Affinage

ACKR2

Atypical chemokine receptor 2 · UniProt O00590

Length
384 aa
Mass
43.4 kDa
Annotated
2026-06-09
100 papers in source corpus 32 papers cited in narrative 31 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ACKR2 (D6) is an atypical, non-signaling chemokine scavenging receptor that suppresses inflammation by binding, internalizing, and degrading the majority of inflammatory CC chemokines (and CXCL10) without coupling to the canonical G-protein calcium/chemotaxis output of conventional chemokine receptors (PMID:9405404, PMID:9139699, PMID:12594248, PMID:33801414). Mechanistically, the receptor constitutively cycles between recycling endosomes and the plasma membrane in a ligand-independent, Rab4/Rab11-dependent manner; internalized chemokines dissociate upon endosomal acidification and are degraded while the receptor recycles back to the surface without downregulation, enabling sustained scavenging (PMID:15004236, PMID:18480427). Internalization proceeds through the clathrin pathway and requires constitutive association with beta-arrestin via an acidic cytoplasmic-tail region, while the conserved C-terminal serine cluster controls constitutive phosphorylation, receptor stability, trafficking itinerary, and prevents ligand-induced inhibition of recycling to permit progressive scavenging (PMID:15084596, PMID:18201974). Ligand engagement triggers a beta-arrestin1-dependent, G-protein-independent Rac1–PAK1–LIMK1–cofilin cascade that drives adaptive surface upregulation and increases scavenging capacity, with chemokine degradation (distinct from mere binding) determined by an N-terminal proline at ligand position 2 (PMID:19632987, PMID:23633677). Expressed prominently on lymphatic endothelial cells, trophoblasts, and hematopoietic cells, ACKR2 limits perilymphatic accumulation of inflammatory leukocytes and preserves CCR7-dependent dendritic cell migration, reciprocally regulates lymphatic vessel density through CCL2 clearance, restricts neutrophil and NK-cell trafficking, and protects against inflammation-driven fetal loss (PMID:17283337, PMID:21979941, PMID:25271254, PMID:25297873, PMID:29445158, PMID:30158126). In vivo loss of ACKR2 produces exacerbated, poorly resolving inflammatory responses with excess local CC chemokines (PMID:15750596). In tumor contexts, ACKR2 also transduces CXCL14-driven EMT and metastatic signaling (PMID:30850359, PMID:37056937).

Mechanistic history

Synthesis pass · year-by-year structured walk · 28 steps
  1. 1997 High

    Established that ACKR2 is a promiscuous CC chemokine binder that, unlike conventional chemokine receptors, fails to flux calcium, defining it as a non-signaling receptor and raising the question of its function.

    Evidence Radioligand binding and calcium flux assays in transfected CHO and HEK293 cells for human and murine D6

    PMID:9139699 PMID:9405404

    Open questions at the time
    • Did not establish the cellular fate of bound chemokines
    • No in vivo function defined
  2. 2001 High

    Localized ACKR2 to lymphatic endothelium of afferent lymphatics and lymph node sinuses, anchoring its function to a specific anatomical compartment rather than blood vasculature.

    Evidence Immunohistochemistry, in situ hybridization, and podoplanin co-staining across human tissues

    PMID:11238036

    Open questions at the time
    • Did not test functional consequence of lymphatic expression
    • Hematopoietic expression not yet defined
  3. 2003 High

    Resolved the receptor's function by showing that ligand engagement leads to efficient internalization and degradation rather than transcytosis or chemotaxis, defining ACKR2 as a chemokine scavenger.

    Evidence Internalization/degradation assays in transfectants and primary lymphatic endothelial cells

    PMID:12594248

    Open questions at the time
    • Trafficking machinery not yet identified
    • Did not determine how the receptor avoids downregulation
  4. 2004 High

    Defined the trafficking logic of scavenging: constitutive ligand-independent recycling with endosomal acidification driving chemokine release and degradation while the receptor returns to the surface.

    Evidence Live-cell imaging, subcellular fractionation, and degradation kinetics comparing D6 to CCR5

    PMID:15004236

    Open questions at the time
    • Specific Rab GTPases not yet identified
    • Endocytic adaptors not yet defined
  5. 2004 High

    Identified the internalization machinery and biochemical features, showing clathrin- and beta-arrestin-dependent uptake via an acidic tail region and confirming the absence of G-protein signaling.

    Evidence Clathrin inhibitors, beta-arrestin Co-IP, C-terminal mutagenesis, G-protein assays, and purified-receptor binding plus metabolic labelling

    PMID:14723600 PMID:15084596

    Open questions at the time
    • Role of C-terminal phosphorylation in trafficking unresolved
    • Did not address adaptive surface regulation
  6. 2004 High

    Defined the ligand spectrum, establishing that ACKR2 scavenges inflammatory but not homeostatic chemokines and that intact chemokine N-termini are required for recognition.

    Evidence Systematic chemokine binding/scavenging panel including CD26-truncated CCL22 in transfectants

    PMID:15067078

    Open questions at the time
    • Did not distinguish binding from degradation determinants
    • Did not extend to CXC chemokines
  7. 2005 High

    Provided the first in vivo loss-of-function evidence that ACKR2 is required to resolve cutaneous inflammation by clearing CC chemokines.

    Evidence Phorbol ester skin inflammation in D6-knockout mice with chemokine ELISA and histopathology

    PMID:15750596

    Open questions at the time
    • Cell-type-specific contributions not dissected
    • Did not address other tissues
  8. 2005 Medium

    Raised an alternative pathogen-related role by implicating D6 as an HIV coreceptor on primary astrocytes.

    Evidence HIV infection assays with siRNA knockdown in primary astrocytes

    PMID:16014924

    Open questions at the time
    • Single lab, single study
    • Conflicts with earlier finding that D6 is not an HIV coreceptor on CD4+ cells
    • Physiological relevance unclear
  9. 2007 High

    Extended scavenging function to the placenta, showing ACKR2 protects against inflammation-driven fetal loss in a chemokine-dependent manner.

    Evidence Placental immunohistochemistry plus D6-/- LPS/antiphospholipid challenge with chemokine-blockade rescue

    PMID:17283337

    Open questions at the time
    • Maternal versus fetal source of ACKR2 not resolved here
    • Mechanism of trophoblast scavenging not detailed
  10. 2008 High

    Identified the trafficking machinery and the adaptive scavenging mechanism: Rab4/Rab11-dependent recycling and ligand-induced membrane redistribution that boosts degradation without transcription.

    Evidence Wortmannin/BFA inhibition, dominant-negative Rab4/Rab11, flow cytometry, and degradation assays

    PMID:18480427

    Open questions at the time
    • Signaling driving redistribution not yet identified
    • Link to C-terminal regulation unresolved
  11. 2008 Medium

    Defined transcriptional control by GATA1 and confirmed functional scavenging on human leukocytes, broadening expression beyond endothelium to hematopoietic cells.

    Evidence GATA1 perturbation, promoter analysis, and leukocyte uptake assays versus D6-null cells

    PMID:18714007 PMID:19039854

    Open questions at the time
    • Single lab
    • Direct GATA1 binding to endogenous locus not fully mapped
  12. 2008 High

    Dissected the C-terminal serine cluster's role in phosphorylation, stability, trafficking, and prevention of ligand-induced inhibition of recycling required for progressive scavenging.

    Evidence C-terminal/serine-cluster mutants of D6-GFP with beta-arrestin recruitment and CCL3 scavenging assays

    PMID:18201974

    Open questions at the time
    • Identity of the kinase phosphorylating the serine cluster unknown
    • Did not connect to the downstream signaling cascade
  13. 2009 Medium

    Separated binding from degradation, identifying a chemokine position-2 proline as the determinant of adaptive upregulation and efficient degradation.

    Evidence Chemokine N-terminal isoform panels with surface D6 flow cytometry and degradation ELISA

    PMID:19632987

    Open questions at the time
    • Single lab
    • Structural basis of proline recognition not determined
  14. 2011 High

    Established the lymphatic physiological role: ACKR2 prevents perilymphatic inflammatory chemokine accumulation to preserve CCR7-dependent dendritic cell and fluid migration.

    Evidence D6-/- intravital microscopy, LEC chemokine flow cytometry, and APC migration/drainage assays

    PMID:21979941

    Open questions at the time
    • Did not address lymphatic developmental patterning
    • Cell-intrinsic versus tissue effects not fully separated
  15. 2011 Medium

    Showed ACKR2 scavenging is a universal feature of innate-like B cells and can suppress CXCR5 function, linking it to B-cell positioning.

    Evidence Chemokine uptake, Ca2+ flux, chemotaxis assays on primary B-cell subsets and D6-/- analysis

    PMID:21450903

    Open questions at the time
    • Single lab
    • Mechanism of CXCR5 suppression unresolved
  16. 2013 High

    Identified the signaling cascade behind adaptive scavenging: a beta-arrestin1/Rac1/PAK1/LIMK1/cofilin pathway driving surface upregulation, reconciling a non-G-protein receptor with active signaling output.

    Evidence Phospho-cofilin immunoblotting, dominant-negative Rac1/PAK1, beta-arrestin1 siRNA, and scavenging assays

    PMID:23633677

    Open questions at the time
    • How ligand binding initiates the cascade not fully defined
    • In vivo relevance of the cascade untested
  17. 2013 Medium

    Connected lymphatic ACKR2 to immune surveillance by showing it controls LEC discrimination between mature and immature dendritic cells, with cytokine and viral IL-6 regulation.

    Evidence LEC overexpression/knockdown DC adhesion assays with IL-6/IFN-gamma and viral IL-6 treatment

    PMID:23479571

    Open questions at the time
    • Single lab
    • Molecular basis of DC discrimination unresolved
  18. 2014 High

    Revealed a developmental role linking CCL2 scavenging to reciprocal control of lymphatic vessel density via macrophage proximity.

    Evidence Reciprocal ACKR2-/- and CCR2-/- mouse phenotyping with embryonic skin imaging and drainage measurement

    PMID:25271254

    Open questions at the time
    • Macrophage signal driving lymphangiogenesis not fully defined
    • Direct CCL2 gradients not measured in vivo
  19. 2014 High

    Demonstrated that trophoblast-intrinsic ACKR2 mediates chemokine scavenging required for normal placental structure and fetal viability.

    Evidence Primary human trophoblast scavenging assays and fetal-specific ACKR2 knockout mouse models

    PMID:25297873

    Open questions at the time
    • Specific pathogenic chemokines in placenta not fully resolved
    • Mechanism of structural defect unclear
  20. 2016 Medium

    Showed ACKR2 controls inflammatory T-cell positioning in skin and protects remote tissues from psoriasiform inflammation spread, induced by IFN-gamma.

    Evidence Imiquimod psoriasiform model in ACKR2-/- mice with T-cell migration assays and clinical biopsies

    PMID:27568525

    Open questions at the time
    • Single lab
    • Remote-tissue protection mechanism partial
  21. 2017 Medium

    Identified post-transcriptional control of ACKR2 by miR-146b and miR-10b, including stress-induced downregulation, providing a mechanism for trauma-triggered loss of scavenging.

    Evidence 3'-UTR luciferase reporters and cell-stretch experiments in primary keratinocytes and LECs

    PMID:29279330

    Open questions at the time
    • Single lab
    • In vivo relevance of miRNA regulation untested
  22. 2018 Medium

    Linked ACKR2 to myeloid development and neutrophil release, showing its deletion enhances anti-metastatic neutrophil activity by raising inflammatory chemokine receptor expression.

    Evidence ACKR2-/- bone marrow profiling and 4T1/B16F10 metastasis models

    PMID:29445158

    Open questions at the time
    • Single lab
    • Cell-intrinsic versus niche effects not fully separated
  23. 2018 Medium

    Showed ACKR2 limits CCR2 expression on KLRG1+ NK cells, restricting their CCL2-driven recruitment and tumoricidal activity.

    Evidence Ackr2-/- metastasis models with NK subset flow cytometry and in vivo killing assays

    PMID:30158126

    Open questions at the time
    • Single lab
    • Mechanism of CCR2 limitation on NK cells unresolved
  24. 2019 Medium

    Reframed ACKR2 in cancer as a signaling receptor mediating CXCL14-induced EMT, migration, and invasion via NOS1 in breast cancer cells.

    Evidence ACKR2 siRNA knockdown with EMT/migration/invasion assays and xenograft/metastasis models

    PMID:30850359

    Open questions at the time
    • Single lab
    • Reconciliation with non-signaling scavenger model not addressed
  25. 2021 Medium

    Expanded the ligand range by establishing CXCL10 as a CC-independent agonist that recruits beta-arrestin and is degraded, with distinct binding-pocket determinants.

    Evidence NanoBiT/NanoBRET beta-arrestin recruitment and internalization assays plus DPP4-processed CXCL10 testing

    PMID:33801414

    Open questions at the time
    • Single lab
    • Structural basis of CXC versus CC recognition not determined
  26. 2021 Medium

    Defined an upstream regulatory axis (SIRT2/p65/miR-146a) controlling trophoblast ACKR2 expression and linked its disruption to preeclampsia.

    Evidence ChIP, miR-146a 3'-UTR luciferase reporters, and SIRT2/miR-146a perturbation in HTR-8/SVneo trophoblasts

    PMID:33409877

    Open questions at the time
    • Single lab
    • In vivo validation of the axis limited
  27. 2023 Medium

    Extended the CXCL14/ACKR2 signaling axis to lung cancer, mapping a PLCβ3/PKCα/c-Src/NF-κB cascade driving EMT and metastasis.

    Evidence ACKR2 knockdown with pathway immunoblotting, NF-kB luciferase, migration assays, and orthotopic metastasis model

    PMID:37056937

    Open questions at the time
    • Single lab
    • Receptor coupling mechanism to PLCβ3 not defined
  28. 2024 Low

    Proposed that ACKR2+ chemoradiotherapy-resistant tumor cells drive CD8+ T-cell senescence through CC-chemokine-induced TGF-beta in a feed-forward loop.

    Evidence Single-cell RNA sequencing of human cervical cancer with mechanistic validation of the ACKR2-TGF-beta-senescence axis

    PMID:38723624

    Open questions at the time
    • Mechanistic claim derived primarily from transcriptomics with limited direct validation
    • Single study
    • Causality of ACKR2 in TGF-beta production not firmly established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the canonical non-signaling scavenging role of ACKR2 mechanistically reconciles with its reported active CXCL14-driven pro-tumor signaling remains unresolved.
  • No structural model linking ligand-binding pocket to either scavenging or signaling output
  • No unified framework explaining context-dependent signaling versus scavenging

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3 GO:0060090 molecular adaptor activity 3 GO:0140313 molecular sequestering activity 3
Localization
GO:0005768 endosome 3 GO:0005886 plasma membrane 2 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-1500931 Cell-Cell communication 3 R-HSA-168256 Immune System 3 R-HSA-5653656 Vesicle-mediated transport 3 R-HSA-162582 Signal Transduction 1
Partners
ARRB1CFL1LIMK1PAK1RAB11ARAB4ARAC1

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 Human ACKR2 (D6) is a promiscuous beta-chemokine receptor that binds the majority of CC chemokines but not alpha-chemokines, C, or CXXXC chemokines; unlike conventional chemokine receptors, it does not flux calcium upon ligand binding, indicating it lacks canonical signaling capacity. Radioligand binding assays in transfected CHO cells; calcium flux assays in HEK293 cells The Journal of biological chemistry High 9139699 9405404
1997 Murine D6 binds multiple beta-chemokines with the order of affinity: murine MIP-1alpha > human/murine MIP-1beta > human RANTES ≈ JE > human MCP-3 > human MCP-1; alpha-chemokines did not compete; D6 does not function as an HIV-1 entry co-receptor on CD4+ cells. Competitive radioligand binding (125I-MIP-1alpha) in CHO transfectants; HIV infection assay The Journal of biological chemistry High 9139699 9405404
2001 ACKR2 (D6) is expressed by lymphatic endothelial cells of afferent lymphatics in human dermis, intestinal mucosa/submucosa, and lymph node sinuses, but not by blood vascular endothelium or peripheral blood cells, establishing its anatomical localization. Immunohistochemistry with monoclonal anti-D6 antibodies; in situ hybridization; co-staining with podoplanin lymphatic marker on serial sections The American journal of pathology High 11238036
2003 ACKR2 (D6) engagement by inflammatory CC chemokines elicits no calcium response or chemotaxis but results in efficient agonist internalization and degradation; in lymphatic endothelium, D6 does not mediate transcytosis in either direction but solely internalizes and degrades chemokines. Calcium flux assays, chemotaxis assays, and chemokine internalization/degradation assays in D6 transfectants and primary lymphatic endothelial cells Journal of immunology High 12594248
2004 D6 constitutively traffics to and from the cell surface via recycling endosomes in a ligand-independent manner; chemokines internalized by D6 dissociate from the receptor upon vesicle acidification and are degraded, while the receptor recycles to the surface without cell surface downregulation—unlike conventional receptors such as CCR5. Live-cell fluorescence microscopy, subcellular fractionation, chemokine internalization and degradation kinetics assays compared between D6 and CCR5 transfectants Molecular biology of the cell High 15004236
2004 ACKR2 (D6) constitutive internalization is mediated by the clathrin-coated pit pathway and requires constitutive association with beta-arrestin; an acidic region in the cytoplasmic tail (but not putative phosphorylation sites) is critical for beta-arrestin interaction and subsequent internalization; D6 does not activate any G-protein-mediated signaling pathway regardless of beta-arrestin coupling status. Clathrin pathway inhibitor studies; co-immunoprecipitation of D6 with beta-arrestin; C-terminal deletion/mutagenesis of D6; G-protein signaling assays in transfected cells The Journal of biological chemistry High 15084596
2004 Purified D6 protein retains full functional activity (displaceable 125I-MIP-1beta binding); D6 is N-glycosylated at the N-terminus (dispensable for ligand binding and high expression), sulphated, and constitutively phosphorylated in a ligand-independent manner; >80% of total cellular D6 is associated with intracellular vesicular structures. Protein purification, radioligand binding (125I-MIP-1beta), MIP-1alpha affinity column, N-terminal glycosylation mutants, metabolic labelling for sulphation and phosphorylation, subcellular fractionation The Biochemical journal High 14723600
2004 D6 efficiently binds and scavenges most inflammatory CCR1–CCR5 agonists but not homeostatic CCR6/CCR7 agonists; CCR4 agonists CCL17 and CCL22 are bound and scavenged by D6 but elicit no calcium flux or chemotaxis; CD26-processed truncated forms of CCL22 (lacking an intact N-terminus) are not recognized by D6. D6 transfectant binding assays, chemokine scavenging assays, calcium flux, chemotaxis assays, and testing of CD26-truncated CCL22 variants Journal of immunology High 15067078
2005 D6-deficient mice develop exacerbated and prolonged cutaneous inflammatory responses following phorbol ester application, with excess beta-chemokines at the site; wild-type mice resolve the response, demonstrating that D6 is required for post-inflammatory clearance of CC chemokines from cutaneous sites. D6-knockout mouse model with phorbol ester-induced skin inflammation; ELISA chemokine quantification; histopathological analysis Nature immunology High 15750596
2005 D6 can function as a coreceptor for primary dual-tropic HIV-1 and HIV-2 isolates on primary astrocytes; siRNA-mediated knockdown of D6 in primary astrocytes inhibited infection by D6-tropic isolates. HIV pseudovirus and primary isolate infection assays; siRNA knockdown of D6 in primary astrocytes; mRNA and immunoreactivity detection in macrophages and astrocytes Journal of virology Medium 16014924
2007 D6 is expressed on the apical surface of syncytiotrophoblast cells and on invading extravillous trophoblasts in placenta; D6-deficient pregnant mice exposed to LPS or antiphospholipid autoantibodies show higher CC chemokine levels and increased leukocyte infiltrate in placenta, causing increased fetal loss that is prevented by blocking inflammatory chemokines. Immunohistochemistry with anti-D6 antibodies in placenta; D6-/- mouse model with LPS and antiphospholipid antibody challenges; chemokine ELISA; antibody-mediated chemokine blockade rescue experiment Proceedings of the National Academy of Sciences of the United States of America High 17283337
2008 D6 scavenging activity depends on Rab4- and Rab11-dependent constitutive recycling; under resting conditions, D6 cycles via a rapid wortmannin-sensitive pathway and a slower BFA-sensitive pathway. Chemokine engagement induces dose-dependent, BFA-sensitive, Rab11-dependent redistribution of D6 to the cell membrane, increasing chemokine degradation rate without transcriptional upregulation. Wortmannin and brefeldin A (BFA) pharmacological inhibition; dominant-negative Rab4 and Rab11 overexpression; flow cytometry of surface D6; chemokine degradation assays in transfected cells Blood High 18480427
2008 D6 expression in hematopoietic cells (B cells, dendritic cells, mast cells, megakaryocytes) is transcriptionally regulated by GATA1; D6 on human leukocytes mediates chemokine uptake as demonstrated by competition assays, whereas D6-null mouse cells fail to clear inflammatory chemokines. GATA1 knockdown/overexpression; promoter analysis; competition chemokine uptake assays in human leukocytes; comparison with D6-null mouse cells Journal of immunology Medium 18714007 19039854
2008 The conserved 58-amino acid C-terminal tail of D6 contains a serine cluster that controls constitutive phosphorylation, intracellular trafficking itinerary, and high receptor stability, and drives beta-arrestin to membranes near the cell surface; however, the C-terminus is dispensable for initial chemokine internalization. Without the C-terminus, initial CCL3 binding inhibits subsequent chemokine uptake, indicating the C-terminus prevents ligand-induced inhibition of receptor recycling and is required for progressive scavenging. C-terminal deletion and serine cluster mutants of D6-GFP; beta-arrestin-GFP recruitment assays; CCL3 scavenging assays in HEK293 cells The Journal of biological chemistry High 18201974
2009 D6-mediated chemokine degradation (but not binding) correlates with the receptor's adaptive surface upregulation; a proline residue at position 2 of D6-binding chemokines is dispensable for binding but is critical for D6 adaptive upregulation and efficient degradation, determining whether a bound chemokine is degraded or merely bound. D6 transfectant assays with panels of CC chemokines and their N-terminally truncated/processed isoforms; flow cytometry of surface D6; ELISA-based degradation assays The Journal of biological chemistry Medium 19632987
2011 D6 expressed on lymphatic endothelial cells prevents inflammatory CC chemokine binding to lymphatic surfaces, thereby avoiding inappropriate perilymphatic accumulation of inflammatory leukocytes; this prevents lymphatic congestion and maintains selective CCR7 ligand presentation, ensuring proper dendritic cell and fluid migration from inflamed tissues to lymph nodes. D6-/- mouse model; intravital microscopy; flow cytometry of LEC-bound chemokines; antigen-presenting cell migration assays; lymph node fluid drainage measurements Blood High 21979941
2011 D6 receptor activity (chemokine internalization) is a universal and unique feature of all known innate-like B-cell populations in mice; D6 on these cells internalizes chemokines but cannot induce Ca2+ fluxes or chemotaxis; additionally, D6 can suppress CXCR5 function in innate-like B cells. Flow cytometry-based chemokine uptake assay on primary B-cell subsets; Ca2+ flux assays; chemotaxis assays; analysis of D6-/- mice for B1 cell populations and anti-phosphorylcholine antibody levels Blood Medium 21450903
2013 Engagement of ACKR2 (D6) by ligands activates a beta-arrestin1-dependent, G-protein-independent signaling pathway resulting in phosphorylation of cofilin through Rac1-PAK1-LIMK1 cascade; this pathway is required for ligand-induced D6 surface upregulation and chemokine-scavenging activity. Phospho-cofilin immunoblotting; dominant-negative Rac1 and PAK1 inhibitors; beta-arrestin1 siRNA knockdown; D6 surface expression and chemokine scavenging assays Science signaling High 23633677
2013 D6 on lymphatic endothelial cells (LECs) specifically regulates LEC discrimination between mature and immature dendritic cells; D6 overexpression reduces immature DC adhesion to LECs whereas D6 knockdown increases iDC adhesion and displacement of mature DCs. LEC D6 expression is upregulated by IL-6 and IFN-γ, and by Kaposi sarcoma-associated herpesvirus viral IL-6. D6 overexpression and knockdown in primary LEC cultures; DC adhesion assays; cytokine treatment; viral IL-6 overexpression in vitro and in vivo Blood Medium 23479571
2013 D6 expressed on apoptotic neutrophils plays a chemokine scavenging-independent role in promoting macrophage-mediated resolution of inflammation; D6-expressing apoptotic PMN suppress macrophage cytokine secretion (immune silencing) and modulate macrophage adhesive responses upon engulfment, effects abolished with D6-deficient PMN cells. In vivo peritonitis model with D6-/- mice; ex vivo macrophage-PMN co-culture efferocytosis and cytokine secretion assays; flow cytometry FASEB journal Medium 22651933
2014 ACKR2 scavenges the CCL2 chemokine to reciprocally regulate lymphatic vessel density: ACKR2-deficient mice display increased lymphatic vessel density that is developmentally established, associated with enhanced macrophage proximity to developing lymphatic vessels; CCR2-deficient mice show the reciprocal phenotype of reduced vessel density. ACKR2-/- and CCR2-/- mouse models; immunofluorescence for lymphatic vessel density and macrophage localization; embryonic skin analysis; fluid drainage measurement The EMBO journal High 25271254
2014 Primary human trophoblasts express ACKR2 at far higher levels than conventional inflammatory CC chemokine receptors and use ACKR2 to rapidly internalize and efficiently scavenge extracellular chemokines; in DBA/1j mice, ACKR2 deficiency in fetal cells causes placental structural defects, increased stillbirth, and reduced fetal weight. RT-PCR and flow cytometry of ACKR2 in primary human trophoblasts; chemokine internalization/scavenging assays; ACKR2-/- and fetal-specific ACKR2 knockout mouse models; placental histology Journal of immunology High 25297873
2016 ACKR2 controls inflammatory T-cell chemotaxis and positioning within skin, preventing epidermal T-cell influx associated with lesion development; localized inflammation and IFN-γ upregulate ACKR2 in remote tissues, protecting them from spread of psoriasiform inflammation. Imiquimod-induced psoriasiform model in ACKR2-/- mice; in vitro T-cell migration assays; IFN-γ treatment of primary human cells; clinical skin biopsy analysis The Journal of investigative dermatology Medium 27568525
2017 miR-146b and miR-10b directly bind the ACKR2 3'-UTR and reduce ACKR2 transcript and protein expression in keratinocytes and lymphatic endothelial cells, respectively; tensile cell stress leads to rapid ACKR2 downregulation concurrent with miR-146b upregulation, providing a mechanism for trauma-induced reduction of ACKR2 (Koebner phenomenon). Luciferase 3'-UTR reporter assays; in silico miRNA target prediction; RT-PCR and Western blot in primary human cells; cell stretch/mechanical stress experiments The Journal of biological chemistry Medium 29279330
2018 ACKR2 is expressed in hematopoietic precursors and downregulated during myeloid differentiation; genetic deletion of ACKR2 increases expression of inflammatory chemokine receptors on neutrophils and promotes their release from bone marrow with enhanced anti-metastatic activity. ACKR2-/- mouse models; flow cytometry of bone marrow and circulating cells; chemokine receptor expression profiling; in vivo metastasis models (4T1 mammary and B16F10 melanoma) Nature communications Medium 29445158
2018 Ackr2 deficiency leads to increased CCR2 expression specifically on KLRG1+ NK cells, resulting in increased recruitment of these cells to CCL2-expressing tumors and enhanced tumor killing; Ackr2 thus limits CCR2 expression on NK cells and restricts their tumoricidal activity. Ackr2-/- mouse models; cell line and spontaneous metastasis models; flow cytometry for NK cell subset markers and CCR2 expression; in vivo tumor killing assays Journal of immunology Medium 30158126
2019 ACKR2 mediates CXCL14-stimulated epithelial-to-mesenchymal transition, migration, and invasion in breast cancer cells; ACKR2 loss-of-function abolishes CXCL14-induced responses, and downregulation of ACKR2 or CXCL14-induced NOS1 attenuates these pro-EMT effects, identifying an autocrine fibroblast CXCL14/ACKR2 pathway. siRNA knockdown of ACKR2 in breast cancer cells; in vitro EMT, migration, invasion assays; in vivo xenograft and tail-vein metastasis models; NOS1 inhibition Clinical cancer research Medium 30850359
2021 CXCL10 (a CXC chemokine) is an agonist ligand for ACKR2, able to recruit beta-arrestin and be internalized and degraded by ACKR2, expanding the receptor's ligand range beyond CC chemokines; CD26/DPP4 N-terminal processing of CXCL10 drastically reduces its activity toward ACKR2, suggesting a different receptor binding pocket occupancy than CC chemokines. Beta-arrestin recruitment assays using NanoBiT and NanoBRET technologies; chemokine internalization and extracellular availability assays; DPP4-processed CXCL10 functional testing Cancers Medium 33801414
2021 Sirtuin 2 (SIRT2) promotes p65 deacetylation to suppress miR-146a expression, which in turn targets ACKR2; downregulation of miR-146a thus upregulates ACKR2 in trophoblasts, enhancing their proliferation, migration, and invasion; this SIRT2/p65/miR-146a/ACKR2 axis is disrupted in preeclampsia. ChIP assay; luciferase reporter assay confirming miR-146a targeting of ACKR2 3'-UTR; SIRT2 overexpression; miR-146a overexpression; HTR-8/SVneo trophoblast cell functional assays Reproductive sciences Medium 33409877
2023 ACKR2 mediates CXCL14-induced lung cancer cell metastasis through activation of PLCβ3, PKCα, and c-Src signaling, subsequently upregulating NF-κB transcription activity leading to EMT and increased cell migration; ACKR2 knockdown abolishes CXCL14-induced cancer cell motility. ACKR2 knockdown studies; Western blot for PLCβ3/PKCα/c-Src/NF-κB pathway activation; luciferase NF-κB reporter assay; migration and wound healing assays; orthotopic mouse metastasis model International journal of biological sciences Medium 37056937
2024 ACKR2+ chemoradiotherapy-resistant tumor cells drive CD8+ T cell senescence by producing TGF-β in response to CC chemokines produced by activated myeloid and T cells; ACKR2 expression in tumor cells is upregulated by chemoradiotherapy and by CC chemokine ligation, creating a feed-forward loop that compromises antitumor immunity. Single-cell RNA sequencing of human cervical cancer tissues before/after CCRT; mechanistic validation of ACKR2-TGF-β-CD8+ T cell senescence axis in functional assays Cell reports. Medicine Low 38723624

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 Application of d6 transition metal complexes in fluorescence cell imaging. Chemical communications (Cambridge, England) 425 20024327
2005 The chemokine receptor D6 limits the inflammatory response in vivo. Nature immunology 252 15750596
2001 The beta-chemokine receptor D6 is expressed by lymphatic endothelium and a subset of vascular tumors. The American journal of pathology 236 11238036
2014 Auxin efflux by PIN-FORMED proteins is activated by two different protein kinases, D6 PROTEIN KINASE and PINOID. eLife 208 24948515
2006 Systemic induction of the angiogenesis switch by the tetraspanin D6.1A/CO-029. Cancer research 178 16849554
1997 Cloning and characterization of a novel promiscuous human beta-chemokine receptor D6. The Journal of biological chemistry 178 9405404
2003 Cutting edge: scavenging of inflammatory CC chemokines by the promiscuous putatively silent chemokine receptor D6. Journal of immunology (Baltimore, Md. : 1950) 165 12594248
2004 The chemokine receptor D6 constitutively traffics to and from the cell surface to internalize and degrade chemokines. Molecular biology of the cell 164 15004236
2007 Protection against inflammation- and autoantibody-caused fetal loss by the chemokine decoy receptor D6. Proceedings of the National Academy of Sciences of the United States of America 153 17283337
2004 beta-Arrestin-dependent constitutive internalization of the human chemokine decoy receptor D6. The Journal of biological chemistry 136 15084596
2009 The lymphatic system controls intestinal inflammation and inflammation-associated Colon Cancer through the chemokine decoy receptor D6. Gut 131 19846409
2007 The atypical chemokine receptor D6 suppresses the development of chemically induced skin tumors. The Journal of clinical investigation 129 17607362
2005 Increased inflammation in mice deficient for the chemokine decoy receptor D6. European journal of immunology 119 15789340
1997 Cloning and characterization of a novel murine beta chemokine receptor, D6. Comparison to three other related macrophage inflammatory protein-1alpha receptors, CCR-1, CCR-3, and CCR-5. The Journal of biological chemistry 117 9139699
2004 Differential recognition and scavenging of native and truncated macrophage-derived chemokine (macrophage-derived chemokine/CC chemokine ligand 22) by the D6 decoy receptor. Journal of immunology (Baltimore, Md. : 1950) 116 15067078
2009 D6 and the atypical chemokine receptor family: novel regulators of immune and inflammatory processes. European journal of immunology 115 19130487
2019 A Novel ACKR2-Dependent Role of Fibroblast-Derived CXCL14 in Epithelial-to-Mesenchymal Transition and Metastasis of Breast Cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 99 30850359
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2006 The chemokine receptor D6 has opposing effects on allergic inflammation and airway reactivity. American journal of respiratory and critical care medicine 75 17095748
2012 The chemokine decoy receptor D6 prevents excessive inflammation and adverse ventricular remodeling after myocardial infarction. Arteriosclerosis, thrombosis, and vascular biology 74 22796582
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2006 Cutting edge: the silent chemokine receptor D6 is required for generating T cell responses that mediate experimental autoimmune encephalomyelitis. Journal of immunology (Baltimore, Md. : 1950) 69 16785491
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2003 The association of the tetraspanin D6.1A with the alpha6beta4 integrin supports cell motility and liver metastasis formation. Journal of cell science 58 13130099
2013 Solution-state 2D NMR spectroscopy of plant cell walls enabled by a dimethylsulfoxide-d6/1-ethyl-3-methylimidazolium acetate solvent. Analytical chemistry 57 23413964
2016 Comparison of differences in development potentials between frozen-thawed D5 and D6 blastocysts and their relationship with pregnancy outcomes. Journal of assisted reproduction and genetics 52 27098058
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2006 Chemokine scavenging by D6: a movable feast? Trends in immunology 52 16814608
2002 Forebrain-specific promoter/enhancer D6 derived from the mouse Dach1 gene controls expression in neural stem cells. Neuroscience 50 12088753
2010 Chemokine scavenger D6 is expressed by trophoblasts and aids the survival of mouse embryos transferred into allogeneic recipients. Journal of immunology (Baltimore, Md. : 1950) 49 20147628
2009 Recognition versus adaptive up-regulation and degradation of CC chemokines by the chemokine decoy receptor D6 are determined by their N-terminal sequence. The Journal of biological chemistry 47 19632987
2009 The atypical chemokine receptor D6 contributes to the development of experimental colitis. Journal of immunology (Baltimore, Md. : 1950) 46 19342683
2005 The tetraspanin D6.1A and its molecular partners on rat carcinoma cells. The Biochemical journal 45 15725074
2021 CXCL10 Is an Agonist of the CC Family Chemokine Scavenger Receptor ACKR2/D6. Cancers 42 33801414
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2013 Expression of the atypical chemokine receptor D6 in human alveolar macrophages in COPD. Chest 39 22797410
2013 Specific humoral immune response to the Thomsen-Friedenreich tumor antigen (CD176) in mice after vaccination with the commensal bacterium Bacteroides ovatus D-6. Cancer immunology, immunotherapy : CII 39 23381581
2012 Elevated expression of the chemokine-scavenging receptor D6 is associated with impaired lesion development in psoriasis. The American journal of pathology 39 22867710
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2024 Chemoradiotherapy-induced ACKR2+ tumor cells drive CD8+ T cell senescence and cervical cancer recurrence. Cell reports. Medicine 36 38723624
2014 ERK-dependent downregulation of the atypical chemokine receptor D6 drives tumor aggressiveness in Kaposi sarcoma. Cancer immunology research 35 24844911
2018 The atypical chemokine receptor ACKR2 drives pulmonary fibrosis by tuning influx of CCR2+ and CCR5+ IFNγ-producing γδT cells in mice. American journal of physiology. Lung cellular and molecular physiology 34 29469612
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2018 The Atypical Chemokine Receptor Ackr2 Constrains NK Cell Migratory Activity and Promotes Metastasis. Journal of immunology (Baltimore, Md. : 1950) 33 30158126
2012 Control of murine Ly6C(high) monocyte traffic and immunosuppressive activities by atypical chemokine receptor D6. Blood 32 22504926
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2002 The mouse enhancer element D6 directs Cre recombinase activity in the neocortex and the hippocampus. Mechanisms of development 31 11744379
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2017 CCL5 Promotes Resolution-Phase Macrophage Reprogramming in Concert with the Atypical Chemokine Receptor D6 and Apoptotic Polymorphonuclear Cells. Journal of immunology (Baltimore, Md. : 1950) 30 28674178
2012 The atypical chemokine receptor D6 controls macrophage efferocytosis and cytokine secretion during the resolution of inflammation. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 30 22651933
2009 The chemokine scavenging receptor D6 limits acute toxic liver injury in vivo. Biological chemistry 30 19642876
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2016 Spread of Psoriasiform Inflammation to Remote Tissues Is Restricted by the Atypical Chemokine Receptor ACKR2. The Journal of investigative dermatology 27 27568525
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2013 Cell-autonomous regulation of neutrophil migration by the D6 chemokine decoy receptor. Journal of immunology (Baltimore, Md. : 1950) 26 23670187
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2022 Multi-Omics Analysis Reveals That SlERF.D6 Synergistically Regulates SGAs and Fruit Development. Frontiers in plant science 20 35463452
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2020 The Aza-Analogous Benzo[c]phenanthridine P8-D6 Acts as a Dual Topoisomerase I and II Poison, thus Exhibiting Potent Genotoxic Properties. Molecules (Basel, Switzerland) 14 32230817
2015 Renal Protection by Genetic Deletion of the Atypical Chemokine Receptor ACKR2 in Diabetic OVE Mice. Journal of diabetes research 14 26798651
2011 Transgenic expression of murine chemokine decoy receptor D6 by islets reveals the role of inflammatory CC chemokines in the development of autoimmune diabetes in NOD mice. Diabetologia 14 21544515
2006 The effects of charge-neutralizing mutation D6.30N on the functions of CB1 and CB2 cannabinoid receptors. FEBS letters 14 16989818
2021 Elucidating the structure and functions of Resolvin D6 isomers on nerve regeneration with a distinctive trigeminal transcriptome. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 13 34245621
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