{"gene":"CCRL2","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":2008,"finding":"CCRL2 binds chemerin as a natural non-signaling ligand without triggering ligand internalization. Instead of internalizing chemerin, CCRL2 increases local concentrations of bioactive chemerin, presenting it to the signaling chemerin receptor CMKLR1 on nearby cells.","method":"Binding assays, in vivo passive cutaneous anaphylaxis model with CCRL2-deficient mice, functional comparison with 'silent' chemokine receptors","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal binding characterization in human and mouse, KO mouse phenotype, replicated across multiple subsequent studies","pmids":["18794339"],"is_preprint":false},{"year":2009,"finding":"CCRL2 (CRAM-B splice variant) binds the homeostatic chemokine CCL19 with affinity similar to CCR7, but unlike CCR7 does not trigger calcium mobilization or cell migration. CCRL2 constitutively recycles via clathrin-coated pits and internalizes CCL19 as well as anti-CRAM antibodies.","method":"Radioactive ligand binding assays, clathrin-mediated recycling assays, calcium flux assays, chemotaxis assays in CRAM-expressing cells","journal":"Immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (binding, functional assays, internalization), single lab","pmids":["20002784"],"is_preprint":false},{"year":2012,"finding":"CCRL2 is upregulated on vascular endothelial cells by proinflammatory stimuli via NF-κB and JAK/STAT signaling pathways. Chemerin binding to CCRL2 on endothelial cells triggers adhesion of CMKLR1+ lymphoid cells through an α4β1 integrin/VCAM-1-dependent mechanism. CCRL2 deficiency elevates plasma chemerin levels and impairs CMKLR1+ NK cell recruitment to airways during LPS-induced inflammation.","method":"Endothelial cell culture stimulation assays, NF-κB/JAK/STAT inhibitor experiments, CCRL2−/− mouse models, in vitro adhesion assays, in vivo LPS pulmonary inflammation model","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (KO mice, in vitro adhesion, signaling pathway inhibition, in vivo model), functional consequence clearly defined","pmids":["22696441"],"is_preprint":false},{"year":2016,"finding":"Chemerin binds CCRL2 with low nanomolar affinity but does not activate G proteins (Gαi1, Gαi2, Gαi3, Gαoa, Gαob) or recruit β-arrestin1/2 to CCRL2, in contrast to CMKLR1 and GPR1. CCRL2 also does not promote ERK1/2 phosphorylation upon chemerin binding, confirming it is a non-signaling receptor.","method":"BRET-based biosensors for G protein activation, β-arrestin recruitment assays, ERK1/2 phosphorylation assays, binding affinity measurements","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal biochemical assays (BRET, β-arrestin, ERK phosphorylation), rigorous comparison across three receptors","pmids":["27716822"],"is_preprint":false},{"year":2017,"finding":"CCRL2 constitutively forms homodimers and heterodimers with CXCR2. By heterodimerization with CXCR2, CCRL2 regulates CXCR2 membrane expression and promotes CXCR2-mediated β2-integrin activation. CCRL2-deficient mice show defective neutrophil recruitment and are protected in inflammatory arthritis models.","method":"Co-immunoprecipitation and dimerization assays, CCRL2−/− mouse inflammatory arthritis models, β2-integrin activation assays, CXCR2 membrane expression quantification","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP for heterodimerization, KO mouse phenotype in two disease models, defined molecular mechanism (β2-integrin activation)","pmids":["28743719"],"is_preprint":false},{"year":2017,"finding":"CCRL2 does not internalize or scavenge its ligand chemerin. CCRL2 undergoes weak constitutive, ligand-independent internalization and recycling (slower kinetics than ACKR3 or signaling receptors), colocalizing with EEA1/Rab5-positive early endosomes and Rab11-positive recycling compartments intracellularly.","method":"Cell membrane analysis, fluorescence colocalization with endosomal markers, scavenging assays in CCRL2-transfected cells and activated mouse endothelial cells, kinetics comparison","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (colocalization, kinetics, scavenging assays), single lab","pmids":["29056935"],"is_preprint":false},{"year":2019,"finding":"CCRL2 expressed by non-hematopoietic (endothelial) cells is required for lung tumor immune surveillance. CCRL2 deletion on endothelial cells reduces NK cell infiltration into lungs, promoting tumor progression. This effect is mediated through the CCRL2/chemerin/CMKLR1 axis.","method":"Ccrl2−/− mice in urethane-induced and KrasG12D/p53Flox lung tumor models, bone marrow chimeras, adoptive transfer experiments, flow cytometry of tumor infiltrates","journal":"Cancer immunology research","confidence":"High","confidence_rationale":"Tier 2 / Strong — bone marrow chimeras establishing non-hematopoietic cell dependency, multiple tumor models, KO phenotype replicated","pmids":["31484658"],"is_preprint":false},{"year":2021,"finding":"CCRL2 interacts directly with TLR4 on the macrophage cell surface to retain membrane TLR4 expression and enhance downstream MyD88-NF-κB inflammatory signaling, thereby promoting immunostimulatory macrophage activation and antitumor T-cell responses.","method":"Co-immunoprecipitation, CCRL2-deficient mouse melanoma models, macrophage depletion experiments, CD8+ T cell depletion, coinjection tumor model, TLR4-deficient mouse comparison","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP demonstrating CCRL2-TLR4 interaction, KO mouse phenotype in multiple tumor models, mechanistic pathway established (MyD88-NF-κB)","pmids":["33846258"],"is_preprint":false},{"year":2021,"finding":"CCRL2 expression by tumor cells can concentrate bioactive chemerin and reduce neoangiogenesis in a manner dependent on the chemerin/CMKLR1 axis. Loss of Ccrl2 accelerated papilloma development in chemical carcinogenesis, while CCRL2 gain-of-function delayed B16 and LLC tumor graft growth; both phenotypes were abrogated by chemerin or Cmklr1 knockout.","method":"DMBA/TPA skin carcinogenesis model, B16/LLC tumor graft models with CCRL2 overexpression/knockout, epistasis with chemerin−/− and Cmklr1−/− mice, angiogenesis assays","journal":"Cancers","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with chemerin and Cmklr1 KO, multiple tumor models, gain- and loss-of-function","pmids":["34638484"],"is_preprint":false},{"year":2022,"finding":"CCRL2 coprecipitates with JAK2 and potentiates JAK2-STAT interaction. CCRL2 knockdown in MDS92 and MDS-L cells decreases JAK2/STAT3/STAT5 phosphorylation. Erythroleukemia cells expressing JAK2V617F show less effect of CCRL2 knockdown, and fedratinib (JAK2 inhibitor) potentiates the CCRL2 knockdown effect, placing CCRL2 upstream of JAK2/STAT signaling.","method":"Co-immunoprecipitation (CCRL2-JAK2), shRNA knockdown, Western blot for phospho-JAK2/STAT3/STAT5, pharmacological JAK2 inhibition, in vivo xenograft models","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP establishing direct interaction, multiple KD experiments, genetic epistasis with JAK2V617F and JAK2 inhibitor","pmids":["35179961"],"is_preprint":false},{"year":2023,"finding":"CCRL2 is expressed as a hallmark of alveolar lung capillary endothelial cells and its expression is epigenetically regulated. Conditional endothelial-targeted ablation of CCRL2 or deletion of chemerin promotes lung tumor progression by reducing recruitment of CD27−CD11b+ mature NK cells. Treatment with 5-aza-2'-deoxycytidine upregulates endothelial CCRL2 expression, increases NK cell recruitment, and reduces lung tumor growth.","method":"scRNA-seq of tumor-infiltrating cells, conditional endothelial CCRL2 knockout, chemerin KO, 5-Aza treatment, flow cytometry of NK cell subsets, Kras/p53Flox lung tumor model","journal":"Cancer immunology research","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO, scRNA-seq, epigenetic regulation, multiple orthogonal methods","pmids":["37343073"],"is_preprint":false},{"year":2023,"finding":"Endothelial CCRL2 induced by disturbed flow recruits chemerin, which activates β2 integrin on monocytes via a protein disulfide isomerase-like enzymatic activity of chemerin (not via monocytic CMKLR1), enhancing ERK1/2 phosphorylation and monocyte adhesion, thereby promoting atherosclerotic plaque formation. CCRL2-/-ApoE-/- mice are protected against plaque formation.","method":"scRNA-seq of carotid arteries, CCRL2−/−ApoE−/− double KO mice on high-fat diet, Di-E-GSSG assay for PDI activity, proximity ligation assay for chemerin-β2 integrin interaction, ERK1/2 phosphorylation assays","journal":"Cardiovascular research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (PLA, enzymatic assay, double KO mice), mechanistic axis defined","pmids":["37279540"],"is_preprint":false},{"year":2023,"finding":"CCRL2 knockdown in MDS/sAML cells downregulates DNA methylation and PRC2 activity pathways and increases DNMT suppression by azacitidine. CCRL2 overexpression decreases azacitidine sensitivity. CCRL2 deletion increased azacitidine efficacy in an MDS-L xenograft model, establishing CCRL2 as a modulator of epigenetic regulatory pathways (DNMT levels) in MDS.","method":"shRNA knockdown and CCRL2 overexpression in MDS cell lines, in vitro azacitidine sensitivity assays, MDS-L xenograft model, pathway analysis","journal":"Haematologica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function, in vivo xenograft, single lab","pmids":["36519323"],"is_preprint":false},{"year":2024,"finding":"CCRL2 expressed on LepR+/CAR stromal cells in alveolar bone binds SFRP1 on the cell surface, amplifying SFRP1-mediated suppression of Wnt signaling under inflammatory conditions, thereby inhibiting osteogenic differentiation and impairing extraction socket bone healing in periodontitis. Ccrl2-KO mice show improved bone healing.","method":"Co-immunoprecipitation/binding assay for CCRL2-SFRP1 interaction, Ccrl2-KO mouse model with extraction socket periodontitis, Wnt signaling pathway analysis, histological assessment of bone healing","journal":"Journal of bone and mineral research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — binding assay and KO mouse phenotype, single lab, pathway placement via Wnt signaling","pmids":["38477792"],"is_preprint":false},{"year":2021,"finding":"CCRL2 functions as a coreceptor for HIV-2 primary isolates in vitro. NP-2/CD4/CCRL2 cells were infected by HIV-2MIR (and to a lesser extent HIV-1HAN2), as detected by viral antigen immunofluorescence, proviral DNA, reverse transcriptase activity, and syncytia formation.","method":"NP-2/CD4/CCRL2 cell infection assay, indirect immunofluorescence, Giemsa staining for syncytia, PCR for proviral DNA, RT activity measurement","journal":"Briefings in bioinformatics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal in vitro assays confirming coreceptor function, single lab, no in vivo validation","pmids":["33253374"],"is_preprint":false},{"year":2023,"finding":"CCRL2 antibody-based neutralization of chemerin binding did not attenuate CXCL8-induced human neutrophil degranulation or CXCL8-induced murine neutrophil recruitment to the peritoneum. This negative finding indicates that the ligand-binding function of CCRL2 is dispensable for CXCL8/CXCR2 signaling in neutrophils, suggesting that CCRL2-CXCR2 heterodimerization effects are independent of CCRL2 chemerin-binding capacity.","method":"Flow cytometry and Surface Plasmon Resonance microscopy (SPRm) for ligand binding confirmation, neutralizing antibody treatment, human neutrophil degranulation assays, murine peritoneal neutrophil recruitment","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — SPRm and flow cytometry confirming ligand specificity; pharmacological neutralization with functional readout; single lab negative result","pmids":["36662882"],"is_preprint":false},{"year":2025,"finding":"CCRL2 drives cell-autonomous IFN-γ signaling in AML with erythroid differentiation and TP53 mutations by promoting STAT1 phosphorylation via JAK2-dependent and JAK2-independent mechanisms, independently of exogenous IFN-γ. CCRL2 KO suppresses erythroleukemia growth in vitro and in vivo.","method":"CCRL2 KO in erythroleukemia cell lines, proteomics and transcriptomics, STAT1 phosphorylation assays, JAK2 inhibitor experiments, in vivo xenograft models","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (proteomics, transcriptomics, phosphorylation assays, in vivo KO), preprint not yet peer-reviewed","pmids":["40060699"],"is_preprint":true},{"year":2025,"finding":"CCRL2 expressed on cardiac fibroblast-recruited macrophages facilitates fibroblast proliferation and migration through interaction with Na+/K+-ATPase on fibroblasts, without directly altering the intensity of the inflammatory response.","method":"Co-culture assays, concurrent heart/liver injury mouse model, CCRL2 expression characterization, fibroblast proliferation and migration assays","journal":"Cellular & molecular immunology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single binding interaction claim with limited mechanistic follow-up detailed in abstract","pmids":["41436601"],"is_preprint":false},{"year":2008,"finding":"CCL5 exposure upregulates CCRL2 (CRAM) surface expression on pre-B cell lines. CCL5 stimulation of CRAM-expressing Nalm6 cells (lacking known CCL5 receptors) induces ERK1/2 phosphorylation that is not inhibited by pertussis toxin, suggesting CRAM does not couple to Gi proteins, and produces no calcium mobilization or migration.","method":"Western blot for ERK1/2 phosphorylation, pertussis toxin treatment, calcium flux assay, chemotaxis assay, surface expression by flow cytometry","journal":"Immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal assays (ERK phosphorylation, calcium flux, migration, pertussis toxin), single lab","pmids":["18397265"],"is_preprint":false},{"year":2010,"finding":"CCRL2 is required for antigen-loaded lung dendritic cell trafficking to mediastinal lymph nodes. CCRL2−/− mice show normal DC recruitment to the lung but defective DC trafficking to lymph nodes, reduced T helper 2 priming, and protection from ovalbumin-induced airway inflammation. Adoptive transfer of CCRL2−/− antigen-loaded DCs into wild-type mice recapitulated the knockout phenotype.","method":"CCRL2−/− mouse model, ovalbumin airway inflammation model, adoptive DC transfer, BAL leukocyte counts, cytokine measurements","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — adoptive transfer establishing DC-intrinsic requirement, KO phenotype, multiple inflammatory readouts","pmids":["20606167"],"is_preprint":false},{"year":2022,"finding":"Computational protein-protein docking and accelerated molecular dynamics identified putative hot-spot residues in the CCRL2-chemerin binding interface, with chemerin's β1 strand and CCRL2's extracellular loop 2 as primary interaction regions, and CCRL2 N-terminus/chemerin loop 3 electrostatic interactions stabilizing the complex while leaving the chemerin C-terminus accessible for CMKLR1 engagement.","method":"Protein-protein docking, accelerated molecular dynamics, principal component analysis, kernel density estimation","journal":"Journal of chemical information and modeling (2025 paper) / Proteins (2022 paper)","confidence":"Low","confidence_rationale":"Tier 4 / Weak — computational modeling only, no experimental validation of predicted binding residues","pmids":["35437825","41380116"],"is_preprint":false}],"current_model":"CCRL2 is a non-signaling, seven-transmembrane atypical chemokine receptor that binds chemerin with high affinity without activating G proteins, β-arrestins, or ERK signaling; instead, it functions as a chemerin-presenting molecule that concentrates bioactive chemerin at the cell surface for transfer to the functional receptor CMKLR1, regulates leukocyte recruitment by forming heterodimers with CXCR2 to modulate CXCR2-mediated β2-integrin activation in neutrophils, interacts with TLR4 to enhance MyD88-NF-κB inflammatory signaling in macrophages, coprecipitates with JAK2 to potentiate JAK2/STAT3/STAT5 signaling in myeloid cells, and binds SFRP1 to amplify Wnt signaling suppression in stromal cells, with its expression on endothelial cells being epigenetically regulated and critical for NK cell homing to the lung."},"narrative":{"mechanistic_narrative":"CCRL2 is a seven-transmembrane atypical chemokine receptor that binds chemerin with low nanomolar affinity but does not internalize it, activate G proteins (Gαi/Gαo), recruit β-arrestins, or trigger ERK phosphorylation, distinguishing it from the signaling chemerin receptors CMKLR1 and GPR1 [PMID:18794339, PMID:27716822]. Rather than scavenging its ligand, CCRL2 concentrates bioactive chemerin at the cell surface and presents it to CMKLR1 on neighboring cells, a mechanism that underlies its physiological functions [PMID:18794339]. On vascular endothelium CCRL2 is upregulated by proinflammatory NF-κB and JAK/STAT signaling and supports adhesion and recruitment of CMKLR1+ leukocytes, including NK cells to the lung, with its endothelial expression epigenetically regulated and required for lung tumor immune surveillance via the CCRL2/chemerin/CMKLR1 axis [PMID:22696441, PMID:31484658, PMID:37343073]. CCRL2 also acts through direct protein–protein interactions: it constitutively heterodimerizes with CXCR2 to control CXCR2 surface expression and β2-integrin activation in neutrophils [PMID:28743719], interacts with TLR4 on macrophages to retain surface TLR4 and enhance MyD88–NF-κB signaling and antitumor responses [PMID:33846258], and coprecipitates with JAK2 to potentiate JAK2/STAT3/STAT5 phosphorylation in myeloid (MDS/AML) cells [PMID:35179961]. Through these activities CCRL2 regulates leukocyte trafficking, inflammation, neoangiogenesis, and tumor progression [PMID:34638484, PMID:20606167], and binds SFRP1 on stromal cells to amplify Wnt-signaling suppression and impair bone healing [PMID:38477792].","teleology":[{"year":2008,"claim":"Established CCRL2 as a non-signaling chemerin-binding receptor that, rather than internalizing ligand, presents bioactive chemerin to the functional receptor CMKLR1 — defining its core mechanistic identity.","evidence":"Binding assays and in vivo passive cutaneous anaphylaxis in CCRL2-deficient mice with comparison to silent chemokine receptors","pmids":["18794339"],"confidence":"High","gaps":["Did not resolve the structural basis of chemerin presentation","Transfer of chemerin to CMKLR1 not directly visualized in vivo"]},{"year":2008,"claim":"Probed whether CCRL2 couples to canonical GPCR signaling using a non-chemerin ligand, showing it does not engage Gi proteins or trigger calcium/migration.","evidence":"ERK1/2 Western blot, pertussis toxin treatment, calcium flux and chemotaxis assays in CRAM-expressing pre-B cells stimulated with CCL5","pmids":["18397265"],"confidence":"Medium","gaps":["PTX-insensitive ERK readout left signaling route ambiguous","Single cell-line context"]},{"year":2009,"claim":"Characterized CCRL2 ligand binding and constitutive trafficking, showing it binds CCL19 yet does not drive migration and recycles via clathrin-coated pits.","evidence":"Radioligand binding, clathrin-mediated recycling, calcium flux and chemotaxis assays in CRAM-expressing cells","pmids":["20002784"],"confidence":"Medium","gaps":["Physiological relevance of CCL19 binding versus chemerin unclear","Single lab"]},{"year":2010,"claim":"Defined a cell-intrinsic in vivo role, demonstrating CCRL2 is required for antigen-loaded lung dendritic cell trafficking to lymph nodes and Th2 priming.","evidence":"CCRL2−/− ovalbumin airway inflammation model with adoptive DC transfer and cytokine measurements","pmids":["20606167"],"confidence":"High","gaps":["Molecular mechanism linking CCRL2 to DC migration not defined","Ligand dependence not established"]},{"year":2012,"claim":"Placed CCRL2 in the endothelial inflammatory program, showing inflammatory induction and chemerin-dependent leukocyte adhesion, and a recruitment defect in vivo.","evidence":"Endothelial stimulation with NF-κB/JAK-STAT inhibitors, in vitro adhesion assays, CCRL2−/− mice in LPS pulmonary inflammation","pmids":["22696441"],"confidence":"High","gaps":["α4β1/VCAM-1 adhesion mechanism downstream of chemerin presentation not fully dissected"]},{"year":2016,"claim":"Definitively confirmed CCRL2 as non-signaling by directly testing G protein and β-arrestin coupling against CMKLR1 and GPR1.","evidence":"BRET G protein and β-arrestin recruitment biosensors, ERK phosphorylation, affinity measurements across three receptors","pmids":["27716822"],"confidence":"High","gaps":["Does not address non-canonical or interaction-driven signaling later attributed to CCRL2"]},{"year":2017,"claim":"Revealed an interaction-based mechanism: CCRL2 heterodimerizes with CXCR2 to regulate its surface expression and β2-integrin activation, controlling neutrophil recruitment.","evidence":"Reciprocal co-IP, CCRL2−/− inflammatory arthritis models, β2-integrin and CXCR2 surface assays","pmids":["28743719"],"confidence":"High","gaps":["Stoichiometry and structural basis of the heterodimer not resolved"]},{"year":2017,"claim":"Clarified intracellular handling, showing CCRL2 does not scavenge chemerin and undergoes only weak ligand-independent recycling.","evidence":"Endosomal marker colocalization, scavenging and kinetics comparison versus ACKR3 in transfected and endothelial cells","pmids":["29056935"],"confidence":"Medium","gaps":["Functional purpose of constitutive recycling unclear","Single lab"]},{"year":2019,"claim":"Demonstrated that non-hematopoietic (endothelial) CCRL2 mediates lung tumor immune surveillance through the chemerin/CMKLR1 axis driving NK cell infiltration.","evidence":"Ccrl2−/− mice in urethane and KrasG12D/p53 lung tumor models, bone marrow chimeras, adoptive transfer, flow cytometry","pmids":["31484658"],"confidence":"High","gaps":["Endothelial signals controlling CCRL2 expression not yet defined"]},{"year":2021,"claim":"Identified a direct CCRL2–TLR4 interaction that retains surface TLR4 and amplifies MyD88-NF-κB signaling, linking CCRL2 to macrophage immunostimulatory activation and antitumor T-cell responses.","evidence":"Co-IP, CCRL2-deficient melanoma models, macrophage and CD8 depletion, TLR4-deficient comparison","pmids":["33846258"],"confidence":"High","gaps":["Whether chemerin binding modulates the TLR4 interaction unknown"]},{"year":2021,"claim":"Showed tumor-cell CCRL2 concentrates chemerin to limit neoangiogenesis, with genetic epistasis confirming dependence on chemerin and CMKLR1.","evidence":"DMBA/TPA carcinogenesis, B16/LLC grafts with gain/loss-of-function, epistasis with chemerin−/− and Cmklr1−/−","pmids":["34638484"],"confidence":"High","gaps":["Cell types mediating the anti-angiogenic chemerin/CMKLR1 effect not fully defined"]},{"year":2021,"claim":"Tested an unexpected function, identifying CCRL2 as an in vitro coreceptor for HIV-2 primary isolates.","evidence":"NP-2/CD4/CCRL2 infection assay with immunofluorescence, proviral DNA PCR, RT activity, syncytia formation","pmids":["33253374"],"confidence":"Medium","gaps":["No in vivo validation","Physiological relevance to HIV infection unestablished"]},{"year":2022,"claim":"Extended interaction-based signaling to myeloid malignancy, showing CCRL2 coprecipitates with JAK2 and acts upstream to potentiate JAK2/STAT3/STAT5 phosphorylation.","evidence":"Co-IP, shRNA knockdown in MDS92/MDS-L cells, phospho-Western blots, JAK2V617F epistasis and fedratinib inhibition, xenografts","pmids":["35179961"],"confidence":"High","gaps":["Mechanism by which a non-signaling receptor engages JAK2 not resolved"]},{"year":2022,"claim":"Generated structural hypotheses for the chemerin-binding interface to rationalize how CCRL2 presents chemerin while leaving its C-terminus free for CMKLR1.","evidence":"Protein-protein docking and accelerated molecular dynamics (computational only)","pmids":["35437825","41380116"],"confidence":"Low","gaps":["No experimental validation of predicted hot-spot residues","In silico model only"]},{"year":2023,"claim":"Connected CCRL2 to MDS/sAML epigenetic regulation, showing it modulates DNMT levels and PRC2 pathways and influences azacitidine sensitivity.","evidence":"shRNA knockdown/overexpression in MDS lines, azacitidine sensitivity assays, MDS-L xenograft, pathway analysis","pmids":["36519323"],"confidence":"Medium","gaps":["Direct molecular link between CCRL2 and DNMT regulation unestablished","Single lab"]},{"year":2023,"claim":"Distinguished CCRL2's ligand-binding function from its heterodimerization effect, showing chemerin-binding neutralization does not block CXCL8/CXCR2 neutrophil responses.","evidence":"SPRm and flow cytometry ligand confirmation, neutralizing antibody, neutrophil degranulation and peritoneal recruitment assays","pmids":["36662882"],"confidence":"Medium","gaps":["Negative result; does not exclude all chemerin contributions","Single lab"]},{"year":2023,"claim":"Defined a flow-dependent endothelial mechanism in atherosclerosis where CCRL2-recruited chemerin activates monocyte β2-integrin via chemerin's PDI-like activity independently of CMKLR1.","evidence":"scRNA-seq, CCRL2−/−ApoE−/− mice on high-fat diet, Di-E-GSSG PDI assay, proximity ligation, ERK phosphorylation","pmids":["37279540"],"confidence":"High","gaps":["Generality of CMKLR1-independent chemerin signaling across tissues unclear"]},{"year":2023,"claim":"Identified CCRL2 as an alveolar capillary endothelial hallmark gene under epigenetic control whose restoration with 5-Aza enhances NK recruitment and limits lung tumors.","evidence":"scRNA-seq, conditional endothelial CCRL2 KO, chemerin KO, 5-Aza treatment, NK subset flow cytometry, Kras/p53 model","pmids":["37343073"],"confidence":"High","gaps":["Specific epigenetic marks/enzymes controlling CCRL2 not pinpointed"]},{"year":2024,"claim":"Revealed a stromal Wnt-modulating role through direct CCRL2–SFRP1 binding that suppresses osteogenesis and bone healing in periodontitis.","evidence":"Co-IP/binding assay, Ccrl2-KO mice in extraction socket periodontitis, Wnt pathway and histological analysis","pmids":["38477792"],"confidence":"Medium","gaps":["Direct effect of CCRL2 on SFRP1 affinity for Wnt ligands not quantified","Single lab"]},{"year":2025,"claim":"Implicated CCRL2 in cell-autonomous IFN-γ/STAT1 signaling in TP53-mutant erythroid AML through JAK2-dependent and -independent STAT1 phosphorylation.","evidence":"CCRL2 KO erythroleukemia lines, proteomics/transcriptomics, STAT1 phospho-assays, JAK2 inhibitor, xenografts (preprint)","pmids":["40060699"],"confidence":"Medium","gaps":["Not peer-reviewed","JAK2-independent route to STAT1 undefined"]},{"year":2025,"claim":"Proposed a cardiac fibrosis function via CCRL2 on macrophages interacting with fibroblast Na+/K+-ATPase to promote fibroblast proliferation.","evidence":"Co-culture, concurrent heart/liver injury mouse model, fibroblast proliferation/migration assays","pmids":["41436601"],"confidence":"Low","gaps":["Single binding claim with limited mechanistic follow-up","Interaction not validated reciprocally"]},{"year":null,"claim":"How a confirmed non-signaling receptor mechanistically couples to JAK2, TLR4, CXCR2, and STAT pathways at the molecular/structural level remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of CCRL2 in complex with chemerin or partner receptors","Stoichiometry and assembly of CCRL2 heterodimers unknown","Mechanism converting ligand presentation into intracellular signaling potentiation undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,3]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4,7,9]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[14]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[4,7]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,4,19]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7,9]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[8,11]}],"complexes":[],"partners":["CXCR2","TLR4","JAK2","SFRP1","CMKLR1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O00421","full_name":"C-C chemokine receptor-like 2","aliases":["Chemokine receptor CCR11","Chemokine receptor X","Putative MCP-1 chemokine receptor"],"length_aa":344,"mass_kda":39.5,"function":"Receptor for CCL19 and chemerin/RARRES2. Does not appear to be a signaling receptor, but may have a role in modulating chemokine-triggered immune responses by capturing and internalizing CCL19 or by presenting RARRES2 ligand to CMKLR1, a functional signaling receptors. Plays a critical role for the development of Th2 responses","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/O00421/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CCRL2","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CCRL2","total_profiled":1310},"omim":[{"mim_id":"612007","title":"CELIAC DISEASE, SUSCEPTIBILITY TO, 9; CELIAC9","url":"https://www.omim.org/entry/612007"},{"mim_id":"608379","title":"CHEMOKINE, CC MOTIF, RECEPTOR-LIKE PROTEIN 2; CCRL2","url":"https://www.omim.org/entry/608379"},{"mim_id":"602227","title":"CHEMOKINE, CC MOTIF, LIGAND 19; CCL19","url":"https://www.omim.org/entry/602227"},{"mim_id":"601973","title":"RETINOIC ACID RECEPTOR RESPONDER 2; RARRES2","url":"https://www.omim.org/entry/601973"},{"mim_id":"187011","title":"CHEMOKINE, CC MOTIF, LIGAND 5; CCL5","url":"https://www.omim.org/entry/187011"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Primary cilium","reliability":"Additional"},{"location":"Primary cilium tip","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in 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Instead of internalizing chemerin, CCRL2 increases local concentrations of bioactive chemerin, presenting it to the signaling chemerin receptor CMKLR1 on nearby cells.\",\n      \"method\": \"Binding assays, in vivo passive cutaneous anaphylaxis model with CCRL2-deficient mice, functional comparison with 'silent' chemokine receptors\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal binding characterization in human and mouse, KO mouse phenotype, replicated across multiple subsequent studies\",\n      \"pmids\": [\"18794339\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CCRL2 (CRAM-B splice variant) binds the homeostatic chemokine CCL19 with affinity similar to CCR7, but unlike CCR7 does not trigger calcium mobilization or cell migration. CCRL2 constitutively recycles via clathrin-coated pits and internalizes CCL19 as well as anti-CRAM antibodies.\",\n      \"method\": \"Radioactive ligand binding assays, clathrin-mediated recycling assays, calcium flux assays, chemotaxis assays in CRAM-expressing cells\",\n      \"journal\": \"Immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (binding, functional assays, internalization), single lab\",\n      \"pmids\": [\"20002784\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CCRL2 is upregulated on vascular endothelial cells by proinflammatory stimuli via NF-κB and JAK/STAT signaling pathways. Chemerin binding to CCRL2 on endothelial cells triggers adhesion of CMKLR1+ lymphoid cells through an α4β1 integrin/VCAM-1-dependent mechanism. CCRL2 deficiency elevates plasma chemerin levels and impairs CMKLR1+ NK cell recruitment to airways during LPS-induced inflammation.\",\n      \"method\": \"Endothelial cell culture stimulation assays, NF-κB/JAK/STAT inhibitor experiments, CCRL2−/− mouse models, in vitro adhesion assays, in vivo LPS pulmonary inflammation model\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (KO mice, in vitro adhesion, signaling pathway inhibition, in vivo model), functional consequence clearly defined\",\n      \"pmids\": [\"22696441\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Chemerin binds CCRL2 with low nanomolar affinity but does not activate G proteins (Gαi1, Gαi2, Gαi3, Gαoa, Gαob) or recruit β-arrestin1/2 to CCRL2, in contrast to CMKLR1 and GPR1. CCRL2 also does not promote ERK1/2 phosphorylation upon chemerin binding, confirming it is a non-signaling receptor.\",\n      \"method\": \"BRET-based biosensors for G protein activation, β-arrestin recruitment assays, ERK1/2 phosphorylation assays, binding affinity measurements\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal biochemical assays (BRET, β-arrestin, ERK phosphorylation), rigorous comparison across three receptors\",\n      \"pmids\": [\"27716822\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CCRL2 constitutively forms homodimers and heterodimers with CXCR2. By heterodimerization with CXCR2, CCRL2 regulates CXCR2 membrane expression and promotes CXCR2-mediated β2-integrin activation. CCRL2-deficient mice show defective neutrophil recruitment and are protected in inflammatory arthritis models.\",\n      \"method\": \"Co-immunoprecipitation and dimerization assays, CCRL2−/− mouse inflammatory arthritis models, β2-integrin activation assays, CXCR2 membrane expression quantification\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP for heterodimerization, KO mouse phenotype in two disease models, defined molecular mechanism (β2-integrin activation)\",\n      \"pmids\": [\"28743719\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CCRL2 does not internalize or scavenge its ligand chemerin. CCRL2 undergoes weak constitutive, ligand-independent internalization and recycling (slower kinetics than ACKR3 or signaling receptors), colocalizing with EEA1/Rab5-positive early endosomes and Rab11-positive recycling compartments intracellularly.\",\n      \"method\": \"Cell membrane analysis, fluorescence colocalization with endosomal markers, scavenging assays in CCRL2-transfected cells and activated mouse endothelial cells, kinetics comparison\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (colocalization, kinetics, scavenging assays), single lab\",\n      \"pmids\": [\"29056935\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CCRL2 expressed by non-hematopoietic (endothelial) cells is required for lung tumor immune surveillance. CCRL2 deletion on endothelial cells reduces NK cell infiltration into lungs, promoting tumor progression. This effect is mediated through the CCRL2/chemerin/CMKLR1 axis.\",\n      \"method\": \"Ccrl2−/− mice in urethane-induced and KrasG12D/p53Flox lung tumor models, bone marrow chimeras, adoptive transfer experiments, flow cytometry of tumor infiltrates\",\n      \"journal\": \"Cancer immunology research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — bone marrow chimeras establishing non-hematopoietic cell dependency, multiple tumor models, KO phenotype replicated\",\n      \"pmids\": [\"31484658\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CCRL2 interacts directly with TLR4 on the macrophage cell surface to retain membrane TLR4 expression and enhance downstream MyD88-NF-κB inflammatory signaling, thereby promoting immunostimulatory macrophage activation and antitumor T-cell responses.\",\n      \"method\": \"Co-immunoprecipitation, CCRL2-deficient mouse melanoma models, macrophage depletion experiments, CD8+ T cell depletion, coinjection tumor model, TLR4-deficient mouse comparison\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP demonstrating CCRL2-TLR4 interaction, KO mouse phenotype in multiple tumor models, mechanistic pathway established (MyD88-NF-κB)\",\n      \"pmids\": [\"33846258\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CCRL2 expression by tumor cells can concentrate bioactive chemerin and reduce neoangiogenesis in a manner dependent on the chemerin/CMKLR1 axis. Loss of Ccrl2 accelerated papilloma development in chemical carcinogenesis, while CCRL2 gain-of-function delayed B16 and LLC tumor graft growth; both phenotypes were abrogated by chemerin or Cmklr1 knockout.\",\n      \"method\": \"DMBA/TPA skin carcinogenesis model, B16/LLC tumor graft models with CCRL2 overexpression/knockout, epistasis with chemerin−/− and Cmklr1−/− mice, angiogenesis assays\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with chemerin and Cmklr1 KO, multiple tumor models, gain- and loss-of-function\",\n      \"pmids\": [\"34638484\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CCRL2 coprecipitates with JAK2 and potentiates JAK2-STAT interaction. CCRL2 knockdown in MDS92 and MDS-L cells decreases JAK2/STAT3/STAT5 phosphorylation. Erythroleukemia cells expressing JAK2V617F show less effect of CCRL2 knockdown, and fedratinib (JAK2 inhibitor) potentiates the CCRL2 knockdown effect, placing CCRL2 upstream of JAK2/STAT signaling.\",\n      \"method\": \"Co-immunoprecipitation (CCRL2-JAK2), shRNA knockdown, Western blot for phospho-JAK2/STAT3/STAT5, pharmacological JAK2 inhibition, in vivo xenograft models\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP establishing direct interaction, multiple KD experiments, genetic epistasis with JAK2V617F and JAK2 inhibitor\",\n      \"pmids\": [\"35179961\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CCRL2 is expressed as a hallmark of alveolar lung capillary endothelial cells and its expression is epigenetically regulated. Conditional endothelial-targeted ablation of CCRL2 or deletion of chemerin promotes lung tumor progression by reducing recruitment of CD27−CD11b+ mature NK cells. Treatment with 5-aza-2'-deoxycytidine upregulates endothelial CCRL2 expression, increases NK cell recruitment, and reduces lung tumor growth.\",\n      \"method\": \"scRNA-seq of tumor-infiltrating cells, conditional endothelial CCRL2 knockout, chemerin KO, 5-Aza treatment, flow cytometry of NK cell subsets, Kras/p53Flox lung tumor model\",\n      \"journal\": \"Cancer immunology research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO, scRNA-seq, epigenetic regulation, multiple orthogonal methods\",\n      \"pmids\": [\"37343073\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Endothelial CCRL2 induced by disturbed flow recruits chemerin, which activates β2 integrin on monocytes via a protein disulfide isomerase-like enzymatic activity of chemerin (not via monocytic CMKLR1), enhancing ERK1/2 phosphorylation and monocyte adhesion, thereby promoting atherosclerotic plaque formation. CCRL2-/-ApoE-/- mice are protected against plaque formation.\",\n      \"method\": \"scRNA-seq of carotid arteries, CCRL2−/−ApoE−/− double KO mice on high-fat diet, Di-E-GSSG assay for PDI activity, proximity ligation assay for chemerin-β2 integrin interaction, ERK1/2 phosphorylation assays\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (PLA, enzymatic assay, double KO mice), mechanistic axis defined\",\n      \"pmids\": [\"37279540\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CCRL2 knockdown in MDS/sAML cells downregulates DNA methylation and PRC2 activity pathways and increases DNMT suppression by azacitidine. CCRL2 overexpression decreases azacitidine sensitivity. CCRL2 deletion increased azacitidine efficacy in an MDS-L xenograft model, establishing CCRL2 as a modulator of epigenetic regulatory pathways (DNMT levels) in MDS.\",\n      \"method\": \"shRNA knockdown and CCRL2 overexpression in MDS cell lines, in vitro azacitidine sensitivity assays, MDS-L xenograft model, pathway analysis\",\n      \"journal\": \"Haematologica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function, in vivo xenograft, single lab\",\n      \"pmids\": [\"36519323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CCRL2 expressed on LepR+/CAR stromal cells in alveolar bone binds SFRP1 on the cell surface, amplifying SFRP1-mediated suppression of Wnt signaling under inflammatory conditions, thereby inhibiting osteogenic differentiation and impairing extraction socket bone healing in periodontitis. Ccrl2-KO mice show improved bone healing.\",\n      \"method\": \"Co-immunoprecipitation/binding assay for CCRL2-SFRP1 interaction, Ccrl2-KO mouse model with extraction socket periodontitis, Wnt signaling pathway analysis, histological assessment of bone healing\",\n      \"journal\": \"Journal of bone and mineral research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — binding assay and KO mouse phenotype, single lab, pathway placement via Wnt signaling\",\n      \"pmids\": [\"38477792\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CCRL2 functions as a coreceptor for HIV-2 primary isolates in vitro. NP-2/CD4/CCRL2 cells were infected by HIV-2MIR (and to a lesser extent HIV-1HAN2), as detected by viral antigen immunofluorescence, proviral DNA, reverse transcriptase activity, and syncytia formation.\",\n      \"method\": \"NP-2/CD4/CCRL2 cell infection assay, indirect immunofluorescence, Giemsa staining for syncytia, PCR for proviral DNA, RT activity measurement\",\n      \"journal\": \"Briefings in bioinformatics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal in vitro assays confirming coreceptor function, single lab, no in vivo validation\",\n      \"pmids\": [\"33253374\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CCRL2 antibody-based neutralization of chemerin binding did not attenuate CXCL8-induced human neutrophil degranulation or CXCL8-induced murine neutrophil recruitment to the peritoneum. This negative finding indicates that the ligand-binding function of CCRL2 is dispensable for CXCL8/CXCR2 signaling in neutrophils, suggesting that CCRL2-CXCR2 heterodimerization effects are independent of CCRL2 chemerin-binding capacity.\",\n      \"method\": \"Flow cytometry and Surface Plasmon Resonance microscopy (SPRm) for ligand binding confirmation, neutralizing antibody treatment, human neutrophil degranulation assays, murine peritoneal neutrophil recruitment\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — SPRm and flow cytometry confirming ligand specificity; pharmacological neutralization with functional readout; single lab negative result\",\n      \"pmids\": [\"36662882\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CCRL2 drives cell-autonomous IFN-γ signaling in AML with erythroid differentiation and TP53 mutations by promoting STAT1 phosphorylation via JAK2-dependent and JAK2-independent mechanisms, independently of exogenous IFN-γ. CCRL2 KO suppresses erythroleukemia growth in vitro and in vivo.\",\n      \"method\": \"CCRL2 KO in erythroleukemia cell lines, proteomics and transcriptomics, STAT1 phosphorylation assays, JAK2 inhibitor experiments, in vivo xenograft models\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (proteomics, transcriptomics, phosphorylation assays, in vivo KO), preprint not yet peer-reviewed\",\n      \"pmids\": [\"40060699\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CCRL2 expressed on cardiac fibroblast-recruited macrophages facilitates fibroblast proliferation and migration through interaction with Na+/K+-ATPase on fibroblasts, without directly altering the intensity of the inflammatory response.\",\n      \"method\": \"Co-culture assays, concurrent heart/liver injury mouse model, CCRL2 expression characterization, fibroblast proliferation and migration assays\",\n      \"journal\": \"Cellular & molecular immunology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single binding interaction claim with limited mechanistic follow-up detailed in abstract\",\n      \"pmids\": [\"41436601\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CCL5 exposure upregulates CCRL2 (CRAM) surface expression on pre-B cell lines. CCL5 stimulation of CRAM-expressing Nalm6 cells (lacking known CCL5 receptors) induces ERK1/2 phosphorylation that is not inhibited by pertussis toxin, suggesting CRAM does not couple to Gi proteins, and produces no calcium mobilization or migration.\",\n      \"method\": \"Western blot for ERK1/2 phosphorylation, pertussis toxin treatment, calcium flux assay, chemotaxis assay, surface expression by flow cytometry\",\n      \"journal\": \"Immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal assays (ERK phosphorylation, calcium flux, migration, pertussis toxin), single lab\",\n      \"pmids\": [\"18397265\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CCRL2 is required for antigen-loaded lung dendritic cell trafficking to mediastinal lymph nodes. CCRL2−/− mice show normal DC recruitment to the lung but defective DC trafficking to lymph nodes, reduced T helper 2 priming, and protection from ovalbumin-induced airway inflammation. Adoptive transfer of CCRL2−/− antigen-loaded DCs into wild-type mice recapitulated the knockout phenotype.\",\n      \"method\": \"CCRL2−/− mouse model, ovalbumin airway inflammation model, adoptive DC transfer, BAL leukocyte counts, cytokine measurements\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — adoptive transfer establishing DC-intrinsic requirement, KO phenotype, multiple inflammatory readouts\",\n      \"pmids\": [\"20606167\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Computational protein-protein docking and accelerated molecular dynamics identified putative hot-spot residues in the CCRL2-chemerin binding interface, with chemerin's β1 strand and CCRL2's extracellular loop 2 as primary interaction regions, and CCRL2 N-terminus/chemerin loop 3 electrostatic interactions stabilizing the complex while leaving the chemerin C-terminus accessible for CMKLR1 engagement.\",\n      \"method\": \"Protein-protein docking, accelerated molecular dynamics, principal component analysis, kernel density estimation\",\n      \"journal\": \"Journal of chemical information and modeling (2025 paper) / Proteins (2022 paper)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — computational modeling only, no experimental validation of predicted binding residues\",\n      \"pmids\": [\"35437825\", \"41380116\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CCRL2 is a non-signaling, seven-transmembrane atypical chemokine receptor that binds chemerin with high affinity without activating G proteins, β-arrestins, or ERK signaling; instead, it functions as a chemerin-presenting molecule that concentrates bioactive chemerin at the cell surface for transfer to the functional receptor CMKLR1, regulates leukocyte recruitment by forming heterodimers with CXCR2 to modulate CXCR2-mediated β2-integrin activation in neutrophils, interacts with TLR4 to enhance MyD88-NF-κB inflammatory signaling in macrophages, coprecipitates with JAK2 to potentiate JAK2/STAT3/STAT5 signaling in myeloid cells, and binds SFRP1 to amplify Wnt signaling suppression in stromal cells, with its expression on endothelial cells being epigenetically regulated and critical for NK cell homing to the lung.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CCRL2 is a seven-transmembrane atypical chemokine receptor that binds chemerin with low nanomolar affinity but does not internalize it, activate G proteins (Gαi/Gαo), recruit β-arrestins, or trigger ERK phosphorylation, distinguishing it from the signaling chemerin receptors CMKLR1 and GPR1 [#0, #3]. Rather than scavenging its ligand, CCRL2 concentrates bioactive chemerin at the cell surface and presents it to CMKLR1 on neighboring cells, a mechanism that underlies its physiological functions [#0]. On vascular endothelium CCRL2 is upregulated by proinflammatory NF-κB and JAK/STAT signaling and supports adhesion and recruitment of CMKLR1+ leukocytes, including NK cells to the lung, with its endothelial expression epigenetically regulated and required for lung tumor immune surveillance via the CCRL2/chemerin/CMKLR1 axis [#2, #6, #10]. CCRL2 also acts through direct protein–protein interactions: it constitutively heterodimerizes with CXCR2 to control CXCR2 surface expression and β2-integrin activation in neutrophils [#4], interacts with TLR4 on macrophages to retain surface TLR4 and enhance MyD88–NF-κB signaling and antitumor responses [#7], and coprecipitates with JAK2 to potentiate JAK2/STAT3/STAT5 phosphorylation in myeloid (MDS/AML) cells [#9]. Through these activities CCRL2 regulates leukocyte trafficking, inflammation, neoangiogenesis, and tumor progression [#8, #19], and binds SFRP1 on stromal cells to amplify Wnt-signaling suppression and impair bone healing [#13].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Established CCRL2 as a non-signaling chemerin-binding receptor that, rather than internalizing ligand, presents bioactive chemerin to the functional receptor CMKLR1 — defining its core mechanistic identity.\",\n      \"evidence\": \"Binding assays and in vivo passive cutaneous anaphylaxis in CCRL2-deficient mice with comparison to silent chemokine receptors\",\n      \"pmids\": [\"18794339\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the structural basis of chemerin presentation\", \"Transfer of chemerin to CMKLR1 not directly visualized in vivo\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Probed whether CCRL2 couples to canonical GPCR signaling using a non-chemerin ligand, showing it does not engage Gi proteins or trigger calcium/migration.\",\n      \"evidence\": \"ERK1/2 Western blot, pertussis toxin treatment, calcium flux and chemotaxis assays in CRAM-expressing pre-B cells stimulated with CCL5\",\n      \"pmids\": [\"18397265\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"PTX-insensitive ERK readout left signaling route ambiguous\", \"Single cell-line context\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Characterized CCRL2 ligand binding and constitutive trafficking, showing it binds CCL19 yet does not drive migration and recycles via clathrin-coated pits.\",\n      \"evidence\": \"Radioligand binding, clathrin-mediated recycling, calcium flux and chemotaxis assays in CRAM-expressing cells\",\n      \"pmids\": [\"20002784\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological relevance of CCL19 binding versus chemerin unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined a cell-intrinsic in vivo role, demonstrating CCRL2 is required for antigen-loaded lung dendritic cell trafficking to lymph nodes and Th2 priming.\",\n      \"evidence\": \"CCRL2−/− ovalbumin airway inflammation model with adoptive DC transfer and cytokine measurements\",\n      \"pmids\": [\"20606167\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism linking CCRL2 to DC migration not defined\", \"Ligand dependence not established\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Placed CCRL2 in the endothelial inflammatory program, showing inflammatory induction and chemerin-dependent leukocyte adhesion, and a recruitment defect in vivo.\",\n      \"evidence\": \"Endothelial stimulation with NF-κB/JAK-STAT inhibitors, in vitro adhesion assays, CCRL2−/− mice in LPS pulmonary inflammation\",\n      \"pmids\": [\"22696441\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"α4β1/VCAM-1 adhesion mechanism downstream of chemerin presentation not fully dissected\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Definitively confirmed CCRL2 as non-signaling by directly testing G protein and β-arrestin coupling against CMKLR1 and GPR1.\",\n      \"evidence\": \"BRET G protein and β-arrestin recruitment biosensors, ERK phosphorylation, affinity measurements across three receptors\",\n      \"pmids\": [\"27716822\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not address non-canonical or interaction-driven signaling later attributed to CCRL2\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Revealed an interaction-based mechanism: CCRL2 heterodimerizes with CXCR2 to regulate its surface expression and β2-integrin activation, controlling neutrophil recruitment.\",\n      \"evidence\": \"Reciprocal co-IP, CCRL2−/− inflammatory arthritis models, β2-integrin and CXCR2 surface assays\",\n      \"pmids\": [\"28743719\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and structural basis of the heterodimer not resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Clarified intracellular handling, showing CCRL2 does not scavenge chemerin and undergoes only weak ligand-independent recycling.\",\n      \"evidence\": \"Endosomal marker colocalization, scavenging and kinetics comparison versus ACKR3 in transfected and endothelial cells\",\n      \"pmids\": [\"29056935\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional purpose of constitutive recycling unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated that non-hematopoietic (endothelial) CCRL2 mediates lung tumor immune surveillance through the chemerin/CMKLR1 axis driving NK cell infiltration.\",\n      \"evidence\": \"Ccrl2−/− mice in urethane and KrasG12D/p53 lung tumor models, bone marrow chimeras, adoptive transfer, flow cytometry\",\n      \"pmids\": [\"31484658\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endothelial signals controlling CCRL2 expression not yet defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified a direct CCRL2–TLR4 interaction that retains surface TLR4 and amplifies MyD88-NF-κB signaling, linking CCRL2 to macrophage immunostimulatory activation and antitumor T-cell responses.\",\n      \"evidence\": \"Co-IP, CCRL2-deficient melanoma models, macrophage and CD8 depletion, TLR4-deficient comparison\",\n      \"pmids\": [\"33846258\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether chemerin binding modulates the TLR4 interaction unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed tumor-cell CCRL2 concentrates chemerin to limit neoangiogenesis, with genetic epistasis confirming dependence on chemerin and CMKLR1.\",\n      \"evidence\": \"DMBA/TPA carcinogenesis, B16/LLC grafts with gain/loss-of-function, epistasis with chemerin−/− and Cmklr1−/−\",\n      \"pmids\": [\"34638484\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell types mediating the anti-angiogenic chemerin/CMKLR1 effect not fully defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Tested an unexpected function, identifying CCRL2 as an in vitro coreceptor for HIV-2 primary isolates.\",\n      \"evidence\": \"NP-2/CD4/CCRL2 infection assay with immunofluorescence, proviral DNA PCR, RT activity, syncytia formation\",\n      \"pmids\": [\"33253374\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vivo validation\", \"Physiological relevance to HIV infection unestablished\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended interaction-based signaling to myeloid malignancy, showing CCRL2 coprecipitates with JAK2 and acts upstream to potentiate JAK2/STAT3/STAT5 phosphorylation.\",\n      \"evidence\": \"Co-IP, shRNA knockdown in MDS92/MDS-L cells, phospho-Western blots, JAK2V617F epistasis and fedratinib inhibition, xenografts\",\n      \"pmids\": [\"35179961\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which a non-signaling receptor engages JAK2 not resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Generated structural hypotheses for the chemerin-binding interface to rationalize how CCRL2 presents chemerin while leaving its C-terminus free for CMKLR1.\",\n      \"evidence\": \"Protein-protein docking and accelerated molecular dynamics (computational only)\",\n      \"pmids\": [\"35437825\", \"41380116\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No experimental validation of predicted hot-spot residues\", \"In silico model only\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Connected CCRL2 to MDS/sAML epigenetic regulation, showing it modulates DNMT levels and PRC2 pathways and influences azacitidine sensitivity.\",\n      \"evidence\": \"shRNA knockdown/overexpression in MDS lines, azacitidine sensitivity assays, MDS-L xenograft, pathway analysis\",\n      \"pmids\": [\"36519323\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between CCRL2 and DNMT regulation unestablished\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Distinguished CCRL2's ligand-binding function from its heterodimerization effect, showing chemerin-binding neutralization does not block CXCL8/CXCR2 neutrophil responses.\",\n      \"evidence\": \"SPRm and flow cytometry ligand confirmation, neutralizing antibody, neutrophil degranulation and peritoneal recruitment assays\",\n      \"pmids\": [\"36662882\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Negative result; does not exclude all chemerin contributions\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined a flow-dependent endothelial mechanism in atherosclerosis where CCRL2-recruited chemerin activates monocyte β2-integrin via chemerin's PDI-like activity independently of CMKLR1.\",\n      \"evidence\": \"scRNA-seq, CCRL2−/−ApoE−/− mice on high-fat diet, Di-E-GSSG PDI assay, proximity ligation, ERK phosphorylation\",\n      \"pmids\": [\"37279540\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality of CMKLR1-independent chemerin signaling across tissues unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified CCRL2 as an alveolar capillary endothelial hallmark gene under epigenetic control whose restoration with 5-Aza enhances NK recruitment and limits lung tumors.\",\n      \"evidence\": \"scRNA-seq, conditional endothelial CCRL2 KO, chemerin KO, 5-Aza treatment, NK subset flow cytometry, Kras/p53 model\",\n      \"pmids\": [\"37343073\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific epigenetic marks/enzymes controlling CCRL2 not pinpointed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed a stromal Wnt-modulating role through direct CCRL2–SFRP1 binding that suppresses osteogenesis and bone healing in periodontitis.\",\n      \"evidence\": \"Co-IP/binding assay, Ccrl2-KO mice in extraction socket periodontitis, Wnt pathway and histological analysis\",\n      \"pmids\": [\"38477792\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct effect of CCRL2 on SFRP1 affinity for Wnt ligands not quantified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Implicated CCRL2 in cell-autonomous IFN-γ/STAT1 signaling in TP53-mutant erythroid AML through JAK2-dependent and -independent STAT1 phosphorylation.\",\n      \"evidence\": \"CCRL2 KO erythroleukemia lines, proteomics/transcriptomics, STAT1 phospho-assays, JAK2 inhibitor, xenografts (preprint)\",\n      \"pmids\": [\"40060699\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Not peer-reviewed\", \"JAK2-independent route to STAT1 undefined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Proposed a cardiac fibrosis function via CCRL2 on macrophages interacting with fibroblast Na+/K+-ATPase to promote fibroblast proliferation.\",\n      \"evidence\": \"Co-culture, concurrent heart/liver injury mouse model, fibroblast proliferation/migration assays\",\n      \"pmids\": [\"41436601\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single binding claim with limited mechanistic follow-up\", \"Interaction not validated reciprocally\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a confirmed non-signaling receptor mechanistically couples to JAK2, TLR4, CXCR2, and STAT pathways at the molecular/structural level remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of CCRL2 in complex with chemerin or partner receptors\", \"Stoichiometry and assembly of CCRL2 heterodimers unknown\", \"Mechanism converting ligand presentation into intracellular signaling potentiation undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4, 7, 9]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [4, 7]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 4, 19]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7, 9]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [8, 11]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CXCR2\", \"TLR4\", \"JAK2\", \"SFRP1\", \"CMKLR1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}