Alternative titles; symbols
HGNC Approved Gene Symbol: ACKR2
Cytogenetic location: 3p22.1 Genomic coordinates (GRCh38): 3:42,809,445-42,867,286 (from NCBI)
Chemokines are small, secreted chemoattractants that regulate migration by signaling through G protein-coupled chemokine receptors on leukocytes and other cell types. Atypical chemokine receptors, such as ACKR2, structurally resemble conventional chemokine receptors, but they cannot couple to signaling pathways used by conventional receptors or stimulate cell migration. ACKR2 is highly expressed in fetal trophoblasts and can efficiently internalize its chemokine ligands and target them for degradation (summary by Teoh et al., 2014).
Nibbs et al. (1997) stated that they had previously identified the mouse cysteine-cysteine (C-C) chemokine receptor D6. To identify the human homolog of D6, they performed PCR on human genomic DNA using primers based on the sequence of the mouse D6 gene. The human D6 gene encodes a predicted 384-amino acid protein that contains the characteristic 7 transmembrane domains and 4 conserved cysteine residues of chemokine receptors. The human and mouse D6 proteins share 71% amino acid identity. By Northern blot analysis, human D6 is expressed as approximately 4- and 6-kb transcripts in several tissues, with the highest expression in placenta.
Bonini et al. (1997) cloned a cDNA encoding CMKBR9, which they called CCR10 because it is homologous to rat 'Ccr10-related receptor' (Ccr10rR). The CMKBR9 and rat Ccr10rR proteins have 72% amino acid identity.
By PCR of a radiation hybrid panel, Bonini et al. (1997) mapped the CMKBR9 gene to 3p21.32-p21.31, a region containing other C-C chemokine receptor genes such as CMKBR1 (601159), CMKBR2 (601267), CMKBR3 (601268), and CMKBR5 (601373). By radiation hybrid analysis and organization of BAC contigs by FISH on combed genomic DNA, Maho et al. (1999) localized the CMKBR9 gene within the CCR cluster at 3p21.3.
Nibbs et al. (1997) found that human D6 bound with relatively high affinity to the majority of members of the beta-chemokine family (e.g., MCP2, 602283), but they were unable to demonstrate any signaling following ligand binding.
Using flow cytometry, Teoh et al. (2014) demonstrated strong expression of ACKR2 relative to conventional cytokine receptors in cultured primary human trophoblasts. ACKR2 on trophoblasts mediated rapid internalization of extracellular chemokines, such as CCL2 (158105). Teoh et al. (2014) concluded that trophoblasts use ACKR2 to scavenge inflammatory chemokines.
Jamieson et al. (2005) found that D6-deficient mice were healthy and fertile with no overtly altered phenotype. After induction of cutaneous inflammation by phorbol esters, wildtype mice showed a transient response. In contrast, Tnf (191160)-dependent inflammation persisted in D6-deficient mice due to an excess concentration of residual chemokines and was accompanied by T cell- and mast cell-dependent psoriasiform lesions. Jamieson et al. (2005) concluded that D6 internalizes and degrades inflammatory beta-chemokines upregulated during inflammation to resolve the inflammatory response in vivo.
Nibbs et al. (2007) showed that D6-deficient mice had increased susceptibility to chemically-induced cutaneous tumors, and D6 deletion was sufficient to make resistant mouse strains susceptible to invasive squamous cell carcinomas. Conversely, transgenic D6 expression in keratinocytes dampened cutaneous inflammation and conferred considerable protection from tumor formation in susceptible mouse strains. Tumor susceptibility consistently correlated with recruitment of T cells and mast cells, which are known to support the development of skin tumors in mice.
In Ackr2-deficient mice, Teoh et al. (2014) observed increased incidence of stillbirth and neonatal death accompanied by placental structural defects and decreased fetal weight. Circulating Ccl2, but not Ccl3 (182283), Ccl5 (187011), or Cxcl1 (155730), was increased in the absence of Ackr2. Loss of Ackr2 expression from fetal cells contributed to the placental defects in these mice. Teoh et al. (2014) concluded that ACKR2 is important for normal placental structure and neonatal survival.
The symbols CCR9 and CCR10 have incorrectly been used to refer to D6 (Murphy et al., 2000); CCR9 and CCR10 refer to different genes described in entries 604738 and 600240, respectively.
Bonini, J. A., Martin, S. K., Dralyuk, F., Roe, M. W., Philipson, L. H., Steiner, D. F. Cloning, expression, and chromosomal mapping of a novel human CC-chemokine receptor (CCR10) that displays high-affinity binding for MCP-1 and MCP-3. DNA Cell Biol. 16: 1249-1256, 1997. [PubMed: 9364936] [Full Text: https://doi.org/10.1089/dna.1997.16.1249]
Jamieson, T., Cook, D. N., Nibbs, R. J. B., Rot, A., Nixon, C., Mclean, P., Alcami, A., Lira, S. A., Wiekowski, M., Graham, G. J. The chemokine receptor D6 limits the inflammatory response in vivo. Nature Immun. 6: 403-411, 2005. [PubMed: 15750596] [Full Text: https://doi.org/10.1038/ni1182]
Maho, A., Bensimon, A., Vassart, G., Parmentier, M. Mapping of the CCXCR1, CX3CR1, CCBP2 and CCR9 genes to the CCR cluster within the 3p21.3 region of the human genome. Cytogenet. Cell Genet. 87: 265-268, 1999. [PubMed: 10702689] [Full Text: https://doi.org/10.1159/000015443]
Murphy, P. M., Baggiolini, M., Charo, I. F., Hebert, C. A., Horuk, R., Matsushima, K., Miller, L. H., Oppenheim, J. J., Power, C. A. International Union of Pharmacology. XXII. Nomenclature for chemokine receptors. Pharm. Rev. 52: 145-176, 2000. [PubMed: 10699158]
Nibbs, R. J. B., Gilchrist, D. S., King, V., Ferra, A., Forrow, S., Hunter, K. D., Graham, G. J. The atypical chemokine receptor D6 suppresses the development of chemically induced skin tumors. J. Clin. Invest. 117: 1884-1892, 2007. [PubMed: 17607362] [Full Text: https://doi.org/10.1172/JCI30068]
Nibbs, R. J. B., Wylie, S. M., Yang, J., Landau, N. R., Graham, G. J. Cloning and characterization of a novel promiscuous human beta-chemokine receptor D6. J. Biol. Chem. 272: 32078-32083, 1997. [PubMed: 9405404] [Full Text: https://doi.org/10.1074/jbc.272.51.32078]
Teoh, P. J., Menzies, F. M., Hansell, C. A. H., Clarke, M., Waddell, C., Burton, G. J., Nelson, S. M., Nibbs, R. J. B. Atypical chemokine receptor ACKR2 mediates chemokine scavenging by primary human trophoblasts and can regulate fetal growth, placental structure, and neonatal mortality in mice. J. Immun. 193: 5218-5228, 2014. [PubMed: 25297873] [Full Text: https://doi.org/10.4049/jimmunol.1401096]