Alternative titles; symbols
HGNC Approved Gene Symbol: CCR1
Cytogenetic location: 3p21.31 Genomic coordinates (GRCh38): 3:46,201,711-46,208,313 (from NCBI)
On the assumption that the beta family chemokine receptors would be similar, 2 groups independently cloned cDNAs for the beta chemokine receptor for MIP1-alpha and RANTES. Neote et al. (1993) used degenerate PCR while Gao et al. (1993) used a probe based on the rabbit IL8 receptor sequence to obtain the same cDNAs from an HL60 neutrophil library. Each cDNA predicted a 355-amino acid protein with 7 potential transmembrane domains similar to other G protein-coupled receptors. The protein is approximately 32% identical to the 2 IL8 receptors. Northern blots showed an approximately 3-kb transcript in myeloid precursor cell lines including U937 and HL60 with highest levels in phorbol myristate acetate-treated THP-1. Transcripts were also found in normal B cells (Neote et al., 1993 and Gao et al., 1993). Gao et al. (1993) cloned the CMKBR1 gene and determined that it has 1 intron in the 5-prime untranslated region. Both Neote et al. (1993) and Gao et al. (1993) expressed the gene in human 293 kidney cells or Xenopus oocytes, respectively, and showed that the recombinantly expressed protein was stimulated by both MCP1-alpha and RANTES.
Gao et al. (1993) mapped the CMKBR1 gene to 3p21 by fluorescence in situ hybridization (FISH). By FISH, Daugherty and Springer (1997) determined that the CMKBR1, CMKBR2 (601267), and CMKBR3 (601268) genes are clustered within 285 kb on 3p21. Kozak et al. (1995) cloned 3 related genes from the mouse (Scya3r, Scya3r-rs1, and Scya3r-rs2) and showed that they mapped to mouse chromosome 9 in a region with homology of synteny to human 3p21.
The chemokines are structurally related proteins that act as chemoattractants and activators of lymphocytes and phagocytes. Kozak et al. (1995) noted that there are 2 separate families of chemokines differentiated by the location of the first 2 of 4 conserved cysteine residues. The alpha family is distinguished by the fact that the first 2 cysteines are separated by a single amino acid (CXC), while in the beta family the cysteines are adjacent (CC). The majority of the alpha chemokines, which includes IL8 (146930), target neutrophils, while the beta family members act largely upon monocytes. Members of the beta-chemokine family include macrophage inflammatory protein 1 alpha (MIP1-alpha; 182283), MIP1-beta (182284), RANTES (regulated on activation, normal T expressed and secreted) (see 187011), MCP-1 (monocyte chemoattractant protein 1; 158105), MCP-2, MCP-3 (158106) and I-309 (182281) (Gao et al., 1993). Two receptors for the alpha family chemokine IL8 have been cloned, IL8RA (146929) and IL8RB (146928), which have features of the G protein-coupled receptors. See also CCR2A/CCR2B (601267).
Charo and Ransohoff (2006) reviewed the many roles of chemokines and chemokine receptors in inflammation. They tabulated 10 members of the CC family of chemokine receptors and indicated the chemokine ligands of each, cell types, and disease connections. They also tabulated 9 members of the CXC, CX3C, and XC families of chemokines and chemokine receptors.
Acute lung injury and the adult respiratory distress syndrome complicate many disease states. The mechanisms underlying this syndrome are unresolved, but the uniform pathologic features of adult respiratory distress syndrome involve sequestration of activated inflammatory cells within the lung, pulmonary microvascular injury, and leakage of intravascular fluid into the tissue spaces. In rodents, a model of these processes dependent on the initiation of acute pancreatitis is produced by overstimulation of pancreatic exocrine acinar cells with a cholecystokinin analog. Gerard et al. (1997) demonstrated that targeted disruption of the CCR1 receptor is associated with protection from pulmonary inflammation secondary to acute pancreatitis in the mouse. The protection from lung injury is associated with decreased levels of TNF-alpha in a temporal sequence indicating that the activation of the CCR1 receptor is an early event in the systemic inflammatory response syndrome.
Neutrophil accumulation is defective in mice lacking Ccr1. Khan et al. (2001) found that Ccr1 -/- mice had a higher susceptibility to Toxoplasma gondii infection with a higher parasite burden in tissues and increased mortality compared with wildtype mice. Histologic analysis showed that intestinal inflammatory pathology was less severe, there were fewer lymphocytes in splenic primary follicles, and there was more intracellular replication of T. gondii in Ccr1 -/- mice compared with parental wildtype mice. In vitro analysis, however, showed that T cell-mediated immunity was not reduced in Ccr1 -/- mice. Khan et al. (2001) concluded that Ccr1-dependent migration of neutrophils to blood and tissues may have a significant impact in controlling parasite replication early in infection.
Charo, I. F., Ransohoff, R. M. The many roles of chemokines and chemokine receptors in inflammation. New Eng. J. Med. 354: 610-621, 2006. [PubMed: 16467548] [Full Text: https://doi.org/10.1056/NEJMra052723]
Daugherty, B. L., Springer, M. S. The beta-chemokine receptor genes CCR1 (CMKBR1), CCR2 (CMKBR2), and CCR3 (CMKBR3) cluster within 285 kb on human chromosome 3p21. Genomics 41: 294-295, 1997. [PubMed: 9143512] [Full Text: https://doi.org/10.1006/geno.1997.4626]
Gao, J.-L., Kuhns, D. B., Tiffany, H. L., McDermott, D., Li, X., Francke, U., Murphy, P. M. Structure and functional expression of the human macrophage inflammatory protein 1-alpha/RANTES receptor. J. Exp. Med. 177: 1421-1427, 1993. [PubMed: 7683036] [Full Text: https://doi.org/10.1084/jem.177.5.1421]
Gerard, C., Frossard, J.-L., Bhatia, M., Saluja, A., Gerard, N. P., Lu, B., Steer, M. Targeted disruption of the beta-chemokine receptor CCR1 protects against pancreatitis-associated lung injury. J. Clin. Invest. 100: 2022-2027, 1997. [PubMed: 9329966] [Full Text: https://doi.org/10.1172/JCI119734]
Khan, I. A., Murphy, P. M., Casciotti, L., Schwartzman, J. D., Collins, J., Gao, J.-L., Yeaman, G. R. Mice lacking the chemokine receptor CCR1 show increased susceptibility to Toxoplasma gondii infection. J. Immun. 166: 1930-1937, 2001. [PubMed: 11160241] [Full Text: https://doi.org/10.4049/jimmunol.166.3.1930]
Kozak, C. A., Gao, J.-L., Murphy, P. M. Mapping of the mouse macrophage inflammatory protein-1-alpha receptor gene Scya3r and two related mouse beta chemokine receptor-like genes to chromosome 9. Genomics 29: 294-296, 1995. [PubMed: 8530091] [Full Text: https://doi.org/10.1006/geno.1995.1250]
Neote, K., DiGregorio, D., Mak, J. Y., Horuk, R., Schall, T. J. Molecular cloning, functional expression, and signaling characteristics of a C-C chemokine receptor. Cell 72: 415-425, 1993. [PubMed: 7679328] [Full Text: https://doi.org/10.1016/0092-8674(93)90118-a]