of CD14 and serum proteins when expressed in CHO fibroblasts. Responses were slower and required higher endotoxin concentrations than CD14-mediated responses, and were not inhibited by anti-CD14 antibodies.","method":"Heterologous expression in CHO cells; NF-κB translocation assay","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstitution in heterologous cell system with functional readout, single lab but multiple comparator conditions","pmids":["7535339"],"is_preprint":false},{"year":1996,"finding":"The CD11c gene promoter activity during myeloid differentiation is controlled by an AP-1 binding site (AP1-60) in the proximal promoter region, with c-Jun transactivating the promoter; mutation of AP1-60 greatly reduces basal and PMA-induced promoter activity in myeloid and B cells.","method":"Electrophoretic mobility shift assay (EMSA), in vivo footprinting, site-directed mutagenesis, reporter gene (luciferase) assays, transactivation by c-Jun","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"High","confidence_rationale":"Tier 1 / Moderate — multiple orthogonal methods (EMSA, footprinting, mutagenesis, transactivation) in a single focused study","pmids":["8621914"],"is_preprint":false},{"year":1997,"finding":"The tissue-specific activity of the CD11c promoter is conferred by two Sp1-binding sites and an adjacent C/EBP-binding element; the AP-1 site mediates differentiation-inducibility by PMA and GM-CSF; an additional element distinct from AP-1 is required for sodium butyrate-triggered induction. Stable transfection of the -361/+43 fragment into U937 cells confirms differentiation-dependent promoter activity.","method":"Promoter deletion/mutation analysis, stable transfection into U937 cells, luciferase reporter assays","journal":"Leukemia & lymphoma","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — functional promoter dissection with mutagenesis and stable transfection, but single lab","pmids":["9250811"],"is_preprint":false},{"year":2007,"finding":"CD11c recognizes ICAM-2 and VCAM-1 as novel ligands. The CD11c-binding site on VCAM-1 is distinct from the alpha4-integrin binding site. CD11c and alpha4beta1 together contribute to monocyte capture and transmigration on inflamed human aortic endothelial cells. Anti-mouse CD11c mAb N418 blocks CD11c binding to iC3b, ICAM-1, and VCAM-1.","method":"Cell adhesion assays, monocyte transmigration assay on human aortic endothelial cells, blocking antibody experiments","journal":"Journal of leukocyte biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional adhesion assays with blocking antibodies and multiple ligands tested, single lab","pmids":["17389580"],"is_preprint":false},{"year":2007,"finding":"CD11c (p150/95) expression is required for development of experimental autoimmune encephalomyelitis (EAE); CD11c-deficient mice show reduced spinal cord T-cell infiltration and altered cytokine profiles (reduced IFN-γ, TNF-α, IL-17, TGF-β; elevated IL-2, IL-4, IL-12). Adoptive transfer experiments show CD11c is required on both T cells and other leukocytes for disease development.","method":"CD11c-knockout mice, EAE model, adoptive transfer of antigen-restimulated T cells, cytokine measurement","journal":"The American journal of pathology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic KO with defined cellular phenotype and adoptive transfer epistasis, single lab but two orthogonal approaches","pmids":["17525267"],"is_preprint":false},{"year":2009,"finding":"CD11c deficiency in mice decreases firm arrest of monocytes on VCAM-1 and E-selectin under shear flow, reduces monocyte/macrophage accumulation in atherosclerotic lesions, and decreases atherosclerosis development in apoE-/- mice on a high-fat diet.","method":"CD11c-/- mouse generation, shear flow adhesion assay on VCAM-1 and E-selectin, histological quantification of atherosclerotic lesions in apoE-/- cross","journal":"Circulation","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic KO with in vitro adhesion assay and in vivo lesion quantification, single lab with multiple orthogonal methods","pmids":["19433759"],"is_preprint":false},{"year":2009,"finding":"CD11c deficiency in mice does not alter weight gain on high-fat diet but decreases T-cell accumulation and activation in adipose tissue, and ameliorates insulin resistance and glucose intolerance associated with diet-induced obesity.","method":"CD11c-/- mice on high-fat diet, flow cytometry of adipose tissue, insulin/glucose tolerance tests","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with defined metabolic and immunological phenotypes, single lab","pmids":["19910635"],"is_preprint":false},{"year":2010,"finding":"Monocytes internalize triglyceride-rich lipoproteins from postprandial blood via LDL-receptor-related protein-1 (LRP-1), which elicits CD11c upregulation and enhanced monocyte arrest on VCAM-1 under shear flow; monocyte arrest correlated with blood triglyceride and CD11c expression levels.","method":"Flow cytometry, lipoprotein internalization assay, lab-on-a-chip shear flow assay","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic pathway (LRP-1 → CD11c upregulation → VCAM-1 adhesion) supported by multiple assays, single lab","pmids":["21030716"],"is_preprint":false},{"year":2013,"finding":"The CD11c alpha-chain is phosphorylated at Ser-1158; this phosphorylation is functionally pivotal for CD11c/CD18-mediated cell adherence and phagocytosis, as shown by site-directed mutagenesis.","method":"Phosphorylation site identification, site-directed mutagenesis of Ser-1158, adherence and phagocytosis assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct identification of PTM site plus mutagenesis with functional readouts (adherence, phagocytosis)","pmids":["24129562"],"is_preprint":false},{"year":2018,"finding":"CD11c/CD18 (CR4) on BCR-activated human B cells is newly synthesized (not redistributed), functional in mediating adhesion and migration of activated B lymphocytes, and its CR4-mediated adhesion promotes proliferation of BCR-activated cells. CD11c expression on tonsillar B cells increases upon BCR activation and occurs in parallel with class switching.","method":"Flow cytometry, de novo synthesis assay, adhesion assay, migration assay, proliferation assay on human tonsillar and blood B cells","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional assays (adhesion, migration, proliferation) with de novo synthesis demonstrated, single lab","pmids":["33133077"],"is_preprint":false},{"year":2021,"finding":"CD11c on dendritic cells participates in antigen presentation by interacting with MHC II and Hsp90, and contributes to phosphorylation of Akt and Erk1/2 upon inflammatory stimulation. Blocking CD11c on human monocyte-derived DCs inhibited CD4+ T cell proliferation and Th1 differentiation; CD11c-deficient recipient mice in allo-BMT showed reduced IFN-γ+ CD4+ Th1 and CD8+ T cell responses.","method":"Co-immunoprecipitation (CD11c with MHC II and Hsp90), phosphorylation analysis, CD11c-blocking antibody experiments, CD11c-deficient murine allo-BMT model, transcriptional analysis","journal":"Immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP identifies binding partners, with functional knockout and blocking antibody validation, single lab","pmids":["33934334"],"is_preprint":false},{"year":2023,"finding":"CD11c regulates neutrophil maturation in the bone marrow; CD11c deficiency impairs neutrophil maturation, increases proliferation and apoptosis of preneutrophils, and leads to exaggerated release of immature neutrophils under LPS challenge. Constitutively active CD11c knock-in mice show accelerated neutrophil maturation with enhanced effector functions and superior bacterial eradication.","method":"CD11c knockout and constitutively active CD11c knock-in mice, bone marrow analysis by flow cytometry, LPS challenge model, bacterial eradication assay","journal":"Blood advances","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO and gain-of-function knock-in with defined cellular phenotypes, replicated across both loss- and gain-of-function models","pmids":["36306384"],"is_preprint":false},{"year":2020,"finding":"CD11c is expressed on short-term hematopoietic stem cells and multipotent progenitor cells (HSPCs). CD11c deficiency does not affect HSPC numbers in healthy mice, but leads to increased apoptosis and significant loss of HSPCs in sepsis and bone marrow transplantation models, demonstrating a distinct role of CD11c in regulating HSPC expansion under stress.","method":"Flow cytometry of HSPCs, CD11c knockout mice, sepsis model (LPS), bone marrow transplantation, apoptosis assays","journal":"Blood advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with defined phenotype in two distinct stress models, single lab","pmids":["33351105"],"is_preprint":false},{"year":2012,"finding":"Upon TLR3/4/9 agonist activation, mouse (but not human) dendritic cells strongly downregulate cell surface CD11c in a MyD88-dependent manner (for TLR4/9) with concomitant increase in cytoplasmic CD11c pools. Poly I:C (TLR3, MyD88-independent) also induces surface CD11c downregulation.","method":"Flow cytometry, intracellular staining, TLR agonist stimulation of mouse BMDC and splenic DCs, MyD88-deficient cells, mixed leukocyte reaction, cytokine secretion assays","journal":"Immunobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic dissection using MyD88-deficient cells and multiple TLR agonists, single lab","pmids":["22445076"],"is_preprint":false},{"year":2018,"finding":"Stearic acid (a saturated fatty acid) induces CD11c expression in monocytes via activation of the nuclear retinoic acid receptor, and cytosolic epidermal fatty acid binding protein (E-FABP) is required for this SA-induced CD11c upregulation. E-FABP depletion inhibits SA-induced CD11c upregulation in vitro and abrogates high-saturated-fat diet-induced skin lesions in obese mice.","method":"In vitro fatty acid treatment of monocytes/macrophages, nuclear receptor activation assay, E-FABP knockout, flow cytometry, in vivo high-fat diet model","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pathway dissection with KO validation in vitro and in vivo, single lab","pmids":["29626089"],"is_preprint":false},{"year":2018,"finding":"CD11c-targeted delivery of double-stranded DNA to human monocyte-derived dendritic cells leads to dendritic cell maturation via cGAS- and STING-dependent pathways, as shown by complete abrogation of maturation marker upregulation in cGAS KO and STING KO cells.","method":"Anti-CD11c antibody-conjugated dsDNA delivery, cGAS KO and STING KO THP-1 cell lines, flow cytometry for DC maturation markers","journal":"Journal of immunotherapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO cell lines establishing pathway position, single lab with two orthogonal KO conditions","pmids":["29189388"],"is_preprint":false},{"year":2019,"finding":"In CD11c+ antigen-presenting cells, the salt-sensing kinase SGK1 mediates high salt-induced expression and assembly of ENaC-α and ENaC-γ subunits (shown by co-immunoprecipitation), activates NADPH oxidase, and promotes formation of IsoLG-protein adducts leading to renal inflammation and hypertension. Mice lacking SGK1 specifically in CD11c+ cells are protected from renal inflammation, endothelial dysfunction, and show blunted salt-sensitive hypertension.","method":"Conditional CD11c-specific SGK1 knockout mice, co-immunoprecipitation of ENaC-α and ENaC-γ, NADPH oxidase activity assays, IsoLG-adduct measurement, blood pressure monitoring","journal":"Hypertension (Dallas, Tex. : 1979)","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP establishing protein complex plus conditional KO with multiple defined functional phenotypes, single lab with multiple orthogonal methods","pmids":["31280647"],"is_preprint":false},{"year":2019,"finding":"TRPV4 is functionally expressed in the plasma membrane of immature CD11c+ bone marrow-derived dendritic cells, with activity and expression downregulated upon LPS-induced maturation. TRPV4 deficiency does not prevent NF-κB activation, pro-inflammatory cytokine upregulation, or maturation marker expression, but specifically reduces Fc receptor-mediated (IgG-coated bead) phagocytosis without affecting non-receptor-mediated internalization.","method":"Intracellular Ca2+ imaging, TRPV4 knockout BMDC, flow cytometry, NF-κB nuclear translocation, phagocytosis assays with IgG-coated vs. uncoated beads","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple assays with KO cells, single lab, distinct negative and positive results reported","pmids":["31295806"],"is_preprint":false},{"year":2023,"finding":"CD11c+ microglia traffic from the brain to the ileum in a mouse model of Parkinson's disease, carrying alpha-synuclein aggregates. Ileal CD11c+ cells are microglia-like by single-cell RNA sequencing, and the same subtype is activated in both brain and ileum. Photo-convertible Dendra2 reporter mice directly demonstrate brain-to-gut migration of CD11c+ cells.","method":"Immunohistochemistry, single-cell RNA sequencing, photo-convertible protein Dendra2 tracing in mice","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct cell tracking with photo-convertible reporter plus scRNA-seq, single lab with multiple orthogonal approaches","pmids":["37981650"],"is_preprint":false},{"year":2023,"finding":"CD11c+ microglia selectively promote white matter repair after ischemic stroke; they exhibit high phagocytic capability, myelin-supportive gene expression, and lipid metabolism genes. Selective depletion of CD11c+ microglia via stereotactic rAAV2/6M-taCasp3 injection in CD11c-Cre mice disrupts white matter repair, oligodendrocyte maturation, and functional recovery.","method":"Mouse tMCAO stroke model, MRI DTI, flow cytometry, RNA sequencing, conditional cell depletion (rAAV-caspase3 in CD11c-Cre mice), Rotarod/adhesive removal/Morris Water Maze tests","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 2 / Moderate — conditional depletion with defined cellular and functional phenotypes across multiple behavioral/imaging readouts, single lab","pmids":["36828819"],"is_preprint":false},{"year":2024,"finding":"Trophoblast-derived galectin-9 activates a perivascular CD11chigh decidual macrophage subset via CD44 binding, suppressing uterine spiral artery remodeling and contributing to preeclampsia. Galectin-9 administration induces preeclampsia-like phenotypes with increased CD11chigh decidual macrophages, while galectin-9 blockade or macrophage-specific CD44 deletion prevents these phenotypes.","method":"Single-cell RNA sequencing, spatial transcriptomics, conditional knockout mice (macrophage-specific CD44 deletion), recombinant galectin-9 mouse model, galectin-9 blockade, cell-based studies","journal":"Circulation","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal approaches including scRNA-seq, conditional KO, and pharmacological blockade across independent mouse models","pmids":["38314577"],"is_preprint":false},{"year":2022,"finding":"Human T-bet governs the development of a distinct CD11chiCD21lo B cell subset by controlling chromatin accessibility of lineage-defining genes including FAS, IL21R, SEC61B, DUSP4, DAPP1, SOX5, CD79B, and CXCR4. A patient with inherited T-bet deficiency lacks these B cells but has largely intact humoral immunity, with skewed class switching to IgG1/IgG4/IgE.","method":"Study of human patient with inherited T-bet deficiency, in vitro B cell differentiation assays, ATAC-seq (chromatin accessibility), flow cytometry, immunoglobulin class switching analysis","journal":"Science immunology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — human genetics combined with chromatin accessibility profiling and functional assays, single patient but multiple orthogonal methods","pmids":["35867801"],"is_preprint":false},{"year":2024,"finding":"ABC (atypical B cell) formation is dependent on the transcription factor Zeb2; CRISPR-Cas9 knockdown of Zeb2 impairs CD11c+ ABC formation. ZEB2 haplo-insufficient patients (Mowat-Wilson syndrome) have decreased circulating ABCs. ABCs drive optimal TFH cell formation and GC responses and reside at the red/white pulp border, permitting antigen presentation to sustain germinal centers during recrudescent blood-stage malaria.","method":"CRISPR-Cas9 knockdown screen, human patient samples (MWS), Cd23 mice with impaired ABC formation, Plasmodium sporozoite immunization model, immune phenotyping","journal":"Science immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR screen plus human genetics plus in vivo infectious disease model, replicated across species","pmids":["38330097"],"is_preprint":false},{"year":2022,"finding":"CD11c+ myeloid cell-derived exosomes reduce intestinal inflammation during colitis; Rab27A deletion in CD11c+ cells exacerbates murine colitis, reversible by administration of DC-derived exosomes. DC exosomes carry miR-146a which is transferred to macrophages and T cells via a Rab27-dependent mechanism, targeting Traf6, IRAK-1, and NLRP3 in macrophages to reduce inflammation.","method":"Cell-specific Rab27A knockout mice, DSS colitis model, exosome administration, miRNA profiling, miR-146a target validation in macrophages","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with rescue experiment and molecular target identification (miR-146a/Traf6/IRAK-1/NLRP3), single lab with multiple orthogonal methods","pmids":["36214220"],"is_preprint":false}],"current_model":"CD11c (ITGAX) encodes the alpha-X subunit of the beta2-integrin heterodimer CD11c/CD18 (CR4, p150/95), which functions as a signaling-competent adhesion receptor that binds LPS, iC3b, fibrinogen, ICAM-1, ICAM-2, and VCAM-1; its alpha-chain is phosphorylated at Ser-1158 (critical for adherence and phagocytosis), its transcription is driven by AP-1/c-Jun and Sp1/C/EBP elements in a myeloid-differentiation-dependent manner, and beyond its canonical role as a dendritic cell marker it regulates neutrophil maturation in the bone marrow, hematopoietic stem/progenitor cell survival under stress, T cell priming by antigen-presenting cells (interacting with MHC II and Hsp90 to activate Akt/Erk1/2 signaling), monocyte adhesion to VCAM-1 driving atherogenesis, exosome-mediated anti-inflammatory crosstalk in the gut (via miR-146a/Traf6/IRAK-1/NLRP3), brain-to-gut trafficking of alpha-synuclein aggregates in neurodegeneration, and uterine spiral artery remodeling through a galectin-9/CD44 axis in preeclampsia."},"narrative":{"mechanistic_narrative":"ITGAX encodes the alpha-X subunit of the beta2-integrin heterodimer CD11c/CD18 (CR4, p150/95), a signaling-competent adhesion receptor central to myeloid cell function across inflammation, immunity, and tissue remodeling [PMID:7535339, PMID:17389580]. As a receptor it transduces signals from lipopolysaccharide independently of CD14 (driving NF-κB translocation) and engages the cell-adhesion ligands ICAM-2 and VCAM-1, with the VCAM-1 contact site distinct from that used by alpha4-integrin [PMID:7535339, PMID:17389580]. Its adhesive and phagocytic functions are gated by phosphorylation of the alpha-chain at Ser-1158 [PMID:24129562]. Transcriptionally, CD11c expression is myeloid-differentiation-dependent, controlled by a proximal AP-1 site transactivated by c-Jun together with Sp1 and C/EBP elements [PMID:8621914, PMID:9250811], and is inducible by metabolic and inflammatory cues including triglyceride-rich lipoprotein uptake via LRP-1 and stearic-acid signaling through the retinoic acid receptor and E-FABP [PMID:21030716, PMID:29626089]. Functionally, CD11c/CD18 supports monocyte firm arrest on VCAM-1 and E-selectin to drive atherogenesis [PMID:19433759], mediates antigen-presenting-cell priming of CD4+ Th1 and CD8+ T cells through interaction with MHC II and Hsp90 and downstream Akt/Erk1/2 activation [PMID:33934334], and is required for autoimmune T-cell-driven pathology in EAE and for diet-induced adipose inflammation and insulin resistance [PMID:17525267, PMID:19910635]. Within the bone marrow CD11c governs neutrophil maturation and protects hematopoietic stem/progenitor cells from stress-induced apoptosis [PMID:36306384, PMID:33351105]. CD11c also marks functionally distinct cell states whose development is directed by the transcription factors T-bet and Zeb2 — the CD11chiCD21lo / atypical B cell subset that supports germinal-center and TFH responses [PMID:35867801, PMID:38330097] — and labels microglial populations that traffic alpha-synuclein aggregates from brain to gut and promote white-matter repair after stroke [PMID:37981650, PMID:36828819]. In disease-specific axes CD11c+ myeloid cells use Rab27-dependent exosomal transfer of miR-146a to suppress intestinal inflammation [PMID:36214220], and a perivascular CD11chi decidual macrophage subset responds to trophoblast galectin-9 via CD44 to impair spiral-artery remodeling in preeclampsia [PMID:38314577].","teleology":[{"year":1995,"claim":"Established that CD11c/CD18 is not merely an adhesion molecule but a transmembrane signaling receptor able to sense LPS and activate NF-κB, defining a CD14-independent endotoxin response pathway.","evidence":"Heterologous expression in CHO fibroblasts with NF-κB translocation readout and anti-CD14 antibody controls","pmids":["7535339"],"confidence":"High","gaps":["Slower, higher-threshold responses than CD14 leave physiological relevance of direct LPS sensing unclear","Downstream signaling intermediates not mapped"]},{"year":1997,"claim":"Defined how CD11c expression is restricted to myeloid lineage, identifying the cis-elements (AP-1, Sp1, C/EBP) and the transactivator c-Jun that couple promoter activity to differentiation cues.","evidence":"EMSA, in vivo footprinting, site-directed mutagenesis, luciferase reporters, and stable transfection in U937 and myeloid/B cell lines","pmids":["8621914","9250811"],"confidence":"High","gaps":["Upstream signals activating these factors during physiological differentiation not fully defined","Distinct butyrate-responsive element remains uncharacterized"]},{"year":2007,"claim":"Expanded the CD11c ligand repertoire to ICAM-2 and VCAM-1 and showed it cooperates with alpha4beta1 in monocyte capture, repositioning CD11c as a contributor to leukocyte recruitment on inflamed endothelium.","evidence":"Cell adhesion and monocyte transmigration assays on human aortic endothelial cells with blocking antibodies","pmids":["17389580"],"confidence":"Medium","gaps":["Affinity and stoichiometry of CD11c-VCAM-1 binding not quantified","Relative in vivo contribution of each ligand unresolved"]},{"year":2009,"claim":"Provided genetic proof that CD11c drives disease by mediating firm monocyte arrest, linking its adhesive function to atherosclerosis progression and to adipose inflammation and insulin resistance.","evidence":"CD11c-/- mice, shear-flow adhesion assays, atherosclerotic lesion quantification in apoE-/- cross, and high-fat-diet metabolic phenotyping","pmids":["19433759","19910635"],"confidence":"High","gaps":["Cell-type-specific contributions (monocyte vs. tissue macrophage vs. T cell) not separated","Signaling link from adhesion to inflammation not defined"]},{"year":2010,"claim":"Connected a metabolic input to CD11c function by showing LRP-1-mediated triglyceride-rich lipoprotein uptake upregulates CD11c and enhances monocyte arrest, providing a postprandial mechanism for atherogenic adhesion.","evidence":"Flow cytometry, lipoprotein internalization, and lab-on-a-chip shear-flow assays correlated with blood triglyceride","pmids":["21030716"],"confidence":"Medium","gaps":["Transcriptional pathway from LRP-1 to ITGAX promoter not traced","Correlative human data not causal"]},{"year":2013,"claim":"Identified a specific post-translational control point, showing phosphorylation of the alpha-chain Ser-1158 is required for CD11c/CD18-mediated adherence and phagocytosis.","evidence":"Phosphosite identification and site-directed mutagenesis with adherence and phagocytosis readouts","pmids":["24129562"],"confidence":"High","gaps":["Kinase responsible for Ser-1158 phosphorylation not identified","Structural basis of how phosphorylation alters integrin activity unknown"]},{"year":2012,"claim":"Showed CD11c surface levels are dynamically regulated upon TLR activation in a partly MyD88-dependent, species-divergent manner, indicating receptor trafficking accompanies dendritic cell maturation.","evidence":"Flow cytometry and intracellular staining of mouse BMDC/splenic DC with multiple TLR agonists and MyD88-deficient cells","pmids":["22445076"],"confidence":"Medium","gaps":["Mechanism of internalization vs. degradation not resolved","Functional consequence of surface downregulation unclear","Human DC behavior differs and is unexplained"]},{"year":2018,"claim":"Demonstrated CD11c is functionally important on activated B cells and can be exploited as a delivery target, showing CR4 mediates B-cell adhesion/migration/proliferation and that CD11c-targeted dsDNA matures DCs via cGAS-STING.","evidence":"De novo synthesis, adhesion, migration and proliferation assays on human B cells; cGAS/STING KO THP-1 cells with antibody-conjugated dsDNA","pmids":["33133077","29189388"],"confidence":"Medium","gaps":["Signaling that couples CR4 adhesion to B-cell proliferation not defined","Whether CD11c itself signals or only delivers cargo in the dsDNA system unresolved"]},{"year":2018,"claim":"Mapped a lipid-sensing input to CD11c, showing stearic acid induces CD11c via the retinoic acid receptor with E-FABP as a required cytosolic mediator linking saturated fat to monocyte activation.","evidence":"In vitro fatty-acid treatment, nuclear receptor assays, E-FABP knockout, and high-saturated-fat diet skin-lesion model","pmids":["29626089"],"confidence":"Medium","gaps":["Direct molecular link between E-FABP and the ITGAX promoter not shown","Generalizability beyond skin pathology untested"]},{"year":2019,"claim":"Established CD11c+ APCs as effectors in salt-sensitive hypertension and dissected ancillary ion-channel biology of CD11c+ DCs, identifying SGK1-driven ENaC assembly and TRPV4-dependent Fc-receptor phagocytosis.","evidence":"CD11c-specific conditional SGK1 KO mice with co-IP of ENaC subunits and blood-pressure phenotyping; TRPV4 KO BMDC with Ca2+ imaging and phagocytosis assays","pmids":["31280647","31295806"],"confidence":"High","gaps":["These pathways operate in CD11c+ cells but do not show CD11c itself as the molecular effector","Crosstalk between integrin signaling and these channels not examined"]},{"year":2021,"claim":"Defined a molecular mechanism for CD11c in T-cell priming, showing it associates with MHC II and Hsp90 and contributes to Akt/Erk1/2 activation required for Th1 and CD8 responses.","evidence":"Co-immunoprecipitation, phosphorylation analysis, CD11c-blocking antibodies on human moDCs, and CD11c-deficient allo-BMT mouse model","pmids":["33934334"],"confidence":"Medium","gaps":["Direct vs. indirect nature of the MHC II/Hsp90 interaction not established by reciprocal validation","How an integrin physically organizes the immunological synapse unclear"]},{"year":2020,"claim":"Revealed stress-restricted roles of CD11c in hematopoiesis, showing it is dispensable in steady state but protects HSPCs from apoptosis and supports their expansion under sepsis and transplantation stress.","evidence":"Flow cytometry of HSPCs, CD11c KO mice, LPS sepsis and bone-marrow transplantation models, apoptosis assays","pmids":["33351105"],"confidence":"Medium","gaps":["Molecular survival pathway downstream of CD11c in HSPCs not identified","Whether effect is HSPC-intrinsic or niche-mediated unresolved"]},{"year":2023,"claim":"Provided bidirectional genetic evidence that CD11c instructs granulopoiesis, with loss impairing and a constitutively active receptor accelerating neutrophil maturation and antibacterial function.","evidence":"CD11c knockout and constitutively active knock-in mice with bone-marrow flow cytometry, LPS challenge, and bacterial eradication assays","pmids":["36306384"],"confidence":"High","gaps":["Signaling output of the activated integrin driving maturation not mapped","Ligand engaged during marrow neutrophil development unknown"]},{"year":2023,"claim":"Identified CD11c-marked microglial states with distinct roles in neurological disease, tracking brain-to-gut migration carrying alpha-synuclein and showing CD11c+ microglia are required for post-stroke white-matter repair.","evidence":"Photo-convertible Dendra2 tracing and scRNA-seq in a Parkinson's model; conditional rAAV-caspase3 depletion in CD11c-Cre mice in a tMCAO stroke model with imaging/behavioral readouts","pmids":["37981650","36828819"],"confidence":"High","gaps":["Whether CD11c the protein, versus CD11c+ cell identity, mediates these functions not separated","Mechanism of trans-tissue migration unknown"]},{"year":2022,"claim":"Placed CD11c+ B cell subsets within defined transcriptional programs, showing T-bet and Zeb2 control development of CD11chiCD21lo and atypical B cells that sustain germinal-center and TFH responses.","evidence":"Human T-bet- and ZEB2-deficient patients, ATAC-seq, CRISPR-Cas9 knockdown, in vitro B-cell differentiation, and Plasmodium immunization model","pmids":["35867801","38330097"],"confidence":"High","gaps":["CD11c is a marker rather than a demonstrated functional driver in these subsets","Direct regulation of ITGAX by T-bet/Zeb2 not shown"]},{"year":2024,"claim":"Defined disease-specific CD11c+ myeloid axes: Rab27-dependent exosomal miR-146a transfer suppressing colitis, and galectin-9/CD44 activation of CD11chi decidual macrophages impairing spiral-artery remodeling in preeclampsia.","evidence":"Cell-specific Rab27A KO with exosome rescue and miR-146a target validation; scRNA-seq, spatial transcriptomics, macrophage-specific CD44 KO and galectin-9 blockade in preeclampsia models","pmids":["36214220","38314577"],"confidence":"High","gaps":["These define CD11c+ cell behaviors but not a molecular role for the CD11c protein itself","Whether CD11c integrin engagement triggers galectin-9 responsiveness untested"]},{"year":null,"claim":"It remains unresolved which findings reflect a direct molecular function of the CD11c/CD18 integrin versus the behavior of CD11c-marked cell populations, and the kinase, ligand-engagement, and downstream signaling logic connecting Ser-1158 phosphorylation, MHC II/Hsp90 association, and Akt/Erk activation to specific cellular outcomes is not integrated.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of CD11c ligand engagement","Kinase for Ser-1158 unidentified","Marker-versus-effector ambiguity across most in vivo phenotypes"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[3,5]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[10]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,9,13]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[13]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[4,10,22]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,8,10]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[5,18,20]}],"complexes":["CD11c/CD18 (CR4, p150/95)"],"partners":["ITGB2","VCAM1","ICAM2","ICAM1","HLA-DR","HSP90","LRP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P20702","full_name":"Integrin alpha-X","aliases":["CD11 antigen-like family member C","Leu M5","Leukocyte adhesion glycoprotein p150,95 alpha chain","Leukocyte adhesion receptor p150,95"],"length_aa":1163,"mass_kda":127.8,"function":"Integrin alpha-X/beta-2 is a receptor for fibrinogen. It recognizes the sequence G-P-R in fibrinogen. It mediates cell-cell interaction during inflammatory responses. It is especially important in monocyte adhesion and chemotaxis. 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diagnosis of mantle cell lymphoma.","date":"2010","source":"American journal of clinical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/20660331","citation_count":21,"is_preprint":false},{"pmid":"8621914","id":"PMC_8621914","title":"AP-1 regulates the basal and developmentally induced transcription of the CD11c leukocyte integrin gene.","date":"1996","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/8621914","citation_count":21,"is_preprint":false},{"pmid":"32163584","id":"PMC_32163584","title":"Immunological characteristics and possible pathogenic role of urinary CD11c+ macrophages in lupus nephritis.","date":"2020","source":"Rheumatology (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/32163584","citation_count":20,"is_preprint":false},{"pmid":"20888334","id":"PMC_20888334","title":"Expression of dendritic cell markers CD11c/BDCA-1 and CD123/BDCA-2 in coronary artery disease upon activation in whole blood.","date":"2010","source":"Journal of immunological methods","url":"https://pubmed.ncbi.nlm.nih.gov/20888334","citation_count":20,"is_preprint":false},{"pmid":"36214220","id":"PMC_36214220","title":"CD11c+ myeloid cell exosomes reduce intestinal inflammation during colitis.","date":"2022","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/36214220","citation_count":19,"is_preprint":false},{"pmid":"29189388","id":"PMC_29189388","title":"CD11c-targeted Delivery of DNA to Dendritic Cells Leads to cGAS- and STING-dependent Maturation.","date":"2018","source":"Journal of immunotherapy (Hagerstown, Md. : 1997)","url":"https://pubmed.ncbi.nlm.nih.gov/29189388","citation_count":18,"is_preprint":false},{"pmid":"33785592","id":"PMC_33785592","title":"CD11c+CD88+CD317+ myeloid cells are critical mediators of persistent CNS autoimmunity.","date":"2021","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/33785592","citation_count":18,"is_preprint":false},{"pmid":"38259450","id":"PMC_38259450","title":"Single-cell profiling of CD11c+ B cells in atherosclerosis.","date":"2024","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/38259450","citation_count":17,"is_preprint":false},{"pmid":"33351105","id":"PMC_33351105","title":"CD11c regulates hematopoietic stem and progenitor cells under stress.","date":"2020","source":"Blood advances","url":"https://pubmed.ncbi.nlm.nih.gov/33351105","citation_count":17,"is_preprint":false},{"pmid":"29930175","id":"PMC_29930175","title":"Hepato-entrained B220+CD11c+NK1.1+ cells regulate pre-metastatic niche formation in the lung.","date":"2018","source":"EMBO molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/29930175","citation_count":17,"is_preprint":false},{"pmid":"28928485","id":"PMC_28928485","title":"Increased TREM-2 expression on the subsets of CD11c+ cells in the lungs and lymph nodes during allergic airway inflammation.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28928485","citation_count":17,"is_preprint":false},{"pmid":"39970232","id":"PMC_39970232","title":"Dysfunctional CD11c-CD21- extrafollicular memory B cells are enriched in the periphery and tumors of patients with cancer.","date":"2025","source":"Science translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/39970232","citation_count":16,"is_preprint":false},{"pmid":"33934334","id":"PMC_33934334","title":"CD11c participates in triggering acute graft-versus-host disease during bone marrow transplantation.","date":"2021","source":"Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/33934334","citation_count":16,"is_preprint":false},{"pmid":"35568024","id":"PMC_35568024","title":"CD11c identifies microbiota and EGR2-dependent MHCII+ serous cavity macrophages with sexually dimorphic fate in mice.","date":"2022","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/35568024","citation_count":16,"is_preprint":false},{"pmid":"38570939","id":"PMC_38570939","title":"Correlation of Professional Antigen-Presenting Tbet+CD11c+ B Cells With Bone Destruction in Untreated Rheumatoid Arthritis.","date":"2024","source":"Arthritis & rheumatology (Hoboken, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/38570939","citation_count":15,"is_preprint":false},{"pmid":"31295806","id":"PMC_31295806","title":"Expression and Functional Role of TRPV4 in Bone Marrow-Derived CD11c+ Cells.","date":"2019","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/31295806","citation_count":15,"is_preprint":false},{"pmid":"35917184","id":"PMC_35917184","title":"Lysosomal acid lipase, CSF1R, and PD-L1 determine functions of CD11c+ myeloid-derived suppressor cells.","date":"2022","source":"JCI 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immunology","url":"https://pubmed.ncbi.nlm.nih.gov/32117307","citation_count":14,"is_preprint":false},{"pmid":"33133077","id":"PMC_33133077","title":"Activated Human Memory B Lymphocytes Use CR4 (CD11c/CD18) for Adhesion, Migration, and Proliferation.","date":"2020","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/33133077","citation_count":14,"is_preprint":false},{"pmid":"32824307","id":"PMC_32824307","title":"Association of Electronegative LDL with Macrophage Foam Cell Formation and CD11c Expression in Rheumatoid Arthritis Patients.","date":"2020","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32824307","citation_count":14,"is_preprint":false},{"pmid":"40103815","id":"PMC_40103815","title":"Multifaceted, unique role of CD11c in leukocyte biology.","date":"2025","source":"Frontiers in 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Responses were slower and required higher endotoxin concentrations than CD14-mediated responses, and were not inhibited by anti-CD14 antibodies.\",\n      \"method\": \"Heterologous expression in CHO cells; NF-κB translocation assay\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstitution in heterologous cell system with functional readout, single lab but multiple comparator conditions\",\n      \"pmids\": [\"7535339\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"The CD11c gene promoter activity during myeloid differentiation is controlled by an AP-1 binding site (AP1-60) in the proximal promoter region, with c-Jun transactivating the promoter; mutation of AP1-60 greatly reduces basal and PMA-induced promoter activity in myeloid and B cells.\",\n      \"method\": \"Electrophoretic mobility shift assay (EMSA), in vivo footprinting, site-directed mutagenesis, reporter gene (luciferase) assays, transactivation by c-Jun\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple orthogonal methods (EMSA, footprinting, mutagenesis, transactivation) in a single focused study\",\n      \"pmids\": [\"8621914\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"The tissue-specific activity of the CD11c promoter is conferred by two Sp1-binding sites and an adjacent C/EBP-binding element; the AP-1 site mediates differentiation-inducibility by PMA and GM-CSF; an additional element distinct from AP-1 is required for sodium butyrate-triggered induction. Stable transfection of the -361/+43 fragment into U937 cells confirms differentiation-dependent promoter activity.\",\n      \"method\": \"Promoter deletion/mutation analysis, stable transfection into U937 cells, luciferase reporter assays\",\n      \"journal\": \"Leukemia & lymphoma\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — functional promoter dissection with mutagenesis and stable transfection, but single lab\",\n      \"pmids\": [\"9250811\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CD11c recognizes ICAM-2 and VCAM-1 as novel ligands. The CD11c-binding site on VCAM-1 is distinct from the alpha4-integrin binding site. CD11c and alpha4beta1 together contribute to monocyte capture and transmigration on inflamed human aortic endothelial cells. Anti-mouse CD11c mAb N418 blocks CD11c binding to iC3b, ICAM-1, and VCAM-1.\",\n      \"method\": \"Cell adhesion assays, monocyte transmigration assay on human aortic endothelial cells, blocking antibody experiments\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional adhesion assays with blocking antibodies and multiple ligands tested, single lab\",\n      \"pmids\": [\"17389580\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CD11c (p150/95) expression is required for development of experimental autoimmune encephalomyelitis (EAE); CD11c-deficient mice show reduced spinal cord T-cell infiltration and altered cytokine profiles (reduced IFN-γ, TNF-α, IL-17, TGF-β; elevated IL-2, IL-4, IL-12). Adoptive transfer experiments show CD11c is required on both T cells and other leukocytes for disease development.\",\n      \"method\": \"CD11c-knockout mice, EAE model, adoptive transfer of antigen-restimulated T cells, cytokine measurement\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with defined cellular phenotype and adoptive transfer epistasis, single lab but two orthogonal approaches\",\n      \"pmids\": [\"17525267\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CD11c deficiency in mice decreases firm arrest of monocytes on VCAM-1 and E-selectin under shear flow, reduces monocyte/macrophage accumulation in atherosclerotic lesions, and decreases atherosclerosis development in apoE-/- mice on a high-fat diet.\",\n      \"method\": \"CD11c-/- mouse generation, shear flow adhesion assay on VCAM-1 and E-selectin, histological quantification of atherosclerotic lesions in apoE-/- cross\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with in vitro adhesion assay and in vivo lesion quantification, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"19433759\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CD11c deficiency in mice does not alter weight gain on high-fat diet but decreases T-cell accumulation and activation in adipose tissue, and ameliorates insulin resistance and glucose intolerance associated with diet-induced obesity.\",\n      \"method\": \"CD11c-/- mice on high-fat diet, flow cytometry of adipose tissue, insulin/glucose tolerance tests\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with defined metabolic and immunological phenotypes, single lab\",\n      \"pmids\": [\"19910635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Monocytes internalize triglyceride-rich lipoproteins from postprandial blood via LDL-receptor-related protein-1 (LRP-1), which elicits CD11c upregulation and enhanced monocyte arrest on VCAM-1 under shear flow; monocyte arrest correlated with blood triglyceride and CD11c expression levels.\",\n      \"method\": \"Flow cytometry, lipoprotein internalization assay, lab-on-a-chip shear flow assay\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic pathway (LRP-1 → CD11c upregulation → VCAM-1 adhesion) supported by multiple assays, single lab\",\n      \"pmids\": [\"21030716\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The CD11c alpha-chain is phosphorylated at Ser-1158; this phosphorylation is functionally pivotal for CD11c/CD18-mediated cell adherence and phagocytosis, as shown by site-directed mutagenesis.\",\n      \"method\": \"Phosphorylation site identification, site-directed mutagenesis of Ser-1158, adherence and phagocytosis assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct identification of PTM site plus mutagenesis with functional readouts (adherence, phagocytosis)\",\n      \"pmids\": [\"24129562\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CD11c/CD18 (CR4) on BCR-activated human B cells is newly synthesized (not redistributed), functional in mediating adhesion and migration of activated B lymphocytes, and its CR4-mediated adhesion promotes proliferation of BCR-activated cells. CD11c expression on tonsillar B cells increases upon BCR activation and occurs in parallel with class switching.\",\n      \"method\": \"Flow cytometry, de novo synthesis assay, adhesion assay, migration assay, proliferation assay on human tonsillar and blood B cells\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays (adhesion, migration, proliferation) with de novo synthesis demonstrated, single lab\",\n      \"pmids\": [\"33133077\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CD11c on dendritic cells participates in antigen presentation by interacting with MHC II and Hsp90, and contributes to phosphorylation of Akt and Erk1/2 upon inflammatory stimulation. Blocking CD11c on human monocyte-derived DCs inhibited CD4+ T cell proliferation and Th1 differentiation; CD11c-deficient recipient mice in allo-BMT showed reduced IFN-γ+ CD4+ Th1 and CD8+ T cell responses.\",\n      \"method\": \"Co-immunoprecipitation (CD11c with MHC II and Hsp90), phosphorylation analysis, CD11c-blocking antibody experiments, CD11c-deficient murine allo-BMT model, transcriptional analysis\",\n      \"journal\": \"Immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP identifies binding partners, with functional knockout and blocking antibody validation, single lab\",\n      \"pmids\": [\"33934334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CD11c regulates neutrophil maturation in the bone marrow; CD11c deficiency impairs neutrophil maturation, increases proliferation and apoptosis of preneutrophils, and leads to exaggerated release of immature neutrophils under LPS challenge. Constitutively active CD11c knock-in mice show accelerated neutrophil maturation with enhanced effector functions and superior bacterial eradication.\",\n      \"method\": \"CD11c knockout and constitutively active CD11c knock-in mice, bone marrow analysis by flow cytometry, LPS challenge model, bacterial eradication assay\",\n      \"journal\": \"Blood advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO and gain-of-function knock-in with defined cellular phenotypes, replicated across both loss- and gain-of-function models\",\n      \"pmids\": [\"36306384\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CD11c is expressed on short-term hematopoietic stem cells and multipotent progenitor cells (HSPCs). CD11c deficiency does not affect HSPC numbers in healthy mice, but leads to increased apoptosis and significant loss of HSPCs in sepsis and bone marrow transplantation models, demonstrating a distinct role of CD11c in regulating HSPC expansion under stress.\",\n      \"method\": \"Flow cytometry of HSPCs, CD11c knockout mice, sepsis model (LPS), bone marrow transplantation, apoptosis assays\",\n      \"journal\": \"Blood advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with defined phenotype in two distinct stress models, single lab\",\n      \"pmids\": [\"33351105\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Upon TLR3/4/9 agonist activation, mouse (but not human) dendritic cells strongly downregulate cell surface CD11c in a MyD88-dependent manner (for TLR4/9) with concomitant increase in cytoplasmic CD11c pools. Poly I:C (TLR3, MyD88-independent) also induces surface CD11c downregulation.\",\n      \"method\": \"Flow cytometry, intracellular staining, TLR agonist stimulation of mouse BMDC and splenic DCs, MyD88-deficient cells, mixed leukocyte reaction, cytokine secretion assays\",\n      \"journal\": \"Immunobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic dissection using MyD88-deficient cells and multiple TLR agonists, single lab\",\n      \"pmids\": [\"22445076\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Stearic acid (a saturated fatty acid) induces CD11c expression in monocytes via activation of the nuclear retinoic acid receptor, and cytosolic epidermal fatty acid binding protein (E-FABP) is required for this SA-induced CD11c upregulation. E-FABP depletion inhibits SA-induced CD11c upregulation in vitro and abrogates high-saturated-fat diet-induced skin lesions in obese mice.\",\n      \"method\": \"In vitro fatty acid treatment of monocytes/macrophages, nuclear receptor activation assay, E-FABP knockout, flow cytometry, in vivo high-fat diet model\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pathway dissection with KO validation in vitro and in vivo, single lab\",\n      \"pmids\": [\"29626089\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CD11c-targeted delivery of double-stranded DNA to human monocyte-derived dendritic cells leads to dendritic cell maturation via cGAS- and STING-dependent pathways, as shown by complete abrogation of maturation marker upregulation in cGAS KO and STING KO cells.\",\n      \"method\": \"Anti-CD11c antibody-conjugated dsDNA delivery, cGAS KO and STING KO THP-1 cell lines, flow cytometry for DC maturation markers\",\n      \"journal\": \"Journal of immunotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO cell lines establishing pathway position, single lab with two orthogonal KO conditions\",\n      \"pmids\": [\"29189388\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In CD11c+ antigen-presenting cells, the salt-sensing kinase SGK1 mediates high salt-induced expression and assembly of ENaC-α and ENaC-γ subunits (shown by co-immunoprecipitation), activates NADPH oxidase, and promotes formation of IsoLG-protein adducts leading to renal inflammation and hypertension. Mice lacking SGK1 specifically in CD11c+ cells are protected from renal inflammation, endothelial dysfunction, and show blunted salt-sensitive hypertension.\",\n      \"method\": \"Conditional CD11c-specific SGK1 knockout mice, co-immunoprecipitation of ENaC-α and ENaC-γ, NADPH oxidase activity assays, IsoLG-adduct measurement, blood pressure monitoring\",\n      \"journal\": \"Hypertension (Dallas, Tex. : 1979)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP establishing protein complex plus conditional KO with multiple defined functional phenotypes, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"31280647\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TRPV4 is functionally expressed in the plasma membrane of immature CD11c+ bone marrow-derived dendritic cells, with activity and expression downregulated upon LPS-induced maturation. TRPV4 deficiency does not prevent NF-κB activation, pro-inflammatory cytokine upregulation, or maturation marker expression, but specifically reduces Fc receptor-mediated (IgG-coated bead) phagocytosis without affecting non-receptor-mediated internalization.\",\n      \"method\": \"Intracellular Ca2+ imaging, TRPV4 knockout BMDC, flow cytometry, NF-κB nuclear translocation, phagocytosis assays with IgG-coated vs. uncoated beads\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple assays with KO cells, single lab, distinct negative and positive results reported\",\n      \"pmids\": [\"31295806\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CD11c+ microglia traffic from the brain to the ileum in a mouse model of Parkinson's disease, carrying alpha-synuclein aggregates. Ileal CD11c+ cells are microglia-like by single-cell RNA sequencing, and the same subtype is activated in both brain and ileum. Photo-convertible Dendra2 reporter mice directly demonstrate brain-to-gut migration of CD11c+ cells.\",\n      \"method\": \"Immunohistochemistry, single-cell RNA sequencing, photo-convertible protein Dendra2 tracing in mice\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct cell tracking with photo-convertible reporter plus scRNA-seq, single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"37981650\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CD11c+ microglia selectively promote white matter repair after ischemic stroke; they exhibit high phagocytic capability, myelin-supportive gene expression, and lipid metabolism genes. Selective depletion of CD11c+ microglia via stereotactic rAAV2/6M-taCasp3 injection in CD11c-Cre mice disrupts white matter repair, oligodendrocyte maturation, and functional recovery.\",\n      \"method\": \"Mouse tMCAO stroke model, MRI DTI, flow cytometry, RNA sequencing, conditional cell depletion (rAAV-caspase3 in CD11c-Cre mice), Rotarod/adhesive removal/Morris Water Maze tests\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional depletion with defined cellular and functional phenotypes across multiple behavioral/imaging readouts, single lab\",\n      \"pmids\": [\"36828819\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Trophoblast-derived galectin-9 activates a perivascular CD11chigh decidual macrophage subset via CD44 binding, suppressing uterine spiral artery remodeling and contributing to preeclampsia. Galectin-9 administration induces preeclampsia-like phenotypes with increased CD11chigh decidual macrophages, while galectin-9 blockade or macrophage-specific CD44 deletion prevents these phenotypes.\",\n      \"method\": \"Single-cell RNA sequencing, spatial transcriptomics, conditional knockout mice (macrophage-specific CD44 deletion), recombinant galectin-9 mouse model, galectin-9 blockade, cell-based studies\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal approaches including scRNA-seq, conditional KO, and pharmacological blockade across independent mouse models\",\n      \"pmids\": [\"38314577\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Human T-bet governs the development of a distinct CD11chiCD21lo B cell subset by controlling chromatin accessibility of lineage-defining genes including FAS, IL21R, SEC61B, DUSP4, DAPP1, SOX5, CD79B, and CXCR4. A patient with inherited T-bet deficiency lacks these B cells but has largely intact humoral immunity, with skewed class switching to IgG1/IgG4/IgE.\",\n      \"method\": \"Study of human patient with inherited T-bet deficiency, in vitro B cell differentiation assays, ATAC-seq (chromatin accessibility), flow cytometry, immunoglobulin class switching analysis\",\n      \"journal\": \"Science immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — human genetics combined with chromatin accessibility profiling and functional assays, single patient but multiple orthogonal methods\",\n      \"pmids\": [\"35867801\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ABC (atypical B cell) formation is dependent on the transcription factor Zeb2; CRISPR-Cas9 knockdown of Zeb2 impairs CD11c+ ABC formation. ZEB2 haplo-insufficient patients (Mowat-Wilson syndrome) have decreased circulating ABCs. ABCs drive optimal TFH cell formation and GC responses and reside at the red/white pulp border, permitting antigen presentation to sustain germinal centers during recrudescent blood-stage malaria.\",\n      \"method\": \"CRISPR-Cas9 knockdown screen, human patient samples (MWS), Cd23 mice with impaired ABC formation, Plasmodium sporozoite immunization model, immune phenotyping\",\n      \"journal\": \"Science immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR screen plus human genetics plus in vivo infectious disease model, replicated across species\",\n      \"pmids\": [\"38330097\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CD11c+ myeloid cell-derived exosomes reduce intestinal inflammation during colitis; Rab27A deletion in CD11c+ cells exacerbates murine colitis, reversible by administration of DC-derived exosomes. DC exosomes carry miR-146a which is transferred to macrophages and T cells via a Rab27-dependent mechanism, targeting Traf6, IRAK-1, and NLRP3 in macrophages to reduce inflammation.\",\n      \"method\": \"Cell-specific Rab27A knockout mice, DSS colitis model, exosome administration, miRNA profiling, miR-146a target validation in macrophages\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with rescue experiment and molecular target identification (miR-146a/Traf6/IRAK-1/NLRP3), single lab with multiple orthogonal methods\",\n      \"pmids\": [\"36214220\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CD11c (ITGAX) encodes the alpha-X subunit of the beta2-integrin heterodimer CD11c/CD18 (CR4, p150/95), which functions as a signaling-competent adhesion receptor that binds LPS, iC3b, fibrinogen, ICAM-1, ICAM-2, and VCAM-1; its alpha-chain is phosphorylated at Ser-1158 (critical for adherence and phagocytosis), its transcription is driven by AP-1/c-Jun and Sp1/C/EBP elements in a myeloid-differentiation-dependent manner, and beyond its canonical role as a dendritic cell marker it regulates neutrophil maturation in the bone marrow, hematopoietic stem/progenitor cell survival under stress, T cell priming by antigen-presenting cells (interacting with MHC II and Hsp90 to activate Akt/Erk1/2 signaling), monocyte adhesion to VCAM-1 driving atherogenesis, exosome-mediated anti-inflammatory crosstalk in the gut (via miR-146a/Traf6/IRAK-1/NLRP3), brain-to-gut trafficking of alpha-synuclein aggregates in neurodegeneration, and uterine spiral artery remodeling through a galectin-9/CD44 axis in preeclampsia.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ITGAX encodes the alpha-X subunit of the beta2-integrin heterodimer CD11c/CD18 (CR4, p150/95), a signaling-competent adhesion receptor central to myeloid cell function across inflammation, immunity, and tissue remodeling [#0, #3]. As a receptor it transduces signals from lipopolysaccharide independently of CD14 (driving NF-\\u03baB translocation) and engages the cell-adhesion ligands ICAM-2 and VCAM-1, with the VCAM-1 contact site distinct from that used by alpha4-integrin [#0, #3]. Its adhesive and phagocytic functions are gated by phosphorylation of the alpha-chain at Ser-1158 [#8]. Transcriptionally, CD11c expression is myeloid-differentiation-dependent, controlled by a proximal AP-1 site transactivated by c-Jun together with Sp1 and C/EBP elements [#1, #2], and is inducible by metabolic and inflammatory cues including triglyceride-rich lipoprotein uptake via LRP-1 and stearic-acid signaling through the retinoic acid receptor and E-FABP [#7, #14]. Functionally, CD11c/CD18 supports monocyte firm arrest on VCAM-1 and E-selectin to drive atherogenesis [#5], mediates antigen-presenting-cell priming of CD4+ Th1 and CD8+ T cells through interaction with MHC II and Hsp90 and downstream Akt/Erk1/2 activation [#10], and is required for autoimmune T-cell-driven pathology in EAE and for diet-induced adipose inflammation and insulin resistance [#4, #6]. Within the bone marrow CD11c governs neutrophil maturation and protects hematopoietic stem/progenitor cells from stress-induced apoptosis [#11, #12]. CD11c also marks functionally distinct cell states whose development is directed by the transcription factors T-bet and Zeb2 \\u2014 the CD11chiCD21lo / atypical B cell subset that supports germinal-center and TFH responses [#21, #22] \\u2014 and labels microglial populations that traffic alpha-synuclein aggregates from brain to gut and promote white-matter repair after stroke [#18, #19]. In disease-specific axes CD11c+ myeloid cells use Rab27-dependent exosomal transfer of miR-146a to suppress intestinal inflammation [#23], and a perivascular CD11chi decidual macrophage subset responds to trophoblast galectin-9 via CD44 to impair spiral-artery remodeling in preeclampsia [#20].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Established that CD11c/CD18 is not merely an adhesion molecule but a transmembrane signaling receptor able to sense LPS and activate NF-\\u03baB, defining a CD14-independent endotoxin response pathway.\",\n      \"evidence\": \"Heterologous expression in CHO fibroblasts with NF-\\u03baB translocation readout and anti-CD14 antibody controls\",\n      \"pmids\": [\"7535339\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Slower, higher-threshold responses than CD14 leave physiological relevance of direct LPS sensing unclear\", \"Downstream signaling intermediates not mapped\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Defined how CD11c expression is restricted to myeloid lineage, identifying the cis-elements (AP-1, Sp1, C/EBP) and the transactivator c-Jun that couple promoter activity to differentiation cues.\",\n      \"evidence\": \"EMSA, in vivo footprinting, site-directed mutagenesis, luciferase reporters, and stable transfection in U937 and myeloid/B cell lines\",\n      \"pmids\": [\"8621914\", \"9250811\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream signals activating these factors during physiological differentiation not fully defined\", \"Distinct butyrate-responsive element remains uncharacterized\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Expanded the CD11c ligand repertoire to ICAM-2 and VCAM-1 and showed it cooperates with alpha4beta1 in monocyte capture, repositioning CD11c as a contributor to leukocyte recruitment on inflamed endothelium.\",\n      \"evidence\": \"Cell adhesion and monocyte transmigration assays on human aortic endothelial cells with blocking antibodies\",\n      \"pmids\": [\"17389580\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Affinity and stoichiometry of CD11c-VCAM-1 binding not quantified\", \"Relative in vivo contribution of each ligand unresolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Provided genetic proof that CD11c drives disease by mediating firm monocyte arrest, linking its adhesive function to atherosclerosis progression and to adipose inflammation and insulin resistance.\",\n      \"evidence\": \"CD11c-/- mice, shear-flow adhesion assays, atherosclerotic lesion quantification in apoE-/- cross, and high-fat-diet metabolic phenotyping\",\n      \"pmids\": [\"19433759\", \"19910635\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-type-specific contributions (monocyte vs. tissue macrophage vs. T cell) not separated\", \"Signaling link from adhesion to inflammation not defined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Connected a metabolic input to CD11c function by showing LRP-1-mediated triglyceride-rich lipoprotein uptake upregulates CD11c and enhances monocyte arrest, providing a postprandial mechanism for atherogenic adhesion.\",\n      \"evidence\": \"Flow cytometry, lipoprotein internalization, and lab-on-a-chip shear-flow assays correlated with blood triglyceride\",\n      \"pmids\": [\"21030716\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Transcriptional pathway from LRP-1 to ITGAX promoter not traced\", \"Correlative human data not causal\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified a specific post-translational control point, showing phosphorylation of the alpha-chain Ser-1158 is required for CD11c/CD18-mediated adherence and phagocytosis.\",\n      \"evidence\": \"Phosphosite identification and site-directed mutagenesis with adherence and phagocytosis readouts\",\n      \"pmids\": [\"24129562\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase responsible for Ser-1158 phosphorylation not identified\", \"Structural basis of how phosphorylation alters integrin activity unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showed CD11c surface levels are dynamically regulated upon TLR activation in a partly MyD88-dependent, species-divergent manner, indicating receptor trafficking accompanies dendritic cell maturation.\",\n      \"evidence\": \"Flow cytometry and intracellular staining of mouse BMDC/splenic DC with multiple TLR agonists and MyD88-deficient cells\",\n      \"pmids\": [\"22445076\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of internalization vs. degradation not resolved\", \"Functional consequence of surface downregulation unclear\", \"Human DC behavior differs and is unexplained\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated CD11c is functionally important on activated B cells and can be exploited as a delivery target, showing CR4 mediates B-cell adhesion/migration/proliferation and that CD11c-targeted dsDNA matures DCs via cGAS-STING.\",\n      \"evidence\": \"De novo synthesis, adhesion, migration and proliferation assays on human B cells; cGAS/STING KO THP-1 cells with antibody-conjugated dsDNA\",\n      \"pmids\": [\"33133077\", \"29189388\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signaling that couples CR4 adhesion to B-cell proliferation not defined\", \"Whether CD11c itself signals or only delivers cargo in the dsDNA system unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Mapped a lipid-sensing input to CD11c, showing stearic acid induces CD11c via the retinoic acid receptor with E-FABP as a required cytosolic mediator linking saturated fat to monocyte activation.\",\n      \"evidence\": \"In vitro fatty-acid treatment, nuclear receptor assays, E-FABP knockout, and high-saturated-fat diet skin-lesion model\",\n      \"pmids\": [\"29626089\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between E-FABP and the ITGAX promoter not shown\", \"Generalizability beyond skin pathology untested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established CD11c+ APCs as effectors in salt-sensitive hypertension and dissected ancillary ion-channel biology of CD11c+ DCs, identifying SGK1-driven ENaC assembly and TRPV4-dependent Fc-receptor phagocytosis.\",\n      \"evidence\": \"CD11c-specific conditional SGK1 KO mice with co-IP of ENaC subunits and blood-pressure phenotyping; TRPV4 KO BMDC with Ca2+ imaging and phagocytosis assays\",\n      \"pmids\": [\"31280647\", \"31295806\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"These pathways operate in CD11c+ cells but do not show CD11c itself as the molecular effector\", \"Crosstalk between integrin signaling and these channels not examined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined a molecular mechanism for CD11c in T-cell priming, showing it associates with MHC II and Hsp90 and contributes to Akt/Erk1/2 activation required for Th1 and CD8 responses.\",\n      \"evidence\": \"Co-immunoprecipitation, phosphorylation analysis, CD11c-blocking antibodies on human moDCs, and CD11c-deficient allo-BMT mouse model\",\n      \"pmids\": [\"33934334\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs. indirect nature of the MHC II/Hsp90 interaction not established by reciprocal validation\", \"How an integrin physically organizes the immunological synapse unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealed stress-restricted roles of CD11c in hematopoiesis, showing it is dispensable in steady state but protects HSPCs from apoptosis and supports their expansion under sepsis and transplantation stress.\",\n      \"evidence\": \"Flow cytometry of HSPCs, CD11c KO mice, LPS sepsis and bone-marrow transplantation models, apoptosis assays\",\n      \"pmids\": [\"33351105\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular survival pathway downstream of CD11c in HSPCs not identified\", \"Whether effect is HSPC-intrinsic or niche-mediated unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Provided bidirectional genetic evidence that CD11c instructs granulopoiesis, with loss impairing and a constitutively active receptor accelerating neutrophil maturation and antibacterial function.\",\n      \"evidence\": \"CD11c knockout and constitutively active knock-in mice with bone-marrow flow cytometry, LPS challenge, and bacterial eradication assays\",\n      \"pmids\": [\"36306384\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling output of the activated integrin driving maturation not mapped\", \"Ligand engaged during marrow neutrophil development unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified CD11c-marked microglial states with distinct roles in neurological disease, tracking brain-to-gut migration carrying alpha-synuclein and showing CD11c+ microglia are required for post-stroke white-matter repair.\",\n      \"evidence\": \"Photo-convertible Dendra2 tracing and scRNA-seq in a Parkinson's model; conditional rAAV-caspase3 depletion in CD11c-Cre mice in a tMCAO stroke model with imaging/behavioral readouts\",\n      \"pmids\": [\"37981650\", \"36828819\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CD11c the protein, versus CD11c+ cell identity, mediates these functions not separated\", \"Mechanism of trans-tissue migration unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Placed CD11c+ B cell subsets within defined transcriptional programs, showing T-bet and Zeb2 control development of CD11chiCD21lo and atypical B cells that sustain germinal-center and TFH responses.\",\n      \"evidence\": \"Human T-bet- and ZEB2-deficient patients, ATAC-seq, CRISPR-Cas9 knockdown, in vitro B-cell differentiation, and Plasmodium immunization model\",\n      \"pmids\": [\"35867801\", \"38330097\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"CD11c is a marker rather than a demonstrated functional driver in these subsets\", \"Direct regulation of ITGAX by T-bet/Zeb2 not shown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined disease-specific CD11c+ myeloid axes: Rab27-dependent exosomal miR-146a transfer suppressing colitis, and galectin-9/CD44 activation of CD11chi decidual macrophages impairing spiral-artery remodeling in preeclampsia.\",\n      \"evidence\": \"Cell-specific Rab27A KO with exosome rescue and miR-146a target validation; scRNA-seq, spatial transcriptomics, macrophage-specific CD44 KO and galectin-9 blockade in preeclampsia models\",\n      \"pmids\": [\"36214220\", \"38314577\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"These define CD11c+ cell behaviors but not a molecular role for the CD11c protein itself\", \"Whether CD11c integrin engagement triggers galectin-9 responsiveness untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved which findings reflect a direct molecular function of the CD11c/CD18 integrin versus the behavior of CD11c-marked cell populations, and the kinase, ligand-engagement, and downstream signaling logic connecting Ser-1158 phosphorylation, MHC II/Hsp90 association, and Akt/Erk activation to specific cellular outcomes is not integrated.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of CD11c ligand engagement\", \"Kinase for Ser-1158 unidentified\", \"Marker-versus-effector ambiguity across most in vivo phenotypes\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [3, 5]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 9, 13]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4, 10, 22]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 8, 10]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [5, 18, 20]}\n    ],\n    \"complexes\": [\"CD11c/CD18 (CR4, p150/95)\"],\n    \"partners\": [\"ITGB2\", \"VCAM1\", \"ICAM2\", \"ICAM1\", \"HLA-DR\", \"HSP90\", \"LRP1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}