{"gene":"MSR1","run_date":"2026-04-28T18:30:28","timeline":{"discoveries":[{"year":2017,"finding":"MSR1 (SR-A/CD204) internalizes DAMPs including HMGB1, peroxiredoxins, and S100A8/S100A9 in vitro; in ischemic brain, DAMP internalization is largely mediated by MSR1, and its expression is controlled by the transcription factor MAFB. Combined deficiency of Msr1 and Marco in infiltrating myeloid cells caused impaired DAMP clearance, more severe inflammation, and exacerbated neuronal injury in murine ischemic stroke.","method":"In vitro internalization assays, murine ischemic stroke model (Msr1/Marco knockout), MAFB-deficient mice, transcription factor analysis","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 — reciprocal genetic KO models with defined cellular phenotype, multiple orthogonal methods, replicated with pharmacological intervention (Am80)","pmids":["28394332"],"is_preprint":false},{"year":2013,"finding":"Scara1 (MSR1/CD204) acts as a receptor for soluble amyloid-β on myeloid cells; Scara1 deficiency accelerates Aβ accumulation and increases mortality in a PS1-APP Alzheimer's mouse model, while pharmacological upregulation of Scara1 on mononuclear phagocytes increases Aβ clearance.","method":"shRNA screening, Scara1 null × PS1-APP mouse cross, in vivo Aβ clearance assay, pharmacological upregulation","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — genetic KO with clear in vivo phenotype plus pharmacological rescue, multiple orthogonal approaches","pmids":["23799536"],"is_preprint":false},{"year":2019,"finding":"Triggering of MSR1 in IL-4-activated (M2) macrophages recruits the TAK1/MKK7/JNK signalling complex to phagosomes via K63 polyubiquitylation of MSR1, leading to enhanced JNK activation and a phenotypic switch from anti-inflammatory to pro-inflammatory state; this effect is abolished upon MSR1 deletion or JNK inhibition.","method":"Proteomics of phagosomal fractions, MSR1 knockout macrophages, K63-ubiquitylation assays, JNK inhibition, IL-4 stimulation, human ovarian cancer tissue validation","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1/2 — mechanistic dissection with proteomics, genetic KO, specific inhibitors, post-translational modification identification, and in vivo tissue validation","pmids":["31028084"],"is_preprint":false},{"year":2011,"finding":"SRA/CD204 (MSR1) directly interacts with the TRAF-C domain of TRAF6, inhibiting TRAF6 dimerization and ubiquitination, thereby suppressing TLR4-induced NF-κB activation. This regulatory function is independent of MSR1's ligand-binding domain, uncoupling its signaling-regulatory role from its endocytic function.","method":"Co-immunoprecipitation, domain mutagenesis, NF-κB reporter assays, SR-A/CD204 knockout macrophages and dendritic cells, LPS endotoxic shock model","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — direct binding interaction mapped to TRAF-C domain by mutagenesis, functional consequences demonstrated in vitro and in vivo","pmids":["21460221"],"is_preprint":false},{"year":2013,"finding":"MSR1 (class A scavenger receptor type 1) binds extracellular dsRNA, mediates its endocytosis and transport to the endosome where TLR3 is engaged, triggering IFN responses in hepatocytes. A series of conserved basic residues in the carboxy-terminus of the collagen superfamily domain are required for dsRNA binding and transport. RNAi-mediated MSR1 knockdown blocks TLR3 sensing of HCV; exogenous MSR1 expression restores TLR3 signaling.","method":"RNAi knockdown, exogenous MSR1 overexpression, domain mutagenesis (collagen superfamily domain basic residues), HCV infection assay in hepatocyte cultures, IFN response measurement","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 1 — reconstitution by exogenous expression, mutagenesis identifying functional domain, RNAi rescue, mechanistic dissection","pmids":["23717201"],"is_preprint":false},{"year":2008,"finding":"SR-AI (MSR1) signals via the receptor tyrosine kinase Mertk during apoptotic cell uptake. SR-A associates with Mertk (directly or indirectly), and apoptotic cell exposure induces SR-A–dependent phosphorylation of Mertk and downstream phospholipase Cγ2, which are required for apoptotic cell ingestion. SR-A−/− macrophages show reduced and delayed Mertk phosphorylation and impaired apoptotic cell ingestion.","method":"Western blotting, co-immunoprecipitation, anti-SR-A blocking antibodies, SR-A−/− peritoneal macrophages, dexamethasone-induced apoptotic thymocytes","journal":"Journal of leukocyte biology","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal co-IP and genetic KO with defined phenotype, single lab","pmids":["18511575"],"is_preprint":false},{"year":2009,"finding":"SRA/CD204 (MSR1) expressed on dendritic cells negatively regulates TLR4 agonist-augmented CD8+ T cell activation; SRA/CD204-deficient DCs display enhanced immunostimulatory activity upon TLR4 engagement, and siRNA silencing of SRA/CD204 in DCs improves antigen-specific CD8+ T cell priming.","method":"SRA/CD204-deficient mice, siRNA-mediated knockdown in DCs, TLR4 agonist stimulation, antigen-specific T cell priming assays, tumor challenge models","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — genetic KO and RNAi knockdown with defined cellular phenotype, confirmed with tumor immunity readout","pmids":["19349620"],"is_preprint":false},{"year":2011,"finding":"SRA/CD204 (MSR1) on dendritic cells suppresses CD4+ T cell activation by inhibiting STAT1, p38 MAPK, and NF-κB signaling in DCs; this suppressive activity is independent of classical endocytic function of SR-A/CD204, and absence of SR-A leads to elevated IL-12p35 expression upon CD40 ligation plus IFN-γ stimulation.","method":"SRA−/− mice, OT-II adoptive transfer, in vitro DC stimulation, STAT1/p38/NF-κB pathway analysis, anti-CD40 + IFN-γ treatment","journal":"Journal of molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 — genetic KO with multiple signaling readouts, single lab","pmids":["22083206"],"is_preprint":false},{"year":2011,"finding":"SRA/CD204 (MSR1) directly interacts with exogenous hsp110; lack of SRA/CD204 reduces hsp110 binding and internalization by DCs but paradoxically enhances T cell stimulation via increased NF-κB activation, demonstrating an immunosuppressive signaling role for SRA/CD204 independent of antigen internalization.","method":"Direct binding assay (hsp110 to DCs ± SRA/CD204), SRA−/− DCs, NF-κB activation assays, antigen-specific T cell stimulation, shRNA lentiviral silencing, in vivo melanoma vaccine model","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — direct binding demonstrated, genetic KO and RNAi, multiple functional readouts, single lab","pmids":["21832164"],"is_preprint":false},{"year":2019,"finding":"SCARA1 (MSR1/CD204) recognizes dead cells specifically through its SRCR domain in a Ca2+-dependent manner, and cellular spectrin (via SPEC repeats) is the binding target of SCARA1 on dead cells. Crystal structure of the SRCR domain (1.8 Å) reveals its Ca2+-binding site. Macrophages internalize dead cells/debris via the SCARA1–spectrin interaction.","method":"Crystal structure determination (1.8 Å), mass spectrometry identification of binding partners, biochemical binding assays, cell-based internalization assays, SRCR domain mutagenesis, Ca2+-dependence assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — crystal structure + MS-identified substrate + cell-based functional validation with domain mutagenesis","pmids":["31653705"],"is_preprint":false},{"year":2018,"finding":"SR-AI (MSR1) on macrophages functions as a clearance receptor for von Willebrand factor (VWF); VWF binding is calcium-dependent and involves the A1 and D4 domains of VWF. SR-AI deficiency in mice reduces VWF clearance. VWF mutants with increased clearance (p.R1205H, p.S2179F) show enhanced binding to SR-AI.","method":"Purified SR-AI binding assay (half-maximum binding measured), SR-AI−/− macrophage binding experiments, hydrodynamic gene transfer in SR-AI−/− mice, antibody inhibition, VWF propeptide/antigen ratio as clearance marker","journal":"Haematologica","confidence":"High","confidence_rationale":"Tier 1/2 — in vitro reconstituted binding with defined affinity, genetic KO in vivo clearance assay, mutant VWF validation","pmids":["29326120"],"is_preprint":false},{"year":2013,"finding":"SR-AI (MSR1) mediates opsonin-independent uptake of dextran-coated superparamagnetic iron oxide (SPIO) nanoparticles via its positively charged collagen-like domain; recognition of the iron oxide crystalline surface is sterically hindered by larger polymer coatings, and computer modeling reveals complementarity between Fe-OH groups on magnetite and charged lysines in the collagen-like domain.","method":"SR-AI transfected cells, J774 macrophages, nanoparticles with varied surface coatings, blocking antibodies, computer molecular modeling","journal":"ACS nano","confidence":"Medium","confidence_rationale":"Tier 2 — transfected cell binding/uptake assays with structural domain modeling, single lab","pmids":["23614696"],"is_preprint":false},{"year":2011,"finding":"MSR1 has a tumor suppressor function in leukemia stem cells (LSCs) of CML: BCR-ABL downregulates Msr1, Msr1 deletion accelerates CML development and markedly increases LSC function by affecting cell cycle progression and apoptosis, and Msr1 exerts its effects through the PI3K-AKT pathway and β-Catenin.","method":"BCR-ABL–induced CML mouse model, Msr1 knockout mice, DNA microarray, gene expression analysis, cell cycle and apoptosis assays, PI3K-AKT and β-catenin pathway analysis","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 — genetic KO in defined disease model with pathway placement, single lab","pmids":["21596859"],"is_preprint":false},{"year":2020,"finding":"Macrophage MSR1 promotes osteogenic differentiation of BMSCs via PI3K/AKT/GSK3β/β-catenin signaling in a co-culture system, and MSR1-activated PI3K/AKT/GSK3β/β-catenin pathway targets PGC1α to facilitate M2-like macrophage polarization by enhancing mitochondrial oxidative phosphorylation. MSR1 knockout mice show delayed intramembranous ossification.","method":"MSR1 KO mice (tibial monocortical defect model), BMDM/RAW264.7/BMSC co-culture system, qPCR, Western blotting, immunofluorescence, RNA sequencing","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 — genetic KO in vivo model with defined pathway and target gene identification, single lab","pmids":["31903103"],"is_preprint":false},{"year":2020,"finding":"MSR1 promotes phagocytosis of myelin debris and foamy macrophage formation after spinal cord injury; in the presence of myelin debris, MSR1-mediated NF-κB signaling drives release of inflammatory mediators and subsequent neuronal apoptosis. MSR1 KO mice show improved recovery from SCI.","method":"MSR1 KO mice (SCI model), in vitro macrophage/RAW264.7 treatment with myelin debris, qPCR, Western blotting, immunofluorescence, NF-κB pathway analysis","journal":"Journal of neuroinflammation","confidence":"Medium","confidence_rationale":"Tier 2 — genetic KO in vivo model with pathway analysis, single lab","pmids":["32066456"],"is_preprint":false},{"year":2022,"finding":"Ferritin acts as a ligand for Msr1 on neutrophils, triggering NET formation through Msr1; ferritin exposure increases Msr1 surface expression on neutrophils and activates NET formation dependent on peptidylarginine deiminase 4, neutrophil elastase, and ROS production. Msr1 ablation protects mice from ferritin-induced tissue damage and hyperinflammatory response.","method":"Ferritin administration mouse model, Msr1 knockout mice, neutrophil depletion, surface receptor expression assays, NET formation assays (PAD4, NE, ROS), AOSD patient samples","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — genetic KO with clear mechanistic pathway, validated in human disease samples (AOSD), multiple orthogonal methods","pmids":["36357401"],"is_preprint":false},{"year":2013,"finding":"Monomeric collagen type I via CD204 (MSR1) induces phospho-Akt expression in alveolar macrophages, shifting them to the profibrotic M2 type and driving CCL18, IL-1ra, and CCL2 production; these effects are abrogated by neutralizing anti-CD204 antibody and PI3K inhibitor LY294002.","method":"Alveolar macrophage culture with collagen monomers, neutralizing anti-CD204 antibody, PI3K inhibitor (LY294002), ELISA, phospho-Akt ELISA, RT-PCR, flow cytometry","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — antibody blocking and PI3K inhibition with defined signaling readouts, single lab","pmids":["24278429"],"is_preprint":false},{"year":2007,"finding":"SR-AI/II (MSR1) contributes to innate lung defense against pneumococcal bacteria: SR-AI/II deficiency causes impaired phagocytosis of bacteria in vivo, diminished bacterial clearance from the lungs, increased pneumonic inflammation, and increased mortality in pneumococcal lung infection.","method":"SR-AI/II-deficient mice, intratracheal pneumococcal challenge, in vivo phagocytosis assay with fluorescent bacteria, survival studies, inflammatory cytokine measurement","journal":"American journal of respiratory cell and molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 — genetic KO with defined in vivo phenotype, single lab","pmids":["16675784"],"is_preprint":false},{"year":2007,"finding":"MARCO and SR-AI/II (MSR1) on alveolar macrophages scavenge oxidized lipids (β-epoxide and PON-GPC) from lung lining fluid; SR-AI/II−/− mice show enhanced acute lung inflammation after intratracheal instillation of oxidized lipids, and normal AMs show greater uptake of β-epoxide compared with MARCO−/− AMs, consistent with SRA function in binding oxidized lipids.","method":"SR-AI/II−/− and MARCO−/− mice, intratracheal lipid instillation, in vitro uptake assay, neutrophil influx quantification, ozone exposure model","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 — genetic KO with specific ligand uptake assay and defined inflammatory phenotype","pmids":["17332894"],"is_preprint":false},{"year":2005,"finding":"SR-AI/II (MSR1/CD204) ligation inhibits IL-12 production in macrophages (opposite to MARCO), and SR-AI/II−/− peritoneal macrophages produce significantly more IL-12 in response to LPS or LPS+IFN-γ. SR-A mediates opsonin-independent phagocytosis in IL-4-pretreated cells. SR-A and MARCO are regulated in opposite directions by Th1/Th2 factors.","method":"MARCO-deficient and SR-AI/II-deficient mice, peritoneal macrophage isolation, IL-12 ELISA, immobilized mAb ligation, cytokine stimulation, phagocytosis assays","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — genetic KO with specific signaling readouts and multiple conditions, single lab","pmids":["16339540"],"is_preprint":false},{"year":2013,"finding":"Macrophage scavenger receptor Msr1 (SR-A) regulates the concentration of soluble autoantigen glucose-6-phosphate isomerase; Msr1−/− macrophages are inefficient at taking up this autoantigen, leading to elevated serum concentrations. This prevents pathogenic autoantibody production and protects from arthritis in the K/BxN model. Bone marrow transplant experiments confirm the macrophage-intrinsic mechanism.","method":"Msr1−/− × K/BxN mice, bone marrow transplantation, autoantigen uptake assay, serum glucose-6-phosphate isomerase measurement, autoantibody production, T and B cell activation analysis","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — genetic KO with defined substrate clearance mechanism and bone marrow transplant confirmation","pmids":["23794629"],"is_preprint":false},{"year":2010,"finding":"SR-AI (MSR1) recognizes complement iC3b (but not C3 or C3b) and mediates NF-κB activation and IL-8 production in response to iC3b-opsonized bacteria. The SRCR domain of SR-AI is essential for binding to serum-sensitized bacteria, identifying SR-AI as a complement receptor.","method":"SR-AI expressed in HEK 293T cells, E. coli challenge with fresh vs. heat-inactivated serum, anti-C3 antibody inhibition, purified iC3b binding, SRCR domain mutagenesis, NF-κB and IL-8 assays","journal":"Protein & cell","confidence":"Medium","confidence_rationale":"Tier 1/2 — direct binding to purified iC3b, SRCR domain mutagenesis, cell-based signaling assay, single lab","pmids":["21203986"],"is_preprint":false},{"year":2022,"finding":"MSR1 mediates M2 macrophage polarization by regulating arginine and proline metabolism, activating the AMPK/mTOR pathway; MSR1 knockdown inhibits M2 polarization and the malignant behavior of gastric cancer cells induced by M2 macrophages.","method":"ATAC-seq, RNA-seq, scRNA-seq, MSR1 siRNA knockdown, AMPK/mTOR pathway analysis, co-culture of macrophages with gastric cancer cells, CIBERSORTx algorithm","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 — multi-omic approach with functional knockdown and pathway identification, single lab","pmids":["36095948"],"is_preprint":false},{"year":2016,"finding":"N-glycosylation of SR-AI (MSR1) at dual N-glycosylation sites (N120Q-N143Q and N143Q-N184Q) is critical for oligomeric amyloid-β internalization; mutations at these sites diminish oAβ internalization even when receptors are normally surface-targeted. SRCR domain mutations affecting β-sheet/α-helix structure obstruct N-glycosylation and surface targeting.","method":"SR-AI mutagenesis (N-glycosylation sites and SRCR domain), transfection and surface targeting assay, oAβ internalization assay, MARCO-SRCR mutant analysis","journal":"Journal of biomedical science","confidence":"Medium","confidence_rationale":"Tier 1 — mutagenesis with defined functional readout, single lab","pmids":["26892079"],"is_preprint":false},{"year":2022,"finding":"MSR1 is a required component of the Mafb/Msr1/PI3K-Akt/NF-κB pathway downstream of RARα activation; Msr1 siRNA blocks RARα agonist (Am80)-induced Akt phosphorylation and anti-inflammatory effects after subarachnoid hemorrhage, and MSR1 promotes M1-to-M2 microglial polarization via this pathway.","method":"SAH rat model, RARα agonist (Am80), Msr1 siRNA, PI3K inhibitor (LY294002), Western blotting, immunofluorescence, BV2/SH-SY5Y co-culture in vitro SAH model","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 — siRNA knockdown with pathway placement and rescue experiments, single lab","pmids":["35237277"],"is_preprint":false},{"year":2022,"finding":"MSR1 is identified as a receptor for ferritin on neutrophils (as well as macrophages), and mediates NET formation-dependent cytokine storm. Activation of MSR1 by ferritin triggers the NETosis pathway (PAD4, NE, ROS). This is relevant to adult-onset Still's disease where enhanced MSR1 signaling on neutrophils is observed.","method":"Msr1 KO mouse model, ferritin administration, neutrophil depletion, NET formation assays, MSR1 surface expression flow cytometry, AOSD patient validation","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — genetic KO, ligand-receptor interaction, mechanistic pathway, human disease validation","pmids":["36357401"],"is_preprint":false},{"year":2022,"finding":"Fatty acids derived from apoptotic chondrocytes are taken up by macrophages mainly through MSR1, subsequently activating PPARα to facilitate lipid droplet generation and fatty acid oxidation (FAO), which upregulates BMP7 via NAD+/SIRT1/EZH2 epigenetic axis to enhance osteoinductive function.","method":"MSR1 KO mice (endochondral ossification model), in vitro fatty acid uptake assay, PPARα activation, FAO measurement, BMP7 expression, NAD+/SIRT1/EZH2 pathway analysis","journal":"Redox biology","confidence":"Medium","confidence_rationale":"Tier 2 — genetic KO with mechanistic pathway dissection, single lab","pmids":["35525025"],"is_preprint":false},{"year":2013,"finding":"LOX-1 abrogation induces MSR1 upregulation (nearly 100% increase at mRNA and protein levels) and CD36 downregulation in macrophages through decreased PPAR-γ expression; PPAR-γ agonist (troglitazone) treatment reverses MSR1 upregulation, identifying PPAR-γ as a negative regulator of MSR1 expression downstream of LOX-1.","method":"LOX-1 KO macrophages, ox-LDL stimulation, PPAR-γ agonist treatment, mRNA and protein quantification, Dil-ox-LDL uptake assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — genetic KO and pharmacological rescue identifying transcriptional regulation mechanism, single lab","pmids":["23333385"],"is_preprint":false},{"year":2017,"finding":"LPS enhances CD204 (MSR1) expression and acetylated-LDL uptake in bone marrow macrophages through the MAPK/ERK pathway; MEK inhibitors (U0126, PD0325901) block LPS-induced CD204 expression and Ac-LDL uptake but not CD36 expression, which is regulated through an ERK-independent pathway.","method":"Mouse bone marrow macrophages, LPS treatment, MEK inhibitors (U0126, PD0325901), Ac-LDL uptake assay, CD204/CD36 expression analysis","journal":"Atherosclerosis","confidence":"Medium","confidence_rationale":"Tier 2 — pharmacological inhibition with defined pathway and expression readouts, single lab","pmids":["29032172"],"is_preprint":false},{"year":2018,"finding":"JNK1 (but not JNK2) mediates LPS-induced SR-AI (MSR1) and CD14 expression in macrophages, controlling LPS-induced oxLDL uptake and foam cell formation; JNK isoform-specific siRNA knockdown demonstrated the isoform specificity.","method":"JNK isoform-specific siRNA, pharmaceutical JNK inhibitor (SP600125), MEK inhibitor (U0126), p38 inhibitor (SB203580), LPS treatment, oxLDL uptake assay, SR-AI/CD14 expression analysis","journal":"Frontiers in physiology","confidence":"Medium","confidence_rationale":"Tier 2 — isoform-specific siRNA with pharmacological validation, single lab","pmids":["29354064"],"is_preprint":false},{"year":2007,"finding":"SR-AI (MSR1) is identified as a cellular receptor for Tamm-Horsfall protein with lower affinity than SREC-I (802 nM vs. 16.8 nM). Interaction is blocked by AcLDL, and SR-AI uptake of THP may play a role in local host defense.","method":"Retroviral expression cloning, affinity binding assays, blocking experiments with AcLDL and anti-receptor antibodies","journal":"Journal of leukocyte biology","confidence":"Low","confidence_rationale":"Tier 3 — single binding assay, lower-affinity interaction, no mechanistic follow-up for MSR1 specifically","pmids":["17928461"],"is_preprint":false}],"current_model":"MSR1 (CD204/SR-A) is a multifunctional class A scavenger receptor on macrophages and dendritic cells that (1) directly binds and internalizes a broad range of ligands—including modified lipoproteins, DAMPs (HMGB1, peroxiredoxins), soluble amyloid-β, dsRNA, von Willebrand factor, ferritin, spectrin on dead cells, and oxidized lipids—via its collagen-like and SRCR domains; (2) transduces intracellular signals by recruiting the TAK1/MKK7/JNK complex through K63-polyubiquitylation, interacting with Mertk to phosphorylate PLC-γ2, directly binding and inhibiting TRAF6 ubiquitination to suppress TLR4-NF-κB signaling, and activating PI3K/AKT/GSK3β/β-catenin and AMPK/mTOR pathways in context-dependent fashion; and (3) regulates innate and adaptive immune responses, macrophage polarization, clearance of apoptotic cells and soluble autoantigens, and leukemia stem cell proliferation, with its expression controlled transcriptionally by MAFB downstream of retinoic acid receptor signaling and by LPS via the MAPK/ERK pathway through a PPAR-γ-dependent mechanism."},"narrative":{"teleology":[{"year":2005,"claim":"The question of whether class A scavenger receptors differentially regulate cytokine output was addressed: SR-AI/II ligation suppresses IL-12 production in macrophages (opposite to MARCO), establishing MSR1 as an anti-inflammatory signal modulator rather than simply an endocytic receptor.","evidence":"MARCO-KO and SR-AI/II-KO peritoneal macrophages stimulated with LPS ± IFN-γ, IL-12 ELISA","pmids":["16339540"],"confidence":"Medium","gaps":["Downstream signaling pathway from SR-AI ligation to IL-12 suppression not mapped","Single lab finding"]},{"year":2007,"claim":"MSR1's role in innate antimicrobial defense and oxidized lipid scavenging in the lung was established: SR-AI/II deficiency impaired bacterial phagocytosis and clearance of oxidized lipids in vivo, leading to enhanced inflammation and mortality.","evidence":"SR-AI/II-KO mice challenged intratracheally with pneumococci or oxidized lipids; in vivo phagocytosis, survival, and neutrophil influx quantified","pmids":["16675784","17332894"],"confidence":"Medium","gaps":["Relative contribution of SR-AI vs. SR-AII isoforms not distinguished","Cooperation with MARCO not fully delineated"]},{"year":2008,"claim":"How MSR1 transduces signals during efferocytosis was unknown; co-immunoprecipitation revealed that SR-A associates with the receptor tyrosine kinase Mertk, and SR-A engagement by apoptotic cells triggers Mertk phosphorylation and downstream PLCγ2 activation required for ingestion.","evidence":"Co-IP in peritoneal macrophages, SR-A-KO macrophages showing reduced Mertk phosphorylation, apoptotic thymocyte uptake assay","pmids":["18511575"],"confidence":"Medium","gaps":["Whether SR-A–Mertk interaction is direct or bridged by a co-receptor not resolved","Single lab"]},{"year":2009,"claim":"MSR1's immunosuppressive function on dendritic cells was demonstrated: SR-A/CD204-deficient DCs showed enhanced TLR4-augmented CD8⁺ T cell priming, establishing MSR1 as a negative regulator of adaptive immunity beyond its macrophage roles.","evidence":"SR-A-KO mice and siRNA-silenced DCs, antigen-specific T cell activation assays, tumor challenge models","pmids":["19349620"],"confidence":"High","gaps":["Precise signaling pathway in DCs linking SR-A to T cell suppression not fully mapped"]},{"year":2011,"claim":"The mechanism of MSR1-mediated NF-κB suppression was resolved: MSR1 directly binds the TRAF-C domain of TRAF6, inhibiting TRAF6 dimerization and ubiquitination, thereby attenuating TLR4 signaling independently of MSR1's ligand-binding and endocytic functions.","evidence":"Co-IP with domain mutagenesis, NF-κB reporter assays, SR-A-KO macrophages and DCs, in vivo LPS endotoxic shock model","pmids":["21460221"],"confidence":"High","gaps":["Structural basis of the MSR1–TRAF6 interaction not determined","Whether this mechanism operates in all MSR1-expressing cell types is untested"]},{"year":2011,"claim":"MSR1 was shown to function as a tumor suppressor in leukemia stem cells: BCR-ABL downregulates Msr1, and Msr1 deletion accelerates CML by enhancing LSC self-renewal through the PI3K-AKT/β-catenin pathway, revealing a non-immune role for MSR1.","evidence":"BCR-ABL-induced CML mouse model crossed with Msr1-KO, microarray, cell cycle and apoptosis assays","pmids":["21596859"],"confidence":"Medium","gaps":["How BCR-ABL transcriptionally silences Msr1 not defined","Relevance to human CML not validated","Single lab"]},{"year":2013,"claim":"MSR1's ligand repertoire was expanded to include dsRNA and soluble amyloid-β with defined domain requirements: basic residues in the collagen-like domain mediate dsRNA binding and transport to TLR3-containing endosomes, while Scara1 deficiency accelerates Aβ accumulation in Alzheimer's models.","evidence":"RNAi knockdown/exogenous rescue in hepatocytes for dsRNA/TLR3; Scara1-null × PS1-APP mouse cross for Aβ clearance","pmids":["23717201","23799536"],"confidence":"High","gaps":["Whether dsRNA transport and Aβ clearance use overlapping or distinct endosomal pathways unknown"]},{"year":2013,"claim":"Transcriptional regulation of MSR1 was clarified: PPARγ negatively regulates MSR1 expression, as demonstrated by LOX-1 abrogation-induced MSR1 upregulation reversed by PPARγ agonist.","evidence":"LOX-1-KO macrophages, troglitazone (PPARγ agonist) rescue, mRNA/protein quantification","pmids":["23333385"],"confidence":"Medium","gaps":["Whether PPARγ directly binds the MSR1 promoter not tested","Single lab"]},{"year":2016,"claim":"Post-translational regulation of MSR1 function was defined: dual N-glycosylation sites are critical for oligomeric Aβ internalization, even when surface targeting is preserved, establishing glycosylation as a determinant of ligand-specific receptor function.","evidence":"N-glycosylation site mutagenesis, surface targeting vs. oAβ internalization assays in transfected cells","pmids":["26892079"],"confidence":"Medium","gaps":["In vivo relevance of glycosylation-dependent Aβ uptake not demonstrated","Single lab"]},{"year":2017,"claim":"MSR1 was established as a central DAMP clearance receptor in ischemic brain, with its transcription controlled by MAFB: combined Msr1/Marco deficiency in myeloid cells impaired DAMP clearance, worsened neuroinflammation, and exacerbated neuronal injury in stroke.","evidence":"Msr1/Marco-KO mice in ischemic stroke model, MAFB-deficient mice, in vitro DAMP internalization assays, Am80 pharmacological rescue","pmids":["28394332"],"confidence":"High","gaps":["Individual contribution of Msr1 vs. Marco to each DAMP class in vivo not fully separated"]},{"year":2017,"claim":"LPS-induced MSR1 upregulation was mapped to the MAPK/ERK pathway: MEK inhibitors specifically blocked LPS-induced CD204 expression and acetylated-LDL uptake without affecting CD36, separating the transcriptional control of these two scavenger receptors.","evidence":"Mouse bone marrow macrophages treated with LPS ± MEK inhibitors (U0126, PD0325901), CD204/CD36 expression and Ac-LDL uptake","pmids":["29032172"],"confidence":"Medium","gaps":["Transcription factor downstream of ERK that directly activates MSR1 promoter not identified","Single lab"]},{"year":2018,"claim":"MSR1 was identified as a clearance receptor for von Willebrand factor, binding VWF in a calcium-dependent manner via VWF A1/D4 domains; SR-AI deficiency reduced VWF clearance in vivo and VWF gain-of-clearance mutants showed enhanced SR-AI binding.","evidence":"Purified SR-AI binding assays, SR-AI-KO mice with hydrodynamic VWF gene transfer, VWF mutant binding studies","pmids":["29326120"],"confidence":"High","gaps":["Relative contribution of MSR1 vs. other VWF clearance receptors (LRP1, ASGPR) not quantified"]},{"year":2019,"claim":"The intracellular signaling mechanism of MSR1 on phagosomes was elucidated: K63-polyubiquitylation of MSR1 recruits the TAK1/MKK7/JNK complex, driving pro-inflammatory reprogramming of M2 macrophages, revealing how MSR1 converts from scavenger to signal transducer.","evidence":"Phagosomal proteomics, K63-ubiquitylation assays, MSR1-KO macrophages, JNK inhibition, human ovarian cancer tissue validation","pmids":["31028084"],"confidence":"High","gaps":["E3 ligase responsible for K63-ubiquitylation of MSR1 not identified","Whether this phagosomal signaling occurs with all MSR1 ligands unknown"]},{"year":2019,"claim":"The structural basis of MSR1-mediated dead cell recognition was solved: crystal structure of the SRCR domain at 1.8 Å revealed a Ca²⁺-binding site, and mass spectrometry identified spectrin as the specific dead-cell ligand recognized by the SRCR domain.","evidence":"X-ray crystallography, mass spectrometry, SRCR domain mutagenesis, cell-based internalization assays","pmids":["31653705"],"confidence":"High","gaps":["How SRCR-mediated and collagen-domain-mediated ligand recognition are coordinated in the native trimer unknown"]},{"year":2020,"claim":"MSR1-mediated PI3K/AKT/GSK3β/β-catenin signaling in macrophages was linked to M2 polarization and osteogenic differentiation: MSR1 activates this pathway targeting PGC1α to enhance mitochondrial oxidative phosphorylation and promote bone formation in vivo.","evidence":"MSR1-KO mice in tibial defect model, BMDM/BMSC co-culture, RNA-seq, Western blotting","pmids":["31903103"],"confidence":"Medium","gaps":["How MSR1 activates PI3K — direct interaction vs. co-receptor involvement — not resolved","Single lab"]},{"year":2022,"claim":"MSR1 was identified as a ferritin receptor on neutrophils that triggers NETosis (via PAD4, NE, ROS), establishing a new cell-type-specific function; Msr1 ablation protected mice from ferritin-induced hyperinflammation, relevant to adult-onset Still's disease.","evidence":"Msr1-KO mice with ferritin administration, neutrophil depletion, NET formation assays, AOSD patient validation","pmids":["36357401"],"confidence":"High","gaps":["Downstream signaling events between MSR1 engagement and PAD4/ROS activation on neutrophils not fully mapped"]},{"year":null,"claim":"Key unresolved questions include: the E3 ubiquitin ligase responsible for K63-polyubiquitylation of MSR1, the structural basis of the MSR1–TRAF6 interaction, how the collagen-like domain and SRCR domain coordinate ligand discrimination in the native trimer, and whether MSR1's diverse signaling outputs (JNK, NF-κB suppression, PI3K/AKT, AMPK/mTOR) are selected by specific ligands or by cell-type context.","evidence":"","pmids":[],"confidence":"Low","gaps":["No E3 ligase identified for MSR1 K63-ubiquitylation","No full-length MSR1 trimer structure available","Ligand-specific vs. cell-type-specific signaling determinants unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[0,1,4,10,15,9]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,6,7]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[18,26]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,4,9,10,15,23]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[2,4]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,6,7,15,17,19]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,3,12,13,22,24]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[5,14]},{"term_id":"R-HSA-109582","term_label":"Hemostasis","supporting_discovery_ids":[10]}],"complexes":[],"partners":["TRAF6","MERTK","TAK1","MKK7","MAFB","SPTBN1"],"other_free_text":[]},"mechanistic_narrative":"MSR1 (SR-A/CD204) is a class A scavenger receptor expressed on macrophages, dendritic cells, and neutrophils that mediates the recognition, binding, and endocytosis of a remarkably diverse array of ligands — including modified lipoproteins, amyloid-β, DAMPs (HMGB1, peroxiredoxins), dsRNA, von Willebrand factor, ferritin, complement iC3b, oxidized lipids, collagen monomers, and spectrin on dead cells — using its collagen-like domain for polyanionic ligands and its SRCR domain for Ca²⁺-dependent dead-cell recognition [PMID:23717201, PMID:31653705, PMID:29326120, PMID:28394332]. Beyond endocytic clearance, MSR1 transduces intracellular signals: it recruits the TAK1/MKK7/JNK complex via K63-polyubiquitylation to switch M2 macrophages toward a pro-inflammatory state, directly binds TRAF6 to inhibit TLR4-NF-κB signaling independently of its ligand-binding domain, cooperates with Mertk to phosphorylate PLCγ2 during apoptotic cell ingestion, and activates PI3K/AKT/GSK3β/β-catenin and AMPK/mTOR pathways to regulate macrophage polarization, osteogenesis, and leukemia stem cell proliferation [PMID:31028084, PMID:21460221, PMID:18511575, PMID:31903103, PMID:21596859]. On dendritic cells, MSR1 suppresses TLR-augmented CD4⁺ and CD8⁺ T cell priming by inhibiting STAT1, p38, and NF-κB, functioning as a negative regulator of adaptive immunity [PMID:19349620, PMID:22083206]. MSR1 expression is transcriptionally controlled by MAFB downstream of retinoic acid receptor signaling, negatively regulated by PPARγ, and induced by LPS through the MAPK/ERK pathway [PMID:28394332, PMID:23333385, PMID:29032172]."},"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). Isoform III does not internalize acetylated LDL (PubMed:9548586)","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/P21757/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MSR1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MSR1","total_profiled":1310},"omim":[{"mim_id":"614266","title":"BARRETT ESOPHAGUS","url":"https://www.omim.org/entry/614266"},{"mim_id":"614215","title":"ACTIVATING SIGNAL COINTEGRATOR 1 COMPLEX, SUBUNIT 1; ASCC1","url":"https://www.omim.org/entry/614215"},{"mim_id":"611306","title":"SCAVENGER RECEPTOR CLASS A, MEMBER 5; SCARA5","url":"https://www.omim.org/entry/611306"},{"mim_id":"610635","title":"COLLAGEN TRIPLE-HELIX REPEAT-CONTAINING PROTEIN 1; CTHRC1","url":"https://www.omim.org/entry/610635"},{"mim_id":"609708","title":"LIPOPROTEIN LIPASE; LPL","url":"https://www.omim.org/entry/609708"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"lung","ntpm":113.2}],"url":"https://www.proteinatlas.org/search/MSR1"},"hgnc":{"alias_symbol":["SCARA1","CD204","SR-AI","SR-AII","SR-AIII","SR-A"],"prev_symbol":[]},"alphafold":{"accession":"P21757","domains":[{"cath_id":"3.10.250.10","chopping":"351-451","consensus_level":"high","plddt":91.8021,"start":351,"end":451}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P21757","model_url":"https://alphafold.ebi.ac.uk/files/AF-P21757-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P21757-F1-predicted_aligned_error_v6.png","plddt_mean":67.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MSR1","jax_strain_url":"https://www.jax.org/strain/search?query=MSR1"},"sequence":{"accession":"P21757","fasta_url":"https://rest.uniprot.org/uniprotkb/P21757.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P21757/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P21757"}},"corpus_meta":[{"pmid":"31903103","id":"PMC_31903103","title":"Macrophage 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Combined deficiency of Msr1 and Marco in infiltrating myeloid cells caused impaired DAMP clearance, more severe inflammation, and exacerbated neuronal injury in murine ischemic stroke.\",\n      \"method\": \"In vitro internalization assays, murine ischemic stroke model (Msr1/Marco knockout), MAFB-deficient mice, transcription factor analysis\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal genetic KO models with defined cellular phenotype, multiple orthogonal methods, replicated with pharmacological intervention (Am80)\",\n      \"pmids\": [\"28394332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Scara1 (MSR1/CD204) acts as a receptor for soluble amyloid-β on myeloid cells; Scara1 deficiency accelerates Aβ accumulation and increases mortality in a PS1-APP Alzheimer's mouse model, while pharmacological upregulation of Scara1 on mononuclear phagocytes increases Aβ clearance.\",\n      \"method\": \"shRNA screening, Scara1 null × PS1-APP mouse cross, in vivo Aβ clearance assay, pharmacological upregulation\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with clear in vivo phenotype plus pharmacological rescue, multiple orthogonal approaches\",\n      \"pmids\": [\"23799536\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Triggering of MSR1 in IL-4-activated (M2) macrophages recruits the TAK1/MKK7/JNK signalling complex to phagosomes via K63 polyubiquitylation of MSR1, leading to enhanced JNK activation and a phenotypic switch from anti-inflammatory to pro-inflammatory state; this effect is abolished upon MSR1 deletion or JNK inhibition.\",\n      \"method\": \"Proteomics of phagosomal fractions, MSR1 knockout macrophages, K63-ubiquitylation assays, JNK inhibition, IL-4 stimulation, human ovarian cancer tissue validation\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — mechanistic dissection with proteomics, genetic KO, specific inhibitors, post-translational modification identification, and in vivo tissue validation\",\n      \"pmids\": [\"31028084\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"SRA/CD204 (MSR1) directly interacts with the TRAF-C domain of TRAF6, inhibiting TRAF6 dimerization and ubiquitination, thereby suppressing TLR4-induced NF-κB activation. This regulatory function is independent of MSR1's ligand-binding domain, uncoupling its signaling-regulatory role from its endocytic function.\",\n      \"method\": \"Co-immunoprecipitation, domain mutagenesis, NF-κB reporter assays, SR-A/CD204 knockout macrophages and dendritic cells, LPS endotoxic shock model\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct binding interaction mapped to TRAF-C domain by mutagenesis, functional consequences demonstrated in vitro and in vivo\",\n      \"pmids\": [\"21460221\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"MSR1 (class A scavenger receptor type 1) binds extracellular dsRNA, mediates its endocytosis and transport to the endosome where TLR3 is engaged, triggering IFN responses in hepatocytes. A series of conserved basic residues in the carboxy-terminus of the collagen superfamily domain are required for dsRNA binding and transport. RNAi-mediated MSR1 knockdown blocks TLR3 sensing of HCV; exogenous MSR1 expression restores TLR3 signaling.\",\n      \"method\": \"RNAi knockdown, exogenous MSR1 overexpression, domain mutagenesis (collagen superfamily domain basic residues), HCV infection assay in hepatocyte cultures, IFN response measurement\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution by exogenous expression, mutagenesis identifying functional domain, RNAi rescue, mechanistic dissection\",\n      \"pmids\": [\"23717201\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"SR-AI (MSR1) signals via the receptor tyrosine kinase Mertk during apoptotic cell uptake. SR-A associates with Mertk (directly or indirectly), and apoptotic cell exposure induces SR-A–dependent phosphorylation of Mertk and downstream phospholipase Cγ2, which are required for apoptotic cell ingestion. SR-A−/− macrophages show reduced and delayed Mertk phosphorylation and impaired apoptotic cell ingestion.\",\n      \"method\": \"Western blotting, co-immunoprecipitation, anti-SR-A blocking antibodies, SR-A−/− peritoneal macrophages, dexamethasone-induced apoptotic thymocytes\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP and genetic KO with defined phenotype, single lab\",\n      \"pmids\": [\"18511575\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"SRA/CD204 (MSR1) expressed on dendritic cells negatively regulates TLR4 agonist-augmented CD8+ T cell activation; SRA/CD204-deficient DCs display enhanced immunostimulatory activity upon TLR4 engagement, and siRNA silencing of SRA/CD204 in DCs improves antigen-specific CD8+ T cell priming.\",\n      \"method\": \"SRA/CD204-deficient mice, siRNA-mediated knockdown in DCs, TLR4 agonist stimulation, antigen-specific T cell priming assays, tumor challenge models\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO and RNAi knockdown with defined cellular phenotype, confirmed with tumor immunity readout\",\n      \"pmids\": [\"19349620\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"SRA/CD204 (MSR1) on dendritic cells suppresses CD4+ T cell activation by inhibiting STAT1, p38 MAPK, and NF-κB signaling in DCs; this suppressive activity is independent of classical endocytic function of SR-A/CD204, and absence of SR-A leads to elevated IL-12p35 expression upon CD40 ligation plus IFN-γ stimulation.\",\n      \"method\": \"SRA−/− mice, OT-II adoptive transfer, in vitro DC stimulation, STAT1/p38/NF-κB pathway analysis, anti-CD40 + IFN-γ treatment\",\n      \"journal\": \"Journal of molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with multiple signaling readouts, single lab\",\n      \"pmids\": [\"22083206\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"SRA/CD204 (MSR1) directly interacts with exogenous hsp110; lack of SRA/CD204 reduces hsp110 binding and internalization by DCs but paradoxically enhances T cell stimulation via increased NF-κB activation, demonstrating an immunosuppressive signaling role for SRA/CD204 independent of antigen internalization.\",\n      \"method\": \"Direct binding assay (hsp110 to DCs ± SRA/CD204), SRA−/− DCs, NF-κB activation assays, antigen-specific T cell stimulation, shRNA lentiviral silencing, in vivo melanoma vaccine model\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct binding demonstrated, genetic KO and RNAi, multiple functional readouts, single lab\",\n      \"pmids\": [\"21832164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SCARA1 (MSR1/CD204) recognizes dead cells specifically through its SRCR domain in a Ca2+-dependent manner, and cellular spectrin (via SPEC repeats) is the binding target of SCARA1 on dead cells. Crystal structure of the SRCR domain (1.8 Å) reveals its Ca2+-binding site. Macrophages internalize dead cells/debris via the SCARA1–spectrin interaction.\",\n      \"method\": \"Crystal structure determination (1.8 Å), mass spectrometry identification of binding partners, biochemical binding assays, cell-based internalization assays, SRCR domain mutagenesis, Ca2+-dependence assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure + MS-identified substrate + cell-based functional validation with domain mutagenesis\",\n      \"pmids\": [\"31653705\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SR-AI (MSR1) on macrophages functions as a clearance receptor for von Willebrand factor (VWF); VWF binding is calcium-dependent and involves the A1 and D4 domains of VWF. SR-AI deficiency in mice reduces VWF clearance. VWF mutants with increased clearance (p.R1205H, p.S2179F) show enhanced binding to SR-AI.\",\n      \"method\": \"Purified SR-AI binding assay (half-maximum binding measured), SR-AI−/− macrophage binding experiments, hydrodynamic gene transfer in SR-AI−/− mice, antibody inhibition, VWF propeptide/antigen ratio as clearance marker\",\n      \"journal\": \"Haematologica\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — in vitro reconstituted binding with defined affinity, genetic KO in vivo clearance assay, mutant VWF validation\",\n      \"pmids\": [\"29326120\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SR-AI (MSR1) mediates opsonin-independent uptake of dextran-coated superparamagnetic iron oxide (SPIO) nanoparticles via its positively charged collagen-like domain; recognition of the iron oxide crystalline surface is sterically hindered by larger polymer coatings, and computer modeling reveals complementarity between Fe-OH groups on magnetite and charged lysines in the collagen-like domain.\",\n      \"method\": \"SR-AI transfected cells, J774 macrophages, nanoparticles with varied surface coatings, blocking antibodies, computer molecular modeling\",\n      \"journal\": \"ACS nano\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — transfected cell binding/uptake assays with structural domain modeling, single lab\",\n      \"pmids\": [\"23614696\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"MSR1 has a tumor suppressor function in leukemia stem cells (LSCs) of CML: BCR-ABL downregulates Msr1, Msr1 deletion accelerates CML development and markedly increases LSC function by affecting cell cycle progression and apoptosis, and Msr1 exerts its effects through the PI3K-AKT pathway and β-Catenin.\",\n      \"method\": \"BCR-ABL–induced CML mouse model, Msr1 knockout mice, DNA microarray, gene expression analysis, cell cycle and apoptosis assays, PI3K-AKT and β-catenin pathway analysis\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO in defined disease model with pathway placement, single lab\",\n      \"pmids\": [\"21596859\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Macrophage MSR1 promotes osteogenic differentiation of BMSCs via PI3K/AKT/GSK3β/β-catenin signaling in a co-culture system, and MSR1-activated PI3K/AKT/GSK3β/β-catenin pathway targets PGC1α to facilitate M2-like macrophage polarization by enhancing mitochondrial oxidative phosphorylation. MSR1 knockout mice show delayed intramembranous ossification.\",\n      \"method\": \"MSR1 KO mice (tibial monocortical defect model), BMDM/RAW264.7/BMSC co-culture system, qPCR, Western blotting, immunofluorescence, RNA sequencing\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO in vivo model with defined pathway and target gene identification, single lab\",\n      \"pmids\": [\"31903103\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"MSR1 promotes phagocytosis of myelin debris and foamy macrophage formation after spinal cord injury; in the presence of myelin debris, MSR1-mediated NF-κB signaling drives release of inflammatory mediators and subsequent neuronal apoptosis. MSR1 KO mice show improved recovery from SCI.\",\n      \"method\": \"MSR1 KO mice (SCI model), in vitro macrophage/RAW264.7 treatment with myelin debris, qPCR, Western blotting, immunofluorescence, NF-κB pathway analysis\",\n      \"journal\": \"Journal of neuroinflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO in vivo model with pathway analysis, single lab\",\n      \"pmids\": [\"32066456\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Ferritin acts as a ligand for Msr1 on neutrophils, triggering NET formation through Msr1; ferritin exposure increases Msr1 surface expression on neutrophils and activates NET formation dependent on peptidylarginine deiminase 4, neutrophil elastase, and ROS production. Msr1 ablation protects mice from ferritin-induced tissue damage and hyperinflammatory response.\",\n      \"method\": \"Ferritin administration mouse model, Msr1 knockout mice, neutrophil depletion, surface receptor expression assays, NET formation assays (PAD4, NE, ROS), AOSD patient samples\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with clear mechanistic pathway, validated in human disease samples (AOSD), multiple orthogonal methods\",\n      \"pmids\": [\"36357401\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Monomeric collagen type I via CD204 (MSR1) induces phospho-Akt expression in alveolar macrophages, shifting them to the profibrotic M2 type and driving CCL18, IL-1ra, and CCL2 production; these effects are abrogated by neutralizing anti-CD204 antibody and PI3K inhibitor LY294002.\",\n      \"method\": \"Alveolar macrophage culture with collagen monomers, neutralizing anti-CD204 antibody, PI3K inhibitor (LY294002), ELISA, phospho-Akt ELISA, RT-PCR, flow cytometry\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — antibody blocking and PI3K inhibition with defined signaling readouts, single lab\",\n      \"pmids\": [\"24278429\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"SR-AI/II (MSR1) contributes to innate lung defense against pneumococcal bacteria: SR-AI/II deficiency causes impaired phagocytosis of bacteria in vivo, diminished bacterial clearance from the lungs, increased pneumonic inflammation, and increased mortality in pneumococcal lung infection.\",\n      \"method\": \"SR-AI/II-deficient mice, intratracheal pneumococcal challenge, in vivo phagocytosis assay with fluorescent bacteria, survival studies, inflammatory cytokine measurement\",\n      \"journal\": \"American journal of respiratory cell and molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with defined in vivo phenotype, single lab\",\n      \"pmids\": [\"16675784\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"MARCO and SR-AI/II (MSR1) on alveolar macrophages scavenge oxidized lipids (β-epoxide and PON-GPC) from lung lining fluid; SR-AI/II−/− mice show enhanced acute lung inflammation after intratracheal instillation of oxidized lipids, and normal AMs show greater uptake of β-epoxide compared with MARCO−/− AMs, consistent with SRA function in binding oxidized lipids.\",\n      \"method\": \"SR-AI/II−/− and MARCO−/− mice, intratracheal lipid instillation, in vitro uptake assay, neutrophil influx quantification, ozone exposure model\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with specific ligand uptake assay and defined inflammatory phenotype\",\n      \"pmids\": [\"17332894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"SR-AI/II (MSR1/CD204) ligation inhibits IL-12 production in macrophages (opposite to MARCO), and SR-AI/II−/− peritoneal macrophages produce significantly more IL-12 in response to LPS or LPS+IFN-γ. SR-A mediates opsonin-independent phagocytosis in IL-4-pretreated cells. SR-A and MARCO are regulated in opposite directions by Th1/Th2 factors.\",\n      \"method\": \"MARCO-deficient and SR-AI/II-deficient mice, peritoneal macrophage isolation, IL-12 ELISA, immobilized mAb ligation, cytokine stimulation, phagocytosis assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with specific signaling readouts and multiple conditions, single lab\",\n      \"pmids\": [\"16339540\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Macrophage scavenger receptor Msr1 (SR-A) regulates the concentration of soluble autoantigen glucose-6-phosphate isomerase; Msr1−/− macrophages are inefficient at taking up this autoantigen, leading to elevated serum concentrations. This prevents pathogenic autoantibody production and protects from arthritis in the K/BxN model. Bone marrow transplant experiments confirm the macrophage-intrinsic mechanism.\",\n      \"method\": \"Msr1−/− × K/BxN mice, bone marrow transplantation, autoantigen uptake assay, serum glucose-6-phosphate isomerase measurement, autoantibody production, T and B cell activation analysis\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with defined substrate clearance mechanism and bone marrow transplant confirmation\",\n      \"pmids\": [\"23794629\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SR-AI (MSR1) recognizes complement iC3b (but not C3 or C3b) and mediates NF-κB activation and IL-8 production in response to iC3b-opsonized bacteria. The SRCR domain of SR-AI is essential for binding to serum-sensitized bacteria, identifying SR-AI as a complement receptor.\",\n      \"method\": \"SR-AI expressed in HEK 293T cells, E. coli challenge with fresh vs. heat-inactivated serum, anti-C3 antibody inhibition, purified iC3b binding, SRCR domain mutagenesis, NF-κB and IL-8 assays\",\n      \"journal\": \"Protein & cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1/2 — direct binding to purified iC3b, SRCR domain mutagenesis, cell-based signaling assay, single lab\",\n      \"pmids\": [\"21203986\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"MSR1 mediates M2 macrophage polarization by regulating arginine and proline metabolism, activating the AMPK/mTOR pathway; MSR1 knockdown inhibits M2 polarization and the malignant behavior of gastric cancer cells induced by M2 macrophages.\",\n      \"method\": \"ATAC-seq, RNA-seq, scRNA-seq, MSR1 siRNA knockdown, AMPK/mTOR pathway analysis, co-culture of macrophages with gastric cancer cells, CIBERSORTx algorithm\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multi-omic approach with functional knockdown and pathway identification, single lab\",\n      \"pmids\": [\"36095948\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"N-glycosylation of SR-AI (MSR1) at dual N-glycosylation sites (N120Q-N143Q and N143Q-N184Q) is critical for oligomeric amyloid-β internalization; mutations at these sites diminish oAβ internalization even when receptors are normally surface-targeted. SRCR domain mutations affecting β-sheet/α-helix structure obstruct N-glycosylation and surface targeting.\",\n      \"method\": \"SR-AI mutagenesis (N-glycosylation sites and SRCR domain), transfection and surface targeting assay, oAβ internalization assay, MARCO-SRCR mutant analysis\",\n      \"journal\": \"Journal of biomedical science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — mutagenesis with defined functional readout, single lab\",\n      \"pmids\": [\"26892079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"MSR1 is a required component of the Mafb/Msr1/PI3K-Akt/NF-κB pathway downstream of RARα activation; Msr1 siRNA blocks RARα agonist (Am80)-induced Akt phosphorylation and anti-inflammatory effects after subarachnoid hemorrhage, and MSR1 promotes M1-to-M2 microglial polarization via this pathway.\",\n      \"method\": \"SAH rat model, RARα agonist (Am80), Msr1 siRNA, PI3K inhibitor (LY294002), Western blotting, immunofluorescence, BV2/SH-SY5Y co-culture in vitro SAH model\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — siRNA knockdown with pathway placement and rescue experiments, single lab\",\n      \"pmids\": [\"35237277\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"MSR1 is identified as a receptor for ferritin on neutrophils (as well as macrophages), and mediates NET formation-dependent cytokine storm. Activation of MSR1 by ferritin triggers the NETosis pathway (PAD4, NE, ROS). This is relevant to adult-onset Still's disease where enhanced MSR1 signaling on neutrophils is observed.\",\n      \"method\": \"Msr1 KO mouse model, ferritin administration, neutrophil depletion, NET formation assays, MSR1 surface expression flow cytometry, AOSD patient validation\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO, ligand-receptor interaction, mechanistic pathway, human disease validation\",\n      \"pmids\": [\"36357401\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Fatty acids derived from apoptotic chondrocytes are taken up by macrophages mainly through MSR1, subsequently activating PPARα to facilitate lipid droplet generation and fatty acid oxidation (FAO), which upregulates BMP7 via NAD+/SIRT1/EZH2 epigenetic axis to enhance osteoinductive function.\",\n      \"method\": \"MSR1 KO mice (endochondral ossification model), in vitro fatty acid uptake assay, PPARα activation, FAO measurement, BMP7 expression, NAD+/SIRT1/EZH2 pathway analysis\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with mechanistic pathway dissection, single lab\",\n      \"pmids\": [\"35525025\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"LOX-1 abrogation induces MSR1 upregulation (nearly 100% increase at mRNA and protein levels) and CD36 downregulation in macrophages through decreased PPAR-γ expression; PPAR-γ agonist (troglitazone) treatment reverses MSR1 upregulation, identifying PPAR-γ as a negative regulator of MSR1 expression downstream of LOX-1.\",\n      \"method\": \"LOX-1 KO macrophages, ox-LDL stimulation, PPAR-γ agonist treatment, mRNA and protein quantification, Dil-ox-LDL uptake assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO and pharmacological rescue identifying transcriptional regulation mechanism, single lab\",\n      \"pmids\": [\"23333385\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"LPS enhances CD204 (MSR1) expression and acetylated-LDL uptake in bone marrow macrophages through the MAPK/ERK pathway; MEK inhibitors (U0126, PD0325901) block LPS-induced CD204 expression and Ac-LDL uptake but not CD36 expression, which is regulated through an ERK-independent pathway.\",\n      \"method\": \"Mouse bone marrow macrophages, LPS treatment, MEK inhibitors (U0126, PD0325901), Ac-LDL uptake assay, CD204/CD36 expression analysis\",\n      \"journal\": \"Atherosclerosis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological inhibition with defined pathway and expression readouts, single lab\",\n      \"pmids\": [\"29032172\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"JNK1 (but not JNK2) mediates LPS-induced SR-AI (MSR1) and CD14 expression in macrophages, controlling LPS-induced oxLDL uptake and foam cell formation; JNK isoform-specific siRNA knockdown demonstrated the isoform specificity.\",\n      \"method\": \"JNK isoform-specific siRNA, pharmaceutical JNK inhibitor (SP600125), MEK inhibitor (U0126), p38 inhibitor (SB203580), LPS treatment, oxLDL uptake assay, SR-AI/CD14 expression analysis\",\n      \"journal\": \"Frontiers in physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — isoform-specific siRNA with pharmacological validation, single lab\",\n      \"pmids\": [\"29354064\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"SR-AI (MSR1) is identified as a cellular receptor for Tamm-Horsfall protein with lower affinity than SREC-I (802 nM vs. 16.8 nM). Interaction is blocked by AcLDL, and SR-AI uptake of THP may play a role in local host defense.\",\n      \"method\": \"Retroviral expression cloning, affinity binding assays, blocking experiments with AcLDL and anti-receptor antibodies\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single binding assay, lower-affinity interaction, no mechanistic follow-up for MSR1 specifically\",\n      \"pmids\": [\"17928461\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MSR1 (CD204/SR-A) is a multifunctional class A scavenger receptor on macrophages and dendritic cells that (1) directly binds and internalizes a broad range of ligands—including modified lipoproteins, DAMPs (HMGB1, peroxiredoxins), soluble amyloid-β, dsRNA, von Willebrand factor, ferritin, spectrin on dead cells, and oxidized lipids—via its collagen-like and SRCR domains; (2) transduces intracellular signals by recruiting the TAK1/MKK7/JNK complex through K63-polyubiquitylation, interacting with Mertk to phosphorylate PLC-γ2, directly binding and inhibiting TRAF6 ubiquitination to suppress TLR4-NF-κB signaling, and activating PI3K/AKT/GSK3β/β-catenin and AMPK/mTOR pathways in context-dependent fashion; and (3) regulates innate and adaptive immune responses, macrophage polarization, clearance of apoptotic cells and soluble autoantigens, and leukemia stem cell proliferation, with its expression controlled transcriptionally by MAFB downstream of retinoic acid receptor signaling and by LPS via the MAPK/ERK pathway through a PPAR-γ-dependent mechanism.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"MSR1 (SR-A/CD204) is a class A scavenger receptor expressed on macrophages, dendritic cells, and neutrophils that mediates the recognition, binding, and endocytosis of a remarkably diverse array of ligands — including modified lipoproteins, amyloid-β, DAMPs (HMGB1, peroxiredoxins), dsRNA, von Willebrand factor, ferritin, complement iC3b, oxidized lipids, collagen monomers, and spectrin on dead cells — using its collagen-like domain for polyanionic ligands and its SRCR domain for Ca²⁺-dependent dead-cell recognition [PMID:23717201, PMID:31653705, PMID:29326120, PMID:28394332]. Beyond endocytic clearance, MSR1 transduces intracellular signals: it recruits the TAK1/MKK7/JNK complex via K63-polyubiquitylation to switch M2 macrophages toward a pro-inflammatory state, directly binds TRAF6 to inhibit TLR4-NF-κB signaling independently of its ligand-binding domain, cooperates with Mertk to phosphorylate PLCγ2 during apoptotic cell ingestion, and activates PI3K/AKT/GSK3β/β-catenin and AMPK/mTOR pathways to regulate macrophage polarization, osteogenesis, and leukemia stem cell proliferation [PMID:31028084, PMID:21460221, PMID:18511575, PMID:31903103, PMID:21596859]. On dendritic cells, MSR1 suppresses TLR-augmented CD4⁺ and CD8⁺ T cell priming by inhibiting STAT1, p38, and NF-κB, functioning as a negative regulator of adaptive immunity [PMID:19349620, PMID:22083206]. MSR1 expression is transcriptionally controlled by MAFB downstream of retinoic acid receptor signaling, negatively regulated by PPARγ, and induced by LPS through the MAPK/ERK pathway [PMID:28394332, PMID:23333385, PMID:29032172].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"The question of whether class A scavenger receptors differentially regulate cytokine output was addressed: SR-AI/II ligation suppresses IL-12 production in macrophages (opposite to MARCO), establishing MSR1 as an anti-inflammatory signal modulator rather than simply an endocytic receptor.\",\n      \"evidence\": \"MARCO-KO and SR-AI/II-KO peritoneal macrophages stimulated with LPS ± IFN-γ, IL-12 ELISA\",\n      \"pmids\": [\"16339540\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream signaling pathway from SR-AI ligation to IL-12 suppression not mapped\", \"Single lab finding\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"MSR1's role in innate antimicrobial defense and oxidized lipid scavenging in the lung was established: SR-AI/II deficiency impaired bacterial phagocytosis and clearance of oxidized lipids in vivo, leading to enhanced inflammation and mortality.\",\n      \"evidence\": \"SR-AI/II-KO mice challenged intratracheally with pneumococci or oxidized lipids; in vivo phagocytosis, survival, and neutrophil influx quantified\",\n      \"pmids\": [\"16675784\", \"17332894\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative contribution of SR-AI vs. SR-AII isoforms not distinguished\", \"Cooperation with MARCO not fully delineated\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"How MSR1 transduces signals during efferocytosis was unknown; co-immunoprecipitation revealed that SR-A associates with the receptor tyrosine kinase Mertk, and SR-A engagement by apoptotic cells triggers Mertk phosphorylation and downstream PLCγ2 activation required for ingestion.\",\n      \"evidence\": \"Co-IP in peritoneal macrophages, SR-A-KO macrophages showing reduced Mertk phosphorylation, apoptotic thymocyte uptake assay\",\n      \"pmids\": [\"18511575\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether SR-A–Mertk interaction is direct or bridged by a co-receptor not resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"MSR1's immunosuppressive function on dendritic cells was demonstrated: SR-A/CD204-deficient DCs showed enhanced TLR4-augmented CD8⁺ T cell priming, establishing MSR1 as a negative regulator of adaptive immunity beyond its macrophage roles.\",\n      \"evidence\": \"SR-A-KO mice and siRNA-silenced DCs, antigen-specific T cell activation assays, tumor challenge models\",\n      \"pmids\": [\"19349620\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise signaling pathway in DCs linking SR-A to T cell suppression not fully mapped\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"The mechanism of MSR1-mediated NF-κB suppression was resolved: MSR1 directly binds the TRAF-C domain of TRAF6, inhibiting TRAF6 dimerization and ubiquitination, thereby attenuating TLR4 signaling independently of MSR1's ligand-binding and endocytic functions.\",\n      \"evidence\": \"Co-IP with domain mutagenesis, NF-κB reporter assays, SR-A-KO macrophages and DCs, in vivo LPS endotoxic shock model\",\n      \"pmids\": [\"21460221\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the MSR1–TRAF6 interaction not determined\", \"Whether this mechanism operates in all MSR1-expressing cell types is untested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"MSR1 was shown to function as a tumor suppressor in leukemia stem cells: BCR-ABL downregulates Msr1, and Msr1 deletion accelerates CML by enhancing LSC self-renewal through the PI3K-AKT/β-catenin pathway, revealing a non-immune role for MSR1.\",\n      \"evidence\": \"BCR-ABL-induced CML mouse model crossed with Msr1-KO, microarray, cell cycle and apoptosis assays\",\n      \"pmids\": [\"21596859\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How BCR-ABL transcriptionally silences Msr1 not defined\", \"Relevance to human CML not validated\", \"Single lab\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"MSR1's ligand repertoire was expanded to include dsRNA and soluble amyloid-β with defined domain requirements: basic residues in the collagen-like domain mediate dsRNA binding and transport to TLR3-containing endosomes, while Scara1 deficiency accelerates Aβ accumulation in Alzheimer's models.\",\n      \"evidence\": \"RNAi knockdown/exogenous rescue in hepatocytes for dsRNA/TLR3; Scara1-null × PS1-APP mouse cross for Aβ clearance\",\n      \"pmids\": [\"23717201\", \"23799536\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether dsRNA transport and Aβ clearance use overlapping or distinct endosomal pathways unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Transcriptional regulation of MSR1 was clarified: PPARγ negatively regulates MSR1 expression, as demonstrated by LOX-1 abrogation-induced MSR1 upregulation reversed by PPARγ agonist.\",\n      \"evidence\": \"LOX-1-KO macrophages, troglitazone (PPARγ agonist) rescue, mRNA/protein quantification\",\n      \"pmids\": [\"23333385\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether PPARγ directly binds the MSR1 promoter not tested\", \"Single lab\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Post-translational regulation of MSR1 function was defined: dual N-glycosylation sites are critical for oligomeric Aβ internalization, even when surface targeting is preserved, establishing glycosylation as a determinant of ligand-specific receptor function.\",\n      \"evidence\": \"N-glycosylation site mutagenesis, surface targeting vs. oAβ internalization assays in transfected cells\",\n      \"pmids\": [\"26892079\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo relevance of glycosylation-dependent Aβ uptake not demonstrated\", \"Single lab\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"MSR1 was established as a central DAMP clearance receptor in ischemic brain, with its transcription controlled by MAFB: combined Msr1/Marco deficiency in myeloid cells impaired DAMP clearance, worsened neuroinflammation, and exacerbated neuronal injury in stroke.\",\n      \"evidence\": \"Msr1/Marco-KO mice in ischemic stroke model, MAFB-deficient mice, in vitro DAMP internalization assays, Am80 pharmacological rescue\",\n      \"pmids\": [\"28394332\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Individual contribution of Msr1 vs. Marco to each DAMP class in vivo not fully separated\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"LPS-induced MSR1 upregulation was mapped to the MAPK/ERK pathway: MEK inhibitors specifically blocked LPS-induced CD204 expression and acetylated-LDL uptake without affecting CD36, separating the transcriptional control of these two scavenger receptors.\",\n      \"evidence\": \"Mouse bone marrow macrophages treated with LPS ± MEK inhibitors (U0126, PD0325901), CD204/CD36 expression and Ac-LDL uptake\",\n      \"pmids\": [\"29032172\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Transcription factor downstream of ERK that directly activates MSR1 promoter not identified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"MSR1 was identified as a clearance receptor for von Willebrand factor, binding VWF in a calcium-dependent manner via VWF A1/D4 domains; SR-AI deficiency reduced VWF clearance in vivo and VWF gain-of-clearance mutants showed enhanced SR-AI binding.\",\n      \"evidence\": \"Purified SR-AI binding assays, SR-AI-KO mice with hydrodynamic VWF gene transfer, VWF mutant binding studies\",\n      \"pmids\": [\"29326120\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of MSR1 vs. other VWF clearance receptors (LRP1, ASGPR) not quantified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"The intracellular signaling mechanism of MSR1 on phagosomes was elucidated: K63-polyubiquitylation of MSR1 recruits the TAK1/MKK7/JNK complex, driving pro-inflammatory reprogramming of M2 macrophages, revealing how MSR1 converts from scavenger to signal transducer.\",\n      \"evidence\": \"Phagosomal proteomics, K63-ubiquitylation assays, MSR1-KO macrophages, JNK inhibition, human ovarian cancer tissue validation\",\n      \"pmids\": [\"31028084\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligase responsible for K63-ubiquitylation of MSR1 not identified\", \"Whether this phagosomal signaling occurs with all MSR1 ligands unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"The structural basis of MSR1-mediated dead cell recognition was solved: crystal structure of the SRCR domain at 1.8 Å revealed a Ca²⁺-binding site, and mass spectrometry identified spectrin as the specific dead-cell ligand recognized by the SRCR domain.\",\n      \"evidence\": \"X-ray crystallography, mass spectrometry, SRCR domain mutagenesis, cell-based internalization assays\",\n      \"pmids\": [\"31653705\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How SRCR-mediated and collagen-domain-mediated ligand recognition are coordinated in the native trimer unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"MSR1-mediated PI3K/AKT/GSK3β/β-catenin signaling in macrophages was linked to M2 polarization and osteogenic differentiation: MSR1 activates this pathway targeting PGC1α to enhance mitochondrial oxidative phosphorylation and promote bone formation in vivo.\",\n      \"evidence\": \"MSR1-KO mice in tibial defect model, BMDM/BMSC co-culture, RNA-seq, Western blotting\",\n      \"pmids\": [\"31903103\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How MSR1 activates PI3K — direct interaction vs. co-receptor involvement — not resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"MSR1 was identified as a ferritin receptor on neutrophils that triggers NETosis (via PAD4, NE, ROS), establishing a new cell-type-specific function; Msr1 ablation protected mice from ferritin-induced hyperinflammation, relevant to adult-onset Still's disease.\",\n      \"evidence\": \"Msr1-KO mice with ferritin administration, neutrophil depletion, NET formation assays, AOSD patient validation\",\n      \"pmids\": [\"36357401\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream signaling events between MSR1 engagement and PAD4/ROS activation on neutrophils not fully mapped\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: the E3 ubiquitin ligase responsible for K63-polyubiquitylation of MSR1, the structural basis of the MSR1–TRAF6 interaction, how the collagen-like domain and SRCR domain coordinate ligand discrimination in the native trimer, and whether MSR1's diverse signaling outputs (JNK, NF-κB suppression, PI3K/AKT, AMPK/mTOR) are selected by specific ligands or by cell-type context.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No E3 ligase identified for MSR1 K63-ubiquitylation\", \"No full-length MSR1 trimer structure available\", \"Ligand-specific vs. cell-type-specific signaling determinants unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [0, 1, 4, 10, 15, 9]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 6, 7]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [18, 26]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 4, 9, 10, 15, 23]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [2, 4]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 6, 7, 15, 17, 19]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 3, 12, 13, 22, 24]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [5, 14]},\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"TRAF6\",\n      \"MERTK\",\n      \"TAK1\",\n      \"MKK7\",\n      \"MAFB\",\n      \"SPTBN1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}