Alternative titles; symbols
HGNC Approved Gene Symbol: CMKLR1
Cytogenetic location: 12q23.3 Genomic coordinates (GRCh38): 12:108,288,046-108,339,311 (from NCBI)
Chemokines, a family of small cytokines, recruit leukocytes during inflammation and immune responses. Chemokine receptors, such as the somatostatin receptors (see, e.g., 182451), belong to the family of 7-transmembrane G protein-coupled receptors. Gantz et al. (1996) cloned CMKLR1 by PCR of genomic DNA with degenerate primers based on the conserved regions of somatostatin receptors 1-4. The predicted 371-amino acid protein has 7 hydrophobic domains. The CMKLR1 gene has over 40% nucleotide sequence homology to the somatostatin receptors 1-4 and over 50% to IL81R (146929) and FPR1 (136537). Northern blot analysis revealed expression of multiple transcripts of different size in all tissues examined.
While attempting to identify new neuropeptide receptors from a neuroblastoma x glioma cell line by RT-PCR with primers based on conserved regions of G protein-coupled neuropeptide receptors, Methner et al. (1997) cloned a mouse Cmklr1 cDNA, which they designated Dez. Using in situ hybridization, Methner et al. (1997) found that Dez is differentially regulated during mouse development, with prominent expression in developing osseous and cartilaginous tissues. Owman et al. (1997) cloned the rat homolog, which they designated Cmkrl3, from a liver cDNA library. Using in situ hybridization, they found that Cmkrl3 is widely expressed in the brain and periphery, particularly in cardiovascular elements.
Using RT-PCR analysis, Wittamer et al. (2003) detected abundant CHEMR23 expression in immature dendritic cells (DCs), spleen, lymph node, and lung, with lower levels in most other tissues examined. FACS analysis confirmed CHEMR23 expression on DCs and macrophages.
By screening a cell line expressing CHEMR23, followed by reverse-phase HPLC and mass spectrophotometric analysis, Wittamer et al. (2003) identified the active product of TIG2 (RARRES2; 601973), which they called chemerin, as the CHEMR23 ligand. Chemerin induced calcium mobilization in and migration of macrophages and immature dendritic cells in a CHEMR23-dependent manner. Monoclonal antibodies to CHEMR23 blocked chemerin-induced calcium mobilization in CHEMR23-expressing cell lines.
By screening cells overexpressing CHEMR23 with a hemofiltrate peptide library, followed by chromatographic purification, Meder et al. (2003) independently identified a 134-amino acid circulating form of TIG2 as the CHEMR23 ligand.
By generating a monoclonal antibody to CHEMR23 and screening circulating leukocytes by FACS analysis, Zabel et al. (2005) demonstrated expression of CHEMR23 on circulating plasmacytoid dendritic cells (DCs), but not on myeloid DCs or other blood cells. In vitro assays identified chemerin in serum, but not plasma, as a chemoattractant for CHEMR23-expressing cells. Zabel et al. (2005) concluded that CHEMR23 may be a key mediator of plasmacytoid DC recruitment from blood to tissue sites enriched in chemerin.
By flow cytometric analysis, Vermi et al. (2005) demonstrated CHEMR23 expression in 40% of myeloid DCs and virtually all plasmacytoid DCs. Transmigration of both DC populations across an endothelial cell layer was dependent on chemerin and CHEMR23. Immunohistochemical analysis of lymph nodes and tonsils showed CHEMR23 expression on DCs, but not on Langerhans cells. Chemerin was expressed on the luminal side of high endothelial venules. Chemerin was not expressed in normal skin, but it was expressed on endothelial cells lining dermal blood vessels of lupus erythematosus skin lesions in which plasmacytoid DCs were abundant. Vermi et al. (2005) proposed that CHEMR23-chemerin interaction has a key role in directing plasmacytoid DC traffic.
Resolvin E1 (RvE1), a bioactive oxygenated product of the essential fatty acid eicosapentaenoic acid (EPA), is found in plasma during the resolution phase of inflammation. Arita et al. (2005) determined the complete structure of RvE1 and found that CHEMR23 mediates RvE1 signaling to attenuate NFKB (164011). Radioligand binding analysis showed that chemerin and RvE1 bound the same region of CHEMR23. RvE1 inhibited Il12 p40 (IL12B; 161561) production induced from mouse splenic DCs by Toxoplasma gondii antigen in a dose-dependent manner. Arita et al. (2005) concluded that EPA, which is present in fish oils and has beneficial effects on inflammatory disorders, and EPA-derived endogenous agonists have antiinflammatory properties.
Gantz et al. (1996) mapped the CMKLR1 gene to chromosome 12q24.1 by fluorescence in situ hybridization.
Arita, M., Bianchini, F., Aliberti, J., Sher, A., Chiang, N., Hong, S., Yang, R., Petasis, N. A., Serhan, C. N. Stereochemical assignment, antiinflammatory properties, and receptor for the omega-3 lipid mediator resolvin E1. J. Exp. Med. 201: 713-722, 2005. [PubMed: 15753205] [Full Text: https://doi.org/10.1084/jem.20042031]
Gantz, I., Konda, Y., Yang, Y.-K., Miller, D. E., Dierick, H. A., Yamada, T. Molecular cloning of a novel receptor (CMKLR1) with homology to the chemotactic factor receptors. Cytogenet. Cell Genet. 74: 286-290, 1996. [PubMed: 8976386] [Full Text: https://doi.org/10.1159/000134436]
Meder, W., Wendland, M., Busmann, A., Kutzleb, C., Spodsberg, N., John, H., Richter, R., Schleuder, D., Meyer, M., Forssmann, W. G. Characterization of human circulating TIG2 as a ligand for the orphan receptor ChemR23. FEBS Lett. 555: 495-499, 2003. [PubMed: 14675762] [Full Text: https://doi.org/10.1016/s0014-5793(03)01312-7]
Methner, A., Hermey, G., Schinke, B., Hermans-Borgmeyer, I. A novel G protein-coupled receptor with homology to neuropeptide and chemoattractant receptors expressed during bone development. Biochem. Biophys. Res. Commun. 233: 336-342, 1997. [PubMed: 9144535] [Full Text: https://doi.org/10.1006/bbrc.1997.6455]
Owman, C., Lolait, S. J., Santen, S., Olde, B. Molecular cloning and tissue distribution of cDNA encoding a novel chemoattractant-like receptor. Biochem. Biophys. Res. Commun. 241: 390-394, 1997. [PubMed: 9425281] [Full Text: https://doi.org/10.1006/bbrc.1997.7822]
Vermi, W., Riboldi, E., Wittamer, V., Gentili, F., Luini, W., Marrelli, S., Vecchi, A., Franssen, J.-D., Communi, D., Massardi, L., Sironi, M., Mantovani, A., Parmentier, M., Facchetti, F., Sozzani, S. Role of ChemR23 in directing the migration of myeloid and plasmacytoid dendritic cells to lymphoid organs and inflamed skin. J. Exp. Med. 201: 509-515, 2005. [PubMed: 15728234] [Full Text: https://doi.org/10.1084/jem.20041310]
Wittamer, V., Franssen, J.-D., Vulcano, M., Mirjolet, J.-F., Le Poul, E., Migeotte, I., Brezillon, S., Tyldesley, R., Blanpain, C., Detheux, M., Mantovani, A., Sozzani, S., Vassart, G., Parmentier, M., Communi, D. Specific recruitment of antigen-presenting cells by chemerin, a novel processed ligand from human inflammatory fluids. J. Exp. Med. 198: 977-985, 2003. [PubMed: 14530373] [Full Text: https://doi.org/10.1084/jem.20030382]
Zabel, B. A., Silverio, A. M., Butcher, E. C. Chemokine-like receptor 1 expression and chemerin-directed chemotaxis distinguish plasmacytoid from myeloid dendritic cells in human blood. J. Immun. 174: 244-251, 2005. [PubMed: 15611246] [Full Text: https://doi.org/10.4049/jimmunol.174.1.244]