{"gene":"MSR1","run_date":"2026-06-10T02:59:51","timeline":{"discoveries":[{"year":2011,"finding":"MSR1/CD204 directly interacts with the TRAF-C domain of TRAF6, inhibiting TRAF6 dimerization and K63-linked ubiquitination, thereby suppressing TLR4-induced NF-κB activation. This regulatory function is independent of MSR1's ligand-binding domain, uncoupling its signaling role from its endocytic function.","method":"Co-immunoprecipitation, domain mutagenesis, NF-κB reporter assays, LPS endotoxic shock model in MSR1-deficient mice","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct protein interaction demonstrated by Co-IP, mutagenesis of TRAF-C domain, and functional rescue; multiple orthogonal methods in single study","pmids":["21460221"],"is_preprint":false},{"year":2019,"finding":"MSR1 undergoes K63-linked polyubiquitylation in IL-4-activated (M2) macrophages, which recruits the TAK1/MKK7/JNK signalling complex to phagosomes. Triggering MSR1 in this context activates JNK, promoting a phenotypic switch from anti-inflammatory to pro-inflammatory state; this switch is abolished by MSR1 deletion or JNK inhibition.","method":"Phagosomal proteomics, ubiquitination assays, JNK phosphorylation assays, MSR1 knockout macrophages, JNK inhibitor experiments","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal methods (proteomics, ubiquitination, genetic KO, pharmacological inhibition), single lab","pmids":["31028084"],"is_preprint":false},{"year":2013,"finding":"MSR1 binds extracellular dsRNA via conserved basic residues in the carboxy-terminal collagen superfamily domain, mediates endocytosis and transport to the endosome where TLR3 is engaged, triggering interferon responses. RNAi knockdown of MSR1 blocks TLR3 sensing of HCV, while exogenous MSR1 restores signalling.","method":"RNAi knockdown, exogenous MSR1 expression, mutagenesis of collagen domain basic residues, dsRNA binding assays, HCV infection assays, TLR3 signalling readouts","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — reconstitution with exogenous expression, mutagenesis, RNAi KD, multiple functional readouts in single study","pmids":["23717201"],"is_preprint":false},{"year":2019,"finding":"SCARA1/MSR1 recognizes dead (but not live) cells specifically through its SRCR domain in a Ca2+-dependent manner. The binding target on dead cells is spectrin; the SRCR domain binds SPEC repeats of spectrin in the presence of Ca2+. Macrophages internalize dead cells and debris through this SCARA1–spectrin interaction.","method":"Crystal structure of SRCR domain at 1.8 Å, cell-based binding assays, mass spectrometry identification of spectrin, Ca2+-dependency assays, phagocytosis assays with dead erythrocytes","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure, MS-based partner identification, biochemical binding assays, and cell-based functional assays in single study","pmids":["31653705"],"is_preprint":false},{"year":2008,"finding":"SR-A/MSR1 associates with the receptor tyrosine kinase Mertk at the cell surface and is required for optimal Mertk phosphorylation during apoptotic cell uptake. Exposure to apoptotic cells induces a time-dependent increase in SR-A/Mertk association; blocking SR-A inhibits phosphorylation of both Mertk and PLCγ2, reducing apoptotic cell ingestion.","method":"Western blotting and co-immunoprecipitation in J774 macrophages and peritoneal macrophages from SR-A−/− mice, anti-SR-A blocking, phosphorylation assays","journal":"Journal of leukocyte biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and functional KO confirmation, but single lab","pmids":["18511575"],"is_preprint":false},{"year":2017,"finding":"MSR1 (and MARCO) mediates internalization of DAMPs (HMGB1, peroxiredoxins, S100A8/S100A9) in vitro and in ischemic brain in vivo. DAMP clearance in infiltrating myeloid cells 3 days after stroke requires MSR1, whose expression is upregulated by the transcription factor Mafb. Combined Msr1/Marco deficiency or Mafb deficiency impairs DAMP clearance, worsening inflammation and neuronal injury.","method":"In vitro DAMP internalization assays, murine ischemic stroke model, Msr1/Marco and Mafb conditional knockout mice, RAR agonist Am80 upregulation of Mafb/MSR1","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vitro and in vivo genetic loss-of-function, multiple DAMPs tested, transcription factor (Mafb) pathway established; replicated in follow-up studies","pmids":["28394332"],"is_preprint":false},{"year":2013,"finding":"Scara1/MSR1 is a receptor for soluble amyloid-β on myeloid cells. Scara1 deficiency in PS1-APP mice markedly accelerates Aβ accumulation and increases mortality; pharmacological upregulation of Scara1 on mononuclear phagocytes increases Aβ clearance.","method":"shRNA screening to identify Scara1 as soluble Aβ receptor, genetic cross of Scara1-null with PS1-APP mice, pharmacological Scara1 upregulation, Aβ clearance assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — shRNA screen, genetic KO cross, pharmacological gain-of-function, in vivo Aβ clearance measurements","pmids":["23799536"],"is_preprint":false},{"year":2013,"finding":"Collagen type I monomers signal through CD204/MSR1 to induce phospho-Akt expression in alveolar macrophages, promoting M2 profibrotic polarization (upregulation of CCL18, IL-1ra, CCL2). This effect is abrogated by neutralizing anti-CD204 antibody and by the PI3K inhibitor LY294002.","method":"Neutralizing anti-CD204 antibody treatment of alveolar macrophages, collagen stimulation assays, phospho-Akt ELISA, cytokine ELISA (CCL18, IL-1ra, CCL2), RT-PCR and flow cytometry for CD204","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — antibody blocking and PI3K inhibitor, multiple readouts, single lab","pmids":["24278429"],"is_preprint":false},{"year":2018,"finding":"SR-AI/MSR1 is a macrophage clearance receptor for von Willebrand factor (VWF). VWF binds SR-AI with half-maximum binding of ~14 nM in a calcium-dependent manner, requiring the A1 and D4 domains of VWF. SR-AI−/− mice show significantly reduced VWF clearance; VWF mutants with increased clearance (R1205H, S2179F) show enhanced binding to SR-AI.","method":"Purified protein binding assays, cell-binding experiments with SR-AI-deficient bone marrow–derived macrophages, hydrodynamic gene transfer in vivo, propeptide/antigen ratio measurements","journal":"Haematologica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro binding with domain-blocking antibodies, cell-based confirmation with KO macrophages, in vivo clearance assay; single lab","pmids":["29326120"],"is_preprint":false},{"year":2022,"finding":"Ferritin acts as a ligand for Msr1 on neutrophils, triggering NET formation and a cytokine storm. Ferritin exposure increases Msr1 surface expression on neutrophils; Msr1 ablation protects mice from ferritin-induced tissue damage and hyperinflammatory response. NET formation depends on PAD4, neutrophil elastase, and ROS downstream of Msr1.","method":"Ferritin administration in vivo, Msr1-knockout mice, neutrophil depletion, flow cytometry for Msr1 surface expression, NET formation assays (PAD4/NE/ROS dependence)","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO, pharmacological interventions, multiple mechanistic readouts, in vivo and in vitro evidence, replicated in human AOSD samples","pmids":["36357401"],"is_preprint":false},{"year":2011,"finding":"MSR1 suppresses Msr1 expression is downregulated by BCR-ABL in CML leukemia stem cells; Msr1 deletion accelerates CML development and increases LSC function by promoting cell cycle progression and inhibiting apoptosis. Msr1 affects CML development by regulating the PI3K-AKT pathway and β-Catenin.","method":"CML mouse model, Msr1 knockout, DNA microarray, cell cycle and apoptosis assays, PI3K-AKT/β-Catenin Western blotting","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO in CML mouse model, multiple pathway readouts, single lab","pmids":["21596859"],"is_preprint":false},{"year":2009,"finding":"MSR1/SRA/CD204 on dendritic cells negatively regulates TLR4-mediated CD8+ T cell activation; SRA-deficient DCs are more immunostimulatory upon TLR4 engagement. siRNA-mediated knockdown of SRA in DCs improves priming of antigen-specific CD8+ T cells, demonstrating that DCs are the major cellular locus of MSR1-mediated immune suppression.","method":"SRA-knockout mice, DC–T cell co-culture assays, siRNA knockdown by RNAi, TLR4 agonist stimulation, tumor growth inhibition assays","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO and RNAi knockdown with functional T cell readout; single lab","pmids":["19349620"],"is_preprint":false},{"year":2011,"finding":"SRA/CD204 suppresses antigen-specific CD4+ T cell activation by reducing the intrinsic immunostimulatory capacity of dendritic cells, independently of classical endocytosis. Molecular mechanism involves SRA/CD204 inhibiting STAT1, p38 MAPK, and NF-κB signalling in DCs stimulated with anti-CD40 and IFN-γ.","method":"SRA−/− mice immunized with OVA, DC–OT-II cell co-culture, STAT1/p38/NF-κB phosphorylation assays, IL-12p35 expression upon CD40 ligation","journal":"Journal of molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO, multiple signalling pathway readouts, single lab","pmids":["22083206"],"is_preprint":false},{"year":2011,"finding":"SRA/CD204 binds exogenous hsp110 and mediates its internalization by dendritic cells; however, SRA−/− DCs pulsed with hsp110-antigen chaperone complexes show profoundly increased T cell stimulation, implicating MSR1 as an immunosuppressive receptor that attenuates heat-shock-protein–based vaccine responses via NF-κB regulation.","method":"Binding/internalization assays with hsp110 in SRA−/− DCs, NF-κB activation assays, shRNA lentiviral silencing, in vivo melanoma tumor model","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding shown, genetic KO and shRNA, multiple readouts; single lab","pmids":["21832164"],"is_preprint":false},{"year":2007,"finding":"SR-AI/MSR1 and MARCO expressed on alveolar macrophages scavenge proinflammatory oxidized lipids (5β,6β-epoxycholesterol, PON-GPC) from lung lining fluid, limiting pulmonary inflammation after oxidant inhalation. SR-AI/II-deficient mice show enhanced acute lung inflammation after β-epoxide instillation; normal AMs showed greater in vitro uptake of β-epoxide than SR-AI-deficient AMs.","method":"SR-AI/II-knockout mice, MARCO-knockout mice, intratracheal instillation of oxidized lipids, in vitro lipid uptake assays, ozone exposure, BAL cell counts and cytokines","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with in vivo and in vitro functional assays; MARCO and SR-AI/II both tested","pmids":["17332894"],"is_preprint":false},{"year":2020,"finding":"MSR1 promotes phagocytosis of myelin debris and subsequent foamy macrophage formation after spinal cord injury. In the presence of myelin debris, MSR1 activates the NF-κB signalling pathway, leading to release of inflammatory mediators and neuronal apoptosis. MSR1-knockout mice show improved recovery from traumatic SCI.","method":"MSR1-knockout mice SCI model, in vitro macrophage myelin debris phagocytosis assays, NF-κB pathway Western blotting, immunofluorescence, qPCR","journal":"Journal of neuroinflammation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO in vivo and in vitro, NF-κB pathway mechanistic readouts; single lab","pmids":["32066456"],"is_preprint":false},{"year":2020,"finding":"Macrophage MSR1 activates the PI3K/AKT/GSK3β/β-catenin pathway in macrophage–BMSC co-culture to promote osteogenic differentiation of BMSCs. MSR1 also promotes M2-like macrophage polarization by enhancing mitochondrial oxidative phosphorylation through the target gene PGC1α downstream of this pathway. MSR1-knockout mice show delayed intramembranous ossification.","method":"MSR1-knockout mouse tibial defect model, macrophage–BMSC co-culture, Western blotting for PI3K/AKT/GSK3β/β-catenin, RNA sequencing, qPCR, immunofluorescence","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO in vivo and co-culture in vitro, pathway proteins confirmed; single lab","pmids":["31903103"],"is_preprint":false},{"year":2013,"finding":"SR-AI/MSR1 mediates opsonin-independent recognition of dextran-coated superparamagnetic iron oxide (SPIO) nanoparticles via its positively charged collagen-like domain. Recognition requires access to the iron oxide crystalline core; polymer coating sterically hinders binding. Computer modelling reveals complementarity between Fe-OH surface groups of magnetite and charged lysines in the collagen-like domain.","method":"Uptake assays in SR-AI-transfected cells and J774 macrophages, nanoparticles with varied coatings, computational docking/modelling of SR-AI collagen domain","journal":"ACS nano","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-based functional assays with receptor transfection, computational structural modelling; single lab","pmids":["23614696"],"is_preprint":false},{"year":2010,"finding":"SR-AI/MSR1 binds complement fragment iC3b (but not C3 or C3b) through its SRCR domain and mediates NF-κB activation and IL-8 production in response to iC3b-opsonized bacteria. SRCR domain mutagenesis abolishes binding to serum-sensitized E. coli and iC3b.","method":"SR-AI expression in HEK 293T cells, binding assays with purified iC3b/C3/C3b, anti-C3 antibody blocking, SRCR domain mutagenesis, NF-κB/IL-8 reporter assays","journal":"Protein & cell","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — mutagenesis of SRCR domain, direct binding assays with purified complement, functional signalling readout; single lab","pmids":["21203986"],"is_preprint":false},{"year":2013,"finding":"Macrophage MSR1 regulates the concentration of soluble autoantigen (glucose-6-phosphate isomerase) in serum. Msr1-deficient macrophages are inefficient at taking up glucose-6-phosphate isomerase, leading to elevated serum autoantigen levels and impaired autoreactive B cell activation, thereby reducing autoantibody-dependent arthritis.","method":"Msr1-knockout K/BxN TCR transgenic mice, bone marrow transplantation, autoantigen uptake assays by macrophages, serum autoantigen measurements","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO, bone marrow transplant rescue experiment, quantitative autoantigen clearance assay; single lab","pmids":["23794629"],"is_preprint":false},{"year":2022,"finding":"MSR1 mediates M2 macrophage polarization by regulating arginine and proline metabolism and activating the AMPK/mTOR pathway, thereby promoting gastric cancer progression. MSR1 knockdown inhibits M2 macrophage polarization and associated malignant behaviour of gastric cancer cells in vitro.","method":"MSR1 knockdown in macrophages, AMPK/mTOR pathway Western blotting, metabolomics (arginine/proline metabolism), scRNA-seq analysis, co-culture with gastric cancer cells","journal":"International immunopharmacology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, mechanistic pathway inferred from KD + metabolomics without full reconstitution","pmids":["36095948"],"is_preprint":false},{"year":2016,"finding":"N-glycosylation of SR-AI at dual N-glycosylation sites (N120Q-N143Q and N143Q-N184Q) is critical for oAβ internalization; cells expressing these SR-AI mutants show diminished oAβ uptake despite normal surface targeting. SRCR domain structural integrity (β-sheet, α-helix, disulfide bond) is required for N-glycosylation and surface targeting of SR-AI.","method":"Site-directed mutagenesis of N-glycosylation sites, cell surface expression assays, oAβ internalization assays in mutant-expressing cells","journal":"Journal of biomedical science","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — mutagenesis with functional internalization readout; single lab","pmids":["26892079"],"is_preprint":false},{"year":2005,"finding":"SR-AI/MSR1 ligation specifically inhibits LPS/IFN-γ-stimulated IL-12 production and macrophage activation, while MARCO ligation has the opposite effect (costimulates IL-12). SR-AI/II-deficient macrophages overproduce IL-12 in response to LPS; SR-AI mediates particle uptake in untreated and IL-4-treated macrophages but not CpG-ODN-pretreated cells.","method":"MARCO- and SR-AI/II-deficient mouse macrophages, mAb ligation experiments, cytokine ELISA (IL-12), phagocytosis assays, regulatory condition comparisons","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO macrophages with multiple conditions, cytokine and phagocytosis readouts; single lab","pmids":["16339540"],"is_preprint":false},{"year":2025,"finding":"MSR1 overexpression in microglial cells enhances phagocytic activity toward myelin; reciprocally, myelin treatment upregulates MSR1 protein levels in microglia. MSR1-positive microglia co-localise with MBP in cortical tissue of PDD patients, indicating a functional role in myelin debris clearance in neurodegenerative dementias.","method":"MSR1 overexpression in microglial cells (phagocytosis assay), myelin treatment upregulation of MSR1 (Western blot), immunohistochemistry co-localisation in human PDD cortex, snRNA-seq","journal":"Genome medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function overexpression assay with functional readout, human tissue validation, single lab","pmids":["40826098"],"is_preprint":false}],"current_model":"MSR1 (CD204/SCARA1/SR-AI) is a trimeric class A scavenger receptor on macrophages, dendritic cells, and microglia that binds diverse ligands—including modified lipoproteins, DAMPs (HMGB1, peroxiredoxins, ferritin), extracellular dsRNA, apoptotic cell marker spectrin, von Willebrand factor, complement iC3b, soluble amyloid-β, and myelin debris—and internalises them via its collagen-like and SRCR domains; it signals intracellularly through K63-polyubiquitylation-dependent recruitment of the TAK1/MKK7/JNK complex (promoting M1 polarisation in M2 macrophages), through direct inhibition of TRAF6 dimerisation and ubiquitination to suppress TLR4/NF-κB activation, through SRCR-domain-mediated engagement of complement iC3b to activate NF-κB, and through a Mertk co-receptor complex required for apoptotic cell clearance, while also acting as an endocytic conduit that transports extracellular dsRNA to endosomal TLR3 and regulates PI3K/AKT/β-catenin and AMPK/mTOR pathways relevant to macrophage polarisation and stem cell differentiation."},"narrative":{"mechanistic_narrative":"MSR1 (CD204/SCARA1/SR-AI) is a trimeric macrophage, dendritic cell, and microglial scavenger receptor that couples broad ligand recognition to phagocytic clearance and tunable intracellular signaling across innate immunity, tissue repair, and neurodegeneration [PMID:31653705, PMID:28394332, PMID:23799536]. Its two functional modules engage distinct ligand classes: the positively charged collagen-like domain binds extracellular dsRNA and anionic crystalline surfaces, transporting dsRNA to endosomal TLR3 to drive interferon responses [PMID:23717201, PMID:23614696], while the Ca2+-dependent SRCR domain recognizes the spectrin SPEC repeats exposed on dead cells and the complement fragment iC3b, the latter activating NF-κB and IL-8 production against opsonized bacteria [PMID:31653705, PMID:21203986]. Through these modules MSR1 acts as a clearance receptor for an array of damage- and disease-associated ligands—soluble amyloid-β, myelin debris, von Willebrand factor, soluble autoantigen (glucose-6-phosphate isomerase), oxidized lipids, and DAMPs including HMGB1, peroxiredoxins, and ferritin—and these uptake functions limit or, in specific contexts, exacerbate inflammation and tissue injury [PMID:28394332, PMID:23799536, PMID:29326120, PMID:17332894, PMID:32066456, PMID:23794629]. MSR1 also operates as a co-receptor, associating with Mertk at the cell surface to support Mertk phosphorylation and apoptotic cell ingestion [PMID:18511575]. Its signaling output is bidirectional and context-dependent: it directly binds the TRAF-C domain of TRAF6 to block TRAF6 dimerization and K63-linked ubiquitination, suppressing TLR4-driven NF-κB activation and IL-12 production and dampening dendritic-cell-mediated T cell priming [PMID:21460221, PMID:19349620, PMID:16339540], yet in IL-4-activated M2 macrophages MSR1 itself becomes K63-polyubiquitylated, recruiting the TAK1/MKK7/JNK complex to phagosomes to drive a switch toward a pro-inflammatory state [PMID:31028084]. MSR1 further engages PI3K/AKT/β-catenin and AMPK/mTOR axes to control macrophage polarization, osteogenic differentiation of co-cultured stromal cells, and leukemia stem cell behavior [PMID:24278429, PMID:21596859, PMID:31903103, PMID:36095948]. N-glycosylation at paired sites and SRCR-domain structural integrity are required for proper surface targeting and ligand internalization [PMID:26892079].","teleology":[{"year":2005,"claim":"Established that scavenger-receptor engagement is not merely uptake but actively modulates macrophage activation, with SR-AI specifically restraining IL-12 production in opposition to MARCO.","evidence":"SR-AI/II- and MARCO-deficient mouse macrophages with mAb ligation, IL-12 ELISA, and phagocytosis assays","pmids":["16339540"],"confidence":"Medium","gaps":["Molecular mechanism linking SR-AI ligation to IL-12 suppression not defined","No receptor domain mapping"]},{"year":2007,"claim":"Defined a tissue-protective scavenging role by showing MSR1 clears proinflammatory oxidized lipids from lung lining fluid to limit pulmonary inflammation.","evidence":"SR-AI/II- and MARCO-knockout mice with intratracheal oxidized lipid instillation and in vitro uptake assays","pmids":["17332894"],"confidence":"Medium","gaps":["Receptor domain responsible for oxidized lipid binding not mapped","Downstream signaling not addressed"]},{"year":2008,"claim":"Showed MSR1 functions as a co-receptor in efferocytosis, associating with Mertk to enable optimal Mertk phosphorylation during apoptotic cell uptake.","evidence":"Reciprocal Co-IP in J774 and peritoneal macrophages, SR-A blocking, and phosphorylation assays in SR-A-/- cells","pmids":["18511575"],"confidence":"Medium","gaps":["Structural basis of SR-A/Mertk association unknown","Single lab; reciprocal validation within one study"]},{"year":2009,"claim":"Localized MSR1's immunosuppressive activity to dendritic cells, where it negatively regulates TLR4-driven CD8+ T cell priming.","evidence":"SRA-knockout mice, DC–T cell co-culture, siRNA knockdown, and tumor growth assays","pmids":["19349620"],"confidence":"Medium","gaps":["Signaling mechanism in DCs not resolved here","Whether suppression requires endocytosis unclear"]},{"year":2011,"claim":"Identified the molecular basis of MSR1's anti-inflammatory signaling: a direct interaction with the TRAF-C domain of TRAF6 that blocks TRAF6 dimerization and K63-ubiquitination, uncoupling signaling from endocytosis.","evidence":"Co-IP, TRAF-C domain mutagenesis, NF-κB reporter assays, and LPS endotoxic shock in MSR1-deficient mice","pmids":["21460221"],"confidence":"High","gaps":["Stoichiometry of MSR1-TRAF6 interaction not defined","How ligand binding regulates this interaction unknown"]},{"year":2011,"claim":"Extended the DC immunosuppression mechanism to CD4+ T cells, showing SRA inhibits STAT1, p38, and NF-κB signaling, and that SRA binds and internalizes hsp110 yet attenuates heat-shock-protein-based vaccine responses.","evidence":"SRA-/- mice, DC–OT-II co-culture, phosphorylation assays, hsp110 binding/internalization, shRNA silencing, and melanoma tumor model","pmids":["22083206","21832164"],"confidence":"Medium","gaps":["Direct link between MSR1 and STAT1/p38 inhibition not mechanistically resolved","Relationship to TRAF6 inhibition not connected"]},{"year":2011,"claim":"Revealed a tumor-suppressive role in CML, where BCR-ABL downregulates Msr1 and Msr1 loss accelerates leukemia via PI3K-AKT and β-catenin.","evidence":"CML mouse model with Msr1 knockout, microarray, cell cycle/apoptosis assays, and pathway Western blotting","pmids":["21596859"],"confidence":"Medium","gaps":["Direct receptor input driving PI3K-AKT/β-catenin not identified","Ligand in the LSC context unknown"]},{"year":2013,"claim":"Demonstrated MSR1 as an endocytic conduit delivering extracellular dsRNA to endosomal TLR3, mapping binding to basic residues of the collagen-like domain.","evidence":"RNAi knockdown, exogenous MSR1 reconstitution, collagen-domain mutagenesis, dsRNA binding, and HCV/TLR3 signaling readouts","pmids":["23717201"],"confidence":"High","gaps":["How dsRNA is handed off to TLR3 in the endosome not defined","Trafficking machinery unidentified"]},{"year":2013,"claim":"Established MSR1 as a soluble amyloid-β receptor on myeloid cells controlling Aβ clearance in vivo.","evidence":"shRNA screen, Scara1-null × PS1-APP genetic cross, pharmacological upregulation, and Aβ clearance assays","pmids":["23799536"],"confidence":"High","gaps":["Receptor domain binding Aβ not mapped here","Signaling consequences of Aβ binding not addressed"]},{"year":2013,"claim":"Showed additional scavenging roles: clearance of soluble autoantigen GPI to limit autoimmune arthritis, profibrotic M2 polarization via collagen-I/PI3K-Akt signaling, and opsonin-independent uptake of iron oxide nanoparticles via the collagen-like domain.","evidence":"Msr1-/- K/BxN mice with BM transplant; anti-CD204 blocking and PI3K inhibitor in alveolar macrophages; nanoparticle uptake with computational docking","pmids":["23794629","24278429","23614696"],"confidence":"Medium","gaps":["Collagen-I receptor engagement vs collagen-like-domain binding not structurally distinguished","Signaling specificity across ligands unresolved"]},{"year":2016,"claim":"Defined post-translational and structural requirements, showing dual N-glycosylation and SRCR-domain integrity are needed for surface targeting and oAβ internalization.","evidence":"Site-directed mutagenesis of N-glycosylation sites and SRCR features, surface expression, and oAβ internalization assays","pmids":["26892079"],"confidence":"Medium","gaps":["How glycosylation affects ligand affinity vs trafficking not separated","Single lab"]},{"year":2017,"claim":"Connected MSR1 scavenging to neuroinflammation resolution, showing Mafb-driven MSR1 clears DAMPs after stroke to protect neurons.","evidence":"In vitro DAMP internalization, ischemic stroke model with Msr1/Marco and Mafb conditional knockouts, and RAR-agonist upregulation","pmids":["28394332"],"confidence":"High","gaps":["Whether DAMP uptake triggers signaling or pure clearance unclear","Individual DAMP binding sites not mapped"]},{"year":2018,"claim":"Identified MSR1 as a calcium-dependent macrophage clearance receptor for von Willebrand factor, with VWF mutants of increased clearance binding more tightly.","evidence":"Purified protein binding (~14 nM), SR-AI-/- BMDM cell binding, domain mapping, and in vivo VWF clearance","pmids":["29326120"],"confidence":"Medium","gaps":["Receptor domain binding VWF A1/D4 not pinpointed","Single lab"]},{"year":2019,"claim":"Resolved the structural basis of dead-cell recognition, showing the SRCR domain binds spectrin SPEC repeats in a Ca2+-dependent manner to mediate efferocytosis.","evidence":"1.8 Å SRCR crystal structure, MS identification of spectrin, Ca2+-dependency, and dead-erythrocyte phagocytosis assays","pmids":["31653705"],"confidence":"High","gaps":["How spectrin recognition integrates with the Mertk co-receptor complex unknown"]},{"year":2019,"claim":"Revealed a signaling switch mechanism: K63-polyubiquitylation of MSR1 itself in M2 macrophages recruits TAK1/MKK7/JNK to phagosomes, driving a pro-inflammatory phenotypic switch.","evidence":"Phagosomal proteomics, ubiquitination and JNK phosphorylation assays, MSR1 knockout macrophages, and JNK inhibition","pmids":["31028084"],"confidence":"High","gaps":["The ubiquitin ligase modifying MSR1 not identified","Trigger linking ligand engagement to MSR1 ubiquitylation unknown"]},{"year":2020,"claim":"Showed context-dependent roles in tissue injury and repair: myelin-debris uptake driving NF-κB-dependent neuronal damage after spinal cord injury, and PI3K/AKT/GSK3β/β-catenin signaling promoting osteogenesis and M2 polarization via PGC1α.","evidence":"MSR1-knockout mouse SCI and tibial-defect models, macrophage–BMSC co-culture, NF-κB and PI3K/AKT pathway Western blotting, and RNA-seq","pmids":["32066456","31903103"],"confidence":"Medium","gaps":["How the same receptor selects NF-κB vs PI3K/AKT outputs unresolved","Direct vs indirect coupling to PGC1α unknown"]},{"year":2022,"claim":"Extended ligand range and pathology, showing ferritin engages neutrophil Msr1 to drive NET formation and cytokine storm, and linking MSR1 metabolic rewiring (arginine/proline, AMPK/mTOR) to M2 polarization in gastric cancer.","evidence":"Ferritin administration with Msr1-knockout mice and NET assays (PAD4/NE/ROS); MSR1 knockdown with metabolomics, AMPK/mTOR Western blotting, and scRNA-seq","pmids":["36357401","36095948"],"confidence":"Medium","gaps":["Ferritin binding site on Msr1 not mapped","Gastric cancer metabolic pathway inferred from knockdown without reconstitution"]},{"year":2025,"claim":"Implicated MSR1 in myelin clearance in human neurodegenerative dementia, with overexpression enhancing microglial phagocytosis and MSR1+ microglia co-localizing with myelin in patient cortex.","evidence":"Microglial overexpression phagocytosis assay, myelin-induced MSR1 upregulation, human PDD cortex immunohistochemistry, and snRNA-seq","pmids":["40826098"],"confidence":"Medium","gaps":["Whether myelin clearance is protective or pathogenic in dementia unresolved","Receptor domain binding myelin not defined"]},{"year":null,"claim":"How a single receptor selects between opposing signaling outputs—TRAF6-mediated NF-κB suppression versus phagosomal JNK activation versus NF-κB and PI3K/AKT activation—depending on ligand, activation state, and post-translational modification remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model linking ligand identity to signaling outcome","Ligase and adaptors controlling MSR1 ubiquitylation unidentified","Structural basis for collagen-domain vs SRCR-domain ligand selection incompletely mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[3,5,6,8]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[2,4,18]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[14]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[2]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,22]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[4,8,21]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[1,2]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,5,11,18,22]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[2,3,6,8,14]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,7,16]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[3,4]}],"complexes":[],"partners":["TRAF6","MERTK","TLR3","MARCO"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P21757","full_name":"Macrophage scavenger receptor types I and II","aliases":["Macrophage acetylated LDL receptor I and II","Scavenger receptor class A member 1"],"length_aa":451,"mass_kda":49.8,"function":"Membrane glycoproteins implicated in the pathologic deposition of cholesterol in arterial walls during atherogenesis. Two types of receptor subunits exist. These receptors mediate the endocytosis of a diverse group of macromolecules, including modified low density lipoproteins (LDL) (PubMed:2251254). 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This regulatory function is independent of MSR1's ligand-binding domain, uncoupling its signaling role from its endocytic function.\",\n      \"method\": \"Co-immunoprecipitation, domain mutagenesis, NF-κB reporter assays, LPS endotoxic shock model in MSR1-deficient mice\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct protein interaction demonstrated by Co-IP, mutagenesis of TRAF-C domain, and functional rescue; multiple orthogonal methods in single study\",\n      \"pmids\": [\"21460221\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MSR1 undergoes K63-linked polyubiquitylation in IL-4-activated (M2) macrophages, which recruits the TAK1/MKK7/JNK signalling complex to phagosomes. Triggering MSR1 in this context activates JNK, promoting a phenotypic switch from anti-inflammatory to pro-inflammatory state; this switch is abolished by MSR1 deletion or JNK inhibition.\",\n      \"method\": \"Phagosomal proteomics, ubiquitination assays, JNK phosphorylation assays, MSR1 knockout macrophages, JNK inhibitor experiments\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal methods (proteomics, ubiquitination, genetic KO, pharmacological inhibition), single lab\",\n      \"pmids\": [\"31028084\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"MSR1 binds extracellular dsRNA via conserved basic residues in the carboxy-terminal collagen superfamily domain, mediates endocytosis and transport to the endosome where TLR3 is engaged, triggering interferon responses. RNAi knockdown of MSR1 blocks TLR3 sensing of HCV, while exogenous MSR1 restores signalling.\",\n      \"method\": \"RNAi knockdown, exogenous MSR1 expression, mutagenesis of collagen domain basic residues, dsRNA binding assays, HCV infection assays, TLR3 signalling readouts\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — reconstitution with exogenous expression, mutagenesis, RNAi KD, multiple functional readouts in single study\",\n      \"pmids\": [\"23717201\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SCARA1/MSR1 recognizes dead (but not live) cells specifically through its SRCR domain in a Ca2+-dependent manner. The binding target on dead cells is spectrin; the SRCR domain binds SPEC repeats of spectrin in the presence of Ca2+. Macrophages internalize dead cells and debris through this SCARA1–spectrin interaction.\",\n      \"method\": \"Crystal structure of SRCR domain at 1.8 Å, cell-based binding assays, mass spectrometry identification of spectrin, Ca2+-dependency assays, phagocytosis assays with dead erythrocytes\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure, MS-based partner identification, biochemical binding assays, and cell-based functional assays in single study\",\n      \"pmids\": [\"31653705\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"SR-A/MSR1 associates with the receptor tyrosine kinase Mertk at the cell surface and is required for optimal Mertk phosphorylation during apoptotic cell uptake. Exposure to apoptotic cells induces a time-dependent increase in SR-A/Mertk association; blocking SR-A inhibits phosphorylation of both Mertk and PLCγ2, reducing apoptotic cell ingestion.\",\n      \"method\": \"Western blotting and co-immunoprecipitation in J774 macrophages and peritoneal macrophages from SR-A−/− mice, anti-SR-A blocking, phosphorylation assays\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and functional KO confirmation, but single lab\",\n      \"pmids\": [\"18511575\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"MSR1 (and MARCO) mediates internalization of DAMPs (HMGB1, peroxiredoxins, S100A8/S100A9) in vitro and in ischemic brain in vivo. DAMP clearance in infiltrating myeloid cells 3 days after stroke requires MSR1, whose expression is upregulated by the transcription factor Mafb. Combined Msr1/Marco deficiency or Mafb deficiency impairs DAMP clearance, worsening inflammation and neuronal injury.\",\n      \"method\": \"In vitro DAMP internalization assays, murine ischemic stroke model, Msr1/Marco and Mafb conditional knockout mice, RAR agonist Am80 upregulation of Mafb/MSR1\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vitro and in vivo genetic loss-of-function, multiple DAMPs tested, transcription factor (Mafb) pathway established; replicated in follow-up studies\",\n      \"pmids\": [\"28394332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Scara1/MSR1 is a receptor for soluble amyloid-β on myeloid cells. Scara1 deficiency in PS1-APP mice markedly accelerates Aβ accumulation and increases mortality; pharmacological upregulation of Scara1 on mononuclear phagocytes increases Aβ clearance.\",\n      \"method\": \"shRNA screening to identify Scara1 as soluble Aβ receptor, genetic cross of Scara1-null with PS1-APP mice, pharmacological Scara1 upregulation, Aβ clearance assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — shRNA screen, genetic KO cross, pharmacological gain-of-function, in vivo Aβ clearance measurements\",\n      \"pmids\": [\"23799536\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Collagen type I monomers signal through CD204/MSR1 to induce phospho-Akt expression in alveolar macrophages, promoting M2 profibrotic polarization (upregulation of CCL18, IL-1ra, CCL2). This effect is abrogated by neutralizing anti-CD204 antibody and by the PI3K inhibitor LY294002.\",\n      \"method\": \"Neutralizing anti-CD204 antibody treatment of alveolar macrophages, collagen stimulation assays, phospho-Akt ELISA, cytokine ELISA (CCL18, IL-1ra, CCL2), RT-PCR and flow cytometry for CD204\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — antibody blocking and PI3K inhibitor, multiple readouts, single lab\",\n      \"pmids\": [\"24278429\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SR-AI/MSR1 is a macrophage clearance receptor for von Willebrand factor (VWF). VWF binds SR-AI with half-maximum binding of ~14 nM in a calcium-dependent manner, requiring the A1 and D4 domains of VWF. SR-AI−/− mice show significantly reduced VWF clearance; VWF mutants with increased clearance (R1205H, S2179F) show enhanced binding to SR-AI.\",\n      \"method\": \"Purified protein binding assays, cell-binding experiments with SR-AI-deficient bone marrow–derived macrophages, hydrodynamic gene transfer in vivo, propeptide/antigen ratio measurements\",\n      \"journal\": \"Haematologica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro binding with domain-blocking antibodies, cell-based confirmation with KO macrophages, in vivo clearance assay; single lab\",\n      \"pmids\": [\"29326120\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Ferritin acts as a ligand for Msr1 on neutrophils, triggering NET formation and a cytokine storm. Ferritin exposure increases Msr1 surface expression on neutrophils; Msr1 ablation protects mice from ferritin-induced tissue damage and hyperinflammatory response. NET formation depends on PAD4, neutrophil elastase, and ROS downstream of Msr1.\",\n      \"method\": \"Ferritin administration in vivo, Msr1-knockout mice, neutrophil depletion, flow cytometry for Msr1 surface expression, NET formation assays (PAD4/NE/ROS dependence)\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO, pharmacological interventions, multiple mechanistic readouts, in vivo and in vitro evidence, replicated in human AOSD samples\",\n      \"pmids\": [\"36357401\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"MSR1 suppresses Msr1 expression is downregulated by BCR-ABL in CML leukemia stem cells; Msr1 deletion accelerates CML development and increases LSC function by promoting cell cycle progression and inhibiting apoptosis. Msr1 affects CML development by regulating the PI3K-AKT pathway and β-Catenin.\",\n      \"method\": \"CML mouse model, Msr1 knockout, DNA microarray, cell cycle and apoptosis assays, PI3K-AKT/β-Catenin Western blotting\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO in CML mouse model, multiple pathway readouts, single lab\",\n      \"pmids\": [\"21596859\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"MSR1/SRA/CD204 on dendritic cells negatively regulates TLR4-mediated CD8+ T cell activation; SRA-deficient DCs are more immunostimulatory upon TLR4 engagement. siRNA-mediated knockdown of SRA in DCs improves priming of antigen-specific CD8+ T cells, demonstrating that DCs are the major cellular locus of MSR1-mediated immune suppression.\",\n      \"method\": \"SRA-knockout mice, DC–T cell co-culture assays, siRNA knockdown by RNAi, TLR4 agonist stimulation, tumor growth inhibition assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO and RNAi knockdown with functional T cell readout; single lab\",\n      \"pmids\": [\"19349620\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"SRA/CD204 suppresses antigen-specific CD4+ T cell activation by reducing the intrinsic immunostimulatory capacity of dendritic cells, independently of classical endocytosis. Molecular mechanism involves SRA/CD204 inhibiting STAT1, p38 MAPK, and NF-κB signalling in DCs stimulated with anti-CD40 and IFN-γ.\",\n      \"method\": \"SRA−/− mice immunized with OVA, DC–OT-II cell co-culture, STAT1/p38/NF-κB phosphorylation assays, IL-12p35 expression upon CD40 ligation\",\n      \"journal\": \"Journal of molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO, multiple signalling pathway readouts, single lab\",\n      \"pmids\": [\"22083206\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"SRA/CD204 binds exogenous hsp110 and mediates its internalization by dendritic cells; however, SRA−/− DCs pulsed with hsp110-antigen chaperone complexes show profoundly increased T cell stimulation, implicating MSR1 as an immunosuppressive receptor that attenuates heat-shock-protein–based vaccine responses via NF-κB regulation.\",\n      \"method\": \"Binding/internalization assays with hsp110 in SRA−/− DCs, NF-κB activation assays, shRNA lentiviral silencing, in vivo melanoma tumor model\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding shown, genetic KO and shRNA, multiple readouts; single lab\",\n      \"pmids\": [\"21832164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"SR-AI/MSR1 and MARCO expressed on alveolar macrophages scavenge proinflammatory oxidized lipids (5β,6β-epoxycholesterol, PON-GPC) from lung lining fluid, limiting pulmonary inflammation after oxidant inhalation. SR-AI/II-deficient mice show enhanced acute lung inflammation after β-epoxide instillation; normal AMs showed greater in vitro uptake of β-epoxide than SR-AI-deficient AMs.\",\n      \"method\": \"SR-AI/II-knockout mice, MARCO-knockout mice, intratracheal instillation of oxidized lipids, in vitro lipid uptake assays, ozone exposure, BAL cell counts and cytokines\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with in vivo and in vitro functional assays; MARCO and SR-AI/II both tested\",\n      \"pmids\": [\"17332894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"MSR1 promotes phagocytosis of myelin debris and subsequent foamy macrophage formation after spinal cord injury. In the presence of myelin debris, MSR1 activates the NF-κB signalling pathway, leading to release of inflammatory mediators and neuronal apoptosis. MSR1-knockout mice show improved recovery from traumatic SCI.\",\n      \"method\": \"MSR1-knockout mice SCI model, in vitro macrophage myelin debris phagocytosis assays, NF-κB pathway Western blotting, immunofluorescence, qPCR\",\n      \"journal\": \"Journal of neuroinflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO in vivo and in vitro, NF-κB pathway mechanistic readouts; single lab\",\n      \"pmids\": [\"32066456\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Macrophage MSR1 activates the PI3K/AKT/GSK3β/β-catenin pathway in macrophage–BMSC co-culture to promote osteogenic differentiation of BMSCs. MSR1 also promotes M2-like macrophage polarization by enhancing mitochondrial oxidative phosphorylation through the target gene PGC1α downstream of this pathway. MSR1-knockout mice show delayed intramembranous ossification.\",\n      \"method\": \"MSR1-knockout mouse tibial defect model, macrophage–BMSC co-culture, Western blotting for PI3K/AKT/GSK3β/β-catenin, RNA sequencing, qPCR, immunofluorescence\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO in vivo and co-culture in vitro, pathway proteins confirmed; single lab\",\n      \"pmids\": [\"31903103\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SR-AI/MSR1 mediates opsonin-independent recognition of dextran-coated superparamagnetic iron oxide (SPIO) nanoparticles via its positively charged collagen-like domain. Recognition requires access to the iron oxide crystalline core; polymer coating sterically hinders binding. Computer modelling reveals complementarity between Fe-OH surface groups of magnetite and charged lysines in the collagen-like domain.\",\n      \"method\": \"Uptake assays in SR-AI-transfected cells and J774 macrophages, nanoparticles with varied coatings, computational docking/modelling of SR-AI collagen domain\",\n      \"journal\": \"ACS nano\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-based functional assays with receptor transfection, computational structural modelling; single lab\",\n      \"pmids\": [\"23614696\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SR-AI/MSR1 binds complement fragment iC3b (but not C3 or C3b) through its SRCR domain and mediates NF-κB activation and IL-8 production in response to iC3b-opsonized bacteria. SRCR domain mutagenesis abolishes binding to serum-sensitized E. coli and iC3b.\",\n      \"method\": \"SR-AI expression in HEK 293T cells, binding assays with purified iC3b/C3/C3b, anti-C3 antibody blocking, SRCR domain mutagenesis, NF-κB/IL-8 reporter assays\",\n      \"journal\": \"Protein & cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — mutagenesis of SRCR domain, direct binding assays with purified complement, functional signalling readout; single lab\",\n      \"pmids\": [\"21203986\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Macrophage MSR1 regulates the concentration of soluble autoantigen (glucose-6-phosphate isomerase) in serum. Msr1-deficient macrophages are inefficient at taking up glucose-6-phosphate isomerase, leading to elevated serum autoantigen levels and impaired autoreactive B cell activation, thereby reducing autoantibody-dependent arthritis.\",\n      \"method\": \"Msr1-knockout K/BxN TCR transgenic mice, bone marrow transplantation, autoantigen uptake assays by macrophages, serum autoantigen measurements\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO, bone marrow transplant rescue experiment, quantitative autoantigen clearance assay; single lab\",\n      \"pmids\": [\"23794629\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"MSR1 mediates M2 macrophage polarization by regulating arginine and proline metabolism and activating the AMPK/mTOR pathway, thereby promoting gastric cancer progression. MSR1 knockdown inhibits M2 macrophage polarization and associated malignant behaviour of gastric cancer cells in vitro.\",\n      \"method\": \"MSR1 knockdown in macrophages, AMPK/mTOR pathway Western blotting, metabolomics (arginine/proline metabolism), scRNA-seq analysis, co-culture with gastric cancer cells\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, mechanistic pathway inferred from KD + metabolomics without full reconstitution\",\n      \"pmids\": [\"36095948\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"N-glycosylation of SR-AI at dual N-glycosylation sites (N120Q-N143Q and N143Q-N184Q) is critical for oAβ internalization; cells expressing these SR-AI mutants show diminished oAβ uptake despite normal surface targeting. SRCR domain structural integrity (β-sheet, α-helix, disulfide bond) is required for N-glycosylation and surface targeting of SR-AI.\",\n      \"method\": \"Site-directed mutagenesis of N-glycosylation sites, cell surface expression assays, oAβ internalization assays in mutant-expressing cells\",\n      \"journal\": \"Journal of biomedical science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis with functional internalization readout; single lab\",\n      \"pmids\": [\"26892079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"SR-AI/MSR1 ligation specifically inhibits LPS/IFN-γ-stimulated IL-12 production and macrophage activation, while MARCO ligation has the opposite effect (costimulates IL-12). SR-AI/II-deficient macrophages overproduce IL-12 in response to LPS; SR-AI mediates particle uptake in untreated and IL-4-treated macrophages but not CpG-ODN-pretreated cells.\",\n      \"method\": \"MARCO- and SR-AI/II-deficient mouse macrophages, mAb ligation experiments, cytokine ELISA (IL-12), phagocytosis assays, regulatory condition comparisons\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO macrophages with multiple conditions, cytokine and phagocytosis readouts; single lab\",\n      \"pmids\": [\"16339540\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MSR1 overexpression in microglial cells enhances phagocytic activity toward myelin; reciprocally, myelin treatment upregulates MSR1 protein levels in microglia. MSR1-positive microglia co-localise with MBP in cortical tissue of PDD patients, indicating a functional role in myelin debris clearance in neurodegenerative dementias.\",\n      \"method\": \"MSR1 overexpression in microglial cells (phagocytosis assay), myelin treatment upregulation of MSR1 (Western blot), immunohistochemistry co-localisation in human PDD cortex, snRNA-seq\",\n      \"journal\": \"Genome medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function overexpression assay with functional readout, human tissue validation, single lab\",\n      \"pmids\": [\"40826098\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MSR1 (CD204/SCARA1/SR-AI) is a trimeric class A scavenger receptor on macrophages, dendritic cells, and microglia that binds diverse ligands—including modified lipoproteins, DAMPs (HMGB1, peroxiredoxins, ferritin), extracellular dsRNA, apoptotic cell marker spectrin, von Willebrand factor, complement iC3b, soluble amyloid-β, and myelin debris—and internalises them via its collagen-like and SRCR domains; it signals intracellularly through K63-polyubiquitylation-dependent recruitment of the TAK1/MKK7/JNK complex (promoting M1 polarisation in M2 macrophages), through direct inhibition of TRAF6 dimerisation and ubiquitination to suppress TLR4/NF-κB activation, through SRCR-domain-mediated engagement of complement iC3b to activate NF-κB, and through a Mertk co-receptor complex required for apoptotic cell clearance, while also acting as an endocytic conduit that transports extracellular dsRNA to endosomal TLR3 and regulates PI3K/AKT/β-catenin and AMPK/mTOR pathways relevant to macrophage polarisation and stem cell differentiation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MSR1 (CD204/SCARA1/SR-AI) is a trimeric macrophage, dendritic cell, and microglial scavenger receptor that couples broad ligand recognition to phagocytic clearance and tunable intracellular signaling across innate immunity, tissue repair, and neurodegeneration [#3, #5, #6]. Its two functional modules engage distinct ligand classes: the positively charged collagen-like domain binds extracellular dsRNA and anionic crystalline surfaces, transporting dsRNA to endosomal TLR3 to drive interferon responses [#2, #17], while the Ca2+-dependent SRCR domain recognizes the spectrin SPEC repeats exposed on dead cells and the complement fragment iC3b, the latter activating NF-\\u03baB and IL-8 production against opsonized bacteria [#3, #18]. Through these modules MSR1 acts as a clearance receptor for an array of damage- and disease-associated ligands\\u2014soluble amyloid-\\u03b2, myelin debris, von Willebrand factor, soluble autoantigen (glucose-6-phosphate isomerase), oxidized lipids, and DAMPs including HMGB1, peroxiredoxins, and ferritin\\u2014and these uptake functions limit or, in specific contexts, exacerbate inflammation and tissue injury [#5, #6, #8, #14, #15, #19]. MSR1 also operates as a co-receptor, associating with Mertk at the cell surface to support Mertk phosphorylation and apoptotic cell ingestion [#4]. Its signaling output is bidirectional and context-dependent: it directly binds the TRAF-C domain of TRAF6 to block TRAF6 dimerization and K63-linked ubiquitination, suppressing TLR4-driven NF-\\u03baB activation and IL-12 production and dampening dendritic-cell-mediated T cell priming [#0, #11, #22], yet in IL-4-activated M2 macrophages MSR1 itself becomes K63-polyubiquitylated, recruiting the TAK1/MKK7/JNK complex to phagosomes to drive a switch toward a pro-inflammatory state [#1]. MSR1 further engages PI3K/AKT/\\u03b2-catenin and AMPK/mTOR axes to control macrophage polarization, osteogenic differentiation of co-cultured stromal cells, and leukemia stem cell behavior [#7, #10, #16, #20]. N-glycosylation at paired sites and SRCR-domain structural integrity are required for proper surface targeting and ligand internalization [#21].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Established that scavenger-receptor engagement is not merely uptake but actively modulates macrophage activation, with SR-AI specifically restraining IL-12 production in opposition to MARCO.\",\n      \"evidence\": \"SR-AI/II- and MARCO-deficient mouse macrophages with mAb ligation, IL-12 ELISA, and phagocytosis assays\",\n      \"pmids\": [\"16339540\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism linking SR-AI ligation to IL-12 suppression not defined\", \"No receptor domain mapping\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defined a tissue-protective scavenging role by showing MSR1 clears proinflammatory oxidized lipids from lung lining fluid to limit pulmonary inflammation.\",\n      \"evidence\": \"SR-AI/II- and MARCO-knockout mice with intratracheal oxidized lipid instillation and in vitro uptake assays\",\n      \"pmids\": [\"17332894\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor domain responsible for oxidized lipid binding not mapped\", \"Downstream signaling not addressed\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showed MSR1 functions as a co-receptor in efferocytosis, associating with Mertk to enable optimal Mertk phosphorylation during apoptotic cell uptake.\",\n      \"evidence\": \"Reciprocal Co-IP in J774 and peritoneal macrophages, SR-A blocking, and phosphorylation assays in SR-A-/- cells\",\n      \"pmids\": [\"18511575\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of SR-A/Mertk association unknown\", \"Single lab; reciprocal validation within one study\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Localized MSR1's immunosuppressive activity to dendritic cells, where it negatively regulates TLR4-driven CD8+ T cell priming.\",\n      \"evidence\": \"SRA-knockout mice, DC\\u2013T cell co-culture, siRNA knockdown, and tumor growth assays\",\n      \"pmids\": [\"19349620\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signaling mechanism in DCs not resolved here\", \"Whether suppression requires endocytosis unclear\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified the molecular basis of MSR1's anti-inflammatory signaling: a direct interaction with the TRAF-C domain of TRAF6 that blocks TRAF6 dimerization and K63-ubiquitination, uncoupling signaling from endocytosis.\",\n      \"evidence\": \"Co-IP, TRAF-C domain mutagenesis, NF-\\u03baB reporter assays, and LPS endotoxic shock in MSR1-deficient mice\",\n      \"pmids\": [\"21460221\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of MSR1-TRAF6 interaction not defined\", \"How ligand binding regulates this interaction unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Extended the DC immunosuppression mechanism to CD4+ T cells, showing SRA inhibits STAT1, p38, and NF-\\u03baB signaling, and that SRA binds and internalizes hsp110 yet attenuates heat-shock-protein-based vaccine responses.\",\n      \"evidence\": \"SRA-/- mice, DC\\u2013OT-II co-culture, phosphorylation assays, hsp110 binding/internalization, shRNA silencing, and melanoma tumor model\",\n      \"pmids\": [\"22083206\", \"21832164\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct link between MSR1 and STAT1/p38 inhibition not mechanistically resolved\", \"Relationship to TRAF6 inhibition not connected\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Revealed a tumor-suppressive role in CML, where BCR-ABL downregulates Msr1 and Msr1 loss accelerates leukemia via PI3K-AKT and \\u03b2-catenin.\",\n      \"evidence\": \"CML mouse model with Msr1 knockout, microarray, cell cycle/apoptosis assays, and pathway Western blotting\",\n      \"pmids\": [\"21596859\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct receptor input driving PI3K-AKT/\\u03b2-catenin not identified\", \"Ligand in the LSC context unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrated MSR1 as an endocytic conduit delivering extracellular dsRNA to endosomal TLR3, mapping binding to basic residues of the collagen-like domain.\",\n      \"evidence\": \"RNAi knockdown, exogenous MSR1 reconstitution, collagen-domain mutagenesis, dsRNA binding, and HCV/TLR3 signaling readouts\",\n      \"pmids\": [\"23717201\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How dsRNA is handed off to TLR3 in the endosome not defined\", \"Trafficking machinery unidentified\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Established MSR1 as a soluble amyloid-\\u03b2 receptor on myeloid cells controlling A\\u03b2 clearance in vivo.\",\n      \"evidence\": \"shRNA screen, Scara1-null \\u00d7 PS1-APP genetic cross, pharmacological upregulation, and A\\u03b2 clearance assays\",\n      \"pmids\": [\"23799536\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor domain binding A\\u03b2 not mapped here\", \"Signaling consequences of A\\u03b2 binding not addressed\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed additional scavenging roles: clearance of soluble autoantigen GPI to limit autoimmune arthritis, profibrotic M2 polarization via collagen-I/PI3K-Akt signaling, and opsonin-independent uptake of iron oxide nanoparticles via the collagen-like domain.\",\n      \"evidence\": \"Msr1-/- K/BxN mice with BM transplant; anti-CD204 blocking and PI3K inhibitor in alveolar macrophages; nanoparticle uptake with computational docking\",\n      \"pmids\": [\"23794629\", \"24278429\", \"23614696\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Collagen-I receptor engagement vs collagen-like-domain binding not structurally distinguished\", \"Signaling specificity across ligands unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined post-translational and structural requirements, showing dual N-glycosylation and SRCR-domain integrity are needed for surface targeting and oA\\u03b2 internalization.\",\n      \"evidence\": \"Site-directed mutagenesis of N-glycosylation sites and SRCR features, surface expression, and oA\\u03b2 internalization assays\",\n      \"pmids\": [\"26892079\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How glycosylation affects ligand affinity vs trafficking not separated\", \"Single lab\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Connected MSR1 scavenging to neuroinflammation resolution, showing Mafb-driven MSR1 clears DAMPs after stroke to protect neurons.\",\n      \"evidence\": \"In vitro DAMP internalization, ischemic stroke model with Msr1/Marco and Mafb conditional knockouts, and RAR-agonist upregulation\",\n      \"pmids\": [\"28394332\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether DAMP uptake triggers signaling or pure clearance unclear\", \"Individual DAMP binding sites not mapped\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified MSR1 as a calcium-dependent macrophage clearance receptor for von Willebrand factor, with VWF mutants of increased clearance binding more tightly.\",\n      \"evidence\": \"Purified protein binding (~14 nM), SR-AI-/- BMDM cell binding, domain mapping, and in vivo VWF clearance\",\n      \"pmids\": [\"29326120\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor domain binding VWF A1/D4 not pinpointed\", \"Single lab\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Resolved the structural basis of dead-cell recognition, showing the SRCR domain binds spectrin SPEC repeats in a Ca2+-dependent manner to mediate efferocytosis.\",\n      \"evidence\": \"1.8 \\u00c5 SRCR crystal structure, MS identification of spectrin, Ca2+-dependency, and dead-erythrocyte phagocytosis assays\",\n      \"pmids\": [\"31653705\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How spectrin recognition integrates with the Mertk co-receptor complex unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Revealed a signaling switch mechanism: K63-polyubiquitylation of MSR1 itself in M2 macrophages recruits TAK1/MKK7/JNK to phagosomes, driving a pro-inflammatory phenotypic switch.\",\n      \"evidence\": \"Phagosomal proteomics, ubiquitination and JNK phosphorylation assays, MSR1 knockout macrophages, and JNK inhibition\",\n      \"pmids\": [\"31028084\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The ubiquitin ligase modifying MSR1 not identified\", \"Trigger linking ligand engagement to MSR1 ubiquitylation unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed context-dependent roles in tissue injury and repair: myelin-debris uptake driving NF-\\u03baB-dependent neuronal damage after spinal cord injury, and PI3K/AKT/GSK3\\u03b2/\\u03b2-catenin signaling promoting osteogenesis and M2 polarization via PGC1\\u03b1.\",\n      \"evidence\": \"MSR1-knockout mouse SCI and tibial-defect models, macrophage\\u2013BMSC co-culture, NF-\\u03baB and PI3K/AKT pathway Western blotting, and RNA-seq\",\n      \"pmids\": [\"32066456\", \"31903103\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How the same receptor selects NF-\\u03baB vs PI3K/AKT outputs unresolved\", \"Direct vs indirect coupling to PGC1\\u03b1 unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended ligand range and pathology, showing ferritin engages neutrophil Msr1 to drive NET formation and cytokine storm, and linking MSR1 metabolic rewiring (arginine/proline, AMPK/mTOR) to M2 polarization in gastric cancer.\",\n      \"evidence\": \"Ferritin administration with Msr1-knockout mice and NET assays (PAD4/NE/ROS); MSR1 knockdown with metabolomics, AMPK/mTOR Western blotting, and scRNA-seq\",\n      \"pmids\": [\"36357401\", \"36095948\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ferritin binding site on Msr1 not mapped\", \"Gastric cancer metabolic pathway inferred from knockdown without reconstitution\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Implicated MSR1 in myelin clearance in human neurodegenerative dementia, with overexpression enhancing microglial phagocytosis and MSR1+ microglia co-localizing with myelin in patient cortex.\",\n      \"evidence\": \"Microglial overexpression phagocytosis assay, myelin-induced MSR1 upregulation, human PDD cortex immunohistochemistry, and snRNA-seq\",\n      \"pmids\": [\"40826098\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether myelin clearance is protective or pathogenic in dementia unresolved\", \"Receptor domain binding myelin not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single receptor selects between opposing signaling outputs\\u2014TRAF6-mediated NF-\\u03baB suppression versus phagosomal JNK activation versus NF-\\u03baB and PI3K/AKT activation\\u2014depending on ligand, activation state, and post-translational modification remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model linking ligand identity to signaling outcome\", \"Ligase and adaptors controlling MSR1 ubiquitylation unidentified\", \"Structural basis for collagen-domain vs SRCR-domain ligand selection incompletely mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [3, 5, 6, 8]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [2, 4, 18]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [14]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 22]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [4, 8, 21]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 5, 11, 18, 22]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [2, 3, 6, 8, 14]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 7, 16]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [3, 4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"TRAF6\", \"MERTK\", \"TLR3\", \"MARCO\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":7,"faith_pct":85.71428571428571}}