Affinage

CCRL2

C-C chemokine receptor-like 2 · UniProt O00421

Round 2 corrected
Length
344 aa
Mass
39.5 kDa
Annotated
2026-04-28
123 papers in source corpus 27 papers cited in narrative 27 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CCRL2 is a non-signaling atypical seven-transmembrane chemokine receptor that orchestrates innate immune cell recruitment, tumor surveillance, and tissue homeostasis by concentrating bioactive ligands at cell surfaces and modulating signaling through heterotypic receptor interactions. CCRL2 binds chemerin with nanomolar affinity without activating G proteins, β-arrestins, or triggering ligand scavenging; instead, it presents chemerin to the signaling receptor CMKLR1 on nearby cells, thereby controlling NK cell and leukocyte recruitment to sites of inflammation and tumors (PMID:18794339, PMID:27716822, PMID:31484658). Beyond chemerin presentation, CCRL2 forms constitutive heterodimers with CXCR2 to regulate β2-integrin activation and neutrophil recruitment (PMID:28743719), interacts with TLR4 to sustain membrane TLR4 expression and potentiate MyD88–NF-κB signaling in macrophages (PMID:33846258), co-precipitates with JAK2 to amplify JAK2–STAT3/STAT5 signaling in myeloid malignancies (PMID:35179961), and binds SFRP1 on stromal cells to suppress Wnt-dependent osteogenic differentiation (PMID:38477792). Endothelial CCRL2, particularly on lung alveolar capillary endothelium, is a critical determinant of anti-tumor NK cell infiltration, and its epigenetic silencing promotes lung tumor progression in Kras-driven cancer models (PMID:37343073, PMID:31484658).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1998 Medium

    Identification of CCRL2 as a novel orphan seven-transmembrane receptor with chemokine receptor homology established it as a candidate immune regulator expressed in hematopoietic tissues.

    Evidence cDNA library screening from human neutrophils, Northern blot, chromosomal mapping to 3p21

    PMID:9473515

    Open questions at the time
    • No ligand identified
    • No functional activity demonstrated
    • Expression restricted to mRNA level
  2. 2002 Medium

    Demonstration that CCRL2 protein is expressed on multiple leukocyte subsets and upregulated by inflammatory stimuli positioned it as an inflammation-responsive receptor on both innate and adaptive immune cells.

    Evidence Monoclonal antibody-based flow cytometry and real-time PCR on primary human blood cells and dendritic cells

    PMID:11828366

    Open questions at the time
    • Ligand still unidentified
    • No functional consequence of upregulation shown
    • No knockout data
  3. 2008 High

    Identification of chemerin as a non-signaling ligand that is presented rather than internalized by CCRL2 resolved the receptor's functional identity as a ligand-concentrating molecule rather than a classical signaling or scavenging receptor.

    Evidence Binding assays, internalization assays, CCRL2-deficient mice in IgE-mediated passive cutaneous anaphylaxis model

    PMID:18794339

    Open questions at the time
    • Structural basis of chemerin binding unknown
    • Relative contribution of CCRL2 versus CMKLR1 in different tissues not resolved
    • Whether other ligands exist remained unclear
  4. 2008 Medium

    The finding that CCRL2 induces pertussis toxin-insensitive ERK1/2 phosphorylation upon CCL5 exposure in pre-B cells without calcium flux or migration demonstrated non-canonical signaling capacity independent of Gαi coupling.

    Evidence Western blot for ERK1/2 phosphorylation, calcium flux assay, pertussis toxin inhibition in pre-B cell lines

    PMID:18397265

    Open questions at the time
    • Mechanism of Gi-independent ERK activation unresolved
    • Physiological relevance of CCL5/CCRL2 interaction debated
    • Later studies with neutralizing antibodies questioned CC chemokine binding
  5. 2010 High

    Demonstration that CCRL2 deficiency impairs antigen-loaded dendritic cell migration to draining lymph nodes revealed a cell-intrinsic role for CCRL2 in DC trafficking and subsequent T helper priming.

    Evidence CCRL2 knockout mice, adoptive DC transfer, OVA-induced lung inflammation model

    PMID:20606167

    Open questions at the time
    • Whether DC trafficking function is chemerin-dependent not tested
    • Mechanism of CCRL2-mediated DC migration unknown
    • Relevance to Th1 or Th17 immunity not explored
  6. 2012 High

    Establishing that endothelial CCRL2 upregulated by NF-κB/JAK-STAT signaling binds chemerin and triggers α4β1 integrin/VCAM-1-dependent adhesion of CMKLR1+ cells demonstrated the in vivo mechanism by which CCRL2 converts circulating chemerin into a tissue-homing cue for NK cells.

    Evidence CCRL2 KO mice, pathway inhibitors, integrin-blocking antibodies, LPS lung inflammation model

    PMID:22696441

    Open questions at the time
    • Whether endothelial CCRL2 interacts with chemerin in trans or cis with CMKLR1 not determined
    • Role in non-pulmonary vascular beds unexplored
  7. 2016 High

    Systematic BRET-based comparison across all Gαi subtypes, Gαo isoforms, and β-arrestins definitively classified CCRL2 as non-signaling upon chemerin binding, distinguishing it from CMKLR1 and GPR1.

    Evidence BRET biosensors for G protein activation and β-arrestin recruitment compared across three chemerin receptors

    PMID:27716822

    Open questions at the time
    • Signaling through non-canonical pathways (e.g., JAK2) not tested in this system
    • No structural explanation for silent coupling
  8. 2017 High

    Discovery that CCRL2 constitutively homodimerizes and heterodimerizes with CXCR2 to regulate β2-integrin activation and neutrophil recruitment revealed a chemerin-independent mechanism by which CCRL2 tunes innate immune responses.

    Evidence Reciprocal co-immunoprecipitation, CCRL2 KO mice, inflammatory arthritis models, β2-integrin activation assays

    PMID:28743719

    Open questions at the time
    • CCRL2 neutralizing antibody studies later found no effect on CXCL8-driven neutrophil responses, raising questions about context-dependence of the CXCR2 interaction
    • Stoichiometry and structural basis of heterodimer unknown
  9. 2017 High

    Confirmation that CCRL2 undergoes slow constitutive recycling through early and recycling endosomes without scavenging chemerin solidified the model that CCRL2 is a surface-presenting rather than internalizing receptor.

    Evidence Internalization assays, colocalization with EEA1/Rab5/Rab11 endosomal markers in transfected and primary endothelial cells

    PMID:29056935

    Open questions at the time
    • What regulates the balance of surface versus endosomal CCRL2 is unknown
    • Whether post-translational modifications control recycling not tested
  10. 2019 High

    Bone marrow chimera experiments assigning anti-tumor function to non-hematopoietic (endothelial) CCRL2 in lung cancer established that endothelial chemerin presentation drives NK cell-dependent tumor immunosurveillance.

    Evidence Bone marrow chimeras, urethane-induced and Kras/p53 genetic lung tumor models, NK cell flow cytometry

    PMID:31484658

    Open questions at the time
    • Whether CCRL2 also regulates T-cell recruitment to lung tumors not resolved
    • Human relevance of endothelial CCRL2 in lung cancer not confirmed
  11. 2021 High

    Identification of a CCRL2–TLR4 interaction that retains surface TLR4 and potentiates MyD88–NF-κB signaling in macrophages revealed a second chemerin-independent mechanism linking CCRL2 to anti-tumor immunity via macrophage–CD8+ T cell crosstalk.

    Evidence Co-immunoprecipitation, surface TLR4 quantification, NF-κB signaling assay, CCRL2 KO mice, melanoma model with macrophage/CD8 depletion

    PMID:33846258

    Open questions at the time
    • Whether TLR4 interaction is direct or adaptor-mediated not resolved
    • Generalizability beyond melanoma not tested
  12. 2022 High

    Co-precipitation of CCRL2 with JAK2 and demonstration that CCRL2 knockdown reduces JAK2–STAT3/STAT5 phosphorylation in MDS cells uncovered a cell-intrinsic oncogenic function distinct from its chemerin-presenting role, establishing CCRL2 as a context-dependent positive regulator of myeloid malignancy.

    Evidence Co-immunoprecipitation, Western blot for phospho-JAK2/STAT, siRNA knockdown, xenograft model, fedratinib epistasis

    PMID:35179961

    Open questions at the time
    • How a seven-transmembrane receptor potentiates JAK2 signaling mechanistically is unknown
    • Whether the JAK2 interaction is relevant outside MDS/AML not tested
  13. 2023 High

    Identification of CCRL2 as a hallmark marker of general alveolar capillary endothelial cells by scRNA-seq, combined with evidence that its epigenetic silencing is reversible by 5-Aza treatment to restore NK recruitment and suppress lung tumors, provided a translational framework for re-activating CCRL2-dependent immunosurveillance.

    Evidence scRNA-seq, conditional endothelial CCRL2 KO, Kras/p53 lung model, 5-Aza pharmacological treatment, NK subset analysis

    PMID:37343073

    Open questions at the time
    • Whether 5-Aza effects are specific to CCRL2 re-expression versus global demethylation not fully dissected
    • Optimal therapeutic window for CCRL2 re-expression undefined
  14. 2023 High

    Demonstration that endothelial CCRL2-presented chemerin activates monocyte β2-integrins via a protein disulfide isomerase-like enzymatic activity—independent of CMKLR1—revealed a novel pro-atherogenic mechanism of CCRL2-mediated monocyte adhesion at disturbed-flow sites.

    Evidence CCRL2−/−ApoE−/− mice on high-fat diet, proximity ligation assay for chemerin–β2-integrin interaction, Di-E-GSSG PDI activity assay, ERK1/2 phosphorylation

    PMID:37279540

    Open questions at the time
    • Whether the PDI-like activity of chemerin is relevant in other vascular beds unknown
    • How disturbed flow specifically induces CCRL2 transcription not fully defined
  15. 2024 Medium

    Discovery that CCRL2 binds SFRP1 on LepR+/CAR stromal cells to amplify Wnt suppression and inhibit osteogenic differentiation identified a novel non-chemerin ligand and a role for CCRL2 in bone homeostasis under inflammatory conditions.

    Evidence Co-immunoprecipitation of CCRL2-SFRP1, Wnt reporter assay, osteogenic differentiation assay, CCRL2 KO mice, micro-CT bone healing quantification

    PMID:38477792

    Open questions at the time
    • Whether SFRP1 binding uses the same site as chemerin not tested
    • Relevance beyond periodontitis-associated bone loss unknown
    • Single study requiring independent replication
  16. 2025 Medium

    Identification of CCRL2+ monocyte-derived macrophages as pro-hypertrophic, profibrotic effectors in heart failure whose TNF-α responsiveness is suppressed by vagal α7nAChR–NRF2 signaling positioned CCRL2 as a functional marker linking neuroimmunomodulation to cardiac remodeling.

    Evidence Optogenetic vagal nerve stimulation, CCRL2+ macrophage depletion, macrophage-specific α7nAChR manipulation, scRNA-seq, cardiac remodeling quantification

    PMID:40580954

    Open questions at the time
    • Whether CCRL2 is mechanistically required or merely a marker of these macrophages not fully resolved
    • Single study requiring independent replication

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of CCRL2's multi-ligand binding (chemerin, SFRP1, and receptor partners), how a non-signaling receptor potentiates JAK2–STAT signaling, the relative contributions of chemerin-dependent versus chemerin-independent mechanisms across tissues, and whether pharmacological modulation of CCRL2 surface expression can be exploited therapeutically.
  • No crystal or cryo-EM structure of CCRL2 or CCRL2–chemerin complex
  • Mechanism of JAK2 potentiation by a seven-transmembrane receptor unexplained
  • Relative weight of CXCR2 heterodimerization versus TLR4 interaction versus chemerin presentation in different cell types not systematically compared

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0038024 cargo receptor activity 5 GO:0060090 molecular adaptor activity 5 GO:0098772 molecular function regulator activity 3
Localization
GO:0005886 plasma membrane 9 GO:0005768 endosome 1 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-168256 Immune System 11 R-HSA-162582 Signal Transduction 5 R-HSA-1643685 Disease 2
Partners
CMKLR1CXCR2JAK2RARRES2SFRP1TLR4

Evidence

Reading pass · 27 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 CCRL2 (originally named HCR) was cloned as a novel seven-transmembrane chemokine receptor from a human neutrophil cDNA library, predicted to encode a 345 amino acid protein with homology to CCR1 (MIP-1α receptor, 43% identity), and mapped to chromosome 3p21. Expression was found in spleen, fetal liver, lymph node, bone marrow, lung, and heart. cDNA library screening, Northern blot, chromosome mapping Biochemical and Biophysical Research Communications Medium 9473515
2002 CCRL2 (designated HCR) is expressed on CD4+ and CD8+ T lymphocytes, monocytes, macrophages, monocyte-derived dendritic cells, neutrophils, and CD34+ hematopoietic precursors in peripheral blood and bone marrow. Expression is upregulated on T cells by OKT3/IL-2, and on dendritic cells by LPS, poly(I:C), IFN-γ, or CD40L stimulation. Monoclonal antibody generation, flow cytometry, real-time PCR European Journal of Immunology Medium 11828366
2004 CCRL2 is expressed on synovial neutrophils and some macrophages in rheumatoid arthritis patients. CCRL2 mRNA is rapidly upregulated in primary neutrophils by LPS or TNF stimulation. HEK293 cells expressing either splice variant CCRL2A or CCRL2B migrated in response to fractions of RA synovial fluid, demonstrating functional receptor activity. Immunocytochemistry, Northern blot, Western blot, RT-PCR, retroviral expression, 48-well chemotaxis chamber Arthritis and Rheumatism Medium 15188357
2008 Chemerin is identified as a natural nonsignaling protein ligand for both human and mouse CCRL2. Unlike other atypical chemokine receptors (DARC, D6), chemerin binding to CCRL2 does not trigger ligand internalization. Instead, CCRL2 binds chemerin and increases local concentrations of bioactive chemerin, thereby presenting it to the signaling chemerin receptor CMKLR1 on nearby cells, linking CCRL2 expression to inflammation. Binding assays, chemerin internalization assays, IgE-mediated passive cutaneous anaphylaxis mouse model, CCRL2-deficient mice The Journal of Experimental Medicine High 18794339
2008 CCRL2 (CRAM-A/B) is expressed on human B lymphocytes in a maturation-stage-dependent manner and is specifically upregulated by CCL5 exposure. CCL5 stimulation through CRAM induces ERK1/2 phosphorylation in pre-B cell lines lacking other known CCL5 receptors, but does not cause calcium mobilization or migration. This ERK1/2 phosphorylation is not inhibitable by pertussis toxin, indicating CCRL2 does not couple to Gi proteins. Flow cytometry, Western blot (ERK1/2 phosphorylation), calcium flux assay, migration assay, pertussis toxin inhibition Immunology Medium 18397265
2009 CCL19 is identified as a specific ligand for CCRL2 (CRAM-B). CCL19 binds CCRL2-expressing cells with nanomolar affinity similar to CCR7. Unlike the CCL19/CCR7 pair, CCL19 stimulation of CCRL2 does not induce calcium mobilization or cell migration. CCRL2 constitutively recycles via clathrin-coated pits and internalizes CCL19 as well as anti-CCRL2 antibodies, classifying it as an atypical non-classical chemokine receptor. Radioactive ligand binding, calcium mobilization assay, migration assay, internalization assay, clathrin-coated pit analysis Immunology Medium 20002784
2010 CCRL2 mRNA is rapidly (within 30 minutes) and transiently (2-4 hours) upregulated during dendritic cell maturation, with protein expression paralleling RNA regulation. CCRL2-deficient mice show normal DC recruitment to the lung but defective trafficking of antigen-loaded lung DCs to mediastinal lymph nodes, resulting in reduced T helper cell 2 priming. Adoptive transfer of CCRL2-deficient antigen-loaded DCs into wild-type mice recapitulates this phenotype. CCRL2 knockout mice, adoptive DC transfer, lung inflammation model (OVA), flow cytometry, BAL analysis Blood High 20606167
2012 CCRL2 is upregulated on vascular endothelial cells by proinflammatory stimuli via NF-κB and JAK/STAT signaling pathways. Endothelial CCRL2 expression enables chemerin binding and triggers robust adhesion of CMKLR1+ lymphoid cells through an α4β1 integrin/VCAM-1-dependent mechanism. In CCRL2-deficient mice, plasma chemerin levels are elevated and CMKLR1+ NK cell recruitment to the airways during acute LPS-induced pulmonary inflammation is significantly impaired. CCRL2 KO mice, NF-κB/JAK/STAT pathway inhibitors, integrin blocking antibodies, lymphocyte adhesion assay, in vivo LPS lung inflammation model, flow cytometry Journal of Immunology High 22696441
2012 CCRL2 overexpression significantly enhances migration rate and invasiveness of glioblastoma cells (U87, U373) without affecting proliferation, as determined by gain-of-function and loss-of-function studies. Overexpression and siRNA knockdown, migration and invasion assays (transwell), proliferation assay Biochemical and Biophysical Research Communications Low 23142225
2016 CCRL2 binds chemerin with low nanomolar affinity, but unlike CMKLR1, chemerin binding to CCRL2 does not activate any of the three Gαi subtypes, two Gαo isoforms, or recruit β-arrestin1 or β-arrestin2. CCRL2 also does not promote receptor internalization or ERK1/2 phosphorylation upon chemerin binding, establishing it as a non-signaling receptor that is functionally distinct from CMKLR1 and GPR1. BRET-based biosensors for G protein activation, β-arrestin recruitment assays, receptor internalization assays, ERK1/2 phosphorylation assay PloS One High 27716822
2016 CCRL2-deficient mice develop exacerbated, non-resolving experimental autoimmune encephalitis (EAE) with protracted inflammation and increased demyelination. This is associated with higher microglia/macrophage activation markers and imbalanced M1/M2 polarization, indicating CCRL2 promotes M2 polarization during the recovery phase to downregulate CNS inflammation. CCRL2 KO mice, EAE model, histological analysis, flow cytometry for M1/M2 markers Journal of Leukocyte Biology Medium 26744451
2017 CCRL2 constitutively forms homodimers and heterodimers with CXCR2 as demonstrated by co-immunoprecipitation. By heterodimerization with CXCR2, CCRL2 regulates membrane CXCR2 expression and promotes CXCR2-mediated functions including activation of β2-integrins. CCRL2-deficient mice have a specific defect in neutrophil recruitment and are protected in two models of inflammatory arthritis. Co-immunoprecipitation (homodimer/heterodimer detection), CCRL2 KO mice, inflammatory arthritis models, β2-integrin activation assay, neutrophil migration assay Blood High 28743719
2017 CCRL2 undergoes weak constitutive ligand-independent internalization and recycling, slower than ACKR3 or other chemotactic receptors. Intracellularly, CCRL2 colocalizes with EEA1- and Rab5-positive early endosomes and Rab11-positive recycling compartments. Critically, CCRL2-transfected cells and activated endothelial cells endogenously expressing CCRL2 cannot scavenge chemerin, confirming CCRL2 is not a decoy/scavenging receptor. Cell membrane internalization assays, immunofluorescence colocalization with endosomal markers (EEA1, Rab5, Rab11), chemerin scavenging assay in transfected and primary endothelial cells Frontiers in Immunology High 29056935
2017 CCRL2 absence in mice leads to exaggerated local and systemic inflammatory responses in zymosan- and thioglycollate-induced acute inflammation, characterized by increased myeloid cell recruitment associated with elevated chemerin and CXCL1 levels. Antibody neutralization of chemerin in CCRL2-deficient mice abrogates the amplified inflammatory response, demonstrating that CCRL2 regulates local chemerin concentration as its primary in vivo mechanism. CCRL2 KO mice, zymosan/thioglycollate peritonitis models, chemerin neutralizing antibody, cytokine/chemokine quantification, flow cytometry Frontiers in Immunology High 29209334
2019 CCRL2 expression by the non-hematopoietic (endothelial) cell compartment, as shown by bone marrow chimeras, is responsible for suppressing lung tumor formation. CCRL2 is expressed by a fraction of CD31+ lung endothelial cells where it controls NK cell infiltration into lung tumors. Genetic deletion of Ccrl2 promotes tumor progression in urethane-induced and Kras-mutant/p53-flox lung cancer models with impaired NK cell recruitment. CCRL2 KO mice, bone marrow chimeras, urethane lung cancer model, Kras/p53 genetic lung tumor model, flow cytometry for NK cells Cancer Immunology Research High 31484658
2020 MTB heat-shock protein Hsp16.3 induces macrophage M2 polarization through direct interaction with chemokine receptors CCRL2 and CX3CR1. Overexpression or silencing of CCRL2 modulates Hsp16.3-induced M2 polarization, and downstream signaling involves the AKT/ERK/p38-MAPK pathway. Overexpression and siRNA silencing, M2 marker quantification (Arg-1, IL-10, TGF-β, CD206), Western blot for AKT/ERK/p38-MAPK phosphorylation Inflammation Low 31748849
2021 CCRL2 interacts with TLR4 on the macrophage cell surface to retain membrane TLR4 expression and enhance TLR4 downstream Myd88-NF-κB inflammatory signaling. CCRL2-deficient mice exhibit accelerated melanoma growth with reduced immunostimulatory macrophages and T-cell responses. Depletion of CD8+ T cells or macrophages eliminates the tumor growth difference between WT and CCRL2-deficient mice. Co-immunoprecipitation (CCRL2-TLR4 interaction), flow cytometry for membrane TLR4, NF-κB signaling assay, CCRL2 KO mice, melanoma tumor model, CD8+ T cell and macrophage depletion PNAS High 33846258
2021 CCRL2 expression by tumor cells concentrates bioactive chemerin and reduces neoangiogenesis in tumor grafts, mimicking the phenotype of chemerin-expressing tumors. Loss of Ccrl2 accelerates papilloma development in a DMBA/TPA skin carcinogenesis model. These phenotypes are abrogated by knockout of chemerin or Cmklr1, demonstrating that CCRL2 acts through the chemerin/CMKLR1 axis. CCRL2 KO mice, DMBA/TPA skin carcinogenesis model, B16/LLC tumor grafts with CCRL2 overexpression or knockout, chemerin and Cmklr1 KO epistasis, angiogenesis quantification Cancers High 34638484
2022 CCRL2 knockdown suppresses MDS92 and MDS-L cell growth and clonogenicity in vitro and in vivo, and decreases JAK2/STAT3/STAT5 phosphorylation. CCRL2 co-precipitates with JAK2 and potentiates JAK2-STAT interaction. Erythroleukemia cells with constitutively active JAK2V617F show less dependence on CCRL2, and JAK2 inhibitor fedratinib potentiates CCRL2 knockdown effects. siRNA knockdown, co-immunoprecipitation (CCRL2-JAK2), Western blot (JAK2/STAT3/STAT5 phosphorylation), xenograft mouse model, pharmacological JAK2 inhibition Science Advances High 35179961
2022 Accelerated molecular dynamics simulation of CCRL2 with chemerin docking identified putative hot-spot residues in the CCRL2 transmembrane domain and extracellular loops most frequently involved in chemerin binding, providing a structural model for the CCRL2-chemerin interaction. Protein-protein docking, accelerated molecular dynamics, principal component analysis, kernel density estimation Proteins Low 35437825
2023 CCRL2 is expressed specifically by general alveolar lung capillary endothelial cells (identified by scRNA-seq as a hallmark marker). Conditional or constitutive endothelial CCRL2 ablation promotes lung tumor progression by reducing recruitment of CD27-CD11b+ mature NK cells. CCRL2 expression in lung endothelium is epigenetically regulated, and in vivo administration of the demethylating agent 5-aza-2'-deoxycytidine (5-Aza) upregulates CCRL2, increases NK cell recruitment, and reduces lung tumor growth. scRNA-seq, conditional/constitutive CCRL2 endothelial KO, Kras/p53 lung tumor model, 5-Aza treatment, flow cytometry for NK cell subsets, epigenetic regulation analysis Cancer Immunology Research High 37343073
2023 Endothelial CCRL2 induced by disturbed flow recruits chemerin, which activates β2 integrin on monocytes via a protein disulfide isomerase-like enzymatic activity of chemerin (rather than through monocytic CMKLR1), enhancing ERK1/2 phosphorylation and monocyte adhesion. CCRL2-deficient ApoE-/- mice are protected against atherosclerotic plaque formation in disturbed-flow areas. CCRL2-/-ApoE-/- mice, high-fat diet atherosclerosis model, scRNA-seq, Di-E-GSSG assay (PDI-like activity), proximity ligation assay (chemerin-β2 integrin interaction), ERK1/2 phosphorylation, monocyte adhesion assay Cardiovascular Research High 37279540
2023 CCRL2 neutralizing antibodies confirm that chemerin (but not previously reported CC chemokines) directly binds CCRL2 by flow cytometry and Surface Plasmon Resonance microscopy. However, antibody-mediated neutralization of CCRL2 ligand-binding does not attenuate CXCL8-induced neutrophil degranulation or CXCL8-induced murine neutrophil peritoneal recruitment, suggesting CCRL2's ligand-binding function is dispensable for CXCR2-mediated CXCL8 signaling in neutrophils. Flow cytometry binding assay, Surface Plasmon Resonance microscopy, CCRL2 neutralizing antibodies, neutrophil degranulation assay, in vivo peritoneal neutrophil recruitment PloS One Medium 36662882
2023 CCRL2 knockdown in MDS/sAML cell lines downregulates DNA methylation and PRC2 activity pathways, increases DNMT suppression by azacitidine, and sensitizes these cells to azacitidine both in vitro and in an MDS-L xenograft model. CCRL2 overexpression conversely decreases azacitidine sensitivity, demonstrating CCRL2 modulates epigenetic regulatory pathways. siRNA knockdown, CCRL2 overexpression, azacitidine sensitivity assays, xenograft model, gene expression profiling (PRC2/DNMT pathways) Haematologica Medium 36519323
2024 CCRL2 binds SFRP1 on the surface of LepR+/CAR stromal cells, amplifying SFRP1's suppressive effect on Wnt signaling under inflammatory conditions. This CCRL2-SFRP1 interaction inhibits osteogenic differentiation of LepR+/CAR cells, resulting in impaired bone healing in periodontitis. CCRL2-knockout mice show significant improvements in extraction socket bone healing. CCRL2 KO mice, co-immunoprecipitation (CCRL2-SFRP1 interaction), Wnt signaling reporter assay, osteogenic differentiation assay, bone healing quantification by micro-CT Journal of Bone and Mineral Research Medium 38477792
2021 CCRL2 functions as a coreceptor for primary HIV-2 isolates (and to a lesser extent HIV-1) in NP-2/CD4/CCRL2 cells. HIV-2MIR infection was demonstrated by immunofluorescence, proviral DNA detection, reverse transcriptase activity measurement, and multinucleated giant cell formation, making CCRL2 a newly identified HIV-2 entry coreceptor. NP-2 cell transduction with CD4 and CCRL2, HIV infection assay, immunofluorescence, PCR for proviral DNA, reverse transcriptase activity assay, Giemsa staining for syncytia Briefings in Bioinformatics Low 33253374
2025 Optogenetic vagal nerve stimulation decreases the proportion of CCRL2+ macrophages, which are monocyte-derived and exhibit a TNF-α-responsive, pro-hypertrophic, profibrotic signature. Elimination of CCRL2+ macrophages prevents cardiac remodeling and heart failure. α7nAChR activation inhibits CCRL2+ macrophage TNF-α responsiveness through increased NRF2 expression. CCRL2+-macrophage-specific overexpression or global loss of α7nAChR eliminates VNS-mediated cardioprotection. Optogenetic VNS, CCRL2+ macrophage depletion, macrophage-specific α7nAChR overexpression/KO, NRF2 expression assay, cardiac remodeling quantification, scRNA-seq Immunity Medium 40580954

Source papers

Stage 0 corpus · 123 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2010 Multiple common variants for celiac disease influencing immune gene expression. Nature genetics 801 20190752
2003 Specific recruitment of antigen-presenting cells by chemerin, a novel processed ligand from human inflammatory fluids. The Journal of experimental medicine 728 14530373
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2004 miR-122, a mammalian liver-specific microRNA, is processed from hcr mRNA and may downregulate the high affinity cationic amino acid transporter CAT-1. RNA biology 660 17179747
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2008 Mast cell-expressed orphan receptor CCRL2 binds chemerin and is required for optimal induction of IgE-mediated passive cutaneous anaphylaxis. The Journal of experimental medicine 249 18794339
2016 Signaling Properties of Chemerin Receptors CMKLR1, GPR1 and CCRL2. PloS one 143 27716822
2010 Chemokine-like receptor 1 (CMKLR1) and chemokine (C-C motif) receptor-like 2 (CCRL2); two multifunctional receptors with unusual properties. Experimental cell research 138 21056554
2012 Expression, regulation, and function of atypical chemerin receptor CCRL2 on endothelial cells. Journal of immunology (Baltimore, Md. : 1950) 122 22696441
2000 A candidate gene for psoriasis near HLA-C, HCR (Pg8), is highly polymorphic with a disease-associated susceptibility allele. Human molecular genetics 109 10888604
2014 Genome-wide association study of CSF levels of 59 alzheimer's disease candidate proteins: significant associations with proteins involved in amyloid processing and inflammation. PLoS genetics 108 25340798
2002 Coding haplotype analysis supports HCR as the putative susceptibility gene for psoriasis at the MHC PSORS1 locus. Human molecular genetics 105 11875053
1997 Two hepatic enhancers, HCR.1 and HCR.2, coordinate the liver expression of the entire human apolipoprotein E/C-I/C-IV/C-II gene cluster. The Journal of biological chemistry 89 9360987
2017 The atypical receptor CCRL2 is required for CXCR2-dependent neutrophil recruitment and tissue damage. Blood 85 28743719
2013 The HIV-1 envelope protein gp120 impairs B cell proliferation by inducing TGF-β1 production and FcRL4 expression. Nature immunology 84 24162774
2000 Identification of CRAM, a novel unc-33 gene family protein that associates with CRMP3 and protein-tyrosine kinase(s) in the developing rat brain. The Journal of biological chemistry 84 10851247
2010 Nonredundant role of CCRL2 in lung dendritic cell trafficking. Blood 77 20606167
2016 The roles of the hybrid cluster protein, Hcp and its reductase, Hcr, in high affinity nitric oxide reduction that protects anaerobic cultures of Escherichia coli against nitrosative stress. Molecular microbiology 65 26879449
2021 Direct characterization of cis-regulatory elements and functional dissection of complex genetic associations using HCR-FlowFISH. Nature genetics 61 34326544
2021 CCRL2 promotes antitumor T-cell immunity via amplifying TLR4-mediated immunostimulatory macrophage activation. Proceedings of the National Academy of Sciences of the United States of America 59 33846258
2004 Up-regulated expression and activation of the orphan chemokine receptor, CCRL2, in rheumatoid arthritis. Arthritis and rheumatism 56 15188357
2015 In situ DNA-hybridization chain reaction (HCR): a facilitated in situ HCR system for the detection of environmental microorganisms. Environmental microbiology 55 25523128
2020 Molecular Basis for CCRL2 Regulation of Leukocyte Migration. Frontiers in cell and developmental biology 54 33363177
2009 CCL19 is a specific ligand of the constitutively recycling atypical human chemokine receptor CRAM-B. Immunology 54 20002784
2007 The CCHCR1 (HCR) gene is relevant for skin steroidogenesis and downregulated in cultured psoriatic keratinocytes. Journal of molecular medicine (Berlin, Germany) 50 17221218
2022 Computer-aided design of reversible hybridization chain reaction (CAD-HCR) enables multiplexed single-cell spatial proteomics imaging. Science advances 48 35030012
2021 Imaging of Cancer Cells and Dictated Cytotoxicity Using Aptamer-Guided Hybridization Chain Reaction (HCR)-Generated G-Quadruplex Chains. Angewandte Chemie (International ed. in English) 48 34350685
2002 Distribution and regulation of expression of the putative human chemokine receptor HCR in leukocyte populations. European journal of immunology 48 11828366
2022 Enhanced chemiluminescence imaging sensor for ultrasensitive detection of nucleic acids based on HCR-CRISPR/Cas12a. Biosensors & bioelectronics 46 35671698
2020 A novel aptasensor based on HCR and G-quadruplex DNAzyme for fluorescence detection of Carcinoembryonic Antigen. Talanta 46 33076074
2011 Genome-wide association study implicates PARD3B-based AIDS restriction. The Journal of infectious diseases 45 21502085
2023 Three-Dimensional CHA-HCR System Using DNA Nanospheres for Sensitive and Rapid Imaging of miRNA in Live Cells and Tissues. Analytical chemistry 44 37506347
2019 A Universal Electrochemical Biosensor Using Nick-HCR Nanostructure as Molecular Gate of Nanochannel for Detecting Chromium(III) Ions and MicroRNA. Analytical chemistry 39 31589033
2013 CCRL2, a fringe member of the atypical chemoattractant receptor family. European journal of immunology 39 23580473
2006 The DNA sequence, annotation and analysis of human chromosome 3. Nature 39 16641997
2021 The TDs/aptamer cTnI biosensors based on HCR and Au/Ti3C2-MXene amplification for screening serious patient in COVID-19 pandemic. Biosensors & bioelectronics 38 34256261
2019 Hybridization chain reaction (HCR) for amplifying nanopore signals. Biosensors & bioelectronics 38 31780404
2019 The Atypical Receptor CCRL2 Is Essential for Lung Cancer Immune Surveillance. Cancer immunology research 37 31484658
2016 CCRL2 regulates M1/M2 polarization during EAE recovery phase. Journal of leukocyte biology 37 26744451
1998 Cloning and characterization of a novel human chemokine receptor. Biochemical and biophysical research communications 37 9473515
2015 HCR-stimulated formation of DNAzyme concatamers on gold nanoparticle for ultrasensitive impedimetric immunoassay. Biosensors & bioelectronics 36 25636020
2001 The HCR gene on 6p21 is unlikely to be a psoriasis susceptibility gene. The Journal of investigative dermatology 36 11348465
2015 The chemokines CCR1 and CCRL2 have a role in colorectal cancer liver metastasis. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 34 26383527
1989 Fused transcripts of c-myc and a new cellular locus, hcr in a primary liver tumor. Oncogene 34 2644611
2022 Quantitative fragmentomics allow affinity mapping of interactomes. Nature communications 33 36115835
2017 A C-HCR assembly of branched DNA nanostructures for amplified uracil-DNA glycosylase assays. Chemical communications (Cambridge, England) 32 29038818
2010 An approach based on a genome-wide association study reveals candidate loci for narcolepsy. Human genetics 32 20677014
2023 The compact integration of a cascaded HCR circuit for highly reliable cancer cell discrimination. Chemical science 31 36845932
2021 A minimal hybridization chain reaction (HCR) system using peptide nucleic acids. Chemical science 31 34194712
2017 The Atypical Receptor CCRL2 (C-C Chemokine Receptor-Like 2) Does Not Act As a Decoy Receptor in Endothelial Cells. Frontiers in immunology 30 29056935
2004 Transgenic mouse models support HCR as an effector gene in the PSORS1 locus. Human molecular genetics 30 15190014
2021 Large-scale preparation of fluorescence multiplex host cell reactivation (FM-HCR) reporters. Nature protocols 29 34363069
1997 The beta-chemokine receptor genes CCR1 (CMKBR1), CCR2 (CMKBR2), and CCR3 (CMKBR3) cluster within 285 kb on human chromosome 3p21. Genomics 29 9143512
2012 Prospective in-patient cohort study of moves between levels of therapeutic security: the DUNDRUM-1 triage security, DUNDRUM-3 programme completion and DUNDRUM-4 recovery scales and the HCR-20. BMC psychiatry 28 22794187
2003 HCR, a candidate gene for psoriasis, is expressed differently in psoriasis and other hyperproliferative skin disorders and is downregulated by interferon-gamma in keratinocytes. The Journal of investigative dermatology 28 14675183
1995 The Hcr (hepatocarcinogen resistance) loci of DBA/2J mice partially suppress phenotypic expression of the Hcs (hepatocarcinogen sensitivity) loci of C3H/HeJ mice. Carcinogenesis 28 7634431
2021 Traditional and new applications of the HCR in biosensing and biomedicine. The Analyst 27 34775502
1989 Structure and expression of hcr, a locus rearranged with c-myc in a woodchuck hepatocellular carcinoma. Oncogene 27 2536918
2023 Endothelial CCRL2 induced by disturbed flow promotes atherosclerosis via chemerin-dependent β2 integrin activation in monocytes. Cardiovascular research 26 37279540
2020 Mycobacterium tuberculosis Heat-Shock Protein 16.3 Induces Macrophage M2 Polarization Through CCRL2/CX3CR1. Inflammation 26 31748849
2008 Human B cells express the orphan chemokine receptor CRAM-A/B in a maturation-stage-dependent and CCL5-modulated manner. Immunology 26 18397265
2019 A novel ECL method for histone acetyltransferases (HATs) activity analysis by integrating HCR signal amplification and ECL silver clusters. Talanta 24 30876576
1998 A short proximal promoter and the distal hepatic control region-1 (HCR-1) contribute to the liver specificity of the human apolipoprotein C-II gene. Hepatic enhancement by HCR-1 requires two proximal hormone response elements which have different binding specificities for orphan receptors HNF-4, ARP-1, and EAR-2. The Journal of biological chemistry 24 9461615
2024 Toehold Strand Displacement-Mediated Exponential HCR for Highly Sensitive and Specific Analysis of miRNA in Living Cells. Analytical chemistry 23 38770734
2021 Accurate and Efficient Lipoprotein Detection Based on the HCR-DNAzyme Platform. Analytical chemistry 23 33834764
2020 A fluorescent amplification strategy for high-sensitive detection of 17 β-estradiol based on EXPAR and HCR. Analytica chimica acta 23 32389184
2012 Elevated chemokine CC-motif receptor-like 2 (CCRL2) promotes cell migration and invasion in glioblastoma. Biochemical and biophysical research communications 23 23142225
2007 A 368-base-pair cis-acting HWP1 promoter region, HCR, of Candida albicans confers hypha-specific gene regulation and binds architectural transcription factors Nhp6 and Gcf1p. Eukaryotic cell 23 17220463
2017 A Nanobiosensor Based on Fluorescent DNA-Hosted Silver Nanocluster and HCR Amplification for Detection of MicroRNA Involved in Progression of Multiple Sclerosis. Journal of fluorescence 22 28478551
2016 A rapid and visual aptasensor for Lipopolysaccharides detection based on the bulb-like triplex turn-on switch coupled with HCR-HRP nanostructures. Biosensors & bioelectronics 21 27816585
1981 Evidence that dimers remaining in preinduced Escherichia coli B/r Hcr+ become insensitive after DNA replication to the extract from Micrococcus luteus. Biophysical journal 21 7030422
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2017 Absence of the Non-Signalling Chemerin Receptor CCRL2 Exacerbates Acute Inflammatory Responses In Vivo. Frontiers in immunology 20 29209334
2011 Role of exonic variation in chemokine receptor genes on AIDS: CCRL2 F167Y association with pneumocystis pneumonia. PLoS genetics 20 22046140
2005 RNA polymerase II subunit 3 is retained in the cytoplasm by its interaction with HCR, the psoriasis vulgaris candidate gene product. Journal of cell science 20 16141233
2023 CCRL2 affects the sensitivity of myelodysplastic syndrome and secondary acute myeloid leukemia cells to azacitidine. Haematologica 19 36519323
2023 Highly sensitive detection of Salmonella based on dual-functional HCR-mediated multivalent aptamer and amplification-free CRISPR/Cas12a system. Analytica chimica acta 19 37996158
2022 The role of the atypical chemokine receptor CCRL2 in myelodysplastic syndrome and secondary acute myeloid leukemia. Science advances 19 35179961
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2015 CRAM-A indicates IFN-γ-associated inflammatory response in breast cancer. Molecular immunology 19 26563945
2024 HCR spectral imaging: 10-plex, quantitative, high-resolution RNA and protein imaging in highly autofluorescent samples. Development (Cambridge, England) 18 38415752
2023 HCR/DNAzyme-triggered cascaded feedback cycle amplification for self-powered dual-photoelectrode detection of femtomolar HPV16. Biosensors & bioelectronics 18 37390640
2015 The human chemokine receptor CCRL2 suppresses chemotaxis and invasion by blocking CCL2-induced phosphorylation of p38 MAPK in human breast cancer cells. Medical oncology (Northwood, London, England) 18 26487662
2025 Supramolecular DNA Nanodevice Assembled via RCA and HCR Cascade Reaction on Tetrahedral DNA Nanostructure for Sensitive Detection and Intracellular Imaging of Dual-miRNAs Associated with Liver Cancer. Analytical chemistry 17 39742445
2022 A novel fluorescence biosensor based on double-stranded DNA branch migration-induced HCR and DNAzyme feedback circuit for sensitive detection of Pseudomonas aeruginosa (clean version). Analytica chimica acta 17 36257735
2023 Hybridization Chain Reaction Fluorescence In Situ Hybridization (HCR-FISH) in Ambystoma mexicanum Tissue. Methods in molecular biology (Clifton, N.J.) 16 36272070
2021 A label-free fluorescent aptasensor based on HCR and G-quadruplex DNAzymes for the detection of prostate-specific antigen. The Analyst 16 33367331
2016 A sensitive impedimetric platform biosensing protein: Insoluble precipitates based on the biocatalysis of manganese(III) meso-tetrakis (4-N-methylpyridiniumyl)-porphyrinin in HCR-assisted dsDNA. Biosensors & bioelectronics 16 27471156
2023 A Fast And Versatile Method for Simultaneous HCR, Immunohistochemistry And Edu Labeling (SHInE). Integrative and comparative biology 15 36866518
2022 The helper oligonucleotides enable detection of folded single-stranded DNA by lateral flow immunoassay after HCR signal amplification. Talanta 15 35661000
2021 Expression of CCRL2 Inhibits Tumor Growth by Concentrating Chemerin and Inhibiting Neoangiogenesis. Cancers 15 34638484
2020 Ccrl2 deficiency deteriorates obesity and insulin resistance through increasing adipose tissue macrophages infiltration. Genes & diseases 15 35224158
2017 Chemokine (CC-motif) receptor-like 2 mRNA is expressed in hepatic stellate cells and is positively associated with characteristics of non-alcoholic steatohepatitis in mice and men. Experimental and molecular pathology 15 28600126
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2004 Genetic polymorphisms of the HCR gene and a genomic segment in close proximity to HLA-C are associated with patients with psoriasis in Taiwan. The British journal of dermatology 15 15214895
1999 Multiple DNA repair mechanisms and alkylator resistance in the human medulloblastoma cell line D-283 Med (4-HCR). Cancer chemotherapy and pharmacology 15 9923544
2022 An electrochemical biosensor for the detection of aflatoxin B1 based on the specific aptamer and HCR biological magnification. Analytical methods : advancing methods and applications 14 36484245
2020 Intramolecular trigger remodeling-induced HCR for amplified detection of protein-specific glycosylation. Talanta 14 32312435
2022 NIR-to-Vis Handheld Platforms for Detecting miRNA Level and Mutation Based on Sub-10 nm Sulfide Nanodots and HCR Amplification. ACS applied materials & interfaces 13 35188756
2023 CCRL2 Expression by Specialized Lung Capillary Endothelial Cells Controls NK-cell Homing in Lung Cancer. Cancer immunology research 12 37343073
2020 Thermotolerant glycosyl hydrolases-producing Bacillus aerius CMCPS1 and its saccharification efficiency on HCR-laccase (LccH)-pretreated corncob biomass. Biotechnology for biofuels 12 32684977
2018 Assessing Individual Neuronal Activity Across the Intact Brain: Using Hybridization Chain Reaction (HCR) to Detect Arc mRNA Localized to the Nucleus in Volumes of Cleared Brain Tissue. Current protocols in neuroscience 12 29944213
2010 Unusual organization, complexity and redundancy at the Escherichia coli hcp-hcr operon promoter. The Biochemical journal 12 20533909
2025 Optogenetic vagal nerve stimulation attenuates heart failure by limiting the generation of monocyte-derived inflammatory CCRL2+ macrophages. Immunity 11 40580954
2024 Dual electrochemical signal "signal-on-off" sensor based on CHA-Td-HCR and CRISPR-Cas12a for MUC1 detection. Talanta 11 39116728
2021 A highly sensitive fluorescence biosensor for detection of Staphylococcus aureus based on HCR-mediated three-way DNA junction nicking enzyme assisted signal amplification. The Analyst 11 34569562
2022 Exploring CCRL2 chemerin binding using accelerated molecular dynamics. Proteins 10 35437825
2010 Polymorphisms in innate immunity genes and patients response to dendritic cell-based HIV immuno-treatment. Vaccine 10 20056178
2024 HCR-Assisted RTF-EXPAR-Based Lateral Flow Analysis for Sensitive Detection of H1N1 Influenza Virus. Analytical chemistry 9 38967348
2024 Leptin receptor (+) stromal cells respond to periodontitis and attenuate alveolar bone repair via CCRL2-mediated Wnt inhibition. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 8 38477792
2024 An Innovative and Efficient Fluorescent Detection Technique for Salmonella in Animal-Derived Foods Using the CRISPR/Cas12a-HCR System Combined with PCR/RAA. Journal of agricultural and food chemistry 8 38575365
2022 Development and validation of a label-free colorimetric aptasensor based on the HCR and hemin/G-quadruplex DNAzyme for the determination of patulin in fruits and fruit-based products from Xinjiang (China). Analytical methods : advancing methods and applications 8 35975688
2022 Target Recognition- and HCR Amplification-Induced In Situ Electrochemical Signal Probe Synthesis Strategy for Trace ctDNA Analysis. Biosensors 8 36354498
1984 Error-free uvr+-dependent inducible DNA repair in Escherichia coli B/r Hcr+ cells. International journal of radiation biology and related studies in physics, chemistry, and medicine 8 6370887
2021 Genomics Links Inflammation With Neurocognitive Impairment in Children Living With Human Immunodeficiency Virus Type-1. The Journal of infectious diseases 7 33373444
2023 Studies with neutralizing antibodies suggest CXCL8-mediated neutrophil activation is independent of C-C motif chemokine receptor-like 2 (CCRL2) ligand binding function. PloS one 5 36662882
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2021 C-C Chemokine receptor-like 2 (CCRL2) acts as coreceptor for human immunodeficiency virus-2. Briefings in bioinformatics 3 33253374