{"gene":"CD163","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":2002,"finding":"CD163 functions as an endocytic receptor that binds haptoglobin-hemoglobin (Hp-Hb) complexes and mediates their internalization into macrophage lysosomes; free hemoglobin or free haptoglobin alone are not recognized, only the complex.","method":"Endocytosis assays, ligand binding studies in macrophages and transfected cells","journal":"The international journal of biochemistry & cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — finding replicated across multiple independent labs using direct receptor-ligand binding and uptake assays in primary macrophages and transfected cell lines","pmids":["11854028","15478309","16164022"],"is_preprint":false},{"year":2004,"finding":"CD163-mediated endocytosis of haptoglobin-hemoglobin complexes leads to lysosomal degradation of the ligand proteins and metabolism of heme by cytosolic heme oxygenase-1 (HO-1), producing anti-inflammatory heme metabolites (CO, biliverdin, iron).","method":"Cell-based uptake assays, heme oxygenase activity measurements, gene expression analysis in macrophages","journal":"Annals of medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — demonstrated across multiple labs using functional uptake assays combined with downstream enzyme activity measurements","pmids":["15478309","23781295"],"is_preprint":false},{"year":2005,"finding":"CD163 acts as a scavenger receptor for free (haptoglobin-independent) hemoglobin via a lower-affinity direct interaction, mediating receptor-dependent endocytosis into an endosomal compartment and inducing heme oxygenase mRNA in CD163+ cells but not CD163- cells; Hp-complex formation critically enhances Hb uptake at low but not high concentrations, supporting a biphasic model of macrophage Hb clearance.","method":"Endocytosis assays in primary human macrophages and CD163-transfected HEK293 cells, competition binding assays, HO-1 mRNA induction, uptake of chemically modified hemoglobins (αα-DBBF crosslinked Hb)","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro reconstitution with transfected cells, competition assays, mutagenesis-like chemical modification of ligand, replicated in multiple cell systems","pmids":["16189277"],"is_preprint":false},{"year":2007,"finding":"CD163 is a cellular receptor that confers susceptibility to porcine reproductive and respiratory syndrome virus (PRRSV); expression of full-length CD163 in non-permissive cells renders them permissive for productive PRRSV infection; CD163 splice variants lacking the C-terminal transmembrane anchor domain do not confer receptor function.","method":"cDNA library functional screen, transient transfection of CD163 from multiple species into non-permissive cell lines, stable cell line generation, viral infection and titration assays","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct functional reconstitution by cDNA expression, domain-deletion analysis, replicated across multiple species and cell lines","pmids":["17494075"],"is_preprint":false},{"year":2007,"finding":"TWEAK (TNF-like weak inducer of apoptosis) binds directly to CD163, competing with Hp-Hb complexes for the same receptor; monocytes (which are CD163+ and Fn14-negative) can sequester soluble TWEAK via CD163, preventing TWEAK-mediated tumor cell apoptosis, indicating that CD163 acts as a TWEAK scavenger or alternate receptor.","method":"Combinatorial peptide library screen, dose-dependent binding assays, anti-CD163 antibody blockade, competition assays with soluble CD163 and Fn14/TweakR, flow cytometry, immunofluorescence, CD163-transfected CHO cell binding assay","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal binding methods (peptide library, competition, transfection) in single lab; functional consequence (TWEAK sequestration) demonstrated","pmids":["17548657"],"is_preprint":false},{"year":2008,"finding":"In PRRSV entry into primary porcine macrophages, sialoadhesin mediates virus internalization while CD163 is required for a subsequent uncoating step; both receptors are needed for efficient productive infection, with co-expression increasing virus production 10–100-fold over CD163 alone.","method":"Antibody blocking at 4°C vs 37°C, confocal microscopy of viral uncoating in cells expressing sialoadhesin alone vs both receptors, stable co-expression cell lines, viral infection assays","journal":"The Journal of general virology","confidence":"High","confidence_rationale":"Tier 2 / Strong — mechanistic dissection using temperature-shift blocking, confocal imaging of uncoating, and genetic reconstitution distinguishing internalization from uncoating steps","pmids":["19008379"],"is_preprint":false},{"year":2012,"finding":"In mice, CD163 mediates plasma clearance of hemoglobin; CD163-knockout mice show slightly slower Hb clearance with a one-phase decay (vs two-phase in wild-type), indicating CD163-dependent and CD163-independent clearance pathways. Notably, mouse haptoglobin does not promote high-affinity binding of mouse Hb to CD163 (unlike the human system).","method":"In vivo plasma clearance studies with fluorescently labeled Hb in CD163-knockout vs wild-type mice, HPLC analysis of serum, in vitro binding assays with purified proteins, ligand uptake in CD163-transfected cells","journal":"Antioxidants & redox signaling","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — combined in vivo knockout model and in vitro reconstitution with purified proteins; multiple orthogonal methods","pmids":["22793784"],"is_preprint":false},{"year":2012,"finding":"Soluble CD163 (sCD163) arises from metalloprotease-mediated ectodomain shedding (TACE/ADAM17) near the cell membrane; inflammatory stimuli increase shedding, producing the plasma biomarker form.","method":"Biochemical cleavage analysis, ADAM17 inhibitor experiments, plasma measurements in endotoxin-challenged humans and septic patients","journal":"Scandinavian journal of clinical and laboratory investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanism inferred from inhibitor studies and enzyme identity established in separate works; single detailed mechanistic characterization cited across multiple reviews","pmids":["22060747","22900885"],"is_preprint":false},{"year":2013,"finding":"CD163 directly suppresses hemoglobin pseudoperoxidase activity via an autocrine mechanism involving shedding of CD163, sequestration of Hb by soluble CD163 (sCD163), and recycling of CD163 on monocytes; paracrinally, sCD163–Hb–IgG complexes are endocytosed into monocytes via FcγR, and monocyte-derived sCD163 and IgG shuttle residual Hb into proximal endothelial cells for further clearance.","method":"Ex vivo coculture experiments, flow cytometry, endocytosis assays, peroxidase activity assays, CD163 recycling experiments","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal functional assays in a single lab; autocrine and paracrine mechanisms distinguished experimentally","pmids":["23589619"],"is_preprint":false},{"year":2014,"finding":"ADAM17 metalloprotease regulates PRRSV infection by mediating ectodomain shedding of CD163 from the cell surface; inhibition of ADAM17 upregulates membrane CD163 and enhances PRRSV entry, while overexpression of ADAM17 downregulates CD163 and reduces infection, demonstrating that ADAM17-mediated shedding of CD163 limits PRRSV receptor availability.","method":"ADAM17 inhibitor treatment, ADAM17 overexpression, siRNA-mediated ADAM17 knockdown in Marc-145 and PAMs; CD163 expression measured by flow cytometry/western blot; PRRSV infection assays in CD163-transfected BHK-21 cells","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 / Strong — gain-of-function, loss-of-function (inhibitor + siRNA), and reconstitution experiments across multiple cell types with consistent results","pmids":["24965453"],"is_preprint":false},{"year":2016,"finding":"Haptoglobin binds HMGB1, and the haptoglobin-HMGB1 complex is taken up via CD163 on macrophages, triggering production of anti-inflammatory HO-1 and IL-10; this pathway is abrogated in CD163-deficient macrophages and in haptoglobin-deficient animals, which show enhanced mortality in sepsis models.","method":"Co-IP/binding assays between haptoglobin and HMGB1, functional assays in WT vs CD163-deficient and haptoglobin-deficient macrophages, mouse sepsis survival experiments with haptoglobin administration","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — ligand-receptor binding established biochemically, functional consequence tested in multiple genetic knockout models with in vivo survival endpoints","pmids":["27294203"],"is_preprint":false},{"year":2017,"finding":"In plasma, approximately 10% of 'soluble CD163' in healthy individuals is actually membrane-associated CD163 carried on extracellular vesicles (EV-CD163), not proteolytically shed ectodomain; endotoxin injection selectively increases shed ectodomain CD163, while septic patients show high levels of both forms, with EV-associated CD163 representing up to 60% of total plasma CD163 in severe sepsis.","method":"Vesicle precipitation from plasma, ELISA quantification of ectodomain vs EV-associated CD163, endotoxin challenge in human volunteers, septic patient plasma analysis","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — physical fractionation distinguishing two CD163 forms, validated in controlled endotoxin challenge and patient cohort","pmids":["28084321"],"is_preprint":false},{"year":2018,"finding":"CD163 is required for macrophage-mediated protumoral activation; CD163 directly interacts with casein kinase 2 (CK2), and CD163 silencing reduces AKT/GSK3β/β-catenin/cyclin D1 pathway activity in glioma cells via CK2, inhibiting glioma cell proliferation and stem cell marker expression.","method":"Co-immunoprecipitation of CD163 and CK2, CD163 siRNA knockdown, pathway analysis by western blot, CD133/ALDH1A1/NANOG/OCT4 marker expression, cell cycle analysis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP establishing direct interaction, functional knockdown with downstream pathway readout; single lab","pmids":["30258108"],"is_preprint":false},{"year":2018,"finding":"CD163 is required for protumoral activation of macrophages in sarcoma; CD163 deficiency in macrophages suppresses production of IL-6 and CXCL2, reducing tumor cell proliferation; 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-deficient mouse sarcoma models (MCA205, LM8), CD163 siRNA in human macrophages, CD163 overexpression rescue experiment, co-culture assays, cytokine measurements","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function (KO mice + siRNA), gain-of-function rescue, in vivo and in vitro experiments with specific cytokine pathway identified","pmids":["29610117"],"is_preprint":false},{"year":2020,"finding":"CD163 deficiency in pigs (CD163-knockout) confers complete resistance to genotype 2 PRRSV and TGEV infection in vivo, confirming that CD163 is an essential entry receptor for PRRSV; CD163-KO pigs showed increased muscle iron, consistent with the physiological role of CD163 in hemoglobin scavenging.","method":"CRISPR gene-editing to produce CD163/pAPN double-knockout pigs, viral challenge experiments in vivo, serological and PCR monitoring","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic knockout with viral challenge and physiological phenotyping in large animal model","pmids":["32876563"],"is_preprint":false},{"year":2020,"finding":"CD163 deficiency in mice strongly enhances collagen-induced arthritis (CIA), with several-fold higher arthritis scores, early onset, prolonged disease, and enhanced progression; CD163-deficient mice show a predominant Th2 response (vs Th1 in WT) in inflamed joints at late time points, demonstrating that CD163 exerts a strong anti-inflammatory function linked to T-cell polarization.","method":"CIA and CAIA models in CD163-deficient vs WT C57BL/6 mice, arthritis scoring, serum anti-collagen antibody isotyping, cytokine profiling, T-cell marker analysis","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo knockout model with quantitative disease scoring and immune profiling; two arthritis models used","pmids":["32710083"],"is_preprint":false},{"year":2020,"finding":"LPS downregulates CD163 expression on porcine alveolar macrophages via the TLR4-NF-κB pathway and activates ADAM17, promoting cleavage of membrane CD163; the resulting reduction in surface CD163 suppresses PRRSV replication.","method":"LPS treatment of PAMs and Marc-145 cells, NF-κB pathway analysis, ADAM17 activation measurement, CD163 expression by western blot/flow cytometry, PRRSV infection assays","journal":"Frontiers in microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pathway analysis with inhibitors and gene expression in a single lab; mechanistic chain from TLR4 activation to CD163 shedding to viral resistance demonstrated","pmids":["32269560"],"is_preprint":false},{"year":2023,"finding":"Recombinant CD163 protein inhibits LPS-induced transformation of M2 macrophages to M1 by disrupting the TWEAK-Fn14 interaction; CD163 knockdown enhances M1-like transformation with increased P38/ERK/JNK/NF-κB signaling, while recombinant CD163 suppresses these pathways; LPS reduces the CD163-TWEAK complex, increasing free TWEAK binding to Fn14.","method":"CD163 siRNA knockdown, recombinant CD163 protein treatment, LPS-induced M2-to-M1 transformation model, western blot for MAPK/NF-κB pathways, cytokine mRNA measurement, co-immunoprecipitation of CD163-TWEAK complex","journal":"Heliyon","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (KD, recombinant protein, Co-IP) in single lab establishing CD163-TWEAK-Fn14 axis mechanistically","pmids":["38148798"],"is_preprint":false},{"year":2024,"finding":"CD163+ macrophages exposed to hemoglobin/haptoglobin (HH) complexes release factors that activate NF-κB in vascular smooth muscle cells, which in turn induces hyaluronan synthase (HAS) transcription, inhibiting vascular calcification; CD163 deletion in ApoE−/− mice increases vascular calcification; blocking NF-κB attenuates the anti-calcific effect of CD163+ macrophage-conditioned medium.","method":"In vitro VSMC culture with CD163+ macrophage supernatant, NF-κB inhibition experiments, HAS knockdown in VSMCs, ApoE−/−/CD163−/− mouse model, immunostaining of human arteries, western blot","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vitro mechanistic pathway (HH → macrophage → NF-κB → HAS in VSMCs) confirmed by genetic KO in vivo and specific HAS knockdown","pmids":["36719758"],"is_preprint":false},{"year":2024,"finding":"CD163+ macrophages exposed to hemoglobin/haptoglobin induce endothelial-to-mesenchymal transition (EndMT) in aortic endothelial cells via NF-κB-mediated upregulation of the transcription factor Snail; CD163 deletion in athero-prone mice reduces EndMT and plaque progression.","method":"Human aortic endothelial cells cultured with HH-exposed macrophage supernatant, western blot for mesenchymal/endothelial markers, NF-κB/Snail pathway analysis, ApoE−/−/CD163−/− mouse model, microarray for apoptosis genes, single-cell RNA-seq from human carotid endarterectomy","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vitro mechanistic pathway confirmed with genetic KO in vivo, multiple orthogonal methods including transcriptomics and human tissue validation","pmids":["38860377"],"is_preprint":false},{"year":2023,"finding":"Small molecules that directly bind the SRCR5 domain of CD163 block the PRRSV GP4–CD163 and GP2a–CD163 protein-protein interactions and potently inhibit PRRSV infection; confirmed physical binding to CD163-SRCR5 with Kd values of 28–39 μM by biophysical assay.","method":"Bimolecular fluorescence complementation (BiFC) PPI screen, direct binding assay to purified CD163-SRCR5 protein (Kd measurement), antiviral assays in PAMs, structure-activity relationship analysis","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — direct binding to purified domain protein established; functional antiviral activity confirmed; single lab","pmids":["37133376"],"is_preprint":false},{"year":2024,"finding":"Deletion of exon 13 of CD163 (encoding the first 12 amino acids of the PSTII domain) in gene-edited pigs confers complete resistance to PRRSV-2 infection without affecting CD163's physiological function (hemoglobin scavenging) in vivo.","method":"CRISPR gene editing to delete exon 13 in pigs, in vivo PRRSV-2 challenge with co-housed WT controls, PCR and serological monitoring, assessment of iron homeostasis and production performance","journal":"Antiviral research","confidence":"High","confidence_rationale":"Tier 2 / Strong — precise domain-deletion in live animals with viral challenge and physiological phenotyping; mechanistically identifies PSTII domain as essential for PRRSV entry","pmids":["38184111"],"is_preprint":false},{"year":2020,"finding":"In vitro, alpha-synuclein activates macrophages and induces shedding of sCD163; sCD163 in turn enhances alpha-synuclein uptake by myeloid cells, suggesting a role for CD163 in alpha-synuclein clearance.","method":"In vitro macrophage stimulation with alpha-synuclein, measurement of sCD163 release, alpha-synuclein uptake assay in myeloid cells","journal":"Movement disorders","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single in vitro experiment, single lab, limited mechanistic detail in abstract","pmids":["33332647"],"is_preprint":false},{"year":1999,"finding":"CD163 gene expression is induced by M-CSF, IL-10, and dexamethasone (glucocorticoids), and suppressed by LPS, IFN-γ, and GM-CSF+IL-4 (dendritic differentiation); the proximal promoter contains glucocorticoid receptor binding sites as well as putative Sp1, C/EBPα, Ets-2, PU.1, and AP-1 sites; multiple isoforms result from alternative splicing and differ in cytoplasmic domain structure and putative phosphorylation sites.","method":"In vitro monocyte culture with cytokines/glucocorticoids, Northern blot/RT-PCR for CD163 mRNA, promoter sequence analysis and identification of transcription factor binding sites, genomic organization analysis","journal":"Pathobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple cytokine/hormone treatments with transcriptional readouts; promoter characterized; single lab","pmids":["10725797"],"is_preprint":false}],"current_model":"CD163 is a macrophage-restricted, SRCR superfamily scavenger receptor that functions as the primary endocytic receptor for haptoglobin-hemoglobin (and, at lower affinity, free hemoglobin) complexes, internalizing them into lysosomes for degradation and heme-oxygenase-1-mediated conversion of heme to anti-inflammatory metabolites; it additionally binds HMGB1-haptoglobin complexes to dampen inflammation, scavenges soluble TWEAK to modulate NF-κB/Fn14 signaling, serves as an essential uncoating receptor for PRRSV (via its SRCR5 and PSTII domains), interacts with casein kinase 2 to regulate AKT/β-catenin signaling in glioma cells, and drives EndMT and inhibits vascular calcification in atherosclerosis through NF-κB/Snail and NF-κB/HAS pathways respectively; the receptor is regulated transcriptionally by glucocorticoids/IL-10 and post-translationally by ADAM17-mediated ectodomain shedding and extracellular vesicle release."},"narrative":{"mechanistic_narrative":"CD163 is a macrophage scavenger receptor that mediates clearance and detoxification of hemoglobin: it binds haptoglobin-hemoglobin complexes — but not free haptoglobin or free hemoglobin alone — and internalizes them into lysosomes, where ligand degradation couples to heme oxygenase-1-mediated conversion of heme into anti-inflammatory metabolites (CO, biliverdin, iron) [PMID:11854028, PMID:15478309, PMID:16164022, PMID:23781295]. The receptor also captures free hemoglobin directly with lower affinity, and haptoglobin complex formation enhances uptake selectively at low hemoglobin concentrations, defining a biphasic clearance model confirmed in vivo where CD163-knockout mice show impaired plasma hemoglobin clearance [PMID:16189277, PMID:22793784]. Beyond erythrophagocytosis, CD163 functions broadly as an anti-inflammatory hub: it endocytoses haptoglobin-HMGB1 complexes to drive HO-1 and IL-10 production, and CD163 deficiency worsens sepsis and collagen-induced arthritis, the latter accompanied by skewed T-cell polarization [PMID:27294203, PMID:32710083]. CD163 binds soluble TWEAK in competition with Hp-Hb ligand, sequestering TWEAK away from its receptor Fn14 to restrain inflammatory MAPK/NF-κB signaling and M1 macrophage polarization [PMID:17548657, PMID:38148798]. In atherosclerosis, hemoglobin/haptoglobin-exposed CD163+ macrophages release factors that activate NF-κB in neighboring vascular cells, driving Snail-dependent endothelial-to-mesenchymal transition while inducing hyaluronan synthase to inhibit vascular calcification; CD163 deletion in athero-prone mice alters both processes [PMID:36719758, PMID:38860377]. In tumors CD163 supports protumoral macrophage function, interacting with casein kinase 2 to sustain AKT/β-catenin signaling in glioma and driving IL-6/CXCL2 production that promotes tumor cell proliferation [PMID:30258108, PMID:29610117]. CD163 is additionally the essential entry receptor for PRRSV, acting downstream of sialoadhesin at a viral uncoating step through its SRCR5 and PSTII domains; genetic deletion of CD163 or of PSTII-domain exon 13 confers complete resistance to PRRSV in pigs without disrupting hemoglobin scavenging [PMID:17494075, PMID:19008379, PMID:38184111]. The receptor is transcriptionally upregulated by glucocorticoids, IL-10, and M-CSF and suppressed by LPS and IFN-γ [PMID:10725797], and is post-translationally regulated by ADAM17-mediated ectodomain shedding that generates plasma soluble CD163 and limits surface receptor availability for both ligand binding and viral entry [PMID:22060747, PMID:22900885, PMID:24965453].","teleology":[{"year":2002,"claim":"Establishing CD163's ligand specificity answered what physiological cargo this macrophage receptor handles, defining it as a dedicated endocytic receptor for haptoglobin-hemoglobin complexes.","evidence":"Endocytosis and ligand-binding assays in macrophages and transfected cells","pmids":["11854028","15478309","16164022"],"confidence":"High","gaps":["Did not resolve which SRCR domains mediate Hp-Hb binding","Quantitative affinity and structural basis of complex recognition not defined"]},{"year":2004,"claim":"Linking CD163 endocytosis to lysosomal degradation and HO-1 metabolism showed how hemoglobin clearance translates into an anti-inflammatory metabolic output.","evidence":"Uptake assays with heme oxygenase activity and gene expression measurement in macrophages","pmids":["15478309","23781295"],"confidence":"High","gaps":["Intracellular trafficking and receptor recycling steps not detailed","Signaling coupling endocytosis to HO-1 induction unresolved"]},{"year":2005,"claim":"Demonstrating lower-affinity recognition of free hemoglobin established a biphasic clearance model in which haptoglobin matters mainly at low hemoglobin loads.","evidence":"Endocytosis and competition assays in primary macrophages and CD163-transfected HEK293 cells with chemically modified hemoglobins","pmids":["16189277"],"confidence":"High","gaps":["Structural determinants distinguishing free-Hb from Hp-Hb binding not mapped"]},{"year":2007,"claim":"Identifying CD163 as a PRRSV susceptibility receptor and a TWEAK ligand expanded its role beyond hemoglobin scavenging into viral entry and cytokine sequestration.","evidence":"cDNA functional screen with domain-deletion in non-permissive cells; combinatorial peptide library and competition binding for TWEAK","pmids":["17494075","17548657"],"confidence":"Medium","gaps":["TWEAK-CD163 finding from a single lab without in vivo confirmation","Mechanism by which CD163 confers PRRSV permissiveness not yet resolved at this stage"]},{"year":2008,"claim":"Dissecting PRRSV entry showed CD163 acts at a post-internalization uncoating step downstream of sialoadhesin, separating internalization from genome release.","evidence":"Temperature-shift antibody blocking, confocal imaging of uncoating, and genetic co-expression in cell lines","pmids":["19008379"],"confidence":"High","gaps":["Molecular interactions enabling uncoating not defined","Generalizability beyond porcine macrophage system unaddressed"]},{"year":2012,"claim":"In vivo knockout and shedding studies established CD163's physiological contribution to plasma hemoglobin clearance and identified ADAM17 as the source of soluble CD163.","evidence":"CD163-knockout mouse clearance studies with in vitro binding; ADAM17 inhibitor and plasma biomarker analysis","pmids":["22793784","22060747","22900885"],"confidence":"High","gaps":["Identity of the CD163-independent clearance pathway in mice unresolved","Species differences in haptoglobin-promoted binding not mechanistically explained"]},{"year":2013,"claim":"Characterizing autocrine and paracrine sCD163 activity revealed how shed receptor and recycling cooperate to suppress hemoglobin pseudoperoxidase activity and shuttle residual Hb between cell types.","evidence":"Ex vivo coculture, flow cytometry, endocytosis and peroxidase assays, recycling experiments","pmids":["23589619"],"confidence":"Medium","gaps":["Single-lab functional model awaits independent confirmation","In vivo relevance of the sCD163-Hb-IgG paracrine route not established"]},{"year":2016,"claim":"Discovery of the haptoglobin-HMGB1-CD163 axis defined a route by which CD163 dampens inflammation and improves sepsis survival via HO-1 and IL-10.","evidence":"HMGB1-haptoglobin binding assays with CD163-deficient and haptoglobin-deficient macrophages and mouse sepsis survival","pmids":["27294203"],"confidence":"High","gaps":["Whether HMGB1-Hp uses the same SRCR binding site as Hp-Hb not determined"]},{"year":2014,"claim":"Showing ADAM17 shedding controls surface CD163 levels connected receptor turnover to PRRSV receptor availability and infection efficiency.","evidence":"ADAM17 inhibition, overexpression, and siRNA knockdown with PRRSV infection assays in multiple cell types","pmids":["24965453"],"confidence":"High","gaps":["Physiological triggers of shedding during natural infection not defined"]},{"year":2017,"claim":"Distinguishing extracellular-vesicle-associated CD163 from proteolytically shed ectodomain refined interpretation of the plasma sCD163 biomarker.","evidence":"Plasma vesicle fractionation with ELISA in endotoxin challenge and septic cohorts","pmids":["28084321"],"confidence":"Medium","gaps":["Functional role of EV-associated CD163 unknown","Biogenesis of CD163+ vesicles not characterized"]},{"year":2018,"claim":"Identifying CD163-CK2 interaction and a cytokine output established a protumoral signaling role for CD163 in tumor-associated macrophages.","evidence":"Co-IP of CD163 with CK2, siRNA knockdown and overexpression rescue, pathway and cytokine readouts in glioma and sarcoma models","pmids":["30258108","29610117"],"confidence":"Medium","gaps":["Direct CD163-CK2 interaction shown by Co-IP in a single lab without structural mapping","How a scavenger receptor couples to intracellular CK2/AKT signaling mechanistically unclear"]},{"year":2020,"claim":"Genetic knockout in pigs proved CD163 is an essential, non-redundant PRRSV entry receptor while confirming its hemoglobin-scavenging role through an iron phenotype.","evidence":"CRISPR CD163-knockout pigs with in vivo viral challenge and physiological phenotyping","pmids":["32876563"],"confidence":"High","gaps":["Whether scavenging and viral-entry functions can be fully separated not resolved here"]},{"year":2020,"claim":"In vivo arthritis models defined a strong anti-inflammatory role for CD163 linked to T-cell polarization, while macrophage studies tied CD163 loss to TLR4-NF-κB-driven shedding.","evidence":"CD163-deficient mouse CIA/CAIA models with immune profiling; LPS treatment with NF-κB and ADAM17 analysis in macrophages; alpha-synuclein uptake assay","pmids":["32710083","32269560","33332647"],"confidence":"Medium","gaps":["Mechanism linking CD163 to Th1/Th2 balance not defined","Alpha-synuclein role rests on a single low-detail in vitro study"]},{"year":2023,"claim":"Mapping the CD163-TWEAK-Fn14 axis and defining the SRCR5 binding pocket clarified how CD163 restrains M1 polarization and how small molecules can block viral interactions.","evidence":"Recombinant CD163 and siRNA in M2-to-M1 model with Co-IP; BiFC PPI screen and direct binding to purified CD163-SRCR5 with antiviral assays","pmids":["38148798","37133376"],"confidence":"Medium","gaps":["TWEAK-Fn14 disruption model from a single lab","SRCR5 small-molecule binding affinities are weak (Kd 28-39 uM)"]},{"year":2024,"claim":"Atherosclerosis models established that CD163+ macrophages, responding to hemoglobin/haptoglobin, drive NF-κB-dependent EndMT via Snail and inhibit calcification via hyaluronan synthase, and exon-13 editing localized PRRSV entry to the PSTII domain.","evidence":"VSMC and endothelial cocultures with NF-κB inhibition and target knockdown, ApoE-/-/CD163-/- mice, human tissue and scRNA-seq; CRISPR exon-13 deletion pigs with viral challenge","pmids":["36719758","38860377","38184111"],"confidence":"High","gaps":["Identity of the macrophage-secreted factors activating vascular NF-κB not defined","How PSTII-domain residues mediate viral entry structurally unresolved"]},{"year":null,"claim":"How CD163's distinct ligand-binding domains coordinate hemoglobin clearance, TWEAK sequestration, and viral uncoating, and how a surface scavenger receptor transmits intracellular signals (CK2/AKT, NF-κB) remains the central open mechanistic question.","evidence":"No timeline discovery resolves the structural and signal-transduction basis of CD163's pleiotropic functions","pmids":[],"confidence":"Low","gaps":["No structural model assigns each function to defined SRCR domains","Mechanism linking ligand endocytosis to cytoplasmic signaling unknown","Cytoplasmic-domain isoforms and phosphorylation functionally uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[3,5,14,21]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[4,17]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[0,2]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3,7,9]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[2]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[7,11]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[10,15,17]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,14,21]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,1,2]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[12,18,19]}],"complexes":[],"partners":["HP","HBB","TNFSF12","HMGB1","CSNK2A1"],"other_free_text":[]}},"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. May play a role in the uptake and recycling of iron, via endocytosis of hemoglobin/haptoglobin and subsequent breakdown of heme. Binds hemoglobin/haptoglobin complexes in a calcium-dependent and pH-dependent manner. Exhibits a higher affinity for complexes of hemoglobin and multimeric haptoglobin of HP*1F phenotype than for complexes of hemoglobin and dimeric haptoglobin of HP*1S phenotype. Induces a cascade of intracellular signals that involves tyrosine kinase-dependent calcium mobilization, inositol triphosphate production and secretion of IL6 and CSF1. Isoform 3 exhibits the higher capacity for ligand endocytosis and the more pronounced surface expression when expressed in cells After shedding, the soluble form (sCD163) may play an anti-inflammatory role, and may be a valuable diagnostic parameter for monitoring macrophage activation in inflammatory conditions","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q86VB7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CD163","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CD163","total_profiled":1310},"omim":[{"mim_id":"618101","title":"MATRIX METALLOPROTEINASE 27; 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research","url":"https://pubmed.ncbi.nlm.nih.gov/31890299","citation_count":21,"is_preprint":false},{"pmid":"35675555","id":"PMC_35675555","title":"Insights from Transcriptomics: CD163+ Profibrotic Lung Macrophages in COVID-19.","date":"2022","source":"American journal of respiratory cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/35675555","citation_count":20,"is_preprint":false},{"pmid":"38184111","id":"PMC_38184111","title":"Genetically modified pigs lacking CD163 PSTII-domain-coding exon 13 are completely resistant to PRRSV infection.","date":"2024","source":"Antiviral research","url":"https://pubmed.ncbi.nlm.nih.gov/38184111","citation_count":20,"is_preprint":false},{"pmid":"32125018","id":"PMC_32125018","title":"CD163-positive macrophage infiltration predicts systemic involvement in sarcoidosis.","date":"2020","source":"Journal of cutaneous pathology","url":"https://pubmed.ncbi.nlm.nih.gov/32125018","citation_count":20,"is_preprint":false},{"pmid":"38148798","id":"PMC_38148798","title":"CD163 protein inhibits lipopolysaccharide-induced macrophage transformation from M2 to M1 involved in disruption of the TWEAK-Fn14 interaction.","date":"2023","source":"Heliyon","url":"https://pubmed.ncbi.nlm.nih.gov/38148798","citation_count":20,"is_preprint":false},{"pmid":"36740088","id":"PMC_36740088","title":"The clinical utility of CD163 in viral diseases.","date":"2023","source":"Clinica chimica acta; international journal of clinical chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/36740088","citation_count":19,"is_preprint":false},{"pmid":"36183584","id":"PMC_36183584","title":"CD163 and CD206 expression define distinct macrophage subsets involved in active ANCA-associated glomerulonephritis.","date":"2022","source":"Journal of autoimmunity","url":"https://pubmed.ncbi.nlm.nih.gov/36183584","citation_count":19,"is_preprint":false},{"pmid":"36146862","id":"PMC_36146862","title":"CD163-Expressing Porcine Macrophages Support NADC30-like and NADC34-like PRRSV Infections.","date":"2022","source":"Viruses","url":"https://pubmed.ncbi.nlm.nih.gov/36146862","citation_count":19,"is_preprint":false},{"pmid":"32953603","id":"PMC_32953603","title":"The expression and meaning of CD68, CD163, CD57, and IgG4 in granulomatous lobular mastitis.","date":"2020","source":"Gland surgery","url":"https://pubmed.ncbi.nlm.nih.gov/32953603","citation_count":19,"is_preprint":false},{"pmid":"33050150","id":"PMC_33050150","title":"CD163 Antibodies Inhibit PRRSV Infection via Receptor Blocking and Transcription Suppression.","date":"2020","source":"Vaccines","url":"https://pubmed.ncbi.nlm.nih.gov/33050150","citation_count":18,"is_preprint":false},{"pmid":"38544785","id":"PMC_38544785","title":"Pigs lacking the SRCR5 domain of CD163 protein demonstrate heritable resistance to the PRRS virus and no changes in animal performance from birth to maturity.","date":"2024","source":"Frontiers in genome editing","url":"https://pubmed.ncbi.nlm.nih.gov/38544785","citation_count":18,"is_preprint":false},{"pmid":"35911758","id":"PMC_35911758","title":"Urine Soluble CD163 Is a Promising Biomarker for the Diagnosis and Evaluation of Lupus Nephritis.","date":"2022","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/35911758","citation_count":18,"is_preprint":false},{"pmid":"39423600","id":"PMC_39423600","title":"Role of CD163 in PRRSV infection.","date":"2024","source":"Virology","url":"https://pubmed.ncbi.nlm.nih.gov/39423600","citation_count":17,"is_preprint":false},{"pmid":"35306602","id":"PMC_35306602","title":"TREM2 and CD163 Ameliorate Microglia-Mediated Inflammatory Environment in the Aging Brain.","date":"2022","source":"Journal of molecular neuroscience : MN","url":"https://pubmed.ncbi.nlm.nih.gov/35306602","citation_count":17,"is_preprint":false},{"pmid":"38548349","id":"PMC_38548349","title":"Development of a CD163-Targeted PET Radiotracer That Images Resident Macrophages in Atherosclerosis.","date":"2024","source":"Journal of nuclear medicine : official publication, Society of Nuclear Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38548349","citation_count":17,"is_preprint":false},{"pmid":"36187992","id":"PMC_36187992","title":"Recent advances in inhibition of porcine reproductive and respiratory syndrome virus through targeting CD163.","date":"2022","source":"Frontiers in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/36187992","citation_count":17,"is_preprint":false},{"pmid":"39693339","id":"PMC_39693339","title":"Imaging of tumor-associated macrophage dynamics during immunotherapy using a CD163-specific nanobody-based immunotracer.","date":"2024","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/39693339","citation_count":16,"is_preprint":false},{"pmid":"33251273","id":"PMC_33251273","title":"Development of a Monoclonal Antibody Against Porcine CD163 SRCR5 Domain Which Partially Blocks Infection of PRRSV.","date":"2020","source":"Frontiers in veterinary science","url":"https://pubmed.ncbi.nlm.nih.gov/33251273","citation_count":16,"is_preprint":false},{"pmid":"36966664","id":"PMC_36966664","title":"Hepatocellular carcinoma progression promoted by 5-lipoxygenase activity in CD163(+) tumor-associated macrophages.","date":"2023","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/36966664","citation_count":16,"is_preprint":false},{"pmid":"24291017","id":"PMC_24291017","title":"Phenotypic and functional heterogeneity of CD169⁺ and CD163⁺ macrophages from porcine lymph nodes and spleen.","date":"2013","source":"Developmental and comparative immunology","url":"https://pubmed.ncbi.nlm.nih.gov/24291017","citation_count":16,"is_preprint":false},{"pmid":"31152786","id":"PMC_31152786","title":"The significance of CD163-expressing macrophages in asthma.","date":"2019","source":"Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/31152786","citation_count":15,"is_preprint":false},{"pmid":"31855290","id":"PMC_31855290","title":"Circulating extracellular vesicle-associated CD163 and CD206 in multiple myeloma.","date":"2020","source":"European journal of haematology","url":"https://pubmed.ncbi.nlm.nih.gov/31855290","citation_count":15,"is_preprint":false},{"pmid":"34370345","id":"PMC_34370345","title":"Correlation between CD163 expression and resting pain in patients with hip osteoarthritis: Possible contribution of CD163+ monocytes/macrophages to pain pathogenesis.","date":"2021","source":"Journal of orthopaedic research : official publication of the Orthopaedic Research Society","url":"https://pubmed.ncbi.nlm.nih.gov/34370345","citation_count":15,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":51522,"output_tokens":6428,"usd":0.125493,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15393,"output_tokens":5256,"usd":0.104182,"stage2_stop_reason":"end_turn"},"total_usd":0.229675,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2002,\n      \"finding\": \"CD163 functions as an endocytic receptor that binds haptoglobin-hemoglobin (Hp-Hb) complexes and mediates their internalization into macrophage lysosomes; free hemoglobin or free haptoglobin alone are not recognized, only the complex.\",\n      \"method\": \"Endocytosis assays, ligand binding studies in macrophages and transfected cells\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — finding replicated across multiple independent labs using direct receptor-ligand binding and uptake assays in primary macrophages and transfected cell lines\",\n      \"pmids\": [\"11854028\", \"15478309\", \"16164022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CD163-mediated endocytosis of haptoglobin-hemoglobin complexes leads to lysosomal degradation of the ligand proteins and metabolism of heme by cytosolic heme oxygenase-1 (HO-1), producing anti-inflammatory heme metabolites (CO, biliverdin, iron).\",\n      \"method\": \"Cell-based uptake assays, heme oxygenase activity measurements, gene expression analysis in macrophages\",\n      \"journal\": \"Annals of medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — demonstrated across multiple labs using functional uptake assays combined with downstream enzyme activity measurements\",\n      \"pmids\": [\"15478309\", \"23781295\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"CD163 acts as a scavenger receptor for free (haptoglobin-independent) hemoglobin via a lower-affinity direct interaction, mediating receptor-dependent endocytosis into an endosomal compartment and inducing heme oxygenase mRNA in CD163+ cells but not CD163- cells; Hp-complex formation critically enhances Hb uptake at low but not high concentrations, supporting a biphasic model of macrophage Hb clearance.\",\n      \"method\": \"Endocytosis assays in primary human macrophages and CD163-transfected HEK293 cells, competition binding assays, HO-1 mRNA induction, uptake of chemically modified hemoglobins (αα-DBBF crosslinked Hb)\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro reconstitution with transfected cells, competition assays, mutagenesis-like chemical modification of ligand, replicated in multiple cell systems\",\n      \"pmids\": [\"16189277\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CD163 is a cellular receptor that confers susceptibility to porcine reproductive and respiratory syndrome virus (PRRSV); expression of full-length CD163 in non-permissive cells renders them permissive for productive PRRSV infection; CD163 splice variants lacking the C-terminal transmembrane anchor domain do not confer receptor function.\",\n      \"method\": \"cDNA library functional screen, transient transfection of CD163 from multiple species into non-permissive cell lines, stable cell line generation, viral infection and titration assays\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct functional reconstitution by cDNA expression, domain-deletion analysis, replicated across multiple species and cell lines\",\n      \"pmids\": [\"17494075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"TWEAK (TNF-like weak inducer of apoptosis) binds directly to CD163, competing with Hp-Hb complexes for the same receptor; monocytes (which are CD163+ and Fn14-negative) can sequester soluble TWEAK via CD163, preventing TWEAK-mediated tumor cell apoptosis, indicating that CD163 acts as a TWEAK scavenger or alternate receptor.\",\n      \"method\": \"Combinatorial peptide library screen, dose-dependent binding assays, anti-CD163 antibody blockade, competition assays with soluble CD163 and Fn14/TweakR, flow cytometry, immunofluorescence, CD163-transfected CHO cell binding assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal binding methods (peptide library, competition, transfection) in single lab; functional consequence (TWEAK sequestration) demonstrated\",\n      \"pmids\": [\"17548657\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"In PRRSV entry into primary porcine macrophages, sialoadhesin mediates virus internalization while CD163 is required for a subsequent uncoating step; both receptors are needed for efficient productive infection, with co-expression increasing virus production 10–100-fold over CD163 alone.\",\n      \"method\": \"Antibody blocking at 4°C vs 37°C, confocal microscopy of viral uncoating in cells expressing sialoadhesin alone vs both receptors, stable co-expression cell lines, viral infection assays\",\n      \"journal\": \"The Journal of general virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mechanistic dissection using temperature-shift blocking, confocal imaging of uncoating, and genetic reconstitution distinguishing internalization from uncoating steps\",\n      \"pmids\": [\"19008379\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In mice, CD163 mediates plasma clearance of hemoglobin; CD163-knockout mice show slightly slower Hb clearance with a one-phase decay (vs two-phase in wild-type), indicating CD163-dependent and CD163-independent clearance pathways. Notably, mouse haptoglobin does not promote high-affinity binding of mouse Hb to CD163 (unlike the human system).\",\n      \"method\": \"In vivo plasma clearance studies with fluorescently labeled Hb in CD163-knockout vs wild-type mice, HPLC analysis of serum, in vitro binding assays with purified proteins, ligand uptake in CD163-transfected cells\",\n      \"journal\": \"Antioxidants & redox signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — combined in vivo knockout model and in vitro reconstitution with purified proteins; multiple orthogonal methods\",\n      \"pmids\": [\"22793784\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Soluble CD163 (sCD163) arises from metalloprotease-mediated ectodomain shedding (TACE/ADAM17) near the cell membrane; inflammatory stimuli increase shedding, producing the plasma biomarker form.\",\n      \"method\": \"Biochemical cleavage analysis, ADAM17 inhibitor experiments, plasma measurements in endotoxin-challenged humans and septic patients\",\n      \"journal\": \"Scandinavian journal of clinical and laboratory investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanism inferred from inhibitor studies and enzyme identity established in separate works; single detailed mechanistic characterization cited across multiple reviews\",\n      \"pmids\": [\"22060747\", \"22900885\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CD163 directly suppresses hemoglobin pseudoperoxidase activity via an autocrine mechanism involving shedding of CD163, sequestration of Hb by soluble CD163 (sCD163), and recycling of CD163 on monocytes; paracrinally, sCD163–Hb–IgG complexes are endocytosed into monocytes via FcγR, and monocyte-derived sCD163 and IgG shuttle residual Hb into proximal endothelial cells for further clearance.\",\n      \"method\": \"Ex vivo coculture experiments, flow cytometry, endocytosis assays, peroxidase activity assays, CD163 recycling experiments\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal functional assays in a single lab; autocrine and paracrine mechanisms distinguished experimentally\",\n      \"pmids\": [\"23589619\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ADAM17 metalloprotease regulates PRRSV infection by mediating ectodomain shedding of CD163 from the cell surface; inhibition of ADAM17 upregulates membrane CD163 and enhances PRRSV entry, while overexpression of ADAM17 downregulates CD163 and reduces infection, demonstrating that ADAM17-mediated shedding of CD163 limits PRRSV receptor availability.\",\n      \"method\": \"ADAM17 inhibitor treatment, ADAM17 overexpression, siRNA-mediated ADAM17 knockdown in Marc-145 and PAMs; CD163 expression measured by flow cytometry/western blot; PRRSV infection assays in CD163-transfected BHK-21 cells\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — gain-of-function, loss-of-function (inhibitor + siRNA), and reconstitution experiments across multiple cell types with consistent results\",\n      \"pmids\": [\"24965453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Haptoglobin binds HMGB1, and the haptoglobin-HMGB1 complex is taken up via CD163 on macrophages, triggering production of anti-inflammatory HO-1 and IL-10; this pathway is abrogated in CD163-deficient macrophages and in haptoglobin-deficient animals, which show enhanced mortality in sepsis models.\",\n      \"method\": \"Co-IP/binding assays between haptoglobin and HMGB1, functional assays in WT vs CD163-deficient and haptoglobin-deficient macrophages, mouse sepsis survival experiments with haptoglobin administration\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — ligand-receptor binding established biochemically, functional consequence tested in multiple genetic knockout models with in vivo survival endpoints\",\n      \"pmids\": [\"27294203\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In plasma, approximately 10% of 'soluble CD163' in healthy individuals is actually membrane-associated CD163 carried on extracellular vesicles (EV-CD163), not proteolytically shed ectodomain; endotoxin injection selectively increases shed ectodomain CD163, while septic patients show high levels of both forms, with EV-associated CD163 representing up to 60% of total plasma CD163 in severe sepsis.\",\n      \"method\": \"Vesicle precipitation from plasma, ELISA quantification of ectodomain vs EV-associated CD163, endotoxin challenge in human volunteers, septic patient plasma analysis\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — physical fractionation distinguishing two CD163 forms, validated in controlled endotoxin challenge and patient cohort\",\n      \"pmids\": [\"28084321\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CD163 is required for macrophage-mediated protumoral activation; CD163 directly interacts with casein kinase 2 (CK2), and CD163 silencing reduces AKT/GSK3β/β-catenin/cyclin D1 pathway activity in glioma cells via CK2, inhibiting glioma cell proliferation and stem cell marker expression.\",\n      \"method\": \"Co-immunoprecipitation of CD163 and CK2, CD163 siRNA knockdown, pathway analysis by western blot, CD133/ALDH1A1/NANOG/OCT4 marker expression, cell cycle analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP establishing direct interaction, functional knockdown with downstream pathway readout; single lab\",\n      \"pmids\": [\"30258108\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CD163 is required for protumoral activation of macrophages in sarcoma; CD163 deficiency in macrophages suppresses production of IL-6 and CXCL2, reducing tumor cell proliferation; 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-deficient mouse sarcoma models (MCA205, LM8), CD163 siRNA in human macrophages, CD163 overexpression rescue experiment, co-culture assays, cytokine measurements\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function (KO mice + siRNA), gain-of-function rescue, in vivo and in vitro experiments with specific cytokine pathway identified\",\n      \"pmids\": [\"29610117\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CD163 deficiency in pigs (CD163-knockout) confers complete resistance to genotype 2 PRRSV and TGEV infection in vivo, confirming that CD163 is an essential entry receptor for PRRSV; CD163-KO pigs showed increased muscle iron, consistent with the physiological role of CD163 in hemoglobin scavenging.\",\n      \"method\": \"CRISPR gene-editing to produce CD163/pAPN double-knockout pigs, viral challenge experiments in vivo, serological and PCR monitoring\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic knockout with viral challenge and physiological phenotyping in large animal model\",\n      \"pmids\": [\"32876563\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CD163 deficiency in mice strongly enhances collagen-induced arthritis (CIA), with several-fold higher arthritis scores, early onset, prolonged disease, and enhanced progression; CD163-deficient mice show a predominant Th2 response (vs Th1 in WT) in inflamed joints at late time points, demonstrating that CD163 exerts a strong anti-inflammatory function linked to T-cell polarization.\",\n      \"method\": \"CIA and CAIA models in CD163-deficient vs WT C57BL/6 mice, arthritis scoring, serum anti-collagen antibody isotyping, cytokine profiling, T-cell marker analysis\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo knockout model with quantitative disease scoring and immune profiling; two arthritis models used\",\n      \"pmids\": [\"32710083\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"LPS downregulates CD163 expression on porcine alveolar macrophages via the TLR4-NF-κB pathway and activates ADAM17, promoting cleavage of membrane CD163; the resulting reduction in surface CD163 suppresses PRRSV replication.\",\n      \"method\": \"LPS treatment of PAMs and Marc-145 cells, NF-κB pathway analysis, ADAM17 activation measurement, CD163 expression by western blot/flow cytometry, PRRSV infection assays\",\n      \"journal\": \"Frontiers in microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pathway analysis with inhibitors and gene expression in a single lab; mechanistic chain from TLR4 activation to CD163 shedding to viral resistance demonstrated\",\n      \"pmids\": [\"32269560\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Recombinant CD163 protein inhibits LPS-induced transformation of M2 macrophages to M1 by disrupting the TWEAK-Fn14 interaction; CD163 knockdown enhances M1-like transformation with increased P38/ERK/JNK/NF-κB signaling, while recombinant CD163 suppresses these pathways; LPS reduces the CD163-TWEAK complex, increasing free TWEAK binding to Fn14.\",\n      \"method\": \"CD163 siRNA knockdown, recombinant CD163 protein treatment, LPS-induced M2-to-M1 transformation model, western blot for MAPK/NF-κB pathways, cytokine mRNA measurement, co-immunoprecipitation of CD163-TWEAK complex\",\n      \"journal\": \"Heliyon\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (KD, recombinant protein, Co-IP) in single lab establishing CD163-TWEAK-Fn14 axis mechanistically\",\n      \"pmids\": [\"38148798\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CD163+ macrophages exposed to hemoglobin/haptoglobin (HH) complexes release factors that activate NF-κB in vascular smooth muscle cells, which in turn induces hyaluronan synthase (HAS) transcription, inhibiting vascular calcification; CD163 deletion in ApoE−/− mice increases vascular calcification; blocking NF-κB attenuates the anti-calcific effect of CD163+ macrophage-conditioned medium.\",\n      \"method\": \"In vitro VSMC culture with CD163+ macrophage supernatant, NF-κB inhibition experiments, HAS knockdown in VSMCs, ApoE−/−/CD163−/− mouse model, immunostaining of human arteries, western blot\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vitro mechanistic pathway (HH → macrophage → NF-κB → HAS in VSMCs) confirmed by genetic KO in vivo and specific HAS knockdown\",\n      \"pmids\": [\"36719758\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CD163+ macrophages exposed to hemoglobin/haptoglobin induce endothelial-to-mesenchymal transition (EndMT) in aortic endothelial cells via NF-κB-mediated upregulation of the transcription factor Snail; CD163 deletion in athero-prone mice reduces EndMT and plaque progression.\",\n      \"method\": \"Human aortic endothelial cells cultured with HH-exposed macrophage supernatant, western blot for mesenchymal/endothelial markers, NF-κB/Snail pathway analysis, ApoE−/−/CD163−/− mouse model, microarray for apoptosis genes, single-cell RNA-seq from human carotid endarterectomy\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vitro mechanistic pathway confirmed with genetic KO in vivo, multiple orthogonal methods including transcriptomics and human tissue validation\",\n      \"pmids\": [\"38860377\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Small molecules that directly bind the SRCR5 domain of CD163 block the PRRSV GP4–CD163 and GP2a–CD163 protein-protein interactions and potently inhibit PRRSV infection; confirmed physical binding to CD163-SRCR5 with Kd values of 28–39 μM by biophysical assay.\",\n      \"method\": \"Bimolecular fluorescence complementation (BiFC) PPI screen, direct binding assay to purified CD163-SRCR5 protein (Kd measurement), antiviral assays in PAMs, structure-activity relationship analysis\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct binding to purified domain protein established; functional antiviral activity confirmed; single lab\",\n      \"pmids\": [\"37133376\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Deletion of exon 13 of CD163 (encoding the first 12 amino acids of the PSTII domain) in gene-edited pigs confers complete resistance to PRRSV-2 infection without affecting CD163's physiological function (hemoglobin scavenging) in vivo.\",\n      \"method\": \"CRISPR gene editing to delete exon 13 in pigs, in vivo PRRSV-2 challenge with co-housed WT controls, PCR and serological monitoring, assessment of iron homeostasis and production performance\",\n      \"journal\": \"Antiviral research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — precise domain-deletion in live animals with viral challenge and physiological phenotyping; mechanistically identifies PSTII domain as essential for PRRSV entry\",\n      \"pmids\": [\"38184111\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In vitro, alpha-synuclein activates macrophages and induces shedding of sCD163; sCD163 in turn enhances alpha-synuclein uptake by myeloid cells, suggesting a role for CD163 in alpha-synuclein clearance.\",\n      \"method\": \"In vitro macrophage stimulation with alpha-synuclein, measurement of sCD163 release, alpha-synuclein uptake assay in myeloid cells\",\n      \"journal\": \"Movement disorders\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single in vitro experiment, single lab, limited mechanistic detail in abstract\",\n      \"pmids\": [\"33332647\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"CD163 gene expression is induced by M-CSF, IL-10, and dexamethasone (glucocorticoids), and suppressed by LPS, IFN-γ, and GM-CSF+IL-4 (dendritic differentiation); the proximal promoter contains glucocorticoid receptor binding sites as well as putative Sp1, C/EBPα, Ets-2, PU.1, and AP-1 sites; multiple isoforms result from alternative splicing and differ in cytoplasmic domain structure and putative phosphorylation sites.\",\n      \"method\": \"In vitro monocyte culture with cytokines/glucocorticoids, Northern blot/RT-PCR for CD163 mRNA, promoter sequence analysis and identification of transcription factor binding sites, genomic organization analysis\",\n      \"journal\": \"Pathobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple cytokine/hormone treatments with transcriptional readouts; promoter characterized; single lab\",\n      \"pmids\": [\"10725797\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CD163 is a macrophage-restricted, SRCR superfamily scavenger receptor that functions as the primary endocytic receptor for haptoglobin-hemoglobin (and, at lower affinity, free hemoglobin) complexes, internalizing them into lysosomes for degradation and heme-oxygenase-1-mediated conversion of heme to anti-inflammatory metabolites; it additionally binds HMGB1-haptoglobin complexes to dampen inflammation, scavenges soluble TWEAK to modulate NF-κB/Fn14 signaling, serves as an essential uncoating receptor for PRRSV (via its SRCR5 and PSTII domains), interacts with casein kinase 2 to regulate AKT/β-catenin signaling in glioma cells, and drives EndMT and inhibits vascular calcification in atherosclerosis through NF-κB/Snail and NF-κB/HAS pathways respectively; the receptor is regulated transcriptionally by glucocorticoids/IL-10 and post-translationally by ADAM17-mediated ectodomain shedding and extracellular vesicle release.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CD163 is a macrophage scavenger receptor that mediates clearance and detoxification of hemoglobin: it binds haptoglobin-hemoglobin complexes — but not free haptoglobin or free hemoglobin alone — and internalizes them into lysosomes, where ligand degradation couples to heme oxygenase-1-mediated conversion of heme into anti-inflammatory metabolites (CO, biliverdin, iron) [#0, #1]. The receptor also captures free hemoglobin directly with lower affinity, and haptoglobin complex formation enhances uptake selectively at low hemoglobin concentrations, defining a biphasic clearance model confirmed in vivo where CD163-knockout mice show impaired plasma hemoglobin clearance [#2, #6]. Beyond erythrophagocytosis, CD163 functions broadly as an anti-inflammatory hub: it endocytoses haptoglobin-HMGB1 complexes to drive HO-1 and IL-10 production, and CD163 deficiency worsens sepsis and collagen-induced arthritis, the latter accompanied by skewed T-cell polarization [#10, #15]. CD163 binds soluble TWEAK in competition with Hp-Hb ligand, sequestering TWEAK away from its receptor Fn14 to restrain inflammatory MAPK/NF-\\u03baB signaling and M1 macrophage polarization [#4, #17]. In atherosclerosis, hemoglobin/haptoglobin-exposed CD163+ macrophages release factors that activate NF-\\u03baB in neighboring vascular cells, driving Snail-dependent endothelial-to-mesenchymal transition while inducing hyaluronan synthase to inhibit vascular calcification; CD163 deletion in athero-prone mice alters both processes [#18, #19]. In tumors CD163 supports protumoral macrophage function, interacting with casein kinase 2 to sustain AKT/\\u03b2-catenin signaling in glioma and driving IL-6/CXCL2 production that promotes tumor cell proliferation [#12, #13]. CD163 is additionally the essential entry receptor for PRRSV, acting downstream of sialoadhesin at a viral uncoating step through its SRCR5 and PSTII domains; genetic deletion of CD163 or of PSTII-domain exon 13 confers complete resistance to PRRSV in pigs without disrupting hemoglobin scavenging [#3, #5, #21]. The receptor is transcriptionally upregulated by glucocorticoids, IL-10, and M-CSF and suppressed by LPS and IFN-\\u03b3 [#23], and is post-translationally regulated by ADAM17-mediated ectodomain shedding that generates plasma soluble CD163 and limits surface receptor availability for both ligand binding and viral entry [#7, #9].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Establishing CD163's ligand specificity answered what physiological cargo this macrophage receptor handles, defining it as a dedicated endocytic receptor for haptoglobin-hemoglobin complexes.\",\n      \"evidence\": \"Endocytosis and ligand-binding assays in macrophages and transfected cells\",\n      \"pmids\": [\"11854028\", \"15478309\", \"16164022\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve which SRCR domains mediate Hp-Hb binding\", \"Quantitative affinity and structural basis of complex recognition not defined\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Linking CD163 endocytosis to lysosomal degradation and HO-1 metabolism showed how hemoglobin clearance translates into an anti-inflammatory metabolic output.\",\n      \"evidence\": \"Uptake assays with heme oxygenase activity and gene expression measurement in macrophages\",\n      \"pmids\": [\"15478309\", \"23781295\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Intracellular trafficking and receptor recycling steps not detailed\", \"Signaling coupling endocytosis to HO-1 induction unresolved\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Demonstrating lower-affinity recognition of free hemoglobin established a biphasic clearance model in which haptoglobin matters mainly at low hemoglobin loads.\",\n      \"evidence\": \"Endocytosis and competition assays in primary macrophages and CD163-transfected HEK293 cells with chemically modified hemoglobins\",\n      \"pmids\": [\"16189277\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural determinants distinguishing free-Hb from Hp-Hb binding not mapped\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identifying CD163 as a PRRSV susceptibility receptor and a TWEAK ligand expanded its role beyond hemoglobin scavenging into viral entry and cytokine sequestration.\",\n      \"evidence\": \"cDNA functional screen with domain-deletion in non-permissive cells; combinatorial peptide library and competition binding for TWEAK\",\n      \"pmids\": [\"17494075\", \"17548657\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"TWEAK-CD163 finding from a single lab without in vivo confirmation\", \"Mechanism by which CD163 confers PRRSV permissiveness not yet resolved at this stage\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Dissecting PRRSV entry showed CD163 acts at a post-internalization uncoating step downstream of sialoadhesin, separating internalization from genome release.\",\n      \"evidence\": \"Temperature-shift antibody blocking, confocal imaging of uncoating, and genetic co-expression in cell lines\",\n      \"pmids\": [\"19008379\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular interactions enabling uncoating not defined\", \"Generalizability beyond porcine macrophage system unaddressed\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"In vivo knockout and shedding studies established CD163's physiological contribution to plasma hemoglobin clearance and identified ADAM17 as the source of soluble CD163.\",\n      \"evidence\": \"CD163-knockout mouse clearance studies with in vitro binding; ADAM17 inhibitor and plasma biomarker analysis\",\n      \"pmids\": [\"22793784\", \"22060747\", \"22900885\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the CD163-independent clearance pathway in mice unresolved\", \"Species differences in haptoglobin-promoted binding not mechanistically explained\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Characterizing autocrine and paracrine sCD163 activity revealed how shed receptor and recycling cooperate to suppress hemoglobin pseudoperoxidase activity and shuttle residual Hb between cell types.\",\n      \"evidence\": \"Ex vivo coculture, flow cytometry, endocytosis and peroxidase assays, recycling experiments\",\n      \"pmids\": [\"23589619\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab functional model awaits independent confirmation\", \"In vivo relevance of the sCD163-Hb-IgG paracrine route not established\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Discovery of the haptoglobin-HMGB1-CD163 axis defined a route by which CD163 dampens inflammation and improves sepsis survival via HO-1 and IL-10.\",\n      \"evidence\": \"HMGB1-haptoglobin binding assays with CD163-deficient and haptoglobin-deficient macrophages and mouse sepsis survival\",\n      \"pmids\": [\"27294203\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether HMGB1-Hp uses the same SRCR binding site as Hp-Hb not determined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showing ADAM17 shedding controls surface CD163 levels connected receptor turnover to PRRSV receptor availability and infection efficiency.\",\n      \"evidence\": \"ADAM17 inhibition, overexpression, and siRNA knockdown with PRRSV infection assays in multiple cell types\",\n      \"pmids\": [\"24965453\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological triggers of shedding during natural infection not defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Distinguishing extracellular-vesicle-associated CD163 from proteolytically shed ectodomain refined interpretation of the plasma sCD163 biomarker.\",\n      \"evidence\": \"Plasma vesicle fractionation with ELISA in endotoxin challenge and septic cohorts\",\n      \"pmids\": [\"28084321\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional role of EV-associated CD163 unknown\", \"Biogenesis of CD163+ vesicles not characterized\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identifying CD163-CK2 interaction and a cytokine output established a protumoral signaling role for CD163 in tumor-associated macrophages.\",\n      \"evidence\": \"Co-IP of CD163 with CK2, siRNA knockdown and overexpression rescue, pathway and cytokine readouts in glioma and sarcoma models\",\n      \"pmids\": [\"30258108\", \"29610117\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct CD163-CK2 interaction shown by Co-IP in a single lab without structural mapping\", \"How a scavenger receptor couples to intracellular CK2/AKT signaling mechanistically unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Genetic knockout in pigs proved CD163 is an essential, non-redundant PRRSV entry receptor while confirming its hemoglobin-scavenging role through an iron phenotype.\",\n      \"evidence\": \"CRISPR CD163-knockout pigs with in vivo viral challenge and physiological phenotyping\",\n      \"pmids\": [\"32876563\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether scavenging and viral-entry functions can be fully separated not resolved here\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"In vivo arthritis models defined a strong anti-inflammatory role for CD163 linked to T-cell polarization, while macrophage studies tied CD163 loss to TLR4-NF-\\u03baB-driven shedding.\",\n      \"evidence\": \"CD163-deficient mouse CIA/CAIA models with immune profiling; LPS treatment with NF-\\u03baB and ADAM17 analysis in macrophages; alpha-synuclein uptake assay\",\n      \"pmids\": [\"32710083\", \"32269560\", \"33332647\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking CD163 to Th1/Th2 balance not defined\", \"Alpha-synuclein role rests on a single low-detail in vitro study\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Mapping the CD163-TWEAK-Fn14 axis and defining the SRCR5 binding pocket clarified how CD163 restrains M1 polarization and how small molecules can block viral interactions.\",\n      \"evidence\": \"Recombinant CD163 and siRNA in M2-to-M1 model with Co-IP; BiFC PPI screen and direct binding to purified CD163-SRCR5 with antiviral assays\",\n      \"pmids\": [\"38148798\", \"37133376\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"TWEAK-Fn14 disruption model from a single lab\", \"SRCR5 small-molecule binding affinities are weak (Kd 28-39 uM)\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Atherosclerosis models established that CD163+ macrophages, responding to hemoglobin/haptoglobin, drive NF-\\u03baB-dependent EndMT via Snail and inhibit calcification via hyaluronan synthase, and exon-13 editing localized PRRSV entry to the PSTII domain.\",\n      \"evidence\": \"VSMC and endothelial cocultures with NF-\\u03baB inhibition and target knockdown, ApoE-/-/CD163-/- mice, human tissue and scRNA-seq; CRISPR exon-13 deletion pigs with viral challenge\",\n      \"pmids\": [\"36719758\", \"38860377\", \"38184111\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the macrophage-secreted factors activating vascular NF-\\u03baB not defined\", \"How PSTII-domain residues mediate viral entry structurally unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CD163's distinct ligand-binding domains coordinate hemoglobin clearance, TWEAK sequestration, and viral uncoating, and how a surface scavenger receptor transmits intracellular signals (CK2/AKT, NF-\\u03baB) remains the central open mechanistic question.\",\n      \"evidence\": \"No timeline discovery resolves the structural and signal-transduction basis of CD163's pleiotropic functions\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model assigns each function to defined SRCR domains\", \"Mechanism linking ligand endocytosis to cytoplasmic signaling unknown\", \"Cytoplasmic-domain isoforms and phosphorylation functionally uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [3, 5, 14, 21]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [4, 17]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 7, 9]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [7, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [10, 15, 17]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 14, 21]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [12, 18, 19]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"HP\", \"HBB\", \"TNFSF12\", \"HMGB1\", \"CSNK2A1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}