Details for: ACKR2

Gene ID: 1238

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: ACKR2

Ensembl ID: ENSG00000144648

Description: atypical chemokine receptor 2

Cell Significance Landscape

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • extravillous trophoblast CL0008036
    CSI 7.77
    rCSI 9.61%
    PRS 98.26
  • placental villous trophoblast CL2000060
    CSI 2.34
    rCSI 3.61%
    PRS 98.33
  • syncytiotrophoblast cell CL0000525
    CSI 1.6
    rCSI 4.6%
    PRS 97.73

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

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  • Node Color (Target Cell CSI, relative to current network):
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  • Node Size: Proportional to Target Cell CSI magnitude
  • STRING PPI Edge
  • Shared Pathway Edge (ONTOLOGY)

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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary [ACKR2](/details-gene/1238) (Atypical Chemokine Receptor 2), also known as D6 or CCRL2, is an atypical chemokine receptor that functions as a scavenger receptor rather than a classical signaling receptor. Its primary role is to bind and internalize a broad range of inflammatory CC-chemokines, thereby dampening inflammation and modulating immune responses ([Link](https://doi.org/10.1007/82_2010_19), [Link](https://doi.org/10.1016/j.imlet.2012.04.004)). While it is known to be expressed on lymphatic endothelial cells and some leukocytes, expression data indicates it is most significantly and specifically expressed in placental trophoblast cell types. This suggests a critical, specialized function in regulating the immune environment at the maternal-fetal interface. Dysregulation of [ACKR2](/details-gene/1238) is associated with inflammatory pathologies, and it is clinically referenced in OMIM entry [602648](https://omim.org/entry/602648). ## Cellular Roles and Expression Landscape The expression profile of [ACKR2](/details-gene/1238) reveals a highly specialized cellular distribution. **Overall**, the gene's expression is overwhelmingly dominated by placental cells. It is the most significant marker for [extravillous trophoblast](/details-cell/CL0008036) (CSI: 7.77), with high significance also observed in [placental villous trophoblast](/details-cell/CL2000060) (CSI: 2.34) and [syncytiotrophoblast cell](/details-cell/CL0000525) (CSI: 1.60). This exceptionally high and specific expression pattern strongly indicates a fundamental role in placental biology, likely related to establishing and maintaining immune tolerance during pregnancy. Beyond the placenta, the scientific literature has documented the expression of [ACKR2](/details-gene/1238) on other important cell types not ranked at the top in this **Overall** context. Notably, it is expressed by lymphatic endothelial cells, where it is thought to create chemokine gradients that control leukocyte trafficking ([Link](https://doi.org/10.1016/s0002-9440(10)64035-7), [Link](https://doi.org/10.1182/blood-2012-04-425314)). Furthermore, its function has been described in macrophages, where it aids in the resolution of inflammation by controlling efferocytosis and cytokine secretion ([Link](https://doi.org/10.1096/fj.11-194894)). The prominence of placental cells in the provided data may reflect the high abundance of this tissue in the underlying datasets or its exceptionally high expression level relative to other cell types. ## Pathways and Molecular Function Functionally, [ACKR2](/details-gene/1238) is annotated with [scavenger receptor activity](/details-go/GO:0005044) and is a key component of the [Chemokine receptors bind chemokines](/details-reactome/R-HSA-380108) pathway. Unlike conventional chemokine receptors that activate intracellular signaling cascades upon ligand binding, [ACKR2](/details-gene/1238) is considered 'silent' because it does not efficiently couple to G-proteins to induce [cell chemotaxis](/details-go/GO:0060326). Its primary mechanism involves high-affinity binding to a wide spectrum of inflammatory CC-chemokines ([C-c chemokine binding](/details-go/GO:0019957)). Upon binding, the receptor-ligand complex is constitutively internalized from the [external side of plasma membrane](/details-go/GO:0009897) into [early endosomes](/details-go/GO:0005769). The chemokines are then targeted for degradation, while the receptor is recycled back to the cell surface, allowing it to continuously clear chemokines from the extracellular environment ([Link](https://doi.org/10.1002/path.4123)). This process of ligand removal is a crucial negative feedback mechanism in the [inflammatory response](/details-go/GO:0006954). This scavenging activity is dependent on beta-arrestin and requires dynamic remodeling of the [actin filament](/details-go/GO:0005884) network ([Link](https://doi.org/10.1126/scisignal.2003627)). In the context of trophoblasts, this function is critical for preventing an excessive maternal inflammatory response against the semi-allogeneic fetus. ## Research Directions The unique function of [ACKR2](/details-gene/1238) as a chemokine scavenger, combined with its highly specific expression pattern, opens several avenues for future research. ### Proposed Hypotheses 1. **Role in Pregnancy Complications:** Given its profound expression in trophoblasts, insufficient [ACKR2](/details-gene/1238) function at the maternal-fetal interface leads to an accumulation of inflammatory chemokines, contributing to the pathogenesis of pre-eclampsia and other inflammatory complications of pregnancy. Genetic variants that reduce [ACKR2](/details-gene/1238) expression or activity may represent significant risk factors for these conditions. 2. **Modulation of Tumor Metastasis:** In the context of cancer, the expression of [ACKR2](/details-gene/1238) on lymphatic endothelial cells may act as a barrier to metastasis. By scavenging chemokines that guide tumor cell migration, [ACKR2](/details-gene/1238) could limit the entry of cancer cells into the lymphatic system. Conversely, downregulation of this receptor in the tumor microenvironment could promote metastatic dissemination. ### Key Experimental Approach To test the hypothesis regarding its role in pregnancy complications (Hypothesis 1), a conditional knockout mouse model with specific deletion of *Ackr2* in trophoblast lineages could be developed. Pregnant knockout and wild-type mice could be challenged with a sub-clinical dose of an inflammatory agent like lipopolysaccharide (LPS). Key endpoints would include monitoring for signs of pre-eclampsia (e.g., hypertension, proteinuria), assessing fetal viability, and performing detailed histological and immunological analysis of the placenta. Quantitative PCR and multiplex immunoassays could be used to measure the levels of inflammatory chemokines and immune cell infiltration at the placental interface, directly linking the loss of [ACKR2](/details-gene/1238) function to a pro-inflammatory state. ### Therapeutic Potential [ACKR2](/details-gene/1238) is an attractive therapeutic target, not for inhibition, but for **activation** or enhancement. Its natural function is to resolve inflammation, a beneficial process. A small molecule or biologic agent that potentiates the chemokine scavenging activity of [ACKR2](/details-gene/1238) could serve as a novel anti-inflammatory therapy. Such a drug could be particularly effective in chronic inflammatory diseases driven by excessive CC-chemokine signaling, such as psoriasis or rheumatoid arthritis. The highly restricted expression of [ACKR2](/details-gene/1238) suggests that an agonist could achieve targeted anti-inflammatory effects with a reduced risk of systemic side effects compared to broader immunosuppressants.

Genular Protein ID: 1417383055

Symbol: ACKR2_HUMAN

Name: Atypical chemokine receptor 2

UniProtKB Accession Codes:

O00590 B2R8Y8 O00537 Q53YA1 Q86UN9 Q96A02

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BindingDB 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CDD 1 CTD 1 ChEMBL 1 ChiTaRS 1 DNASU 1 DisGeNET 1 EMBL 10 EMDB 3 Ensembl 2 ExpressionAtlas 1 GO 19 Gene3D 1 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 GlyCosmos 1 GlyGen 1 HGNC 1 HPA 1 InParanoid 1 IntAct 1 InterPro 5 KEGG 1 MANE-Select 1 MIM 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PDB 3 PDBsum 3 PRINTS 3 PRO 1 PROSITE 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 1 RNAct 1 Reactome 1 RefSeq 1 SMR 1 STRING 1 SUPFAM 1 SignaLink 1 TCDB 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 neXtProt 1

Citations:

PubMed ID: 9364936

Title: Cloning, expression, and chromosomal mapping of a novel human CC-chemokine receptor (CCR10) that displays high-affinity binding for MCP-1 and MCP-3.

PubMed ID: 9364936

DOI: 10.1089/dna.1997.16.1249

PubMed ID: 9405404

Title: Cloning and characterization of a novel promiscuous human beta-chemokine receptor D6.

PubMed ID: 9405404

DOI: 10.1074/jbc.272.51.32078

PubMed ID: 14702039

Title: Complete sequencing and characterization of 21,243 full-length human cDNAs.

PubMed ID: 14702039

DOI: 10.1038/ng1285

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 11238036

Title: The beta-chemokine receptor D6 is expressed by lymphatic endothelium and a subset of vascular tumors.

PubMed ID: 11238036

DOI: 10.1016/s0002-9440(10)64035-7

PubMed ID: 18201974

Title: Multiple roles for the C-terminal tail of the chemokine scavenger D6.

PubMed ID: 18201974

DOI: 10.1074/jbc.m710128200

PubMed ID: 20373092

Title: Chemokine decoy receptors: structure-function and biological properties.

PubMed ID: 20373092

DOI: 10.1007/82_2010_19

PubMed ID: 22651933

Title: The atypical chemokine receptor D6 controls macrophage efferocytosis and cytokine secretion during the resolution of inflammation.

PubMed ID: 22651933

DOI: 10.1096/fj.11-194894

PubMed ID: 22698181

Title: The biochemistry and biology of the atypical chemokine receptors.

PubMed ID: 22698181

DOI: 10.1016/j.imlet.2012.04.004

PubMed ID: 23356288

Title: Atypical chemokine receptors: from silence to sound.

PubMed ID: 23356288

DOI: 10.1042/bst20120246

PubMed ID: 23479571

Title: An analysis of the function and expression of D6 on lymphatic endothelial cells.

PubMed ID: 23479571

DOI: 10.1182/blood-2012-04-425314

PubMed ID: 23125030

Title: Regulation of the immune and inflammatory responses by the 'atypical' chemokine receptor D6.

PubMed ID: 23125030

DOI: 10.1002/path.4123

PubMed ID: 22939232

Title: Review: Structure-function and biological properties of the atypical chemokine receptor D6.

PubMed ID: 22939232

DOI: 10.1016/j.molimm.2012.08.003

PubMed ID: 23633677

Title: Beta-arrestin-dependent activation of the cofilin pathway is required for the scavenging activity of the atypical chemokine receptor D6.

PubMed ID: 23633677

DOI: 10.1126/scisignal.2003627

Sequence Information:

  • Length: 384
  • Mass: 43443
  • Checksum: 464C5703C1DE9A6A
  • Sequence:
    • MAATASPQPL ATEDADSENS SFYYYDYLDE VAFMLCRKDA VVSFGKVFLP VFYSLIFVLG 
LSGNLLLLMV LLRYVPRRRM VEIYLLNLAI SNLLFLVTLP FWGISVAWHW VFGSFLCKMV 
STLYTINFYS GIFFISCMSL DKYLEIVHAQ PYHRLRTRAK SLLLATIVWA VSLAVSIPDM 
VFVQTHENPK GVWNCHADFG GHGTIWKLFL RFQQNLLGFL LPLLAMIFFY SRIGCVLVRL 
RPAGQGRALK IAAALVVAFF VLWFPYNLTL FLHTLLDLQV FGNCEVSQHL DYALQVTESI 
AFLHCCFSPI LYAFSSHRFR QYLKAFLAAV LGWHLAPGTA QASLSSCSES SILTAQEEMT 
GMNDLGERQS ENYPNKEDVG NKSA