{"gene":"MARCO","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":1998,"finding":"The bacteria-binding region of human MARCO was localized to a region proximal to the cysteine-rich part of the COOH-terminal domain V (SRCR domain). The intrachain disulfide bond pattern of domain V was established: cysteine pairs C1-C5, C2-C6, and C3-C4. The human MARCO polypeptide lacks the intracellular cysteine present in mouse MARCO and two extracellular cysteines that form interchain disulfide bonds in murine protein.","method":"Binding studies with full-length and truncated MARCO variants expressed in cells; structural analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct mutagenesis/truncation binding assays plus disulfide bond mapping in a focused mechanistic study","pmids":["9468508"],"is_preprint":false},{"year":1999,"finding":"MARCO mediates binding of unopsonized environmental particles (TiO2, Fe2O3, latex beads) and unopsonized bacteria (E. coli, S. aureus) by alveolar macrophages. Transfection of COS cells with MARCO cDNA conferred particle-binding activity inhibitable by anti-MARCO mAb PAL-1, demonstrating MARCO is sufficient for this function.","method":"Monoclonal antibody inhibition assay, COS cell transfection with MARCO cDNA, flow cytometry, immunoprecipitation","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — COS cell reconstitution plus antibody inhibition replicated across hamster, mouse, and human systems in the same and subsequent papers","pmids":["10224290"],"is_preprint":false},{"year":1999,"finding":"MARCO expression on marginal zone macrophages of spleen and lymph node macrophages is required for capturing heat-killed bacteria in the splenic marginal zone in vivo. Inhibitory anti-MARCO mAbs blocked this capturing. LPS stimulation up-regulates MARCO surface expression on macrophages in a dose- and time-dependent fashion.","method":"In vivo bacterial clearance with inhibitory mAbs; LPS stimulation of J774.2 cells; immunohistochemistry","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo antibody blockade plus in vitro LPS upregulation, single lab","pmids":["9916718"],"is_preprint":false},{"year":1999,"finding":"Ectopic expression of MARCO in non-macrophage cell lines (CHO, HeLa, NIH3T3, 293) induces dramatic cell shape changes including formation of large lamellipodia-like structures and long dendritic processes, accompanied by disassembly of actin stress fibers and loss of focal adhesions. These morphogenic effects are dependent on cell adhesion, partially inhibited by dominant-negative Rac1 but not Cdc42, and require the proximal segment of the cysteine-rich domain V.","method":"Ectopic expression in cell lines, dominant-negative Rac1/Cdc42 mutants, truncated MARCO variants, fluorescence microscopy","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — multiple orthogonal methods (dominant-negative mutants, domain truncations, multiple cell lines) in one study","pmids":["10196178"],"is_preprint":false},{"year":2002,"finding":"The primary bacteria-binding region of MARCO is localized to domain V (SRCR domain). An arginine-rich segment containing the RXR motif within domain V is essential for high-affinity bacterial binding, as shown by deletion and single amino acid substitution variants. This differs from SR-A and SRCL, whose ligand-binding is localized to the collagenous domain.","method":"Deletion and single amino acid substitution mutagenesis of human and mouse MARCO; bacterial binding assays in transfected cells","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — systematic mutagenesis with multiple MARCO variants, focused mechanistic study","pmids":["11820786"],"is_preprint":false},{"year":2002,"finding":"Soluble recombinant MARCO (sMARCO) has a triple-helical collagenous structure confirmed by circular dichroism and rotary shadowing electron microscopy. sMARCO binds heat-killed and living bacteria and LPS. The O-side chain of LPS is not needed for bacterial recognition. The isolated monomeric SRCR domain showed low bacteria-binding activity, suggesting cooperation between the SRCR domain and the collagenous domain, or that the SRCR domain must be trimeric for high-affinity bacterial binding.","method":"Circular dichroism, protease-sensitive assay, rotary shadowing electron microscopy, cell-free bacterial binding assays, recombinant SRCR domain binding studies","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — multiple biophysical methods in a reconstituted cell-free system","pmids":["12097327"],"is_preprint":false},{"year":2003,"finding":"MARCO expression in dendritic cells (DCs) and microglia is associated with profound actin cytoskeleton rearrangements. Simple expression of MARCO was sufficient to induce cytoskeleton modifications (round, non-adherent morphology with punctate actin) in DCs. Knockdown of MARCO prevented DCs from reaching mature phenotype. MARCO expression is also associated with decreased antigen internalization capacity.","method":"MARCO transfection in immature DCs, MARCO knockdown (siRNA/antisense), actin cytoskeleton imaging, antigen uptake assays","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Moderate — gain-of-function and loss-of-function experiments with functional readouts in the same study","pmids":["12842997"],"is_preprint":false},{"year":2004,"finding":"MARCO-deficient mice show impaired clearance of S. pneumoniae from lungs, increased pulmonary inflammation and cytokine release, and diminished survival. In vitro binding of S. pneumoniae and in vivo uptake of unopsonized TiO2 particles by MARCO-/- alveolar macrophages were dramatically impaired. MARCO-mediated clearance of inert particles by alveolar macrophages prevents inflammatory responses otherwise initiated by other lung cells.","method":"MARCO-/- mouse model, pneumococcal pneumonia challenge, in vitro bacterial binding assay, in vivo particle uptake, cytokine measurement","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse with multiple orthogonal in vivo and in vitro readouts; replicated findings across multiple papers","pmids":["15263032"],"is_preprint":false},{"year":2005,"finding":"MARCO is the major binding receptor for unopsonized particles and bacteria on human alveolar macrophages. Anti-human MARCO mAb PLK-1 inhibited AM binding of TiO2 (63%), latex beads (67%), E. coli (~84%), and S. aureus (~41%). PLK-1 epitope was mapped to MARCO domain V between amino acid residues 420-431. Other SR antibodies failed to inhibit TiO2 or S. aureus binding.","method":"Functional screening of anti-AM hybridomas, mAb inhibition assay, COS cell transfection with truncated MARCO forms, flow cytometry, immunoprecipitation","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — inhibitory mAb plus COS cell transfection reconstitution, human alveolar macrophage validation, replicated across studies","pmids":["16237101"],"is_preprint":false},{"year":2005,"finding":"Ligation of MARCO on peritoneal macrophages costimulates IL-12 production (in contrast to SR-AI/II which inhibits it). MARCO-deficient macrophages show 2.7x lower IL-12 production in response to LPS+IFN-γ. Th1 adjuvants (LPS, CpG-ODN, IL-12, GM-CSF) increase MARCO expression, while Th2 factors (IL-4, M-CSF) decrease it—opposite to SR-A regulation.","method":"MARCO-/- and SR-AI/II-/- peritoneal macrophages, IL-12 ELISA, immobilized mAb ligation, pharmacological manipulation of macrophage polarization","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — KO macrophages plus receptor ligation experiments, multiple readouts","pmids":["16339540"],"is_preprint":false},{"year":2005,"finding":"Genetic ablation of MARCO leads to changes in splenic marginal zone organization and significant reduction of resident peritoneal macrophage population, suggesting roles in adhesion and migration. In MARCO/SR-A double-KO mice these effects are more apparent. MARCO-/- mice show impaired response to thymus-independent type 2 antigen (pneumococcal polysaccharide vaccine), dependent on intact marginal zone.","method":"MARCO-/- and MARCO/SR-A double-KO mice, histological analysis, macrophage population counts, pneumococcal polysaccharide vaccination, macrophage depletion/reconstitution","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — KO mouse model with multiple cellular and immunological readouts","pmids":["16339556"],"is_preprint":false},{"year":2006,"finding":"MARCO is the critical scavenger receptor for silica uptake and cytotoxicity in primary alveolar macrophages from C57BL/6 mice. No silica particle uptake or cell death occurred in MARCO-/- alveolar macrophages. Silica uptake was proportional to cell surface MARCO expression. Transfection of CHO cells with human MARCO conferred silica binding and silica-induced apoptosis.","method":"MARCO-/-, CD204-/-, CD36-/- single and double null mice, anti-MARCO antibody blockade, CHO cell transfection with human MARCO, particle uptake and cytotoxicity assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse plus reconstitution in CHO cells plus antibody blockade, multiple orthogonal approaches","pmids":["16984918"],"is_preprint":false},{"year":2006,"finding":"MARCO and SR-AI/II differentially recognize polyanionic ligands and surface proteins from Neisseria meningitidis; acetylated LDL (AcLDL) is a ligand for SR-A but not MARCO. Both mouse and human MARCO bind NM independently of NM LPS. MARCO and SR-A contribute independently to NM binding but neither is required for TNF-α and nitric oxide release.","method":"MARCO-/-, SR-A-/-, SR-A-MARCO-/- peritoneal macrophages; binding assays; TNF-α and NO measurement","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO macrophages with binding assays and cytokine readouts, single lab","pmids":["16525990"],"is_preprint":false},{"year":2006,"finding":"MARCO binds and costimulates macrophage responses to CpG oligodeoxynucleotides (PS-linked). MARCO-deficient thioglycollate-elicited peritoneal macrophages fail to produce IL-12 and NO in response to PS-CpG-ODN. MARCO is a signaling receptor that costimulates TLR9-mediated NO and IL-12 production.","method":"MARCO-/- peritoneal macrophages, IL-12 and NO assays, immobilized mAb MARCO ligation","journal":"Journal of leukocyte biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO macrophages plus receptor ligation, single lab","pmids":["16882874"],"is_preprint":false},{"year":2007,"finding":"Crystal structure of mouse MARCO SRCR domain was determined at 1.77-1.78 Å resolution. The monomer has a compact globular fold with a twisted five-stranded antiparallel β-sheet and a long loop covering a single α-helix. The dimer forms via β-strand swapping generating an eight-stranded β-sheet. A basic cluster (arginines on β-sheet) and an acidic cluster (in the long loop) both contribute to ligand binding. All arginines of the basic cluster are involved in ligand binding via cooperative mechanism. The acidic cluster binds Ca2+ ions, and Ca2+ depletion affects ligand binding.","method":"X-ray crystallography, SRCR domain mutants expressed in cells, ligand-binding assays, Ca2+ depletion experiments","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure at high resolution plus functional mutagenesis validation","pmids":["17405873"],"is_preprint":false},{"year":2007,"finding":"MARCO and SR-AI/II on alveolar macrophages protect against inhaled oxidants by scavenging oxidized lipids from lung lining fluid. MARCO-/- mice show greater lung injury after ozone exposure. Normal AMs show greater in vitro uptake of 5β,6β-epoxycholesterol compared to MARCO-/- AMs. Instillation of oxidized lipids (beta-epoxide, PON-GPC) causes neutrophil influx in MARCO-/- but not MARCO+/+ mice.","method":"MARCO-/- and SR-AI/II-/- mice, ozone and oxidized lipid exposure, BAL neutrophil counts, in vitro oxidized lipid uptake assay","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Moderate — KO mice with in vivo and in vitro experiments, multiple oxidant challenges","pmids":["17332894"],"is_preprint":false},{"year":2007,"finding":"MARCO and SR-AI/II expressed on lung dendritic cells limit DC migration from lung to draining lymph nodes. SR-A-deficient mice show significantly higher traffic of labeled DCs to thoracic lymph nodes after allergen challenge and enhanced T cell proliferation. This identifies a role for scavenger receptors on DCs in downregulating adaptive immune responses to aeroallergens.","method":"SR-AI/II-/- and MARCO-/- mice, OVA sensitization/challenge model, fluorescent antigen trafficking, adoptive transfer of OVA-specific T cells, lymph node DC counts","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mice with in vivo DC migration and T cell proliferation readouts, single lab","pmids":["17442975"],"is_preprint":false},{"year":2007,"finding":"Murine scavenger receptor MARCO recognizes polystyrene nanoparticles (20 nm, 200 nm, 1 μm). MARCO-transfected COS-7 cells associated with all three sizes of particles in a time-dependent manner; uptake was partially inhibited by polyG.","method":"COS-7 cell transfection with MARCO cDNA, fluorescence microscopy, atomic force microscopy, polyG inhibition","journal":"Toxicological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reconstitution in transfected cells, multiple particle sizes tested","pmids":["17361018"],"is_preprint":false},{"year":2008,"finding":"The SRCR domain of MARCO is required for particle binding of all tested particles (amorphous silica, crystalline silica, TiO2). TiO2 uniquely required divalent cations (Ca2+/Mg2+) for MARCO binding. TiO2 and silica particles bound to different motifs within the SRCR domain of MARCO, as shown by competitive binding studies.","method":"CHO cells transfected with human MARCO and MARCO mutants, competitive binding studies, divalent cation chelation, anti-MARCO antibody blockade","journal":"Toxicological sciences","confidence":"High","confidence_rationale":"Tier 1 / Moderate — domain mutagenesis with competitive binding and ion chelation in reconstituted cell system","pmids":["18836211"],"is_preprint":false},{"year":2009,"finding":"MARCO is required for macrophage cytokine responses to mycobacterial trehalose dimycolate (TDM/cord factor). MARCO tethers TDM to the macrophage and activates the TLR2/CD14 signaling pathway. TDM-induced NF-κB signaling requires MARCO in addition to TLR2 and CD14. MARCO-/- and MARCO-/-SRA-/- macrophages are defective in ERK1/2 activation and pro-inflammatory cytokine production in response to TDM. MARCO-expressing macrophages also produce markedly higher pro-inflammatory cytokines in response to virulent M. tuberculosis infection.","method":"NF-κB-luciferase reporter assay, MARCO-/-, TLR2-/-, CD14-/- macrophages, ERK1/2 phosphorylation, cytokine ELISA, M. tuberculosis infection","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple KO cell types, NF-κB reporter, kinase phosphorylation, cytokine assays, replicated with live bacteria","pmids":["19521507"],"is_preprint":false},{"year":2009,"finding":"MARCO deficiency in BXSB mice results in impaired clearance of apoptotic cells and a generalized defect in both endocytosis and phagocytosis. Reduced MARCO expression contributes to the development of SLE-like disease by failure to clear apoptotic cells, leading to anti-dsDNA antibody production.","method":"BXSB congenic mice, apoptotic cell clearance assays, endocytosis and phagocytosis assays, anti-dsDNA antibody measurement","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — congenic mouse model with functional phagocytosis assays and autoimmune readout","pmids":["19201851"],"is_preprint":false},{"year":2010,"finding":"SR-A and MARCO attenuate TLR4-mediated responses while enhancing responses by intracellular sensors TLR3, NOD2, and NALP3. This occurs because SR-A/MARCO-mediated rapid ligand internalization prevents sensing by surface TLRs while increasing ligand availability in intracellular compartments.","method":"SR-A-/-, MARCO-/-, SR-A-/-MARCO-/- mice; NF-κB reporter; TLR3, NOD2, NALP3 agonists; cytokine assays","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Moderate — triple KO mouse system with multiple innate receptor agonists and reporter assays","pmids":["21098741"],"is_preprint":false},{"year":2010,"finding":"MARCO physically interacts with formyl peptide receptors FPR and FPRL1, as demonstrated by co-immunoprecipitation and fluorescence microscopy. MARCO functionally interacts with FPRL1 in fucoidan-mediated ERK1/2 phosphorylation and cAMP signaling in glial cells. FPRL1 (not MARCO alone) is the primary mediator of Aβ1-42-induced ERK1/2 signaling.","method":"Co-immunoprecipitation, fluorescence microscopy, siRNA knockdown, ERK1/2 phosphorylation assay, cAMP measurement in astrocytes/microglia and HEK293 transfectants","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus functional signaling assays, single lab","pmids":["20141570"],"is_preprint":false},{"year":2011,"finding":"MARCO mediates cellular uptake of carbon nanotubes (MWCNTs) in MARCO-transfected CHO-K1 cells. MWCNTs are first tethered to MARCO-induced dendritic structures and then taken up via membrane ruffling (macropinocytosis-like). MARCO transfection also caused formation of dynamic dendritic structures.","method":"MARCO transfection in CHO-K1 cells, live cell microscopy, transmission electron microscopy, cytotoxicity assays","journal":"Toxicology and applied pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reconstitution in transfected cells with live imaging and EM, single lab","pmids":["22209804"],"is_preprint":false},{"year":2011,"finding":"MARCO is required for maximal TLR2- and Nod2-dependent NF-κB activation and signaling during S. pneumoniae nasopharyngeal colonization. MARCO-/- mice show impaired clearance, abrogated cytokine/chemokine production including type I IFNs, and reduced cellular recruitment to the nasopharynx.","method":"MARCO-/-, SRA-/-, MR-/- KO mice; nasopharyngeal colonization model; NF-κB reporter assays; cytokine/chemokine ELISA","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple KO mouse strains plus NF-κB reporter and cytokine assays","pmids":["23197261"],"is_preprint":false},{"year":2013,"finding":"HSV-1 glycoprotein C binds directly to purified MARCO with high affinity. MARCO functions together with heparan sulfate proteoglycans to mediate HSV-1 adsorption to epithelial cells. MARCO-/- mice have reduced susceptibility to HSV-1 infection. Ligands of MARCO inhibit HSV-1 adsorption and infection. Increasing MARCO expression enhances HSV-1 infection.","method":"Direct binding assay with purified MARCO and HSV-1 glycoprotein C, MARCO-/- mice infection model, MARCO overexpression, MARCO ligand competition assays, co-localization studies","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct binding assay with purified proteins plus in vivo KO mouse plus overexpression, multiple methods","pmids":["23739639"],"is_preprint":false},{"year":2014,"finding":"Vaccinia virus binds directly to MARCO on keratinocytes. Overexpression of MARCO increased susceptibility to VV infection. Ligands with affinity for MARCO or excess soluble MARCO competitively inhibited VV infection.","method":"Direct binding assay, MARCO overexpression, competitive inhibition with MARCO ligands, infection assays","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding plus overexpression plus competitive inhibition, single lab","pmids":["25089661"],"is_preprint":false},{"year":2014,"finding":"The SRCR domain of MARCO is critical for ligand binding, phagocytosis, TLR2-mediated pro-inflammatory signaling, and cellular adhesion. A naturally occurring transcript variant MARCOII lacking the SRCR domain abolished ligand binding. Co-expression of MARCO and MARCOII impaired phagocytic function (dominant-negative effect). MARCOII did not enhance TLR2-mediated signaling. MARCO-expressing cells were more adherent with dendritic-like phenotype, MARCOII-expressing cells were less adherent.","method":"MARCOII natural variant expression, co-expression dominant-negative assays, ligand binding, TLR2 NF-κB reporter, adhesion assays","journal":"Immunology and cell biology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — natural variant plus domain deletion plus dominant-negative approach, multiple functional readouts","pmids":["26888252"],"is_preprint":false},{"year":2014,"finding":"In the absence of MARCO, NLRP3 inflammasome activation and IL-1β release are increased in response to silica particles in alveolar macrophages. MARCO-/- AMs show greater cathepsin B release, caspase-1 activation, and acid sphingomyelinase activity, consistent with lysosomal membrane permeabilization (LMP). MARCO contributes to normal cholesterol recycling in macrophages; absence of MARCO leads to increased susceptibility to LMP.","method":"MARCO-/- vs. WT alveolar macrophages, NLRP3 inflammasome assays, cathepsin B and caspase-1 activation, cholesterol sequestration assay, U18666A treatment","journal":"Journal of immunology research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO macrophages with multiple mechanistic readouts, single lab","pmids":["25054161"],"is_preprint":false},{"year":2015,"finding":"MARCO is internalized by two pathways: (1) macropinocytosis via plasma membrane ruffling generating large vesicles, and (2) endocytosis followed by fusion with autophagosomes (amphisomes) generating small puncta that co-localize with LC3B and lysosomes. Trafficking of small puncta is regulated by tubulin but not actin.","method":"GFP-MARCO stable transfection in CHO-K1 cells, live fluorescence microscopy, co-localization with LC3B/lysosome markers, pharmacological inhibitors, tubulin/actin disruption","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live cell imaging with GFP-MARCO plus co-localization and pharmacological dissection, single lab","pmids":["26545255"],"is_preprint":false},{"year":2016,"finding":"HIF-2α suppresses MARCO-dependent phagocytosis under non-hypoxic conditions. Loss of HIF-2α induces MARCO expression via the antioxidant transcription factor NRF2 (shown by chromatin immunoprecipitation). Inhibition of mitochondrial ROS suppresses MARCO expression and phagocytic uptake. IL-4-induced HIF-2α also suppresses MARCO-dependent phagocytosis in vivo.","method":"Hif-2α-/- macrophages, chromatin immunoprecipitation for NRF2, mitochondrial ROS inhibition, phagocytosis assays, IL-4 treatment, in vivo bacterial clearance","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus KO macrophages plus pharmacological interventions, single lab","pmids":["27671111"],"is_preprint":false},{"year":2017,"finding":"MARCO mediates rapid adenovirus (HAdV-C5) transduction of macrophages. MARCO-blocking antibodies, MARCO gene-deficient cells, and soluble extracellular SR-A6 domain reduced adenovirus binding and transduction. MARCO-mediated adenovirus infection contributes to efficient innate virus recognition through the cytoplasmic DNA sensor cGAS, leading to IL-6, type I IFN, and IL-1α production.","method":"MARCO gene-deficient cells, MARCO-transfected cells, anti-MARCO blocking antibodies, soluble MARCO domain, cGAS pathway assays, cytokine measurement","journal":"mBio","confidence":"High","confidence_rationale":"Tier 2 / Moderate — KO cells plus reconstitution plus antibody blockade, multiple functional readouts including downstream cGAS signaling","pmids":["28765216"],"is_preprint":false},{"year":2017,"finding":"Akt and Nrf2 regulate MARCO expression in alveolar macrophages. Activation of Nrf2 (sulforaphane) or Akt (SC79) increases MARCO expression and improves MARCO-dependent phagocytosis. Akt increases MARCO expression through TFEB (transcription factor E-box); Akt-mediated MARCO increase was abrogated in TFEB-knockdown cells.","method":"RNAseq, pharmacological Nrf2/Akt activators, TFEB overexpression and knockdown, phagocytosis assays in IFN-γ-treated macrophages, in vivo mouse model","journal":"American journal of physiology. Lung cellular and molecular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pathway activation plus TFEB knockdown, single lab","pmids":["28408365"],"is_preprint":false},{"year":2017,"finding":"Free extracellular actin inhibits MARCO-dependent bacterial binding and uptake by macrophages. Actin binding was reduced in MARCO/SR-AI/II-deficient cell line and in MARCO-/- alveolar macrophages. Scavenger receptor inhibitors reduced binding of fluorescent actin, indicating actin binds to MARCO/SR-A.","method":"MARCO/SR-AI/II-deficient cell line, MARCO-/- mouse AMs, SR inhibitor competition assays, bacterial phagocytosis with free actin, Western blot for actin in BAL","journal":"American journal of physiology. Lung cellular and molecular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO cell line plus KO mice plus pharmacological blockade, single lab","pmids":["28385809"],"is_preprint":false},{"year":2018,"finding":"SR-A6 (MARCO) is an entry receptor for human adenovirus type C5 (HAdV-C5) in murine alveolar macrophage-like MPI cells. Knockout of SR-A6 reduced HAdV-C5 binding and transduction; expression of murine SR-A6 boosted virion binding and transduction in human cells. Deletion of the negatively charged hypervariable region 1 (HVR1) of hexon reduced HAdV-C5 binding, identifying hexon as the viral ligand for SR-A6. SR-A6 also facilitates macrophage entry of HAdV-B35 and HAdV-D26.","method":"SR-A6 KO cells, SR-A6 overexpression, soluble extracellular SR-A6 domain, proximity localization, hexon HVR1 deletion mutant, binding and transduction assays","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO plus overexpression plus viral mutant plus soluble receptor domain, multiple adenovirus types tested","pmids":["29522575"],"is_preprint":false},{"year":2019,"finding":"Multiple alphaviruses (CHIKV, RRV, ONNV) are cleared from murine circulation by MARCO (SR-A6) expressed on liver Kupffer cells. Clearance is independent of natural antibodies or complement factor C3, and strictly dependent on lysine residues at specific positions of the E2 glycoprotein (CHIKV/ONNV E2 K200, RRV E2 K251). Lysine-to-arginine substitutions at these sites allow escape from MARCO-mediated clearance.","method":"MARCO-/- mice, complement C3-/- mice, alphavirus E2 mutants (K→R), viremia measurements, Kupffer cell depletion","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mice plus viral mutagenesis with multiple alphavirus species, mutant escape approach","pmids":["31596239"],"is_preprint":false},{"year":2020,"finding":"MARCO mediates cellular internalization of exosomes via dynamin-dependent endocytosis and macropinocytosis. Exosome and nanoparticle association was greater in CHO-MARCO cells than controls. Exosomes and nanoparticles co-localized with GFP-MARCO. Inhibitory studies showed actin reorganization and dynamin are required for MARCO-mediated exosome internalization.","method":"CHO-K1 MARCO transfection, fluorescence microscopy, GFP-MARCO co-localization, dynamin inhibition (dynasore), actin disruption, quantitative uptake analysis","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reconstituted MARCO expression with pharmacological pathway dissection, single lab","pmids":["33311558"],"is_preprint":false},{"year":2020,"finding":"PI3K signaling (via PTEN deletion in macrophages) drives a beneficial adipose tissue macrophage (ATM) population characterized by MARCO-dependent lipid uptake and catabolism. Dual MARCO and myeloid PTEN deficiencies prevent lipid-buffering ATM generation, reversing the metabolic benefits. MARCO thus mediates PI3K-driven lipid uptake in adipose tissue macrophages.","method":"Macrophage-specific PTEN deletion mice, bone marrow chimeras with additional PTEN copies, dual MARCO/PTEN-KO mice, metabolic phenotyping, ATM characterization","journal":"Nature metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic models (PTEN-KO, dual MARCO/PTEN-KO, bone marrow chimeras) with metabolic and cellular readouts","pmids":["33199895"],"is_preprint":false},{"year":2020,"finding":"IL-10 enhances phagocytosis and bacterial killing of Acinetobacter baumannii by macrophages by upregulating MARCO expression via STAT3 activation. A. baumannii-induced STAT3 activation was impaired in IL-10-deficient macrophages, and STAT3 is essential for MARCO expression.","method":"IL-10-/- mice, recombinant IL-10 treatment, MARCO expression assays, STAT3 inhibition, phagocytosis assays, adoptive macrophage transfer","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mice plus STAT3 inhibition plus adoptive transfer, single lab","pmids":["32153580"],"is_preprint":false},{"year":2020,"finding":"Cigarette smoke extract (CSE) decreases MARCO expression by causing proteasomal degradation of the histone acetyltransferase p300. LPS-induced MARCO upregulation is Nrf2-dependent; CSE blocks Nrf2 acetylation by degrading p300, thereby suppressing MARCO expression. Proteasome inhibitors blocked CSE-induced p300 degradation and rescued MARCO expression.","method":"siRNA knockdown of Nrf2 and p300, CSE treatment, immunofluorescence, immunoprecipitation, proteasome inhibitors, qRT-PCR, flow cytometry","journal":"Respirology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA plus pharmacological inhibition with immunoprecipitation, single lab","pmids":["32512637"],"is_preprint":false},{"year":2021,"finding":"MARCO-expressing lymphatic endothelial cells (LECs) in the draining lymph node rapidly capture arthritogenic alphavirus particles following subcutaneous inoculation, limiting viral spread to the bloodstream. Upon reaching the bloodstream, alphavirus particles are cleared by MARCO-expressing Kupffer cells in the liver. MARCO-/- mice show elevated viremia, higher viral tissue burdens, and more severe disease.","method":"MARCO-/- mice, subcutaneous alphavirus inoculation, intravital imaging, LEC identification, Kupffer cell studies, viremia and tissue burden measurements","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mice plus cell-type identification plus imaging, identifying new cell type (LEC) for MARCO function","pmids":["34618370"],"is_preprint":false},{"year":2021,"finding":"MARCO directly binds to β5 integrin of tumor (SL4) cells, as shown by Co-IP. MARCO overexpression in macrophages elevated SYK, PI3K, and Rac1 activity, promoted formation of stress fibers and pseudopodia, and enhanced phagocytosis of tumor cells. MARCO knockdown decreased engulfment pseudopodia and inhibited tumor cell phagocytosis.","method":"Lentiviral MARCO knockdown/overexpression, Co-IP for β5 integrin interaction, SYK/PI3K/Rac1 activity assays, macrophage morphology analysis, tumor cell phagocytosis assay","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus KD/OE with downstream signaling and functional readouts, single lab","pmids":["34626585"],"is_preprint":false},{"year":2021,"finding":"TLR2 potentiates MARCO-mediated neuroinflammation by directly interacting with the SRCR domain of MARCO. Deletion of the SRCR domain disrupted both the inflammatory response and the TLR2-MARCO interaction. TLR2 knockdown in microglia and mouse substantia nigra decreased MARCO expression.","method":"MARCO overexpression/silencing, SRCR domain deletion mutants, TLR2 knockdown, neuroinflammation assays in microglia, in vivo substantia nigra injections, co-immunoprecipitation","journal":"Molecular neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain deletion mutants plus TLR2 KD plus co-IP, single lab","pmids":["34398403"],"is_preprint":false},{"year":2023,"finding":"MARCO SRCR domain mediates binding and internalization of CHIKV, ONNV, and RRV in vitro. MARCO SRCR domain shows species-specific effects on CHIKV internalization: SRCR domains from known amplification hosts (e.g., rhesus macaque) fail to promote CHIKV internalization, consistent with inefficient clearance of CHIKV from rhesus macaque circulation in vivo.","method":"MARCO expression constructs with SRCR domain mutations/swaps, in vitro virus binding and internalization assays, in vivo rhesus macaque viremia studies","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — domain-swap mutagenesis plus in vitro reconstitution plus in vivo species comparison","pmids":["37083332"],"is_preprint":false},{"year":2023,"finding":"MARCO suppresses IFN-β secretion from tumor-associated macrophages, reducing antigen presentation, CD8+ T cell infiltration, and function. Mechanistically, MARCO promotes clearance of dying tumor cells by macrophages, reducing tumor-derived cGAMP and ATP accumulation in the tumor microenvironment and inhibiting STING-IFN-β pathway activation mediated by P2X7R in MARCO+ TAMs.","method":"Clinical specimens, in vitro macrophage assays, in vivo mouse tumor models, cGAMP/ATP measurement, STING pathway assays, anti-MARCO + anti-PD-L1 combination treatment","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo experiments with mechanistic pathway assays, single lab","pmids":["38065400"],"is_preprint":false},{"year":2023,"finding":"Cancer cells upregulate MARCO on human macrophages via IL-6-induced STAT3 activation and also via sphingosine-1-phosphate receptor (S1PR)-mediated IL-6 and IL-10 expression followed by STAT3 activation. MARCO ligation activates the MEK/ERK/p90RSK/CREB signaling cascade, leading to IL-10 expression and STAT3-dependent PD-L1 upregulation.","method":"Human macrophage MARCO expression assays, STAT3 inhibition, S1PR inhibition, MARCO ligation with mAb, MEK/ERK/CREB pathway assays, PD-L1 expression measurement","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological pathway inhibition and receptor ligation assays, single lab","pmids":["37212598"],"is_preprint":false},{"year":2006,"finding":"Phage display screening of soluble MARCO revealed that the SRCR domain contains the major ligand-binding site. Surface plasmon resonance showed sMARCO binds LPS and lipoteichoic acid, but with much lower affinity than polyinosinic acid. Hydrophobic peptides (VRWGSFAAWL, RLNWAWWLSY) bound to the SRCR domain. Minor sequence changes in the MARCO SRCR domain can profoundly affect binding of acetylated LDL, identifying the SRCR domain as crucial for AcLDL binding in MARCO.","method":"Phage display, surface plasmon resonance, chimeric scavenger receptor binding studies, acetylated LDL binding assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — surface plasmon resonance plus phage display plus chimeric receptor mutagenesis in one study","pmids":["16524885"],"is_preprint":false}],"current_model":"MARCO (SR-A6) is a trimeric class A scavenger receptor constitutively expressed on alveolar macrophages, splenic marginal zone macrophages, and lymph node macrophages, with inducible expression on other macrophages during infection; it uses its C-terminal SRCR domain—containing a basic arginine-rich cluster and a Ca2+-dependent acidic cluster—to directly bind unopsonized bacteria (via LPS, lipoteichoic acid, and bacterial surface components), environmental particles (silica, TiO2, nanoparticles), oxidized lipids, and diverse viral ligands including HSV-1 gC and adenovirus hexon, mediating phagocytosis and clearance; upon ligand engagement, MARCO acts as a co-receptor that cooperates with TLR2/CD14 (for TDM and S. pneumoniae), TLR9 (for CpG-ODN), and Nod2 to amplify NF-κB and MAPK (ERK1/2) pro-inflammatory signaling, while simultaneously internalizing surface TLR4 ligands to limit surface TLR4 responses and enhance intracellular TLR3/NOD2/NALP3 sensing; its expression is positively regulated by LPS via NF-κB, by Nrf2 (whose acetylation by p300 is blocked by cigarette smoke), and by the Akt-TFEB axis, and is suppressed by HIF-2α through tempering of mitochondrial ROS; MARCO expression in dendritic cells and microglia drives Rac1-dependent actin cytoskeleton rearrangement and morphological maturation while reducing antigen internalization, and in adipose tissue macrophages mediates PI3K-driven lipid uptake to preserve metabolic health; in the circulation, MARCO on liver Kupffer cells and lymphatic endothelial cells clears alphaviruses in a species- and SRCR domain-dependent manner dictated by specific lysine residues on viral E2 glycoproteins."},"narrative":{"mechanistic_narrative":"MARCO (SR-A6) is a trimeric class A scavenger receptor of macrophages that mediates the direct, opsonin-independent recognition and clearance of bacteria, environmental particles, modified lipids, and viruses, while doubling as a signaling co-receptor that shapes innate and adaptive immune responses [PMID:10224290, PMID:15263032, PMID:19521507]. Its ligand-binding activity resides in the C-terminal SRCR domain (domain V): an arginine-rich basic cluster centered on an RXR motif and a Ca2+-coordinating acidic cluster cooperatively engage diverse ligands, with the trimeric, collagen-stalked architecture conferring high-affinity binding [PMID:11820786, PMID:12097327, PMID:17405873, PMID:16524885]. Through this domain MARCO is sufficient to bind and internalize unopsonized bacteria, TiO2, silica, nanoparticles, oxidized lipids, exosomes, and viral ligands including HSV-1 glycoprotein C and the adenovirus hexon hypervariable region, and is required in vivo for alveolar-macrophage clearance of S. pneumoniae and inhaled particles and for splenic marginal-zone capture of bacteria [PMID:10224290, PMID:9916718, PMID:15263032, PMID:16237101, PMID:16984918, PMID:17332894, PMID:18836211, PMID:23739639, PMID:29522575, PMID:33311558, PMID:16524885]. Beyond clearance, MARCO functions as a co-receptor: it tethers mycobacterial trehalose dimycolate and pneumococcal ligands to amplify TLR2/CD14- and Nod2-dependent NF-κB and ERK1/2 signaling and costimulates TLR9 responses to CpG, yet by rapidly internalizing surface ligands it dampens TLR4 responses while routing ligands to intracellular sensors (TLR3, NOD2, NALP3, cGAS) [PMID:16882874, PMID:19521507, PMID:21098741, PMID:23197261, PMID:28765216]. Ectopic MARCO expression remodels the actin cytoskeleton through Rac1, driving lamellipodia and dendritic processes, focal-adhesion loss, dendritic-cell maturation with reduced antigen uptake, and constraint of DC migration to lymph nodes [PMID:10196178, PMID:12842997, PMID:17442975]. MARCO expression is induced by LPS and IL-10/STAT3, by the Akt–TFEB axis, and by Nrf2 (whose p300-dependent acetylation is disrupted by cigarette smoke), and is suppressed by HIF-2α via mitochondrial ROS [PMID:9916718, PMID:27671111, PMID:28408365, PMID:32153580, PMID:32512637]. In the circulation, MARCO on liver Kupffer cells and lymph-node lymphatic endothelial cells clears arthritogenic alphaviruses in a species- and SRCR-domain-dependent manner dictated by specific E2 lysine residues, and in adipose-tissue macrophages it drives PI3K-dependent lipid uptake supporting metabolic health [PMID:31596239, PMID:33199895, PMID:34618370, PMID:37083332]. Loss of MARCO impairs apoptotic-cell clearance and predisposes to SLE-like autoimmunity, and in tumors MARCO+ macrophages suppress STING/IFN-β responses, linking the receptor to disease [PMID:19201851, PMID:38065400].","teleology":[{"year":1998,"claim":"Localizing the bacteria-binding region established that MARCO recognizes ligands through its C-terminal SRCR domain rather than its collagenous stalk, defining where engagement occurs.","evidence":"Binding assays with truncated MARCO variants plus disulfide-bond mapping of domain V","pmids":["9468508"],"confidence":"High","gaps":["Atomic basis of binding not resolved at this stage","Did not identify which residues contact ligand"]},{"year":1999,"claim":"Reconstitution and in vivo blockade showed MARCO is sufficient and required for opsonin-independent capture of bacteria and environmental particles, defining its core scavenging function and LPS-inducible expression.","evidence":"COS-cell transfection, anti-MARCO mAb inhibition, in vivo splenic bacterial capture, LPS upregulation","pmids":["10224290","9916718"],"confidence":"High","gaps":["Downstream fate of internalized particles not defined","Signaling consequences of ligation not addressed"]},{"year":1999,"claim":"Ectopic expression revealed that MARCO is not merely a sink but actively remodels the actin cytoskeleton through Rac1, linking the receptor to cell morphology and adhesion.","evidence":"Ectopic expression in multiple cell lines with dominant-negative Rac1/Cdc42 and domain truncations","pmids":["10196178"],"confidence":"High","gaps":["Mechanism coupling SRCR domain to Rac1 not defined","No intracellular adaptor identified"]},{"year":2002,"claim":"Mutagenesis and biophysical reconstitution pinned ligand binding to an arginine-rich RXR motif and showed high-affinity binding requires the trimeric collagenous architecture, explaining how MARCO differs from related scavenger receptors.","evidence":"Deletion/substitution mutagenesis, circular dichroism, rotary-shadowing EM, cell-free binding of recombinant MARCO","pmids":["11820786","12097327"],"confidence":"High","gaps":["Three-dimensional structure not yet solved","Role of metal ions in binding not yet shown"]},{"year":2003,"claim":"Gain- and loss-of-function in dendritic cells and microglia established MARCO as a driver of cytoskeletal remodeling and maturation that simultaneously reduces antigen internalization, bridging scavenging and adaptive-immune regulation.","evidence":"MARCO transfection and knockdown in DCs with actin imaging and antigen-uptake assays","pmids":["12842997"],"confidence":"High","gaps":["Signaling pathway from MARCO to maturation not mapped","In vivo relevance to DC function not tested here"]},{"year":2004,"claim":"The MARCO-knockout mouse demonstrated a non-redundant in vivo role in clearing S. pneumoniae and inert particles from the lung, with loss causing excess inflammation, establishing physiological importance.","evidence":"MARCO-/- mice in pneumococcal challenge and particle-uptake assays with cytokine readouts","pmids":["15263032"],"confidence":"High","gaps":["Did not dissect signaling versus uptake contributions","Other lung pathogens not surveyed"]},{"year":2005,"claim":"Studies in alveolar and peritoneal macrophages and KO mice showed MARCO both confers human particle/bacterial binding and costimulates IL-12, and revealed its Th1-biased, SR-A-opposite expression regulation and roles in marginal-zone architecture.","evidence":"Inhibitory mAb mapping, COS-cell reconstitution, MARCO-/- macrophage IL-12 assays, splenic histology, vaccination","pmids":["16237101","16339540","16339556"],"confidence":"High","gaps":["Receptor that transduces costimulatory signal not identified","Mechanism of marginal-zone maintenance unclear"]},{"year":2006,"claim":"Ligand-spectrum mapping (phage display, SPR, KO macrophages) defined the SRCR domain as the dominant binding site distinguishing MARCO from SR-A, and extended ligands to CpG-ODN, nanoparticles, and Neisseria, establishing MARCO as a TLR9 costimulator.","evidence":"Phage display, surface plasmon resonance, chimeric receptor binding, COS-7 nanoparticle uptake, MARCO-/- CpG/IL-12 assays","pmids":["16524885","16882874","17361018","16525990"],"confidence":"High","gaps":["Relative affinities for physiological ligands not fully ranked","How MARCO delivers CpG to TLR9 compartment unclear"]},{"year":2007,"claim":"The crystal structure of the SRCR domain provided the atomic framework, showing a basic arginine cluster and a Ca2+-binding acidic loop that cooperatively engage ligands, and KO/DC studies extended function to oxidized-lipid scavenging and dampening adaptive responses.","evidence":"X-ray crystallography of mouse SRCR domain with mutagenesis; MARCO-/- mice in ozone/oxidized-lipid and DC-migration models","pmids":["17405873","17332894","17442975"],"confidence":"High","gaps":["Full-length trimer structure not determined","Structural basis for distinct particle-binding motifs not resolved"]},{"year":2009,"claim":"Mechanistic dissection of mycobacterial cord-factor sensing showed MARCO tethers TDM and is required for TLR2/CD14-dependent NF-κB and ERK1/2 activation, defining MARCO as a bona fide signaling co-receptor; KO mice also linked MARCO to apoptotic-cell clearance and autoimmunity.","evidence":"NF-κB reporter, MARCO/TLR2/CD14-/- macrophages, ERK phosphorylation, M. tuberculosis infection; BXSB mouse SLE model","pmids":["19521507","19201851"],"confidence":"High","gaps":["Physical MARCO-TLR2 contact not directly shown here","Adaptor coupling MARCO to MAPK unknown"]},{"year":2010,"claim":"Triple-KO studies clarified MARCO's dual signaling logic—internalization attenuates surface TLR4 responses while enhancing intracellular TLR3/NOD2/NALP3 sensing—and a co-IP identified formyl-peptide receptors as physical partners coupling MARCO to ERK/cAMP signaling.","evidence":"SR-A/MARCO single and double KO mice with innate-receptor agonists; co-IP and signaling assays with FPR/FPRL1 in glial cells","pmids":["21098741","20141570"],"confidence":"High","gaps":["FPRL1 interaction rests on single-lab co-IP without reciprocal in vivo validation","Compartmental routing mechanism not molecularly defined"]},{"year":2011,"claim":"In vivo colonization studies extended MARCO co-receptor function to Nod2- and TLR2-dependent NF-κB signaling during pneumococcal colonization, and cell studies showed nanotube uptake proceeds via MARCO-induced dendritic structures and macropinocytosis.","evidence":"MARCO/SRA/MR KO mice in nasopharyngeal colonization with NF-κB reporters; CHO-K1 MARCO transfection with live imaging and EM","pmids":["23197261","22209804"],"confidence":"High","gaps":["Order of Nod2 versus TLR2 engagement not resolved","Internalization route generality across ligands unclear"]},{"year":2013,"claim":"Direct binding of HSV-1 glycoprotein C to purified MARCO, with KO and overexpression mice, established MARCO as a viral receptor cooperating with heparan sulfate, broadening its role from bacterial to viral recognition.","evidence":"Direct binding assay with purified proteins, MARCO-/- and overexpression infection models, ligand competition","pmids":["23739639"],"confidence":"High","gaps":["Post-binding entry steps not detailed","Whether MARCO signals upon HSV-1 binding not addressed"]},{"year":2014,"claim":"Vaccinia binding, the SRCR-lacking MARCOII dominant-negative variant, particle-motif mapping, and silica/inflammasome studies together cemented the SRCR domain as essential for binding, phagocytosis, adhesion, and TLR2 signaling, and revealed MARCO restrains NLRP3 activation by limiting lysosomal damage.","evidence":"VV binding/competition; MARCOII co-expression dominant-negative; CHO competitive binding/ion chelation; MARCO-/- AM inflammasome assays","pmids":["25089661","26888252","18836211","25054161"],"confidence":"High","gaps":["Endogenous regulation of MARCOII splicing unknown","Link between cholesterol recycling and LMP not fully mechanistic"]},{"year":2015,"claim":"Live-imaging of GFP-MARCO defined two internalization routes—macropinocytosis and endocytosis to LC3B-positive amphisomes—clarifying the intracellular trafficking that underlies ligand delivery to degradative and sensing compartments.","evidence":"GFP-MARCO stable CHO-K1 cells with co-localization and pharmacological/cytoskeletal dissection","pmids":["26545255"],"confidence":"Medium","gaps":["Single-lab reconstituted system, not primary macrophages","Sorting determinants between the two routes unknown"]},{"year":2016,"claim":"Transcriptional-regulation studies positioned MARCO downstream of an NRF2-activating, HIF-2α-suppressing axis tuned by mitochondrial ROS, beginning to explain how phagocytic capacity is set by macrophage metabolic state.","evidence":"Hif-2α-/- macrophages, NRF2 ChIP, mitochondrial ROS inhibition, phagocytosis and bacterial-clearance assays","pmids":["27671111"],"confidence":"Medium","gaps":["Single-lab finding","Direct NRF2 occupancy of human MARCO promoter not shown"]},{"year":2017,"claim":"Adenovirus studies identified MARCO as a macrophage entry receptor via the negatively charged hexon HVR1, coupling viral uptake to cGAS sensing, while the Akt–TFEB and Nrf2 pathways and free extracellular actin were shown to regulate MARCO expression and ligand binding.","evidence":"MARCO KO/reconstituted cells, soluble SR-A6 domain, hexon HVR1 mutant, cGAS readouts; Akt/Nrf2/TFEB pharmacology and knockdown; actin competition in KO cells/mice","pmids":["28765216","28408365","28385809"],"confidence":"High","gaps":["Whether MARCO-cGAS coupling requires specific trafficking step unclear","Physiological source of free actin ligand in vivo uncertain"]},{"year":2018,"claim":"Receptor swaps and a hexon HVR1 deletion mutant formally defined hexon as the adenoviral ligand for SR-A6 across multiple adenovirus types, with species differences in receptor activity.","evidence":"SR-A6 KO and cross-species overexpression, soluble receptor domain, hexon HVR1 deletion, binding/transduction assays","pmids":["29522575"],"confidence":"High","gaps":["Structural basis of hexon-SRCR recognition not solved","In vivo consequence for adenoviral pathogenesis not established"]},{"year":2019,"claim":"Alphavirus clearance studies showed MARCO on Kupffer cells removes circulating CHIKV/RRV/ONNV in an antibody- and complement-independent manner dictated by specific E2 lysines, defining a sequence-specific antiviral clearance mechanism.","evidence":"MARCO-/- and C3-/- mice, alphavirus E2 K→R mutants, viremia, Kupffer-cell depletion","pmids":["31596239"],"confidence":"High","gaps":["Atomic contacts between E2 lysines and SRCR domain not resolved","Fate of captured virions in Kupffer cells unclear"]},{"year":2020,"claim":"Multiple studies expanded MARCO's roles: exosome internalization via dynamin/macropinocytosis, PI3K-driven beneficial lipid-buffering adipose macrophages, IL-10/STAT3-dependent induction enhancing bacterial killing, and cigarette-smoke suppression via p300 degradation blocking Nrf2 acetylation.","evidence":"CHO-MARCO exosome uptake; macrophage PTEN-KO and dual MARCO/PTEN-KO mice; IL-10-/- mice with STAT3 inhibition; CSE with siRNA and proteasome inhibition","pmids":["33311558","33199895","32153580","32512637"],"confidence":"High","gaps":["Direct exosome ligand on MARCO not identified","Whether smoke-induced MARCO loss explains COPD susceptibility not tested in patients"]},{"year":2021,"claim":"MARCO was shown to bind β5 integrin to drive SYK/PI3K/Rac1-dependent tumor-cell phagocytosis, to interact physically with TLR2 via its SRCR domain in neuroinflammation, and to capture alphaviruses on lymph-node lymphatic endothelial cells upstream of Kupffer-cell clearance.","evidence":"Co-IP for β5 integrin and TLR2 with SRCR deletion; MARCO KD/OE phagocytosis; MARCO-/- mice with intravital imaging of LEC alphavirus capture","pmids":["34626585","34398403","34618370"],"confidence":"Medium","gaps":["β5-integrin and TLR2 interactions rest on single-lab co-IPs without reciprocal validation","Whether LEC capture uses same E2-lysine determinants as Kupffer cells not tested"]},{"year":2023,"claim":"Domain-swap studies tied alphavirus internalization to the SRCR domain with species-specific efficiency matching amplification-host status, and tumor studies defined MARCO+ TAMs as immunosuppressive by clearing dying cells and damping STING/IFN-β signaling.","evidence":"SRCR domain mutants/swaps with in vitro virus internalization and rhesus viremia; clinical specimens, tumor models, cGAMP/ATP and STING assays, anti-MARCO+anti-PD-L1 treatment","pmids":["37083332","38065400","37212598"],"confidence":"High","gaps":["Mechanistic link between SRCR sequence and host range incomplete","Tumor STING-suppression pathway elements from single labs"]},{"year":null,"claim":"How MARCO physically couples ligand engagement to intracellular signaling (the adaptor or transducing partner driving Rac1, MAPK, and co-receptor amplification) and the full-length trimeric receptor structure remain undefined.","evidence":"No timeline discovery resolves a cytoplasmic signaling adaptor or full-length structure","pmids":[],"confidence":"Low","gaps":["No cytoplasmic signaling adaptor identified","No full-length trimer structure","Mechanism of ligand handoff to TLR/Nod/cGAS sensors not molecularly defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[1,7,8,11,25,34,36]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[25,31,34,35,40,43]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[15,37,46]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[19,21,24,13]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[19,21,42]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,8,11,25,34]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[29,36]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[29,28]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[7,19,21,24]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[1,7,11,29,36]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[19,21,31,24]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[20,44]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[15,37]}],"complexes":[],"partners":["TLR2","CD14","NOD2","TLR9","FPRL1","ITGB5"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UEW3","full_name":"Macrophage receptor MARCO","aliases":["Macrophage receptor with collagenous structure","Scavenger receptor class A member 2"],"length_aa":520,"mass_kda":52.7,"function":"Pattern recognition receptor (PRR) which binds Gram-positive and Gram-negative bacteria (PubMed:9468508). Also plays a role in binding of unopsonized particles by alveolar macrophages (By similarity). Binds to the secretoglobin SCGB3A2 (PubMed:12847263)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q9UEW3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MARCO","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MARCO","total_profiled":1310},"omim":[{"mim_id":"620129","title":"NYN DOMAIN- AND RETROVIRAL INTEGRASE-CONTAINING PROTEIN; NYNRIN","url":"https://www.omim.org/entry/620129"},{"mim_id":"620115","title":"DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 108; DEE108","url":"https://www.omim.org/entry/620115"},{"mim_id":"619862","title":"SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE 32; SCAR32","url":"https://www.omim.org/entry/619862"},{"mim_id":"619414","title":"MITOCHONDRIAL FISSION REGULATOR 1; MTFR1","url":"https://www.omim.org/entry/619414"},{"mim_id":"619089","title":"GIPC PDZ DOMAIN-CONTAINING FAMILY, MEMBER 2; GIPC2","url":"https://www.omim.org/entry/619089"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Golgi apparatus","reliability":"Approved"},{"location":"Vesicles","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"liver","ntpm":88.8},{"tissue":"lung","ntpm":188.3},{"tissue":"lymphoid tissue","ntpm":83.1}],"url":"https://www.proteinatlas.org/search/MARCO"},"hgnc":{"alias_symbol":["SCARA2","SR-A6"],"prev_symbol":[]},"alphafold":{"accession":"Q9UEW3","domains":[{"cath_id":"3.10.250.10","chopping":"424-520","consensus_level":"high","plddt":97.1139,"start":424,"end":520}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UEW3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UEW3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UEW3-F1-predicted_aligned_error_v6.png","plddt_mean":58.34},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MARCO","jax_strain_url":"https://www.jax.org/strain/search?query=MARCO"},"sequence":{"accession":"Q9UEW3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UEW3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UEW3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UEW3"}},"corpus_meta":[{"pmid":"15263032","id":"PMC_15263032","title":"The scavenger receptor MARCO is required for lung defense against pneumococcal pneumonia and inhaled particles.","date":"2004","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/15263032","citation_count":268,"is_preprint":false},{"pmid":"19521507","id":"PMC_19521507","title":"MARCO, TLR2, and CD14 are required for macrophage cytokine responses to mycobacterial trehalose dimycolate and Mycobacterium tuberculosis.","date":"2009","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/19521507","citation_count":253,"is_preprint":false},{"pmid":"9916718","id":"PMC_9916718","title":"Regulation and functional involvement of macrophage scavenger receptor MARCO in clearance of bacteria in vivo.","date":"1999","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/9916718","citation_count":204,"is_preprint":false},{"pmid":"33293426","id":"PMC_33293426","title":"Targeting MARCO and IL37R on Immunosuppressive Macrophages in Lung Cancer 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infection","url":"https://pubmed.ncbi.nlm.nih.gov/10758408","citation_count":149,"is_preprint":false},{"pmid":"16984918","id":"PMC_16984918","title":"MARCO mediates silica uptake and toxicity in alveolar macrophages from C57BL/6 mice.","date":"2006","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16984918","citation_count":140,"is_preprint":false},{"pmid":"9468508","id":"PMC_9468508","title":"Structure of the human macrophage MARCO receptor and characterization of its bacteria-binding region.","date":"1998","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9468508","citation_count":117,"is_preprint":false},{"pmid":"17332894","id":"PMC_17332894","title":"Protection against inhaled oxidants through scavenging of oxidized lipids by macrophage receptors MARCO and SR-AI/II.","date":"2007","source":"The Journal of clinical 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immunology","url":"https://pubmed.ncbi.nlm.nih.gov/28743433","citation_count":11,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50257,"output_tokens":12332,"usd":0.167876,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":23991,"output_tokens":7733,"usd":0.15664,"stage2_stop_reason":"end_turn"},"total_usd":0.324516,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"The bacteria-binding region of human MARCO was localized to a region proximal to the cysteine-rich part of the COOH-terminal domain V (SRCR domain). The intrachain disulfide bond pattern of domain V was established: cysteine pairs C1-C5, C2-C6, and C3-C4. The human MARCO polypeptide lacks the intracellular cysteine present in mouse MARCO and two extracellular cysteines that form interchain disulfide bonds in murine protein.\",\n      \"method\": \"Binding studies with full-length and truncated MARCO variants expressed in cells; structural analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct mutagenesis/truncation binding assays plus disulfide bond mapping in a focused mechanistic study\",\n      \"pmids\": [\"9468508\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"MARCO mediates binding of unopsonized environmental particles (TiO2, Fe2O3, latex beads) and unopsonized bacteria (E. coli, S. aureus) by alveolar macrophages. Transfection of COS cells with MARCO cDNA conferred particle-binding activity inhibitable by anti-MARCO mAb PAL-1, demonstrating MARCO is sufficient for this function.\",\n      \"method\": \"Monoclonal antibody inhibition assay, COS cell transfection with MARCO cDNA, flow cytometry, immunoprecipitation\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — COS cell reconstitution plus antibody inhibition replicated across hamster, mouse, and human systems in the same and subsequent papers\",\n      \"pmids\": [\"10224290\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"MARCO expression on marginal zone macrophages of spleen and lymph node macrophages is required for capturing heat-killed bacteria in the splenic marginal zone in vivo. Inhibitory anti-MARCO mAbs blocked this capturing. LPS stimulation up-regulates MARCO surface expression on macrophages in a dose- and time-dependent fashion.\",\n      \"method\": \"In vivo bacterial clearance with inhibitory mAbs; LPS stimulation of J774.2 cells; immunohistochemistry\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo antibody blockade plus in vitro LPS upregulation, single lab\",\n      \"pmids\": [\"9916718\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Ectopic expression of MARCO in non-macrophage cell lines (CHO, HeLa, NIH3T3, 293) induces dramatic cell shape changes including formation of large lamellipodia-like structures and long dendritic processes, accompanied by disassembly of actin stress fibers and loss of focal adhesions. These morphogenic effects are dependent on cell adhesion, partially inhibited by dominant-negative Rac1 but not Cdc42, and require the proximal segment of the cysteine-rich domain V.\",\n      \"method\": \"Ectopic expression in cell lines, dominant-negative Rac1/Cdc42 mutants, truncated MARCO variants, fluorescence microscopy\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — multiple orthogonal methods (dominant-negative mutants, domain truncations, multiple cell lines) in one study\",\n      \"pmids\": [\"10196178\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The primary bacteria-binding region of MARCO is localized to domain V (SRCR domain). An arginine-rich segment containing the RXR motif within domain V is essential for high-affinity bacterial binding, as shown by deletion and single amino acid substitution variants. This differs from SR-A and SRCL, whose ligand-binding is localized to the collagenous domain.\",\n      \"method\": \"Deletion and single amino acid substitution mutagenesis of human and mouse MARCO; bacterial binding assays in transfected cells\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — systematic mutagenesis with multiple MARCO variants, focused mechanistic study\",\n      \"pmids\": [\"11820786\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Soluble recombinant MARCO (sMARCO) has a triple-helical collagenous structure confirmed by circular dichroism and rotary shadowing electron microscopy. sMARCO binds heat-killed and living bacteria and LPS. The O-side chain of LPS is not needed for bacterial recognition. The isolated monomeric SRCR domain showed low bacteria-binding activity, suggesting cooperation between the SRCR domain and the collagenous domain, or that the SRCR domain must be trimeric for high-affinity bacterial binding.\",\n      \"method\": \"Circular dichroism, protease-sensitive assay, rotary shadowing electron microscopy, cell-free bacterial binding assays, recombinant SRCR domain binding studies\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple biophysical methods in a reconstituted cell-free system\",\n      \"pmids\": [\"12097327\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"MARCO expression in dendritic cells (DCs) and microglia is associated with profound actin cytoskeleton rearrangements. Simple expression of MARCO was sufficient to induce cytoskeleton modifications (round, non-adherent morphology with punctate actin) in DCs. Knockdown of MARCO prevented DCs from reaching mature phenotype. MARCO expression is also associated with decreased antigen internalization capacity.\",\n      \"method\": \"MARCO transfection in immature DCs, MARCO knockdown (siRNA/antisense), actin cytoskeleton imaging, antigen uptake assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function and loss-of-function experiments with functional readouts in the same study\",\n      \"pmids\": [\"12842997\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"MARCO-deficient mice show impaired clearance of S. pneumoniae from lungs, increased pulmonary inflammation and cytokine release, and diminished survival. In vitro binding of S. pneumoniae and in vivo uptake of unopsonized TiO2 particles by MARCO-/- alveolar macrophages were dramatically impaired. MARCO-mediated clearance of inert particles by alveolar macrophages prevents inflammatory responses otherwise initiated by other lung cells.\",\n      \"method\": \"MARCO-/- mouse model, pneumococcal pneumonia challenge, in vitro bacterial binding assay, in vivo particle uptake, cytokine measurement\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse with multiple orthogonal in vivo and in vitro readouts; replicated findings across multiple papers\",\n      \"pmids\": [\"15263032\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"MARCO is the major binding receptor for unopsonized particles and bacteria on human alveolar macrophages. Anti-human MARCO mAb PLK-1 inhibited AM binding of TiO2 (63%), latex beads (67%), E. coli (~84%), and S. aureus (~41%). PLK-1 epitope was mapped to MARCO domain V between amino acid residues 420-431. Other SR antibodies failed to inhibit TiO2 or S. aureus binding.\",\n      \"method\": \"Functional screening of anti-AM hybridomas, mAb inhibition assay, COS cell transfection with truncated MARCO forms, flow cytometry, immunoprecipitation\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — inhibitory mAb plus COS cell transfection reconstitution, human alveolar macrophage validation, replicated across studies\",\n      \"pmids\": [\"16237101\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Ligation of MARCO on peritoneal macrophages costimulates IL-12 production (in contrast to SR-AI/II which inhibits it). MARCO-deficient macrophages show 2.7x lower IL-12 production in response to LPS+IFN-γ. Th1 adjuvants (LPS, CpG-ODN, IL-12, GM-CSF) increase MARCO expression, while Th2 factors (IL-4, M-CSF) decrease it—opposite to SR-A regulation.\",\n      \"method\": \"MARCO-/- and SR-AI/II-/- peritoneal macrophages, IL-12 ELISA, immobilized mAb ligation, pharmacological manipulation of macrophage polarization\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO macrophages plus receptor ligation experiments, multiple readouts\",\n      \"pmids\": [\"16339540\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Genetic ablation of MARCO leads to changes in splenic marginal zone organization and significant reduction of resident peritoneal macrophage population, suggesting roles in adhesion and migration. In MARCO/SR-A double-KO mice these effects are more apparent. MARCO-/- mice show impaired response to thymus-independent type 2 antigen (pneumococcal polysaccharide vaccine), dependent on intact marginal zone.\",\n      \"method\": \"MARCO-/- and MARCO/SR-A double-KO mice, histological analysis, macrophage population counts, pneumococcal polysaccharide vaccination, macrophage depletion/reconstitution\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse model with multiple cellular and immunological readouts\",\n      \"pmids\": [\"16339556\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"MARCO is the critical scavenger receptor for silica uptake and cytotoxicity in primary alveolar macrophages from C57BL/6 mice. No silica particle uptake or cell death occurred in MARCO-/- alveolar macrophages. Silica uptake was proportional to cell surface MARCO expression. Transfection of CHO cells with human MARCO conferred silica binding and silica-induced apoptosis.\",\n      \"method\": \"MARCO-/-, CD204-/-, CD36-/- single and double null mice, anti-MARCO antibody blockade, CHO cell transfection with human MARCO, particle uptake and cytotoxicity assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse plus reconstitution in CHO cells plus antibody blockade, multiple orthogonal approaches\",\n      \"pmids\": [\"16984918\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"MARCO and SR-AI/II differentially recognize polyanionic ligands and surface proteins from Neisseria meningitidis; acetylated LDL (AcLDL) is a ligand for SR-A but not MARCO. Both mouse and human MARCO bind NM independently of NM LPS. MARCO and SR-A contribute independently to NM binding but neither is required for TNF-α and nitric oxide release.\",\n      \"method\": \"MARCO-/-, SR-A-/-, SR-A-MARCO-/- peritoneal macrophages; binding assays; TNF-α and NO measurement\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO macrophages with binding assays and cytokine readouts, single lab\",\n      \"pmids\": [\"16525990\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"MARCO binds and costimulates macrophage responses to CpG oligodeoxynucleotides (PS-linked). MARCO-deficient thioglycollate-elicited peritoneal macrophages fail to produce IL-12 and NO in response to PS-CpG-ODN. MARCO is a signaling receptor that costimulates TLR9-mediated NO and IL-12 production.\",\n      \"method\": \"MARCO-/- peritoneal macrophages, IL-12 and NO assays, immobilized mAb MARCO ligation\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO macrophages plus receptor ligation, single lab\",\n      \"pmids\": [\"16882874\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Crystal structure of mouse MARCO SRCR domain was determined at 1.77-1.78 Å resolution. The monomer has a compact globular fold with a twisted five-stranded antiparallel β-sheet and a long loop covering a single α-helix. The dimer forms via β-strand swapping generating an eight-stranded β-sheet. A basic cluster (arginines on β-sheet) and an acidic cluster (in the long loop) both contribute to ligand binding. All arginines of the basic cluster are involved in ligand binding via cooperative mechanism. The acidic cluster binds Ca2+ ions, and Ca2+ depletion affects ligand binding.\",\n      \"method\": \"X-ray crystallography, SRCR domain mutants expressed in cells, ligand-binding assays, Ca2+ depletion experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure at high resolution plus functional mutagenesis validation\",\n      \"pmids\": [\"17405873\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"MARCO and SR-AI/II on alveolar macrophages protect against inhaled oxidants by scavenging oxidized lipids from lung lining fluid. MARCO-/- mice show greater lung injury after ozone exposure. Normal AMs show greater in vitro uptake of 5β,6β-epoxycholesterol compared to MARCO-/- AMs. Instillation of oxidized lipids (beta-epoxide, PON-GPC) causes neutrophil influx in MARCO-/- but not MARCO+/+ mice.\",\n      \"method\": \"MARCO-/- and SR-AI/II-/- mice, ozone and oxidized lipid exposure, BAL neutrophil counts, in vitro oxidized lipid uptake assay\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mice with in vivo and in vitro experiments, multiple oxidant challenges\",\n      \"pmids\": [\"17332894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"MARCO and SR-AI/II expressed on lung dendritic cells limit DC migration from lung to draining lymph nodes. SR-A-deficient mice show significantly higher traffic of labeled DCs to thoracic lymph nodes after allergen challenge and enhanced T cell proliferation. This identifies a role for scavenger receptors on DCs in downregulating adaptive immune responses to aeroallergens.\",\n      \"method\": \"SR-AI/II-/- and MARCO-/- mice, OVA sensitization/challenge model, fluorescent antigen trafficking, adoptive transfer of OVA-specific T cells, lymph node DC counts\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mice with in vivo DC migration and T cell proliferation readouts, single lab\",\n      \"pmids\": [\"17442975\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Murine scavenger receptor MARCO recognizes polystyrene nanoparticles (20 nm, 200 nm, 1 μm). MARCO-transfected COS-7 cells associated with all three sizes of particles in a time-dependent manner; uptake was partially inhibited by polyG.\",\n      \"method\": \"COS-7 cell transfection with MARCO cDNA, fluorescence microscopy, atomic force microscopy, polyG inhibition\",\n      \"journal\": \"Toxicological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reconstitution in transfected cells, multiple particle sizes tested\",\n      \"pmids\": [\"17361018\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The SRCR domain of MARCO is required for particle binding of all tested particles (amorphous silica, crystalline silica, TiO2). TiO2 uniquely required divalent cations (Ca2+/Mg2+) for MARCO binding. TiO2 and silica particles bound to different motifs within the SRCR domain of MARCO, as shown by competitive binding studies.\",\n      \"method\": \"CHO cells transfected with human MARCO and MARCO mutants, competitive binding studies, divalent cation chelation, anti-MARCO antibody blockade\",\n      \"journal\": \"Toxicological sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — domain mutagenesis with competitive binding and ion chelation in reconstituted cell system\",\n      \"pmids\": [\"18836211\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"MARCO is required for macrophage cytokine responses to mycobacterial trehalose dimycolate (TDM/cord factor). MARCO tethers TDM to the macrophage and activates the TLR2/CD14 signaling pathway. TDM-induced NF-κB signaling requires MARCO in addition to TLR2 and CD14. MARCO-/- and MARCO-/-SRA-/- macrophages are defective in ERK1/2 activation and pro-inflammatory cytokine production in response to TDM. MARCO-expressing macrophages also produce markedly higher pro-inflammatory cytokines in response to virulent M. tuberculosis infection.\",\n      \"method\": \"NF-κB-luciferase reporter assay, MARCO-/-, TLR2-/-, CD14-/- macrophages, ERK1/2 phosphorylation, cytokine ELISA, M. tuberculosis infection\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple KO cell types, NF-κB reporter, kinase phosphorylation, cytokine assays, replicated with live bacteria\",\n      \"pmids\": [\"19521507\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"MARCO deficiency in BXSB mice results in impaired clearance of apoptotic cells and a generalized defect in both endocytosis and phagocytosis. Reduced MARCO expression contributes to the development of SLE-like disease by failure to clear apoptotic cells, leading to anti-dsDNA antibody production.\",\n      \"method\": \"BXSB congenic mice, apoptotic cell clearance assays, endocytosis and phagocytosis assays, anti-dsDNA antibody measurement\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — congenic mouse model with functional phagocytosis assays and autoimmune readout\",\n      \"pmids\": [\"19201851\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SR-A and MARCO attenuate TLR4-mediated responses while enhancing responses by intracellular sensors TLR3, NOD2, and NALP3. This occurs because SR-A/MARCO-mediated rapid ligand internalization prevents sensing by surface TLRs while increasing ligand availability in intracellular compartments.\",\n      \"method\": \"SR-A-/-, MARCO-/-, SR-A-/-MARCO-/- mice; NF-κB reporter; TLR3, NOD2, NALP3 agonists; cytokine assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — triple KO mouse system with multiple innate receptor agonists and reporter assays\",\n      \"pmids\": [\"21098741\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"MARCO physically interacts with formyl peptide receptors FPR and FPRL1, as demonstrated by co-immunoprecipitation and fluorescence microscopy. MARCO functionally interacts with FPRL1 in fucoidan-mediated ERK1/2 phosphorylation and cAMP signaling in glial cells. FPRL1 (not MARCO alone) is the primary mediator of Aβ1-42-induced ERK1/2 signaling.\",\n      \"method\": \"Co-immunoprecipitation, fluorescence microscopy, siRNA knockdown, ERK1/2 phosphorylation assay, cAMP measurement in astrocytes/microglia and HEK293 transfectants\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus functional signaling assays, single lab\",\n      \"pmids\": [\"20141570\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"MARCO mediates cellular uptake of carbon nanotubes (MWCNTs) in MARCO-transfected CHO-K1 cells. MWCNTs are first tethered to MARCO-induced dendritic structures and then taken up via membrane ruffling (macropinocytosis-like). MARCO transfection also caused formation of dynamic dendritic structures.\",\n      \"method\": \"MARCO transfection in CHO-K1 cells, live cell microscopy, transmission electron microscopy, cytotoxicity assays\",\n      \"journal\": \"Toxicology and applied pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reconstitution in transfected cells with live imaging and EM, single lab\",\n      \"pmids\": [\"22209804\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"MARCO is required for maximal TLR2- and Nod2-dependent NF-κB activation and signaling during S. pneumoniae nasopharyngeal colonization. MARCO-/- mice show impaired clearance, abrogated cytokine/chemokine production including type I IFNs, and reduced cellular recruitment to the nasopharynx.\",\n      \"method\": \"MARCO-/-, SRA-/-, MR-/- KO mice; nasopharyngeal colonization model; NF-κB reporter assays; cytokine/chemokine ELISA\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple KO mouse strains plus NF-κB reporter and cytokine assays\",\n      \"pmids\": [\"23197261\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"HSV-1 glycoprotein C binds directly to purified MARCO with high affinity. MARCO functions together with heparan sulfate proteoglycans to mediate HSV-1 adsorption to epithelial cells. MARCO-/- mice have reduced susceptibility to HSV-1 infection. Ligands of MARCO inhibit HSV-1 adsorption and infection. Increasing MARCO expression enhances HSV-1 infection.\",\n      \"method\": \"Direct binding assay with purified MARCO and HSV-1 glycoprotein C, MARCO-/- mice infection model, MARCO overexpression, MARCO ligand competition assays, co-localization studies\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct binding assay with purified proteins plus in vivo KO mouse plus overexpression, multiple methods\",\n      \"pmids\": [\"23739639\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Vaccinia virus binds directly to MARCO on keratinocytes. Overexpression of MARCO increased susceptibility to VV infection. Ligands with affinity for MARCO or excess soluble MARCO competitively inhibited VV infection.\",\n      \"method\": \"Direct binding assay, MARCO overexpression, competitive inhibition with MARCO ligands, infection assays\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding plus overexpression plus competitive inhibition, single lab\",\n      \"pmids\": [\"25089661\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The SRCR domain of MARCO is critical for ligand binding, phagocytosis, TLR2-mediated pro-inflammatory signaling, and cellular adhesion. A naturally occurring transcript variant MARCOII lacking the SRCR domain abolished ligand binding. Co-expression of MARCO and MARCOII impaired phagocytic function (dominant-negative effect). MARCOII did not enhance TLR2-mediated signaling. MARCO-expressing cells were more adherent with dendritic-like phenotype, MARCOII-expressing cells were less adherent.\",\n      \"method\": \"MARCOII natural variant expression, co-expression dominant-negative assays, ligand binding, TLR2 NF-κB reporter, adhesion assays\",\n      \"journal\": \"Immunology and cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — natural variant plus domain deletion plus dominant-negative approach, multiple functional readouts\",\n      \"pmids\": [\"26888252\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In the absence of MARCO, NLRP3 inflammasome activation and IL-1β release are increased in response to silica particles in alveolar macrophages. MARCO-/- AMs show greater cathepsin B release, caspase-1 activation, and acid sphingomyelinase activity, consistent with lysosomal membrane permeabilization (LMP). MARCO contributes to normal cholesterol recycling in macrophages; absence of MARCO leads to increased susceptibility to LMP.\",\n      \"method\": \"MARCO-/- vs. WT alveolar macrophages, NLRP3 inflammasome assays, cathepsin B and caspase-1 activation, cholesterol sequestration assay, U18666A treatment\",\n      \"journal\": \"Journal of immunology research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO macrophages with multiple mechanistic readouts, single lab\",\n      \"pmids\": [\"25054161\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MARCO is internalized by two pathways: (1) macropinocytosis via plasma membrane ruffling generating large vesicles, and (2) endocytosis followed by fusion with autophagosomes (amphisomes) generating small puncta that co-localize with LC3B and lysosomes. Trafficking of small puncta is regulated by tubulin but not actin.\",\n      \"method\": \"GFP-MARCO stable transfection in CHO-K1 cells, live fluorescence microscopy, co-localization with LC3B/lysosome markers, pharmacological inhibitors, tubulin/actin disruption\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live cell imaging with GFP-MARCO plus co-localization and pharmacological dissection, single lab\",\n      \"pmids\": [\"26545255\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"HIF-2α suppresses MARCO-dependent phagocytosis under non-hypoxic conditions. Loss of HIF-2α induces MARCO expression via the antioxidant transcription factor NRF2 (shown by chromatin immunoprecipitation). Inhibition of mitochondrial ROS suppresses MARCO expression and phagocytic uptake. IL-4-induced HIF-2α also suppresses MARCO-dependent phagocytosis in vivo.\",\n      \"method\": \"Hif-2α-/- macrophages, chromatin immunoprecipitation for NRF2, mitochondrial ROS inhibition, phagocytosis assays, IL-4 treatment, in vivo bacterial clearance\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus KO macrophages plus pharmacological interventions, single lab\",\n      \"pmids\": [\"27671111\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"MARCO mediates rapid adenovirus (HAdV-C5) transduction of macrophages. MARCO-blocking antibodies, MARCO gene-deficient cells, and soluble extracellular SR-A6 domain reduced adenovirus binding and transduction. MARCO-mediated adenovirus infection contributes to efficient innate virus recognition through the cytoplasmic DNA sensor cGAS, leading to IL-6, type I IFN, and IL-1α production.\",\n      \"method\": \"MARCO gene-deficient cells, MARCO-transfected cells, anti-MARCO blocking antibodies, soluble MARCO domain, cGAS pathway assays, cytokine measurement\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO cells plus reconstitution plus antibody blockade, multiple functional readouts including downstream cGAS signaling\",\n      \"pmids\": [\"28765216\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Akt and Nrf2 regulate MARCO expression in alveolar macrophages. Activation of Nrf2 (sulforaphane) or Akt (SC79) increases MARCO expression and improves MARCO-dependent phagocytosis. Akt increases MARCO expression through TFEB (transcription factor E-box); Akt-mediated MARCO increase was abrogated in TFEB-knockdown cells.\",\n      \"method\": \"RNAseq, pharmacological Nrf2/Akt activators, TFEB overexpression and knockdown, phagocytosis assays in IFN-γ-treated macrophages, in vivo mouse model\",\n      \"journal\": \"American journal of physiology. Lung cellular and molecular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pathway activation plus TFEB knockdown, single lab\",\n      \"pmids\": [\"28408365\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Free extracellular actin inhibits MARCO-dependent bacterial binding and uptake by macrophages. Actin binding was reduced in MARCO/SR-AI/II-deficient cell line and in MARCO-/- alveolar macrophages. Scavenger receptor inhibitors reduced binding of fluorescent actin, indicating actin binds to MARCO/SR-A.\",\n      \"method\": \"MARCO/SR-AI/II-deficient cell line, MARCO-/- mouse AMs, SR inhibitor competition assays, bacterial phagocytosis with free actin, Western blot for actin in BAL\",\n      \"journal\": \"American journal of physiology. Lung cellular and molecular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO cell line plus KO mice plus pharmacological blockade, single lab\",\n      \"pmids\": [\"28385809\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SR-A6 (MARCO) is an entry receptor for human adenovirus type C5 (HAdV-C5) in murine alveolar macrophage-like MPI cells. Knockout of SR-A6 reduced HAdV-C5 binding and transduction; expression of murine SR-A6 boosted virion binding and transduction in human cells. Deletion of the negatively charged hypervariable region 1 (HVR1) of hexon reduced HAdV-C5 binding, identifying hexon as the viral ligand for SR-A6. SR-A6 also facilitates macrophage entry of HAdV-B35 and HAdV-D26.\",\n      \"method\": \"SR-A6 KO cells, SR-A6 overexpression, soluble extracellular SR-A6 domain, proximity localization, hexon HVR1 deletion mutant, binding and transduction assays\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO plus overexpression plus viral mutant plus soluble receptor domain, multiple adenovirus types tested\",\n      \"pmids\": [\"29522575\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Multiple alphaviruses (CHIKV, RRV, ONNV) are cleared from murine circulation by MARCO (SR-A6) expressed on liver Kupffer cells. Clearance is independent of natural antibodies or complement factor C3, and strictly dependent on lysine residues at specific positions of the E2 glycoprotein (CHIKV/ONNV E2 K200, RRV E2 K251). Lysine-to-arginine substitutions at these sites allow escape from MARCO-mediated clearance.\",\n      \"method\": \"MARCO-/- mice, complement C3-/- mice, alphavirus E2 mutants (K→R), viremia measurements, Kupffer cell depletion\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mice plus viral mutagenesis with multiple alphavirus species, mutant escape approach\",\n      \"pmids\": [\"31596239\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"MARCO mediates cellular internalization of exosomes via dynamin-dependent endocytosis and macropinocytosis. Exosome and nanoparticle association was greater in CHO-MARCO cells than controls. Exosomes and nanoparticles co-localized with GFP-MARCO. Inhibitory studies showed actin reorganization and dynamin are required for MARCO-mediated exosome internalization.\",\n      \"method\": \"CHO-K1 MARCO transfection, fluorescence microscopy, GFP-MARCO co-localization, dynamin inhibition (dynasore), actin disruption, quantitative uptake analysis\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reconstituted MARCO expression with pharmacological pathway dissection, single lab\",\n      \"pmids\": [\"33311558\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PI3K signaling (via PTEN deletion in macrophages) drives a beneficial adipose tissue macrophage (ATM) population characterized by MARCO-dependent lipid uptake and catabolism. Dual MARCO and myeloid PTEN deficiencies prevent lipid-buffering ATM generation, reversing the metabolic benefits. MARCO thus mediates PI3K-driven lipid uptake in adipose tissue macrophages.\",\n      \"method\": \"Macrophage-specific PTEN deletion mice, bone marrow chimeras with additional PTEN copies, dual MARCO/PTEN-KO mice, metabolic phenotyping, ATM characterization\",\n      \"journal\": \"Nature metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic models (PTEN-KO, dual MARCO/PTEN-KO, bone marrow chimeras) with metabolic and cellular readouts\",\n      \"pmids\": [\"33199895\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IL-10 enhances phagocytosis and bacterial killing of Acinetobacter baumannii by macrophages by upregulating MARCO expression via STAT3 activation. A. baumannii-induced STAT3 activation was impaired in IL-10-deficient macrophages, and STAT3 is essential for MARCO expression.\",\n      \"method\": \"IL-10-/- mice, recombinant IL-10 treatment, MARCO expression assays, STAT3 inhibition, phagocytosis assays, adoptive macrophage transfer\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mice plus STAT3 inhibition plus adoptive transfer, single lab\",\n      \"pmids\": [\"32153580\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Cigarette smoke extract (CSE) decreases MARCO expression by causing proteasomal degradation of the histone acetyltransferase p300. LPS-induced MARCO upregulation is Nrf2-dependent; CSE blocks Nrf2 acetylation by degrading p300, thereby suppressing MARCO expression. Proteasome inhibitors blocked CSE-induced p300 degradation and rescued MARCO expression.\",\n      \"method\": \"siRNA knockdown of Nrf2 and p300, CSE treatment, immunofluorescence, immunoprecipitation, proteasome inhibitors, qRT-PCR, flow cytometry\",\n      \"journal\": \"Respirology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA plus pharmacological inhibition with immunoprecipitation, single lab\",\n      \"pmids\": [\"32512637\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MARCO-expressing lymphatic endothelial cells (LECs) in the draining lymph node rapidly capture arthritogenic alphavirus particles following subcutaneous inoculation, limiting viral spread to the bloodstream. Upon reaching the bloodstream, alphavirus particles are cleared by MARCO-expressing Kupffer cells in the liver. MARCO-/- mice show elevated viremia, higher viral tissue burdens, and more severe disease.\",\n      \"method\": \"MARCO-/- mice, subcutaneous alphavirus inoculation, intravital imaging, LEC identification, Kupffer cell studies, viremia and tissue burden measurements\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mice plus cell-type identification plus imaging, identifying new cell type (LEC) for MARCO function\",\n      \"pmids\": [\"34618370\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MARCO directly binds to β5 integrin of tumor (SL4) cells, as shown by Co-IP. MARCO overexpression in macrophages elevated SYK, PI3K, and Rac1 activity, promoted formation of stress fibers and pseudopodia, and enhanced phagocytosis of tumor cells. MARCO knockdown decreased engulfment pseudopodia and inhibited tumor cell phagocytosis.\",\n      \"method\": \"Lentiviral MARCO knockdown/overexpression, Co-IP for β5 integrin interaction, SYK/PI3K/Rac1 activity assays, macrophage morphology analysis, tumor cell phagocytosis assay\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus KD/OE with downstream signaling and functional readouts, single lab\",\n      \"pmids\": [\"34626585\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TLR2 potentiates MARCO-mediated neuroinflammation by directly interacting with the SRCR domain of MARCO. Deletion of the SRCR domain disrupted both the inflammatory response and the TLR2-MARCO interaction. TLR2 knockdown in microglia and mouse substantia nigra decreased MARCO expression.\",\n      \"method\": \"MARCO overexpression/silencing, SRCR domain deletion mutants, TLR2 knockdown, neuroinflammation assays in microglia, in vivo substantia nigra injections, co-immunoprecipitation\",\n      \"journal\": \"Molecular neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain deletion mutants plus TLR2 KD plus co-IP, single lab\",\n      \"pmids\": [\"34398403\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MARCO SRCR domain mediates binding and internalization of CHIKV, ONNV, and RRV in vitro. MARCO SRCR domain shows species-specific effects on CHIKV internalization: SRCR domains from known amplification hosts (e.g., rhesus macaque) fail to promote CHIKV internalization, consistent with inefficient clearance of CHIKV from rhesus macaque circulation in vivo.\",\n      \"method\": \"MARCO expression constructs with SRCR domain mutations/swaps, in vitro virus binding and internalization assays, in vivo rhesus macaque viremia studies\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — domain-swap mutagenesis plus in vitro reconstitution plus in vivo species comparison\",\n      \"pmids\": [\"37083332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MARCO suppresses IFN-β secretion from tumor-associated macrophages, reducing antigen presentation, CD8+ T cell infiltration, and function. Mechanistically, MARCO promotes clearance of dying tumor cells by macrophages, reducing tumor-derived cGAMP and ATP accumulation in the tumor microenvironment and inhibiting STING-IFN-β pathway activation mediated by P2X7R in MARCO+ TAMs.\",\n      \"method\": \"Clinical specimens, in vitro macrophage assays, in vivo mouse tumor models, cGAMP/ATP measurement, STING pathway assays, anti-MARCO + anti-PD-L1 combination treatment\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo experiments with mechanistic pathway assays, single lab\",\n      \"pmids\": [\"38065400\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Cancer cells upregulate MARCO on human macrophages via IL-6-induced STAT3 activation and also via sphingosine-1-phosphate receptor (S1PR)-mediated IL-6 and IL-10 expression followed by STAT3 activation. MARCO ligation activates the MEK/ERK/p90RSK/CREB signaling cascade, leading to IL-10 expression and STAT3-dependent PD-L1 upregulation.\",\n      \"method\": \"Human macrophage MARCO expression assays, STAT3 inhibition, S1PR inhibition, MARCO ligation with mAb, MEK/ERK/CREB pathway assays, PD-L1 expression measurement\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological pathway inhibition and receptor ligation assays, single lab\",\n      \"pmids\": [\"37212598\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Phage display screening of soluble MARCO revealed that the SRCR domain contains the major ligand-binding site. Surface plasmon resonance showed sMARCO binds LPS and lipoteichoic acid, but with much lower affinity than polyinosinic acid. Hydrophobic peptides (VRWGSFAAWL, RLNWAWWLSY) bound to the SRCR domain. Minor sequence changes in the MARCO SRCR domain can profoundly affect binding of acetylated LDL, identifying the SRCR domain as crucial for AcLDL binding in MARCO.\",\n      \"method\": \"Phage display, surface plasmon resonance, chimeric scavenger receptor binding studies, acetylated LDL binding assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — surface plasmon resonance plus phage display plus chimeric receptor mutagenesis in one study\",\n      \"pmids\": [\"16524885\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MARCO (SR-A6) is a trimeric class A scavenger receptor constitutively expressed on alveolar macrophages, splenic marginal zone macrophages, and lymph node macrophages, with inducible expression on other macrophages during infection; it uses its C-terminal SRCR domain—containing a basic arginine-rich cluster and a Ca2+-dependent acidic cluster—to directly bind unopsonized bacteria (via LPS, lipoteichoic acid, and bacterial surface components), environmental particles (silica, TiO2, nanoparticles), oxidized lipids, and diverse viral ligands including HSV-1 gC and adenovirus hexon, mediating phagocytosis and clearance; upon ligand engagement, MARCO acts as a co-receptor that cooperates with TLR2/CD14 (for TDM and S. pneumoniae), TLR9 (for CpG-ODN), and Nod2 to amplify NF-κB and MAPK (ERK1/2) pro-inflammatory signaling, while simultaneously internalizing surface TLR4 ligands to limit surface TLR4 responses and enhance intracellular TLR3/NOD2/NALP3 sensing; its expression is positively regulated by LPS via NF-κB, by Nrf2 (whose acetylation by p300 is blocked by cigarette smoke), and by the Akt-TFEB axis, and is suppressed by HIF-2α through tempering of mitochondrial ROS; MARCO expression in dendritic cells and microglia drives Rac1-dependent actin cytoskeleton rearrangement and morphological maturation while reducing antigen internalization, and in adipose tissue macrophages mediates PI3K-driven lipid uptake to preserve metabolic health; in the circulation, MARCO on liver Kupffer cells and lymphatic endothelial cells clears alphaviruses in a species- and SRCR domain-dependent manner dictated by specific lysine residues on viral E2 glycoproteins.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"MARCO (SR-A6) is a trimeric class A scavenger receptor of macrophages that mediates the direct, opsonin-independent recognition and clearance of bacteria, environmental particles, modified lipids, and viruses, while doubling as a signaling co-receptor that shapes innate and adaptive immune responses [#1, #7, #19]. Its ligand-binding activity resides in the C-terminal SRCR domain (domain V): an arginine-rich basic cluster centered on an RXR motif and a Ca2+-coordinating acidic cluster cooperatively engage diverse ligands, with the trimeric, collagen-stalked architecture conferring high-affinity binding [#4, #5, #14, #46]. Through this domain MARCO is sufficient to bind and internalize unopsonized bacteria, TiO2, silica, nanoparticles, oxidized lipids, exosomes, and viral ligands including HSV-1 glycoprotein C and the adenovirus hexon hypervariable region, and is required in vivo for alveolar-macrophage clearance of S. pneumoniae and inhaled particles and for splenic marginal-zone capture of bacteria [#1, #2, #7, #8, #11, #15, #18, #25, #34, #36, #46]. Beyond clearance, MARCO functions as a co-receptor: it tethers mycobacterial trehalose dimycolate and pneumococcal ligands to amplify TLR2/CD14- and Nod2-dependent NF-\\u03baB and ERK1/2 signaling and costimulates TLR9 responses to CpG, yet by rapidly internalizing surface ligands it dampens TLR4 responses while routing ligands to intracellular sensors (TLR3, NOD2, NALP3, cGAS) [#13, #19, #21, #24, #31]. Ectopic MARCO expression remodels the actin cytoskeleton through Rac1, driving lamellipodia and dendritic processes, focal-adhesion loss, dendritic-cell maturation with reduced antigen uptake, and constraint of DC migration to lymph nodes [#3, #6, #16]. MARCO expression is induced by LPS and IL-10/STAT3, by the Akt\\u2013TFEB axis, and by Nrf2 (whose p300-dependent acetylation is disrupted by cigarette smoke), and is suppressed by HIF-2\\u03b1 via mitochondrial ROS [#2, #30, #32, #38, #39]. In the circulation, MARCO on liver Kupffer cells and lymph-node lymphatic endothelial cells clears arthritogenic alphaviruses in a species- and SRCR-domain-dependent manner dictated by specific E2 lysine residues, and in adipose-tissue macrophages it drives PI3K-dependent lipid uptake supporting metabolic health [#35, #37, #40, #43]. Loss of MARCO impairs apoptotic-cell clearance and predisposes to SLE-like autoimmunity, and in tumors MARCO+ macrophages suppress STING/IFN-\\u03b2 responses, linking the receptor to disease [#20, #44].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Localizing the bacteria-binding region established that MARCO recognizes ligands through its C-terminal SRCR domain rather than its collagenous stalk, defining where engagement occurs.\",\n      \"evidence\": \"Binding assays with truncated MARCO variants plus disulfide-bond mapping of domain V\",\n      \"pmids\": [\"9468508\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic basis of binding not resolved at this stage\", \"Did not identify which residues contact ligand\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Reconstitution and in vivo blockade showed MARCO is sufficient and required for opsonin-independent capture of bacteria and environmental particles, defining its core scavenging function and LPS-inducible expression.\",\n      \"evidence\": \"COS-cell transfection, anti-MARCO mAb inhibition, in vivo splenic bacterial capture, LPS upregulation\",\n      \"pmids\": [\"10224290\", \"9916718\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream fate of internalized particles not defined\", \"Signaling consequences of ligation not addressed\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Ectopic expression revealed that MARCO is not merely a sink but actively remodels the actin cytoskeleton through Rac1, linking the receptor to cell morphology and adhesion.\",\n      \"evidence\": \"Ectopic expression in multiple cell lines with dominant-negative Rac1/Cdc42 and domain truncations\",\n      \"pmids\": [\"10196178\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism coupling SRCR domain to Rac1 not defined\", \"No intracellular adaptor identified\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Mutagenesis and biophysical reconstitution pinned ligand binding to an arginine-rich RXR motif and showed high-affinity binding requires the trimeric collagenous architecture, explaining how MARCO differs from related scavenger receptors.\",\n      \"evidence\": \"Deletion/substitution mutagenesis, circular dichroism, rotary-shadowing EM, cell-free binding of recombinant MARCO\",\n      \"pmids\": [\"11820786\", \"12097327\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Three-dimensional structure not yet solved\", \"Role of metal ions in binding not yet shown\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Gain- and loss-of-function in dendritic cells and microglia established MARCO as a driver of cytoskeletal remodeling and maturation that simultaneously reduces antigen internalization, bridging scavenging and adaptive-immune regulation.\",\n      \"evidence\": \"MARCO transfection and knockdown in DCs with actin imaging and antigen-uptake assays\",\n      \"pmids\": [\"12842997\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling pathway from MARCO to maturation not mapped\", \"In vivo relevance to DC function not tested here\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"The MARCO-knockout mouse demonstrated a non-redundant in vivo role in clearing S. pneumoniae and inert particles from the lung, with loss causing excess inflammation, establishing physiological importance.\",\n      \"evidence\": \"MARCO-/- mice in pneumococcal challenge and particle-uptake assays with cytokine readouts\",\n      \"pmids\": [\"15263032\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not dissect signaling versus uptake contributions\", \"Other lung pathogens not surveyed\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Studies in alveolar and peritoneal macrophages and KO mice showed MARCO both confers human particle/bacterial binding and costimulates IL-12, and revealed its Th1-biased, SR-A-opposite expression regulation and roles in marginal-zone architecture.\",\n      \"evidence\": \"Inhibitory mAb mapping, COS-cell reconstitution, MARCO-/- macrophage IL-12 assays, splenic histology, vaccination\",\n      \"pmids\": [\"16237101\", \"16339540\", \"16339556\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor that transduces costimulatory signal not identified\", \"Mechanism of marginal-zone maintenance unclear\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Ligand-spectrum mapping (phage display, SPR, KO macrophages) defined the SRCR domain as the dominant binding site distinguishing MARCO from SR-A, and extended ligands to CpG-ODN, nanoparticles, and Neisseria, establishing MARCO as a TLR9 costimulator.\",\n      \"evidence\": \"Phage display, surface plasmon resonance, chimeric receptor binding, COS-7 nanoparticle uptake, MARCO-/- CpG/IL-12 assays\",\n      \"pmids\": [\"16524885\", \"16882874\", \"17361018\", \"16525990\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative affinities for physiological ligands not fully ranked\", \"How MARCO delivers CpG to TLR9 compartment unclear\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"The crystal structure of the SRCR domain provided the atomic framework, showing a basic arginine cluster and a Ca2+-binding acidic loop that cooperatively engage ligands, and KO/DC studies extended function to oxidized-lipid scavenging and dampening adaptive responses.\",\n      \"evidence\": \"X-ray crystallography of mouse SRCR domain with mutagenesis; MARCO-/- mice in ozone/oxidized-lipid and DC-migration models\",\n      \"pmids\": [\"17405873\", \"17332894\", \"17442975\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length trimer structure not determined\", \"Structural basis for distinct particle-binding motifs not resolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Mechanistic dissection of mycobacterial cord-factor sensing showed MARCO tethers TDM and is required for TLR2/CD14-dependent NF-\\u03baB and ERK1/2 activation, defining MARCO as a bona fide signaling co-receptor; KO mice also linked MARCO to apoptotic-cell clearance and autoimmunity.\",\n      \"evidence\": \"NF-\\u03baB reporter, MARCO/TLR2/CD14-/- macrophages, ERK phosphorylation, M. tuberculosis infection; BXSB mouse SLE model\",\n      \"pmids\": [\"19521507\", \"19201851\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physical MARCO-TLR2 contact not directly shown here\", \"Adaptor coupling MARCO to MAPK unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Triple-KO studies clarified MARCO's dual signaling logic\\u2014internalization attenuates surface TLR4 responses while enhancing intracellular TLR3/NOD2/NALP3 sensing\\u2014and a co-IP identified formyl-peptide receptors as physical partners coupling MARCO to ERK/cAMP signaling.\",\n      \"evidence\": \"SR-A/MARCO single and double KO mice with innate-receptor agonists; co-IP and signaling assays with FPR/FPRL1 in glial cells\",\n      \"pmids\": [\"21098741\", \"20141570\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"FPRL1 interaction rests on single-lab co-IP without reciprocal in vivo validation\", \"Compartmental routing mechanism not molecularly defined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"In vivo colonization studies extended MARCO co-receptor function to Nod2- and TLR2-dependent NF-\\u03baB signaling during pneumococcal colonization, and cell studies showed nanotube uptake proceeds via MARCO-induced dendritic structures and macropinocytosis.\",\n      \"evidence\": \"MARCO/SRA/MR KO mice in nasopharyngeal colonization with NF-\\u03baB reporters; CHO-K1 MARCO transfection with live imaging and EM\",\n      \"pmids\": [\"23197261\", \"22209804\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Order of Nod2 versus TLR2 engagement not resolved\", \"Internalization route generality across ligands unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Direct binding of HSV-1 glycoprotein C to purified MARCO, with KO and overexpression mice, established MARCO as a viral receptor cooperating with heparan sulfate, broadening its role from bacterial to viral recognition.\",\n      \"evidence\": \"Direct binding assay with purified proteins, MARCO-/- and overexpression infection models, ligand competition\",\n      \"pmids\": [\"23739639\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Post-binding entry steps not detailed\", \"Whether MARCO signals upon HSV-1 binding not addressed\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Vaccinia binding, the SRCR-lacking MARCOII dominant-negative variant, particle-motif mapping, and silica/inflammasome studies together cemented the SRCR domain as essential for binding, phagocytosis, adhesion, and TLR2 signaling, and revealed MARCO restrains NLRP3 activation by limiting lysosomal damage.\",\n      \"evidence\": \"VV binding/competition; MARCOII co-expression dominant-negative; CHO competitive binding/ion chelation; MARCO-/- AM inflammasome assays\",\n      \"pmids\": [\"25089661\", \"26888252\", \"18836211\", \"25054161\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous regulation of MARCOII splicing unknown\", \"Link between cholesterol recycling and LMP not fully mechanistic\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Live-imaging of GFP-MARCO defined two internalization routes\\u2014macropinocytosis and endocytosis to LC3B-positive amphisomes\\u2014clarifying the intracellular trafficking that underlies ligand delivery to degradative and sensing compartments.\",\n      \"evidence\": \"GFP-MARCO stable CHO-K1 cells with co-localization and pharmacological/cytoskeletal dissection\",\n      \"pmids\": [\"26545255\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab reconstituted system, not primary macrophages\", \"Sorting determinants between the two routes unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Transcriptional-regulation studies positioned MARCO downstream of an NRF2-activating, HIF-2\\u03b1-suppressing axis tuned by mitochondrial ROS, beginning to explain how phagocytic capacity is set by macrophage metabolic state.\",\n      \"evidence\": \"Hif-2\\u03b1-/- macrophages, NRF2 ChIP, mitochondrial ROS inhibition, phagocytosis and bacterial-clearance assays\",\n      \"pmids\": [\"27671111\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab finding\", \"Direct NRF2 occupancy of human MARCO promoter not shown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Adenovirus studies identified MARCO as a macrophage entry receptor via the negatively charged hexon HVR1, coupling viral uptake to cGAS sensing, while the Akt\\u2013TFEB and Nrf2 pathways and free extracellular actin were shown to regulate MARCO expression and ligand binding.\",\n      \"evidence\": \"MARCO KO/reconstituted cells, soluble SR-A6 domain, hexon HVR1 mutant, cGAS readouts; Akt/Nrf2/TFEB pharmacology and knockdown; actin competition in KO cells/mice\",\n      \"pmids\": [\"28765216\", \"28408365\", \"28385809\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether MARCO-cGAS coupling requires specific trafficking step unclear\", \"Physiological source of free actin ligand in vivo uncertain\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Receptor swaps and a hexon HVR1 deletion mutant formally defined hexon as the adenoviral ligand for SR-A6 across multiple adenovirus types, with species differences in receptor activity.\",\n      \"evidence\": \"SR-A6 KO and cross-species overexpression, soluble receptor domain, hexon HVR1 deletion, binding/transduction assays\",\n      \"pmids\": [\"29522575\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of hexon-SRCR recognition not solved\", \"In vivo consequence for adenoviral pathogenesis not established\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Alphavirus clearance studies showed MARCO on Kupffer cells removes circulating CHIKV/RRV/ONNV in an antibody- and complement-independent manner dictated by specific E2 lysines, defining a sequence-specific antiviral clearance mechanism.\",\n      \"evidence\": \"MARCO-/- and C3-/- mice, alphavirus E2 K\\u2192R mutants, viremia, Kupffer-cell depletion\",\n      \"pmids\": [\"31596239\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic contacts between E2 lysines and SRCR domain not resolved\", \"Fate of captured virions in Kupffer cells unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Multiple studies expanded MARCO's roles: exosome internalization via dynamin/macropinocytosis, PI3K-driven beneficial lipid-buffering adipose macrophages, IL-10/STAT3-dependent induction enhancing bacterial killing, and cigarette-smoke suppression via p300 degradation blocking Nrf2 acetylation.\",\n      \"evidence\": \"CHO-MARCO exosome uptake; macrophage PTEN-KO and dual MARCO/PTEN-KO mice; IL-10-/- mice with STAT3 inhibition; CSE with siRNA and proteasome inhibition\",\n      \"pmids\": [\"33311558\", \"33199895\", \"32153580\", \"32512637\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct exosome ligand on MARCO not identified\", \"Whether smoke-induced MARCO loss explains COPD susceptibility not tested in patients\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"MARCO was shown to bind \\u03b25 integrin to drive SYK/PI3K/Rac1-dependent tumor-cell phagocytosis, to interact physically with TLR2 via its SRCR domain in neuroinflammation, and to capture alphaviruses on lymph-node lymphatic endothelial cells upstream of Kupffer-cell clearance.\",\n      \"evidence\": \"Co-IP for \\u03b25 integrin and TLR2 with SRCR deletion; MARCO KD/OE phagocytosis; MARCO-/- mice with intravital imaging of LEC alphavirus capture\",\n      \"pmids\": [\"34626585\", \"34398403\", \"34618370\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"\\u03b25-integrin and TLR2 interactions rest on single-lab co-IPs without reciprocal validation\", \"Whether LEC capture uses same E2-lysine determinants as Kupffer cells not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Domain-swap studies tied alphavirus internalization to the SRCR domain with species-specific efficiency matching amplification-host status, and tumor studies defined MARCO+ TAMs as immunosuppressive by clearing dying cells and damping STING/IFN-\\u03b2 signaling.\",\n      \"evidence\": \"SRCR domain mutants/swaps with in vitro virus internalization and rhesus viremia; clinical specimens, tumor models, cGAMP/ATP and STING assays, anti-MARCO+anti-PD-L1 treatment\",\n      \"pmids\": [\"37083332\", \"38065400\", \"37212598\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanistic link between SRCR sequence and host range incomplete\", \"Tumor STING-suppression pathway elements from single labs\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How MARCO physically couples ligand engagement to intracellular signaling (the adaptor or transducing partner driving Rac1, MAPK, and co-receptor amplification) and the full-length trimeric receptor structure remain undefined.\",\n      \"evidence\": \"No timeline discovery resolves a cytoplasmic signaling adaptor or full-length structure\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No cytoplasmic signaling adaptor identified\", \"No full-length trimer structure\", \"Mechanism of ligand handoff to TLR/Nod/cGAS sensors not molecularly defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [1, 7, 8, 11, 25, 34, 36]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [25, 31, 34, 35, 40, 43]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [15, 37, 46]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [19, 21, 24, 13]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [19, 21, 42]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 8, 11, 25, 34]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [29, 36]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [29, 28]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [7, 19, 21, 24]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [1, 7, 11, 29, 36]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [19, 21, 31, 24]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [20, 44]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [15, 37]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"TLR2\", \"CD14\", \"NOD2\", \"TLR9\", \"FPRL1\", \"ITGB5\"],\n    \"other_free_text\": []\n  }\n}\n```","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":8,"faith_total":8,"faith_pct":100.0}}