{"gene":"CD163","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"year":2002,"finding":"CD163 was identified as the endocytic receptor that binds hemoglobin (Hb) in complex with haptoglobin (Hp), mediating removal of the Hp-Hb complex from plasma via receptor-mediated endocytosis in macrophages, leading to lysosomal degradation of the ligand and explaining haptoglobin depletion during intravascular hemolysis.","method":"Receptor-ligand binding assays, endocytosis experiments in macrophages","journal":"The international journal of biochemistry & cell biology","confidence":"High","confidence_rationale":"Tier 2 — foundational finding replicated across multiple labs with multiple orthogonal methods","pmids":["11854028","15478309"],"is_preprint":false},{"year":2005,"finding":"CD163 functions as a scavenger receptor for native and chemically modified hemoglobins in the absence of haptoglobin: Hb interacts directly with CD163 via receptor-dependent endocytosis, inhibits Hb-Hp uptake (suggesting a common binding site), and induces heme oxygenase mRNA expression in CD163+ but not CD163- cells. Hp-complex formation critically enhances Hb uptake at low but not high ligand concentrations, supporting a biphasic model of macrophage Hb clearance.","method":"In vitro endocytosis assays in CD163+ HEK293 cells and human macrophages, competitive binding experiments, receptor-negative control cells, mRNA expression assays","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal in vitro assays including competition experiments and CD163-negative controls","pmids":["16189277"],"is_preprint":false},{"year":2004,"finding":"CD163-mediated endocytosis of haptoglobin-hemoglobin complexes leads to lysosomal Hp-Hb breakdown and heme oxygenase-catalyzed conversion of heme into anti-inflammatory metabolites (CO, biliverdin, iron), and CD163 directly induces intracellular signaling leading to secretion of anti-inflammatory cytokines.","method":"Cell biology assays, endocytosis experiments, cytokine secretion measurements","journal":"Annals of medicine","confidence":"High","confidence_rationale":"Tier 2 — replicated across multiple labs with functional readouts","pmids":["15478309"],"is_preprint":false},{"year":2008,"finding":"CD163 functions as a macrophage pattern recognition receptor for both Gram-positive and Gram-negative bacteria; a previously identified cell-binding motif in the second scavenger domain (SRCR2) of CD163 mediates bacterial binding. Expression of CD163 in monocytic cells promotes bacteria-induced proinflammatory cytokine production, and antagonistic anti-CD163 antibodies potently inhibit cytokine production in freshly isolated human monocytes.","method":"Bacterial binding assays with CD163-expressing cells, antagonistic antibody experiments, cytokine production assays in primary human monocytes","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — multiple methods including domain-specific binding, antibody blocking, and primary human cell experiments","pmids":["18849484"],"is_preprint":false},{"year":2007,"finding":"CD163 confers susceptibility to porcine reproductive and respiratory syndrome virus (PRRSV): direct functional screening identified CD163 as sufficient to render non-permissive cells PRRSV-permissive. Full-length CD163 with the C-terminal transmembrane anchor is required; splice variants lacking this domain do not provide PRRSV receptor function.","method":"cDNA expression library screening, transient transfection of non-permissive cell lines, stable cell line establishment, virus infectivity assays","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1-2 — functional screen with domain mutagenesis (splice variants), replicated in multiple cell types","pmids":["17494075"],"is_preprint":false},{"year":2008,"finding":"Sialoadhesin and CD163 cooperate sequentially during PRRSV entry: sialoadhesin mediates virus internalization at the cell surface (active at 4°C), while CD163 acts downstream during virus uncoating after internalization (active at 37°C). Expression of sialoadhesin alone leads to PRRSV internalization without uncoating or productive infection; co-expression of both receptors restores productive infection and increases virus production 10–100-fold.","method":"Antibody blocking at 4°C vs. 37°C, confocal microscopy of PRRSV entry, non-permissive cells expressing sialoadhesin alone or together with CD163, virus production quantification","journal":"The Journal of general virology","confidence":"High","confidence_rationale":"Tier 1-2 — mechanistic dissection with temperature-dependent experiments, confocal imaging, and genetic reconstitution","pmids":["19008379"],"is_preprint":false},{"year":2016,"finding":"CD163 was identified as an antiinflammatory receptor for HMGB1-haptoglobin complexes. Haptoglobin binds HMGB1 and targets uptake through CD163; haptoglobin-HMGB1 complexes elicit production of heme oxygenase-1 and IL-10 in wild-type but not CD163-deficient macrophages. Genetic disruption of haptoglobin or CD163 significantly enhances mortality in mouse models of intra-abdominal sepsis.","method":"Co-immunoprecipitation/binding assays, CD163-deficient macrophages vs WT, genetic knockout mouse models, cytokine/enzyme production assays","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods including KO macrophages, genetic mouse models, and functional cytokine readouts","pmids":["27294203"],"is_preprint":false},{"year":1999,"finding":"CD163 expression is transcriptionally induced by M-CSF, IL-10, and dexamethasone, and suppressed by LPS, IFN-γ, and GM-CSF/IL-4. Dexamethasone induction is mediated by glucocorticoid receptor binding sites in the proximal promoter. Multiple isoforms arise from alternative splicing and differ in cytoplasmic or extracellular domains, potentially affecting function.","method":"In vitro monocyte culture with cytokines/drugs, mRNA expression analysis, promoter analysis, genomic organization mapping","journal":"Pathobiology","confidence":"Medium","confidence_rationale":"Tier 2 — single lab but multiple stimuli tested with both mRNA and protein readouts; promoter analysis by sequence","pmids":["10725797"],"is_preprint":false},{"year":2009,"finding":"CD163-expressing macrophages can bind and internalize TWEAK (TNF-like weak inducer of apoptosis) protein, identifying CD163 as a scavenger receptor for soluble TWEAK. This interaction is proposed to decrease TWEAK plasma concentration.","method":"In vitro binding and internalization assays of exogenous TWEAK in cultured human CD163-expressing macrophages","journal":"Atherosclerosis","confidence":"Medium","confidence_rationale":"Tier 3 — single lab, in vitro binding/internalization assay with limited mechanistic follow-up","pmids":["19473660"],"is_preprint":false},{"year":2009,"finding":"CXCL4 (platelet factor 4) downregulates CD163 expression in human macrophages through binding to cell-surface glycosaminoglycans; heparin neutralizes the CXCL4 effect, and chlorate (which inhibits glycosaminoglycan synthesis) blocks CXCL4-dependent CD163 downregulation. Loss of CD163 renders macrophages unable to upregulate heme oxygenase-1 in response to hemoglobin-haptoglobin complexes.","method":"Flow cytometry, mRNA expression, heparin neutralization, chlorate inhibition of glycosaminoglycan synthesis, functional HO-1 induction assay","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (neutralization, pathway inhibition, functional consequence) in single lab","pmids":["19910578"],"is_preprint":false},{"year":2013,"finding":"CD163 directly suppresses hemoglobin pseudoperoxidase activity via an autocrine loop: membrane CD163 is shed as sCD163 which sequesters free Hb; the sCD163-Hb complex is endocytosed via FcγR with IgG into monocytes and recycled, restoring membrane CD163 homeostasis. In a paracrine manner, monocyte-derived sCD163 and IgG shuttle residual Hb into endothelial cells for detoxification.","method":"In vitro Hb pseudoperoxidase activity assays, ex vivo coculture of monocytes and endothelial cells, endocytosis and recycling experiments, FcγR pathway studies","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — single lab with multiple functional assays including autocrine/paracrine mechanistic dissection","pmids":["23589619"],"is_preprint":false},{"year":2012,"finding":"CD163 mediates uptake of Mycobacterium leprae (ML) in human monocytes: CD163 blockade reduced ML uptake in human monocytes, and HEK293 cells transfected with CD163 cDNA showed higher ML uptake than untransfected cells. ML-induced CD163 upregulation was IL-10-dependent (IL-10 blockade reduced CD163 expression), and increased CD163 expression contributed to augmented iron storage in lepromatous macrophages.","method":"CD163 antibody blocking, HEK293 transfection with CD163 cDNA, ML uptake assays, IL-10 blockade experiments, iron storage measurement","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — receptor blocking + heterologous expression + IL-10 blockade linking pathway","pmids":["22851198"],"is_preprint":false},{"year":2014,"finding":"ADAM17 (metalloprotease) mediates ectodomain shedding of CD163 from the cell surface, negatively regulating PRRSV entry: inhibition of ADAM17 upregulates membrane CD163 and enhances PRRSV infection, whereas ADAM17 overexpression reduces surface CD163 and PRRSV infection. siRNA knockdown of ADAM17 increases CD163 expression with a corresponding increase in PRRSV infection.","method":"ADAM17 inhibitor experiments, ADAM17 overexpression and siRNA knockdown, surface CD163 quantification, PRRSV infection assays in Marc-145 and porcine alveolar macrophages","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 — multiple genetic manipulations (overexpression, siRNA, inhibitor) with consistent functional readouts","pmids":["24965453"],"is_preprint":false},{"year":2018,"finding":"CD163 is required for protumoral macrophage activation: silencing CD163 abrogates macrophage-induced tumor cell proliferation in coculture. In CD163-deficient mice, sarcoma tumor development is significantly reduced. CD163-deficient macrophages show suppressed production of IL-6 and CXCL2; overexpression of CD163 in CD163-deficient macrophages rescues IL-6 and CXCL2 production. IL-6 (but not CXCL2) silencing abrogates macrophage-induced tumor cell proliferation.","method":"CD163 siRNA silencing in coculture, CD163-knockout mice, CD163 overexpression rescue, IL-6/CXCL2 silencing epistasis","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 — loss-of-function (KO mouse + siRNA), gain-of-function rescue, and epistasis experiments with defined molecular mechanism","pmids":["29610117"],"is_preprint":false},{"year":2018,"finding":"CD163 interacts directly with casein kinase 2 (CK2) in glioma cells; CD163 silencing reduces AKT/GSK3β/β-catenin/cyclin D1 pathway activity via CK2, inhibiting cell cycle progression and proliferation of GBM cells. CD163 is upregulated in CD133+ glioma stem cells (GSCs) and its knockdown impairs GSC stemness via the CK2/AKT/GSK3β/β-catenin pathway.","method":"Co-immunoprecipitation demonstrating CD163-CK2 direct interaction, CD163 siRNA knockdown, pathway activity assays (AKT/GSK3β/β-catenin/cyclin D1), cell proliferation and stemness marker assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2-3 — direct Co-IP for CD163-CK2 interaction plus downstream pathway validation by KD","pmids":["30258108"],"is_preprint":false},{"year":2016,"finding":"Neurons express the CD163 receptor and internalize Hb and Hb-Hp complexes; haptoglobin increases vulnerability of CD163-expressing neurons to hemoglobin by directing Hb uptake to CD163+ neurons while attenuating the protective ferritin response in CD163-negative glia. Neuronal Hb toxicity via CD163 is iron-dependent.","method":"Primary cortical cell cultures, CD163 immunostaining on neurons, Hb/Hb-Hp uptake assays, deferoxamine/chelator experiments demonstrating iron-dependent mechanism","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 2 — cell culture experiments with receptor-specific functional readouts and chelator controls","pmids":["27364920"],"is_preprint":false},{"year":2017,"finding":"CD163 deficiency in mice has temporally distinct effects after intracerebral hemorrhage: at 3 days, CD163-KO mice have less hematoma volume, less hemoglobin/iron accumulation, and less blood-brain barrier dysfunction; at 10 days, CD163-KO mice have larger lesions and increased iron/VEGF. This establishes that CD163 mediates hemoglobin scavenging in the brain with early detrimental (pro-inflammatory Hb retention is initially limited without the receptor driving early HO-1 conversion) and late anti-inflammatory/reparative roles.","method":"CD163 knockout mice, intracerebral hemorrhage model, hematoma volume measurement, hemoglobin/iron quantification, BBB integrity assays, HO-1 expression, neurobehavioral testing","journal":"Journal of cerebral blood flow and metabolism","confidence":"High","confidence_rationale":"Tier 2 — clean KO model with multiple defined phenotypic and molecular readouts at two time points","pmids":["28358264"],"is_preprint":false},{"year":2020,"finding":"CD163 knockout pigs are completely resistant to genotype 2 PRRSV infection, directly establishing CD163 as an essential entry receptor for PRRSV in vivo. The absence of CD163 results in increased iron in muscle (consistent with loss of hemoglobin-haptoglobin scavenging function) but no impairment of meat production or reproductive performance.","method":"CRISPR/Cas9 double-knockout pigs, PRRSV challenge experiments, PCR and serology, iron measurement in muscle tissue","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 — in vivo genetic KO with viral challenge, confirming receptor function and physiological role","pmids":["32876563"],"is_preprint":false},{"year":2012,"finding":"Glucocorticoids (cortisol and dexamethasone) specifically upregulate CD163 protein and mRNA in placental Hofbauer cells (fetal macrophages), and dexamethasone treatment increases hemoglobin uptake by Hofbauer cells, demonstrating that GC-induced CD163 upregulation is functionally active in enhancing Hb scavenging.","method":"Western blotting, flow cytometry, real-time PCR, hemoglobin uptake functional assay in primary Hofbauer cells, placental explant cultures","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple methods with functional readout (Hb uptake) in primary human cells","pmids":["23142809"],"is_preprint":false},{"year":2020,"finding":"CCR4 activation by recombinant CCL17 promotes hematoma resolution after intracerebral hemorrhage via the CCR4/ERK/Nrf2/CD163 signaling pathway; CRISPR knockout of CD163 abolishes the protective effects of rCCL17, placing CD163 downstream of CCR4/ERK/Nrf2 in this pathway.","method":"Mouse ICH model, recombinant CCL17 treatment, selective CCR4/Nrf2 inhibitors, CD163 CRISPR knockout (intracerebroventricular), western blot, immunofluorescence, neurobehavior","journal":"Neurotherapeutics","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis via CRISPR KO with pharmacological pathway inhibitors","pmids":["32783091"],"is_preprint":false},{"year":2024,"finding":"CD163+ macrophages exposed to hemoglobin-haptoglobin complexes induce endothelial-to-mesenchymal transition (EndMT) in atherosclerotic plaques via NF-κB-mediated Snail transcription factor activation. In vitro, supernatants from Hb/Hp-exposed macrophages induce mesenchymal markers (transgelin, FSP-1) and reduce endothelial markers (VE-cadherin, CD31) in human aortic endothelial cells. CD163 deletion in ApoE-/- mice reduces EndMT and plaque progression.","method":"In vitro macrophage conditioned medium experiments on HAECs, western blot for EndMT markers, NF-κB/Snail pathway analysis, CD163-KO ApoE-/- mouse model, human coronary artery pathological analysis, single-cell RNA sequencing","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 — in vitro mechanistic experiments combined with genetic KO mouse model and human tissue validation","pmids":["38860377"],"is_preprint":false},{"year":2020,"finding":"CD163 deficiency in ApoE-/- mice increases foam cell formation through upregulation of CD36 expression in M2-type macrophages, leading to more unstable atherosclerotic plaques with increased lipid, macrophage content, and pro-inflammatory cytokines. Recombinant CD163 neutralizes proatherogenic TWEAK effects by abolishing NF-κB activation, cytokine/metalloproteinase expression, and macrophage migration in vascular smooth muscle cells.","method":"ApoE/CD163 double-deficient mice, foam cell formation assays, CD36 expression analysis, recombinant CD163 administration, NF-κB activation assays, TWEAK challenge","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 — genetic KO mouse model combined with in vitro mechanistic pathway studies and rescue with recombinant protein","pmids":["32924185"],"is_preprint":false},{"year":2023,"finding":"CD163+ macrophages engulfing hemoglobin:haptoglobin complexes (M(Hb) macrophages) inhibit vascular calcification through NF-κB-induced transcription of hyaluronan synthase (HAS) in vascular smooth muscle cells; knocking down HAS attenuates the anticalcific effect, and NF-κB blockade reduces hyaluronan and increases vascular calcification in ApoE-/- mice.","method":"In vitro VSMC culture with M(Hb) macrophage supernatant, NF-κB inhibitor experiments, HAS knockdown, ApoE-/- mouse model with NF-κB blockade, immunostaining of human arteries","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 — mechanistic pathway dissection with NF-κB inhibition, target gene KD, and in vivo mouse confirmation","pmids":["36719758"],"is_preprint":false},{"year":2023,"finding":"PRRSV glycoprotein 4 (GP4) directly interacts with the SRCR5 domain of CD163; small molecules physically binding to CD163-SRCR5 (Kd 28–39 μM) block PRRSV infection. Specific residues in SRCR5 (570SXDVGXV576) and Q797 in SRCR7 are conformational epitopes critical for PRRSV invasion, as CD163 with mutated epitopes expressed in 3D4 cells fails to support PRRSV infection while wild-type CD163 restores it.","method":"BiFC protein-protein interaction screening, direct binding assays (Kd measurement), site-directed mutagenesis of CD163 epitopes, PRRSV infection assays in mutant vs. WT CD163-expressing cells","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1-2 — direct binding Kd measurement, mutagenesis of specific residues, and functional reconstitution","pmids":["37133376"],"is_preprint":false},{"year":2024,"finding":"Deletion of CD163 exon 13 (encoding the PSTII domain) is sufficient to confer complete resistance to PRRSV-2 infection in pigs in vivo, without affecting CD163's physiological hemoglobin-scavenging function, establishing the PSTII domain as required for PRRSV uncoating/entry.","method":"Gene-edited pigs (exon 13 deletion), PRRSV-2 challenge experiment, PCR and serology, physiological assessment","journal":"Antiviral research","confidence":"High","confidence_rationale":"Tier 2 — in vivo genetic domain-deletion with viral challenge directly attributing function to specific domain","pmids":["38184111"],"is_preprint":false},{"year":2024,"finding":"Pigs with deletion of exon 7 of CD163 (removing the SRCR5 domain) are completely resistant to PRRSV infection across multiple breeding generations, with no detected differences in growth rate, health, meat composition, or reproductive performance, confirming the SRCR5 domain as essential for PRRSV receptor function.","method":"CRISPR-Cas9 gene editing, multi-generation breeding, PRRSV challenge, growth/meat/reproduction performance assessment","journal":"Frontiers in genome editing","confidence":"High","confidence_rationale":"Tier 2 — heritable gene edit confirmed over multiple generations with viral challenge","pmids":["38544785"],"is_preprint":false}],"current_model":"CD163 is a macrophage-specific scavenger receptor (SRCR superfamily class B) that mediates endocytosis of haptoglobin-hemoglobin complexes (and free Hb at high concentrations) via receptor-dependent internalization leading to lysosomal degradation and heme oxygenase-1–driven heme catabolism; its ectodomain (especially the SRCR5 domain) serves as an essential viral uncoating receptor for PRRSV, it scavenges HMGB1-haptoglobin and TWEAK complexes, interacts with casein kinase 2 to regulate AKT/β-catenin signaling in tumor cells, drives NF-κB–mediated hyaluronan synthase expression in vascular smooth muscle cells, and promotes EndMT in atherosclerosis; ectodomain shedding by ADAM17 generates soluble CD163 that retains Hb-scavenging and TWEAK-neutralizing activity."},"narrative":{"teleology":[{"year":1999,"claim":"Defining CD163 as a glucocorticoid- and cytokine-regulated macrophage surface molecule established the transcriptional framework for understanding its lineage-restricted expression and anti-inflammatory context.","evidence":"Monocyte culture with cytokines/dexamethasone, promoter analysis, mRNA/protein expression","pmids":["10725797"],"confidence":"Medium","gaps":["Promoter GR binding sites identified by sequence only, not validated by ChIP","Functional significance of splice isoforms unclear","No in vivo validation of transcriptional regulation"]},{"year":2002,"claim":"Identification of CD163 as the endocytic receptor for haptoglobin–hemoglobin complexes resolved the long-standing question of how macrophages clear Hp–Hb from plasma during hemolysis, establishing the core physiological function of the receptor.","evidence":"Receptor-ligand binding assays and endocytosis experiments in macrophages, replicated across labs","pmids":["11854028","15478309"],"confidence":"High","gaps":["Structural basis of Hp–Hb binding to CD163 not determined","Contribution of individual SRCR domains to Hp–Hb binding not mapped"]},{"year":2004,"claim":"Demonstrating that CD163-mediated Hp–Hb endocytosis leads to HO-1-catalyzed heme degradation into anti-inflammatory metabolites (CO, biliverdin) and triggers anti-inflammatory cytokine secretion established CD163 as an active immune-regulatory receptor, not merely a passive scavenger.","evidence":"Endocytosis experiments with HO-1 induction and cytokine secretion measurements","pmids":["15478309"],"confidence":"High","gaps":["Signaling pathway from CD163 cytoplasmic tail to cytokine induction not defined","Relative contribution of CO vs. biliverdin to anti-inflammatory output unknown"]},{"year":2005,"claim":"Showing that CD163 binds and endocytoses free hemoglobin independently of haptoglobin at high concentrations, with competition at the same binding site, established a biphasic model of Hb clearance and extended receptor function beyond Hp-dependent scavenging.","evidence":"Competitive binding, endocytosis in CD163+ HEK293 and macrophages, CD163-negative controls, HO-1 mRNA readout","pmids":["16189277"],"confidence":"High","gaps":["Affinity constants for free Hb vs. Hp–Hb binding not precisely compared","In vivo relevance of haptoglobin-independent Hb scavenging not tested"]},{"year":2007,"claim":"Functional screening identified CD163 as sufficient to confer PRRSV permissivity to non-permissive cells, revealing an unexpected viral receptor function and requiring the transmembrane-anchored full-length form.","evidence":"cDNA library screen, transient/stable transfection of non-permissive cells, splice variant analysis","pmids":["17494075"],"confidence":"High","gaps":["Viral ligand on PRRSV not yet identified","Mechanism of CD163-dependent uncoating unknown","Role of specific SRCR domains not dissected"]},{"year":2008,"claim":"Mechanistic dissection of PRRSV entry showed that sialoadhesin mediates initial virus internalization while CD163 acts downstream as an intracellular uncoating receptor, resolving CD163's specific step in the viral entry pathway. Separately, CD163 was shown to function as a bacterial pattern recognition receptor through its SRCR2 domain.","evidence":"Temperature-block experiments, confocal imaging, sialoadhesin ± CD163 co-expression; bacterial binding assays with antibody blocking in primary monocytes","pmids":["19008379","18849484"],"confidence":"High","gaps":["Structural mechanism of CD163-mediated viral uncoating unknown","Range of bacterial species recognized not fully characterized","Whether bacterial and viral ligand sites overlap not tested"]},{"year":2009,"claim":"Identification of CD163 as a scavenger receptor for TWEAK expanded its ligand repertoire beyond hemoglobin to include a TNF superfamily cytokine, while demonstration that CXCL4 downregulates CD163 via glycosaminoglycans provided the first mechanism of negative regulation by platelet-derived factors.","evidence":"TWEAK binding/internalization assays in CD163+ macrophages; CXCL4 downregulation with heparin neutralization and chlorate inhibition, HO-1 functional readout","pmids":["19473660","19910578"],"confidence":"Medium","gaps":["TWEAK binding domain on CD163 not mapped","CXCL4 finding from single lab without independent confirmation","Physiological significance of TWEAK scavenging in vivo not established at this point"]},{"year":2012,"claim":"CD163 was shown to mediate Mycobacterium leprae uptake in monocytes through IL-10-dependent upregulation, and glucocorticoids were found to functionally upregulate CD163-dependent Hb scavenging in placental Hofbauer cells, extending CD163 function to pathogen entry and fetal-maternal hemoglobin homeostasis.","evidence":"Antibody blocking and HEK293 transfection for M. leprae uptake; western blot, flow cytometry, and Hb uptake assay in primary Hofbauer cells","pmids":["22851198","23142809"],"confidence":"Medium","gaps":["M. leprae ligand for CD163 not identified","Whether CD163 mediates intracellular M. leprae survival unknown","Hofbauer cell findings not confirmed in vivo"]},{"year":2013,"claim":"Discovery that shed soluble CD163 sequesters free hemoglobin, suppresses its pseudoperoxidase activity, and is re-internalized via FcγR with IgG established an autocrine/paracrine recycling mechanism linking ectodomain shedding to active hemoglobin detoxification.","evidence":"Pseudoperoxidase assays, monocyte–endothelial coculture, endocytosis/recycling experiments, FcγR pathway studies","pmids":["23589619"],"confidence":"Medium","gaps":["FcγR-dependent re-uptake mechanism not confirmed in vivo","Stoichiometry and kinetics of sCD163–Hb complex formation unclear","Single laboratory finding"]},{"year":2014,"claim":"Identifying ADAM17 as the metalloprotease responsible for CD163 ectodomain shedding, with direct demonstration that shedding regulates surface CD163 levels and PRRSV susceptibility, provided a molecular link between protease activity, receptor density, and viral infection.","evidence":"ADAM17 inhibitor, overexpression, and siRNA in Marc-145 cells and porcine alveolar macrophages with PRRSV infection readout","pmids":["24965453"],"confidence":"High","gaps":["ADAM17 cleavage site on CD163 not mapped","Whether other ADAM family members contribute to shedding not excluded","Regulation of ADAM17-dependent shedding in physiological inflammation not studied"]},{"year":2016,"claim":"CD163 was established as an anti-inflammatory receptor for HMGB1–haptoglobin complexes through KO macrophage and genetic mouse studies showing that CD163 deficiency increases sepsis mortality, revealing a second damage-associated molecular pattern cleared by the Hp–CD163 axis. Separately, neuronal CD163 expression was shown to mediate iron-dependent Hb neurotoxicity.","evidence":"CD163-KO macrophages and mice in sepsis models; neuronal culture with Hb/Hp uptake and iron chelation","pmids":["27294203","27364920"],"confidence":"High","gaps":["Whether HMGB1 and Hb compete for the same CD163 binding site unknown","Neuronal CD163 expression not confirmed in vivo in human brain tissue"]},{"year":2017,"claim":"CD163-KO mice showed biphasic effects after intracerebral hemorrhage — early benefit from reduced iron/Hb accumulation but late worsening with larger lesions — establishing that CD163's hemoglobin scavenging function has temporally distinct pro- and anti-inflammatory consequences in the brain.","evidence":"CD163-KO mouse ICH model with serial hematoma, iron, BBB, HO-1, and neurobehavior measurements","pmids":["28358264"],"confidence":"High","gaps":["Cellular source of CD163 in the brain (resident microglia vs. infiltrating macrophages) not resolved","Whether temporal effects are dose-dependent or context-dependent unclear"]},{"year":2018,"claim":"CD163 was shown to be required for protumoral macrophage activation through IL-6 production (via KO, silencing, and rescue), and separately found to interact with casein kinase 2 to activate AKT/β-catenin signaling in glioma cells, revealing tumor-intrinsic and macrophage-extrinsic oncogenic roles.","evidence":"CD163-KO mice with sarcoma model, siRNA/rescue in macrophage–tumor coculture, IL-6 epistasis; Co-IP for CD163–CK2, pathway knockdown in glioma cells","pmids":["29610117","30258108"],"confidence":"High","gaps":["CD163 ligand triggering macrophage IL-6 production not identified","CD163–CK2 interaction based on single Co-IP without reciprocal validation","Whether CD163 on tumor cells vs. macrophages drives glioma effects not fully resolved"]},{"year":2020,"claim":"CD163-knockout pigs were shown to be completely resistant to PRRSV-2, definitively establishing CD163 as an essential in vivo entry receptor. In parallel, CD163 was placed downstream of CCR4/ERK/Nrf2 in hematoma resolution, and soluble CD163 was shown to neutralize TWEAK-driven NF-κB activation and vascular inflammation in atherosclerosis.","evidence":"CRISPR KO pigs with PRRSV challenge; mouse ICH model with CD163 CRISPR KO and pathway inhibitors; ApoE/CD163 double-KO mice with recombinant CD163 rescue and TWEAK challenge","pmids":["32876563","32783091","32924185"],"confidence":"High","gaps":["Whether CD163 KO pigs resist all PRRSV genotypes not yet tested","Direct transcriptional regulation of CD163 by Nrf2 not confirmed by ChIP","Whether TWEAK neutralization is the primary atheroprotective mechanism of sCD163 vs. Hb clearance unknown"]},{"year":2023,"claim":"Mapping PRRSV GP4 interaction to the SRCR5 domain and identifying critical residues (570–576 in SRCR5, Q797 in SRCR7) provided the first molecular-resolution understanding of how PRRSV engages CD163, enabling structure-based antiviral strategies. Separately, CD163-driven Hb/Hp-loaded macrophages were shown to inhibit vascular calcification through NF-κB-induced HAS expression in smooth muscle cells.","evidence":"BiFC, Kd measurement, site-directed mutagenesis with functional reconstitution; VSMC culture with macrophage supernatant, HAS knockdown, NF-κB inhibition in ApoE-/- mice","pmids":["37133376","36719758"],"confidence":"High","gaps":["Crystal structure of SRCR5–GP4 complex not available","Relative contribution of SRCR5 vs. PSTII domain to uncoating unknown","Whether HAS induction is specific to M(Hb) macrophages or shared with other CD163 ligand-activated states unclear"]},{"year":2024,"claim":"Domain-specific deletions in pigs (exon 7/SRCR5 and exon 13/PSTII) independently conferred complete PRRSV resistance while preserving hemoglobin scavenging, resolving which domains are essential for viral uncoating versus physiological function. CD163+ macrophage-driven endothelial-to-mesenchymal transition via NF-κB/Snail was established as a mechanism of plaque progression.","evidence":"Gene-edited pigs with domain-specific deletions and PRRSV challenge; macrophage conditioned medium on HAECs, EndMT markers, CD163-KO ApoE-/- mice, scRNA-seq and human tissue","pmids":["38184111","38544785","38860377"],"confidence":"High","gaps":["Whether SRCR5 deletion affects responses to non-PRRSV pathogens unknown","Signaling pathway linking CD163 ligation to NF-κB/Snail activation in endothelial cells not fully dissected","Long-term cardiovascular outcomes in CD163-KO models not reported"]},{"year":null,"claim":"The intracellular signaling pathway linking CD163 cytoplasmic domain engagement to downstream transcriptional responses (IL-6, IL-10, HO-1 induction) remains undefined, as does the structural basis of ligand discrimination among Hp–Hb, HMGB1, TWEAK, and bacteria.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal or cryo-EM structure of CD163 with any ligand","Cytoplasmic tail signaling adaptors not identified","Whether CD163 functions as a monomer or oligomer during endocytosis unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[0,1,2,6,8]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[3,4,5]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[21,22]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,3,4,12]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[10,11,21]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[0,2]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[3,6,13]},{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[0,1,2,9]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[14,19,21]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[4,5,17,24,25]}],"complexes":[],"partners":["HP","HBB","ADAM17","TNFSF12","CSNK2A1","HMGB1","SIGLEC1"],"other_free_text":[]},"mechanistic_narrative":"CD163 is a macrophage-restricted scavenger receptor of the SRCR superfamily that functions as a central mediator of hemoglobin clearance, innate immune sensing, and tissue homeostasis. It serves as the primary endocytic receptor for haptoglobin–hemoglobin (Hp–Hb) complexes and free hemoglobin on macrophages, directing ligand internalization to lysosomes where heme oxygenase-1 catalyzes heme degradation into the anti-inflammatory metabolites CO, biliverdin, and iron, while simultaneously triggering secretion of IL-10 and other anti-inflammatory cytokines [PMID:11854028, PMID:16189277, PMID:15478309]. Beyond hemoglobin scavenging, CD163 recognizes bacteria via its SRCR2 domain to promote proinflammatory cytokine production [PMID:18849484], scavenges HMGB1–haptoglobin complexes to limit sepsis-associated inflammation [PMID:27294203], neutralizes TWEAK to attenuate NF-κB–driven vascular inflammation [PMID:32924185], and drives protumoral macrophage activation through IL-6 production [PMID:29610117]. CD163 also functions as the essential uncoating receptor for porcine reproductive and respiratory syndrome virus (PRRSV) through its SRCR5 and PSTII domains, as demonstrated by complete PRRSV resistance in CD163-knockout and domain-deletion pigs [PMID:32876563, PMID:38544785, PMID:38184111]. ADAM17-mediated ectodomain shedding generates soluble CD163 that retains Hb-scavenging and TWEAK-neutralizing capacity, linking surface receptor density to both hemoglobin clearance and viral susceptibility [PMID:24965453, PMID:23589619]."},"prefetch_data":{"uniprot":{"accession":"Q86VB7","full_name":"Scavenger receptor cysteine-rich type 1 protein M130","aliases":["Hemoglobin scavenger receptor"],"length_aa":1156,"mass_kda":125.5,"function":"Acute phase-regulated receptor involved in clearance and endocytosis of hemoglobin/haptoglobin complexes by macrophages and may thereby protect tissues from free hemoglobin-mediated oxidative damage. 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Hp-complex formation critically enhances Hb uptake at low but not high ligand concentrations, supporting a biphasic model of macrophage Hb clearance.\",\n      \"method\": \"In vitro endocytosis assays in CD163+ HEK293 cells and human macrophages, competitive binding experiments, receptor-negative control cells, mRNA expression assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal in vitro assays including competition experiments and CD163-negative controls\",\n      \"pmids\": [\"16189277\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CD163-mediated endocytosis of haptoglobin-hemoglobin complexes leads to lysosomal Hp-Hb breakdown and heme oxygenase-catalyzed conversion of heme into anti-inflammatory metabolites (CO, biliverdin, iron), and CD163 directly induces intracellular signaling leading to secretion of anti-inflammatory cytokines.\",\n      \"method\": \"Cell biology assays, endocytosis experiments, cytokine secretion measurements\",\n      \"journal\": \"Annals of medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — replicated across multiple labs with functional readouts\",\n      \"pmids\": [\"15478309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CD163 functions as a macrophage pattern recognition receptor for both Gram-positive and Gram-negative bacteria; a previously identified cell-binding motif in the second scavenger domain (SRCR2) of CD163 mediates bacterial binding. Expression of CD163 in monocytic cells promotes bacteria-induced proinflammatory cytokine production, and antagonistic anti-CD163 antibodies potently inhibit cytokine production in freshly isolated human monocytes.\",\n      \"method\": \"Bacterial binding assays with CD163-expressing cells, antagonistic antibody experiments, cytokine production assays in primary human monocytes\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple methods including domain-specific binding, antibody blocking, and primary human cell experiments\",\n      \"pmids\": [\"18849484\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CD163 confers susceptibility to porcine reproductive and respiratory syndrome virus (PRRSV): direct functional screening identified CD163 as sufficient to render non-permissive cells PRRSV-permissive. Full-length CD163 with the C-terminal transmembrane anchor is required; splice variants lacking this domain do not provide PRRSV receptor function.\",\n      \"method\": \"cDNA expression library screening, transient transfection of non-permissive cell lines, stable cell line establishment, virus infectivity assays\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — functional screen with domain mutagenesis (splice variants), replicated in multiple cell types\",\n      \"pmids\": [\"17494075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Sialoadhesin and CD163 cooperate sequentially during PRRSV entry: sialoadhesin mediates virus internalization at the cell surface (active at 4°C), while CD163 acts downstream during virus uncoating after internalization (active at 37°C). Expression of sialoadhesin alone leads to PRRSV internalization without uncoating or productive infection; co-expression of both receptors restores productive infection and increases virus production 10–100-fold.\",\n      \"method\": \"Antibody blocking at 4°C vs. 37°C, confocal microscopy of PRRSV entry, non-permissive cells expressing sialoadhesin alone or together with CD163, virus production quantification\",\n      \"journal\": \"The Journal of general virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mechanistic dissection with temperature-dependent experiments, confocal imaging, and genetic reconstitution\",\n      \"pmids\": [\"19008379\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CD163 was identified as an antiinflammatory receptor for HMGB1-haptoglobin complexes. Haptoglobin binds HMGB1 and targets uptake through CD163; haptoglobin-HMGB1 complexes elicit production of heme oxygenase-1 and IL-10 in wild-type but not CD163-deficient macrophages. Genetic disruption of haptoglobin or CD163 significantly enhances mortality in mouse models of intra-abdominal sepsis.\",\n      \"method\": \"Co-immunoprecipitation/binding assays, CD163-deficient macrophages vs WT, genetic knockout mouse models, cytokine/enzyme production assays\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including KO macrophages, genetic mouse models, and functional cytokine readouts\",\n      \"pmids\": [\"27294203\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"CD163 expression is transcriptionally induced by M-CSF, IL-10, and dexamethasone, and suppressed by LPS, IFN-γ, and GM-CSF/IL-4. Dexamethasone induction is mediated by glucocorticoid receptor binding sites in the proximal promoter. Multiple isoforms arise from alternative splicing and differ in cytoplasmic or extracellular domains, potentially affecting function.\",\n      \"method\": \"In vitro monocyte culture with cytokines/drugs, mRNA expression analysis, promoter analysis, genomic organization mapping\",\n      \"journal\": \"Pathobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — single lab but multiple stimuli tested with both mRNA and protein readouts; promoter analysis by sequence\",\n      \"pmids\": [\"10725797\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CD163-expressing macrophages can bind and internalize TWEAK (TNF-like weak inducer of apoptosis) protein, identifying CD163 as a scavenger receptor for soluble TWEAK. This interaction is proposed to decrease TWEAK plasma concentration.\",\n      \"method\": \"In vitro binding and internalization assays of exogenous TWEAK in cultured human CD163-expressing macrophages\",\n      \"journal\": \"Atherosclerosis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, in vitro binding/internalization assay with limited mechanistic follow-up\",\n      \"pmids\": [\"19473660\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CXCL4 (platelet factor 4) downregulates CD163 expression in human macrophages through binding to cell-surface glycosaminoglycans; heparin neutralizes the CXCL4 effect, and chlorate (which inhibits glycosaminoglycan synthesis) blocks CXCL4-dependent CD163 downregulation. Loss of CD163 renders macrophages unable to upregulate heme oxygenase-1 in response to hemoglobin-haptoglobin complexes.\",\n      \"method\": \"Flow cytometry, mRNA expression, heparin neutralization, chlorate inhibition of glycosaminoglycan synthesis, functional HO-1 induction assay\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (neutralization, pathway inhibition, functional consequence) in single lab\",\n      \"pmids\": [\"19910578\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CD163 directly suppresses hemoglobin pseudoperoxidase activity via an autocrine loop: membrane CD163 is shed as sCD163 which sequesters free Hb; the sCD163-Hb complex is endocytosed via FcγR with IgG into monocytes and recycled, restoring membrane CD163 homeostasis. In a paracrine manner, monocyte-derived sCD163 and IgG shuttle residual Hb into endothelial cells for detoxification.\",\n      \"method\": \"In vitro Hb pseudoperoxidase activity assays, ex vivo coculture of monocytes and endothelial cells, endocytosis and recycling experiments, FcγR pathway studies\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — single lab with multiple functional assays including autocrine/paracrine mechanistic dissection\",\n      \"pmids\": [\"23589619\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CD163 mediates uptake of Mycobacterium leprae (ML) in human monocytes: CD163 blockade reduced ML uptake in human monocytes, and HEK293 cells transfected with CD163 cDNA showed higher ML uptake than untransfected cells. ML-induced CD163 upregulation was IL-10-dependent (IL-10 blockade reduced CD163 expression), and increased CD163 expression contributed to augmented iron storage in lepromatous macrophages.\",\n      \"method\": \"CD163 antibody blocking, HEK293 transfection with CD163 cDNA, ML uptake assays, IL-10 blockade experiments, iron storage measurement\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — receptor blocking + heterologous expression + IL-10 blockade linking pathway\",\n      \"pmids\": [\"22851198\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ADAM17 (metalloprotease) mediates ectodomain shedding of CD163 from the cell surface, negatively regulating PRRSV entry: inhibition of ADAM17 upregulates membrane CD163 and enhances PRRSV infection, whereas ADAM17 overexpression reduces surface CD163 and PRRSV infection. siRNA knockdown of ADAM17 increases CD163 expression with a corresponding increase in PRRSV infection.\",\n      \"method\": \"ADAM17 inhibitor experiments, ADAM17 overexpression and siRNA knockdown, surface CD163 quantification, PRRSV infection assays in Marc-145 and porcine alveolar macrophages\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple genetic manipulations (overexpression, siRNA, inhibitor) with consistent functional readouts\",\n      \"pmids\": [\"24965453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CD163 is required for protumoral macrophage activation: silencing CD163 abrogates macrophage-induced tumor cell proliferation in coculture. In CD163-deficient mice, sarcoma tumor development is significantly reduced. CD163-deficient macrophages show suppressed production of IL-6 and CXCL2; overexpression of CD163 in CD163-deficient macrophages rescues IL-6 and CXCL2 production. IL-6 (but not CXCL2) silencing abrogates macrophage-induced tumor cell proliferation.\",\n      \"method\": \"CD163 siRNA silencing in coculture, CD163-knockout mice, CD163 overexpression rescue, IL-6/CXCL2 silencing epistasis\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function (KO mouse + siRNA), gain-of-function rescue, and epistasis experiments with defined molecular mechanism\",\n      \"pmids\": [\"29610117\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CD163 interacts directly with casein kinase 2 (CK2) in glioma cells; CD163 silencing reduces AKT/GSK3β/β-catenin/cyclin D1 pathway activity via CK2, inhibiting cell cycle progression and proliferation of GBM cells. CD163 is upregulated in CD133+ glioma stem cells (GSCs) and its knockdown impairs GSC stemness via the CK2/AKT/GSK3β/β-catenin pathway.\",\n      \"method\": \"Co-immunoprecipitation demonstrating CD163-CK2 direct interaction, CD163 siRNA knockdown, pathway activity assays (AKT/GSK3β/β-catenin/cyclin D1), cell proliferation and stemness marker assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — direct Co-IP for CD163-CK2 interaction plus downstream pathway validation by KD\",\n      \"pmids\": [\"30258108\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Neurons express the CD163 receptor and internalize Hb and Hb-Hp complexes; haptoglobin increases vulnerability of CD163-expressing neurons to hemoglobin by directing Hb uptake to CD163+ neurons while attenuating the protective ferritin response in CD163-negative glia. Neuronal Hb toxicity via CD163 is iron-dependent.\",\n      \"method\": \"Primary cortical cell cultures, CD163 immunostaining on neurons, Hb/Hb-Hp uptake assays, deferoxamine/chelator experiments demonstrating iron-dependent mechanism\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — cell culture experiments with receptor-specific functional readouts and chelator controls\",\n      \"pmids\": [\"27364920\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CD163 deficiency in mice has temporally distinct effects after intracerebral hemorrhage: at 3 days, CD163-KO mice have less hematoma volume, less hemoglobin/iron accumulation, and less blood-brain barrier dysfunction; at 10 days, CD163-KO mice have larger lesions and increased iron/VEGF. This establishes that CD163 mediates hemoglobin scavenging in the brain with early detrimental (pro-inflammatory Hb retention is initially limited without the receptor driving early HO-1 conversion) and late anti-inflammatory/reparative roles.\",\n      \"method\": \"CD163 knockout mice, intracerebral hemorrhage model, hematoma volume measurement, hemoglobin/iron quantification, BBB integrity assays, HO-1 expression, neurobehavioral testing\",\n      \"journal\": \"Journal of cerebral blood flow and metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO model with multiple defined phenotypic and molecular readouts at two time points\",\n      \"pmids\": [\"28358264\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CD163 knockout pigs are completely resistant to genotype 2 PRRSV infection, directly establishing CD163 as an essential entry receptor for PRRSV in vivo. The absence of CD163 results in increased iron in muscle (consistent with loss of hemoglobin-haptoglobin scavenging function) but no impairment of meat production or reproductive performance.\",\n      \"method\": \"CRISPR/Cas9 double-knockout pigs, PRRSV challenge experiments, PCR and serology, iron measurement in muscle tissue\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo genetic KO with viral challenge, confirming receptor function and physiological role\",\n      \"pmids\": [\"32876563\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Glucocorticoids (cortisol and dexamethasone) specifically upregulate CD163 protein and mRNA in placental Hofbauer cells (fetal macrophages), and dexamethasone treatment increases hemoglobin uptake by Hofbauer cells, demonstrating that GC-induced CD163 upregulation is functionally active in enhancing Hb scavenging.\",\n      \"method\": \"Western blotting, flow cytometry, real-time PCR, hemoglobin uptake functional assay in primary Hofbauer cells, placental explant cultures\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple methods with functional readout (Hb uptake) in primary human cells\",\n      \"pmids\": [\"23142809\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CCR4 activation by recombinant CCL17 promotes hematoma resolution after intracerebral hemorrhage via the CCR4/ERK/Nrf2/CD163 signaling pathway; CRISPR knockout of CD163 abolishes the protective effects of rCCL17, placing CD163 downstream of CCR4/ERK/Nrf2 in this pathway.\",\n      \"method\": \"Mouse ICH model, recombinant CCL17 treatment, selective CCR4/Nrf2 inhibitors, CD163 CRISPR knockout (intracerebroventricular), western blot, immunofluorescence, neurobehavior\",\n      \"journal\": \"Neurotherapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis via CRISPR KO with pharmacological pathway inhibitors\",\n      \"pmids\": [\"32783091\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CD163+ macrophages exposed to hemoglobin-haptoglobin complexes induce endothelial-to-mesenchymal transition (EndMT) in atherosclerotic plaques via NF-κB-mediated Snail transcription factor activation. In vitro, supernatants from Hb/Hp-exposed macrophages induce mesenchymal markers (transgelin, FSP-1) and reduce endothelial markers (VE-cadherin, CD31) in human aortic endothelial cells. CD163 deletion in ApoE-/- mice reduces EndMT and plaque progression.\",\n      \"method\": \"In vitro macrophage conditioned medium experiments on HAECs, western blot for EndMT markers, NF-κB/Snail pathway analysis, CD163-KO ApoE-/- mouse model, human coronary artery pathological analysis, single-cell RNA sequencing\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vitro mechanistic experiments combined with genetic KO mouse model and human tissue validation\",\n      \"pmids\": [\"38860377\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CD163 deficiency in ApoE-/- mice increases foam cell formation through upregulation of CD36 expression in M2-type macrophages, leading to more unstable atherosclerotic plaques with increased lipid, macrophage content, and pro-inflammatory cytokines. Recombinant CD163 neutralizes proatherogenic TWEAK effects by abolishing NF-κB activation, cytokine/metalloproteinase expression, and macrophage migration in vascular smooth muscle cells.\",\n      \"method\": \"ApoE/CD163 double-deficient mice, foam cell formation assays, CD36 expression analysis, recombinant CD163 administration, NF-κB activation assays, TWEAK challenge\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO mouse model combined with in vitro mechanistic pathway studies and rescue with recombinant protein\",\n      \"pmids\": [\"32924185\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CD163+ macrophages engulfing hemoglobin:haptoglobin complexes (M(Hb) macrophages) inhibit vascular calcification through NF-κB-induced transcription of hyaluronan synthase (HAS) in vascular smooth muscle cells; knocking down HAS attenuates the anticalcific effect, and NF-κB blockade reduces hyaluronan and increases vascular calcification in ApoE-/- mice.\",\n      \"method\": \"In vitro VSMC culture with M(Hb) macrophage supernatant, NF-κB inhibitor experiments, HAS knockdown, ApoE-/- mouse model with NF-κB blockade, immunostaining of human arteries\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic pathway dissection with NF-κB inhibition, target gene KD, and in vivo mouse confirmation\",\n      \"pmids\": [\"36719758\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PRRSV glycoprotein 4 (GP4) directly interacts with the SRCR5 domain of CD163; small molecules physically binding to CD163-SRCR5 (Kd 28–39 μM) block PRRSV infection. Specific residues in SRCR5 (570SXDVGXV576) and Q797 in SRCR7 are conformational epitopes critical for PRRSV invasion, as CD163 with mutated epitopes expressed in 3D4 cells fails to support PRRSV infection while wild-type CD163 restores it.\",\n      \"method\": \"BiFC protein-protein interaction screening, direct binding assays (Kd measurement), site-directed mutagenesis of CD163 epitopes, PRRSV infection assays in mutant vs. WT CD163-expressing cells\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct binding Kd measurement, mutagenesis of specific residues, and functional reconstitution\",\n      \"pmids\": [\"37133376\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Deletion of CD163 exon 13 (encoding the PSTII domain) is sufficient to confer complete resistance to PRRSV-2 infection in pigs in vivo, without affecting CD163's physiological hemoglobin-scavenging function, establishing the PSTII domain as required for PRRSV uncoating/entry.\",\n      \"method\": \"Gene-edited pigs (exon 13 deletion), PRRSV-2 challenge experiment, PCR and serology, physiological assessment\",\n      \"journal\": \"Antiviral research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo genetic domain-deletion with viral challenge directly attributing function to specific domain\",\n      \"pmids\": [\"38184111\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Pigs with deletion of exon 7 of CD163 (removing the SRCR5 domain) are completely resistant to PRRSV infection across multiple breeding generations, with no detected differences in growth rate, health, meat composition, or reproductive performance, confirming the SRCR5 domain as essential for PRRSV receptor function.\",\n      \"method\": \"CRISPR-Cas9 gene editing, multi-generation breeding, PRRSV challenge, growth/meat/reproduction performance assessment\",\n      \"journal\": \"Frontiers in genome editing\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — heritable gene edit confirmed over multiple generations with viral challenge\",\n      \"pmids\": [\"38544785\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CD163 is a macrophage-specific scavenger receptor (SRCR superfamily class B) that mediates endocytosis of haptoglobin-hemoglobin complexes (and free Hb at high concentrations) via receptor-dependent internalization leading to lysosomal degradation and heme oxygenase-1–driven heme catabolism; its ectodomain (especially the SRCR5 domain) serves as an essential viral uncoating receptor for PRRSV, it scavenges HMGB1-haptoglobin and TWEAK complexes, interacts with casein kinase 2 to regulate AKT/β-catenin signaling in tumor cells, drives NF-κB–mediated hyaluronan synthase expression in vascular smooth muscle cells, and promotes EndMT in atherosclerosis; ectodomain shedding by ADAM17 generates soluble CD163 that retains Hb-scavenging and TWEAK-neutralizing activity.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CD163 is a macrophage-restricted scavenger receptor of the SRCR superfamily that functions as a central mediator of hemoglobin clearance, innate immune sensing, and tissue homeostasis. It serves as the primary endocytic receptor for haptoglobin–hemoglobin (Hp–Hb) complexes and free hemoglobin on macrophages, directing ligand internalization to lysosomes where heme oxygenase-1 catalyzes heme degradation into the anti-inflammatory metabolites CO, biliverdin, and iron, while simultaneously triggering secretion of IL-10 and other anti-inflammatory cytokines [PMID:11854028, PMID:16189277, PMID:15478309]. Beyond hemoglobin scavenging, CD163 recognizes bacteria via its SRCR2 domain to promote proinflammatory cytokine production [PMID:18849484], scavenges HMGB1–haptoglobin complexes to limit sepsis-associated inflammation [PMID:27294203], neutralizes TWEAK to attenuate NF-κB–driven vascular inflammation [PMID:32924185], and drives protumoral macrophage activation through IL-6 production [PMID:29610117]. CD163 also functions as the essential uncoating receptor for porcine reproductive and respiratory syndrome virus (PRRSV) through its SRCR5 and PSTII domains, as demonstrated by complete PRRSV resistance in CD163-knockout and domain-deletion pigs [PMID:32876563, PMID:38544785, PMID:38184111]. ADAM17-mediated ectodomain shedding generates soluble CD163 that retains Hb-scavenging and TWEAK-neutralizing capacity, linking surface receptor density to both hemoglobin clearance and viral susceptibility [PMID:24965453, PMID:23589619].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Defining CD163 as a glucocorticoid- and cytokine-regulated macrophage surface molecule established the transcriptional framework for understanding its lineage-restricted expression and anti-inflammatory context.\",\n      \"evidence\": \"Monocyte culture with cytokines/dexamethasone, promoter analysis, mRNA/protein expression\",\n      \"pmids\": [\"10725797\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Promoter GR binding sites identified by sequence only, not validated by ChIP\", \"Functional significance of splice isoforms unclear\", \"No in vivo validation of transcriptional regulation\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Identification of CD163 as the endocytic receptor for haptoglobin–hemoglobin complexes resolved the long-standing question of how macrophages clear Hp–Hb from plasma during hemolysis, establishing the core physiological function of the receptor.\",\n      \"evidence\": \"Receptor-ligand binding assays and endocytosis experiments in macrophages, replicated across labs\",\n      \"pmids\": [\"11854028\", \"15478309\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of Hp–Hb binding to CD163 not determined\", \"Contribution of individual SRCR domains to Hp–Hb binding not mapped\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstrating that CD163-mediated Hp–Hb endocytosis leads to HO-1-catalyzed heme degradation into anti-inflammatory metabolites (CO, biliverdin) and triggers anti-inflammatory cytokine secretion established CD163 as an active immune-regulatory receptor, not merely a passive scavenger.\",\n      \"evidence\": \"Endocytosis experiments with HO-1 induction and cytokine secretion measurements\",\n      \"pmids\": [\"15478309\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling pathway from CD163 cytoplasmic tail to cytokine induction not defined\", \"Relative contribution of CO vs. biliverdin to anti-inflammatory output unknown\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Showing that CD163 binds and endocytoses free hemoglobin independently of haptoglobin at high concentrations, with competition at the same binding site, established a biphasic model of Hb clearance and extended receptor function beyond Hp-dependent scavenging.\",\n      \"evidence\": \"Competitive binding, endocytosis in CD163+ HEK293 and macrophages, CD163-negative controls, HO-1 mRNA readout\",\n      \"pmids\": [\"16189277\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Affinity constants for free Hb vs. Hp–Hb binding not precisely compared\", \"In vivo relevance of haptoglobin-independent Hb scavenging not tested\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Functional screening identified CD163 as sufficient to confer PRRSV permissivity to non-permissive cells, revealing an unexpected viral receptor function and requiring the transmembrane-anchored full-length form.\",\n      \"evidence\": \"cDNA library screen, transient/stable transfection of non-permissive cells, splice variant analysis\",\n      \"pmids\": [\"17494075\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Viral ligand on PRRSV not yet identified\", \"Mechanism of CD163-dependent uncoating unknown\", \"Role of specific SRCR domains not dissected\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Mechanistic dissection of PRRSV entry showed that sialoadhesin mediates initial virus internalization while CD163 acts downstream as an intracellular uncoating receptor, resolving CD163's specific step in the viral entry pathway. Separately, CD163 was shown to function as a bacterial pattern recognition receptor through its SRCR2 domain.\",\n      \"evidence\": \"Temperature-block experiments, confocal imaging, sialoadhesin ± CD163 co-expression; bacterial binding assays with antibody blocking in primary monocytes\",\n      \"pmids\": [\"19008379\", \"18849484\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural mechanism of CD163-mediated viral uncoating unknown\", \"Range of bacterial species recognized not fully characterized\", \"Whether bacterial and viral ligand sites overlap not tested\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identification of CD163 as a scavenger receptor for TWEAK expanded its ligand repertoire beyond hemoglobin to include a TNF superfamily cytokine, while demonstration that CXCL4 downregulates CD163 via glycosaminoglycans provided the first mechanism of negative regulation by platelet-derived factors.\",\n      \"evidence\": \"TWEAK binding/internalization assays in CD163+ macrophages; CXCL4 downregulation with heparin neutralization and chlorate inhibition, HO-1 functional readout\",\n      \"pmids\": [\"19473660\", \"19910578\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"TWEAK binding domain on CD163 not mapped\", \"CXCL4 finding from single lab without independent confirmation\", \"Physiological significance of TWEAK scavenging in vivo not established at this point\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"CD163 was shown to mediate Mycobacterium leprae uptake in monocytes through IL-10-dependent upregulation, and glucocorticoids were found to functionally upregulate CD163-dependent Hb scavenging in placental Hofbauer cells, extending CD163 function to pathogen entry and fetal-maternal hemoglobin homeostasis.\",\n      \"evidence\": \"Antibody blocking and HEK293 transfection for M. leprae uptake; western blot, flow cytometry, and Hb uptake assay in primary Hofbauer cells\",\n      \"pmids\": [\"22851198\", \"23142809\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"M. leprae ligand for CD163 not identified\", \"Whether CD163 mediates intracellular M. leprae survival unknown\", \"Hofbauer cell findings not confirmed in vivo\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Discovery that shed soluble CD163 sequesters free hemoglobin, suppresses its pseudoperoxidase activity, and is re-internalized via FcγR with IgG established an autocrine/paracrine recycling mechanism linking ectodomain shedding to active hemoglobin detoxification.\",\n      \"evidence\": \"Pseudoperoxidase assays, monocyte–endothelial coculture, endocytosis/recycling experiments, FcγR pathway studies\",\n      \"pmids\": [\"23589619\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"FcγR-dependent re-uptake mechanism not confirmed in vivo\", \"Stoichiometry and kinetics of sCD163–Hb complex formation unclear\", \"Single laboratory finding\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identifying ADAM17 as the metalloprotease responsible for CD163 ectodomain shedding, with direct demonstration that shedding regulates surface CD163 levels and PRRSV susceptibility, provided a molecular link between protease activity, receptor density, and viral infection.\",\n      \"evidence\": \"ADAM17 inhibitor, overexpression, and siRNA in Marc-145 cells and porcine alveolar macrophages with PRRSV infection readout\",\n      \"pmids\": [\"24965453\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"ADAM17 cleavage site on CD163 not mapped\", \"Whether other ADAM family members contribute to shedding not excluded\", \"Regulation of ADAM17-dependent shedding in physiological inflammation not studied\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"CD163 was established as an anti-inflammatory receptor for HMGB1–haptoglobin complexes through KO macrophage and genetic mouse studies showing that CD163 deficiency increases sepsis mortality, revealing a second damage-associated molecular pattern cleared by the Hp–CD163 axis. Separately, neuronal CD163 expression was shown to mediate iron-dependent Hb neurotoxicity.\",\n      \"evidence\": \"CD163-KO macrophages and mice in sepsis models; neuronal culture with Hb/Hp uptake and iron chelation\",\n      \"pmids\": [\"27294203\", \"27364920\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether HMGB1 and Hb compete for the same CD163 binding site unknown\", \"Neuronal CD163 expression not confirmed in vivo in human brain tissue\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"CD163-KO mice showed biphasic effects after intracerebral hemorrhage — early benefit from reduced iron/Hb accumulation but late worsening with larger lesions — establishing that CD163's hemoglobin scavenging function has temporally distinct pro- and anti-inflammatory consequences in the brain.\",\n      \"evidence\": \"CD163-KO mouse ICH model with serial hematoma, iron, BBB, HO-1, and neurobehavior measurements\",\n      \"pmids\": [\"28358264\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cellular source of CD163 in the brain (resident microglia vs. infiltrating macrophages) not resolved\", \"Whether temporal effects are dose-dependent or context-dependent unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"CD163 was shown to be required for protumoral macrophage activation through IL-6 production (via KO, silencing, and rescue), and separately found to interact with casein kinase 2 to activate AKT/β-catenin signaling in glioma cells, revealing tumor-intrinsic and macrophage-extrinsic oncogenic roles.\",\n      \"evidence\": \"CD163-KO mice with sarcoma model, siRNA/rescue in macrophage–tumor coculture, IL-6 epistasis; Co-IP for CD163–CK2, pathway knockdown in glioma cells\",\n      \"pmids\": [\"29610117\", \"30258108\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"CD163 ligand triggering macrophage IL-6 production not identified\", \"CD163–CK2 interaction based on single Co-IP without reciprocal validation\", \"Whether CD163 on tumor cells vs. macrophages drives glioma effects not fully resolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"CD163-knockout pigs were shown to be completely resistant to PRRSV-2, definitively establishing CD163 as an essential in vivo entry receptor. In parallel, CD163 was placed downstream of CCR4/ERK/Nrf2 in hematoma resolution, and soluble CD163 was shown to neutralize TWEAK-driven NF-κB activation and vascular inflammation in atherosclerosis.\",\n      \"evidence\": \"CRISPR KO pigs with PRRSV challenge; mouse ICH model with CD163 CRISPR KO and pathway inhibitors; ApoE/CD163 double-KO mice with recombinant CD163 rescue and TWEAK challenge\",\n      \"pmids\": [\"32876563\", \"32783091\", \"32924185\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CD163 KO pigs resist all PRRSV genotypes not yet tested\", \"Direct transcriptional regulation of CD163 by Nrf2 not confirmed by ChIP\", \"Whether TWEAK neutralization is the primary atheroprotective mechanism of sCD163 vs. Hb clearance unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Mapping PRRSV GP4 interaction to the SRCR5 domain and identifying critical residues (570–576 in SRCR5, Q797 in SRCR7) provided the first molecular-resolution understanding of how PRRSV engages CD163, enabling structure-based antiviral strategies. Separately, CD163-driven Hb/Hp-loaded macrophages were shown to inhibit vascular calcification through NF-κB-induced HAS expression in smooth muscle cells.\",\n      \"evidence\": \"BiFC, Kd measurement, site-directed mutagenesis with functional reconstitution; VSMC culture with macrophage supernatant, HAS knockdown, NF-κB inhibition in ApoE-/- mice\",\n      \"pmids\": [\"37133376\", \"36719758\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Crystal structure of SRCR5–GP4 complex not available\", \"Relative contribution of SRCR5 vs. PSTII domain to uncoating unknown\", \"Whether HAS induction is specific to M(Hb) macrophages or shared with other CD163 ligand-activated states unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Domain-specific deletions in pigs (exon 7/SRCR5 and exon 13/PSTII) independently conferred complete PRRSV resistance while preserving hemoglobin scavenging, resolving which domains are essential for viral uncoating versus physiological function. CD163+ macrophage-driven endothelial-to-mesenchymal transition via NF-κB/Snail was established as a mechanism of plaque progression.\",\n      \"evidence\": \"Gene-edited pigs with domain-specific deletions and PRRSV challenge; macrophage conditioned medium on HAECs, EndMT markers, CD163-KO ApoE-/- mice, scRNA-seq and human tissue\",\n      \"pmids\": [\"38184111\", \"38544785\", \"38860377\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SRCR5 deletion affects responses to non-PRRSV pathogens unknown\", \"Signaling pathway linking CD163 ligation to NF-κB/Snail activation in endothelial cells not fully dissected\", \"Long-term cardiovascular outcomes in CD163-KO models not reported\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The intracellular signaling pathway linking CD163 cytoplasmic domain engagement to downstream transcriptional responses (IL-6, IL-10, HO-1 induction) remains undefined, as does the structural basis of ligand discrimination among Hp–Hb, HMGB1, TWEAK, and bacteria.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No crystal or cryo-EM structure of CD163 with any ligand\", \"Cytoplasmic tail signaling adaptors not identified\", \"Whether CD163 functions as a monomer or oligomer during endocytosis unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [0, 1, 2, 6, 8]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [3, 4, 5]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [21, 22]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 3, 4, 12]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [10, 11, 21]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [3, 6, 13]},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [0, 1, 2, 9]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [14, 19, 21]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [4, 5, 17, 24, 25]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"HP\",\n      \"HBB\",\n      \"ADAM17\",\n      \"TNFSF12\",\n      \"CSNK2A1\",\n      \"HMGB1\",\n      \"SIGLEC1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}