|, CC-CKR-2, CCR-2, CCR2A, CCR2B, CD192, CKR2, CKR2A, CKR2B, CMKBR2, MCP-1-R, C-C motif chemokine receptor 2|
This gene encodes two isoforms of a receptor for monocyte chemoattractant protein-1 (CCL2), a chemokine which specifically mediates monocyte chemotaxis. Monocyte chemoattractant protein-1 is involved in monocyte infiltration in inflammatory diseases such as rheumatoid arthritis as well as in the inflammatory response against tumors. The receptors encoded by this gene mediate agonist-dependent calcium mobilization and inhibition of adenylyl cyclase.
CCR2 deficient mice have been shown to develop an accelerated Alzheimer's-like pathology in comparison to wild type mice. This is not the first time that immune function and inflammation have been linked to age-related cognitive decline (i.e. dementia).
Within the fat (adipose) tissue of CCR2 deficient mice, there is an increased number of eosinophils, greater alternative macrophage activation, and a propensity towards type 2 cytokine expression. Furthermore, this effect was exaggerated when the mice became obese from a high fat diet.
CCR2 surface expression on blood monocytes changes in a time-of-day–dependent manner (being higher at the beginning of the active phase) and affects monocytes recruitment in tissues including the heart. As a consequence when an acute ischemic event happens during the active phase, monocytes are more susceptible to invade the heart . An excessive monocytes infiltration generates higher inflammation and increases the risk of heart failure.
In an observational study of gene expression in blood leukocytes in humans, Harries et al. found evidence of a relationship between expression of CCR2 and cognitive function (assessed using the mini-mental state examination, MMSE). Higher CCR2 expression was associated with worse performance on the MMSE assessment of cognitive function. The same study found that CCR2 expression was also associated with cognitive decline over 9-years in a sub-analysis on inflammatory related transcripts only. Harries et al. suggest that CCR2 signaling may have a direct role in human cognition, partly because expression of CCR2 was associated with the ApoE haplotype (previously associated with Alzheimer's disease), but also because CCL2 is expressed at high concentrations in macrophages found in atherosclerotic plaques and in brain microglia. The difference in observations between mice (CCR2 depletion causes cognitive decline) and humans (higher CCR2 associated with lower cognitive function) could be due to increased demand for macrophage activation during cognitive decline, associated with increased β-amyloid deposition (a core feature of Alzheimer's disease progression).
- GRCh38: Ensembl release 89: ENSG00000121807 - Ensembl, May 2017
- "Human PubMed Reference:".
- "Mouse PubMed Reference:".
- "Entrez Gene: CCR2 chemokine (C-C motif) receptor 2".
- El Khoury J, Toft M, Hickman SE, Means TK, Terada K, Geula C, Luster AD (April 2007). "Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease". Nature Medicine. 13 (4): 432–8. doi:10.1038/nm1555. PMID 17351623.
- Philipson O, Lord A, Gumucio A, O'Callaghan P, Lannfelt L, Nilsson LN (March 2010). "Animal models of amyloid-beta-related pathologies in Alzheimer's disease". The FEBS Journal. 277 (6): 1389–409. doi:10.1111/j.1742-4658.2010.07564.x. PMID 20136653.
- Gorelick PB (October 2010). "Role of inflammation in cognitive impairment: results of observational epidemiological studies and clinical trials". Annals of the New York Academy of Sciences. 1207: 155–62. doi:10.1111/j.1749-6632.2010.05726.x. PMID 20955439.
- Bolus WR, Gutierrez DA, Kennedy AJ, Anderson-Baucum EK, Hasty AH (October 2015). "CCR2 deficiency leads to increased eosinophils, alternative macrophage activation, and type 2 cytokine expression in adipose tissue". Journal of Leukocyte Biology. 98 (4): 467–77. doi:10.1189/jlb.3HI0115-018R. PMC 4763864. PMID 25934927. Archived from the original on 2017-05-09. Retrieved 2016-09-08.
- Schloss MJ, Hilby M, Nitz K, Guillamat Prats R, Ferraro B, Leoni G, Soehnlein O, Kessler T, He W, Luckow B, Horckmans M, Weber C, Duchene J, Steffens S (June 2017). "Ly6C(high) Monocytes Oscillate in the Heart During Homeostasis and After Myocardial Infarction". Arteriosclerosis, Thrombosis, and Vascular Biology. doi:10.1161/ATVBAHA.117.309259. PMID 28663258.
- Harries LW, Bradley-Smith RM, Llewellyn DJ, Pilling LC, Fellows A, Henley W, Hernandez D, Guralnik JM, Bandinelli S, Singleton A, Ferrucci L, Melzer D (August 2012). "Leukocyte CCR2 expression is associated with mini-mental state examination score in older adults". Rejuvenation Research. 15 (4): 395–404. doi:10.1089/rej.2011.1302. PMC 3419848. PMID 22607625.
- Sozzani S, Introna M, Bernasconi S, Polentarutti N, Cinque P, Poli G, Sica A, Mantovani A (July 1997). "MCP-1 and CCR2 in HIV infection: regulation of agonist and receptor expression". Journal of Leukocyte Biology. 62 (1): 30–3. PMID 9225989.
- Choe H, Martin KA, Farzan M, Sodroski J, Gerard NP, Gerard C (June 1998). "Structural interactions between chemokine receptors, gp120 Env and CD4". Seminars in Immunology. 10 (3): 249–57. doi:10.1006/smim.1998.0127. PMID 9653051.
- Cunningham AL, Li S, Juarez J, Lynch G, Alali M, Naif H (September 2000). "The level of HIV infection of macrophages is determined by interaction of viral and host cell genotypes". Journal of Leukocyte Biology. 68 (3): 311–7. PMID 10985245.
- Ruibal-Ares BH, Belmonte L, Baré PC, Parodi CM, Massud I, de Bracco MM (January 2004). "HIV-1 infection and chemokine receptor modulation". Current HIV Research. 2 (1): 39–50. doi:10.2174/1570162043484997. PMID 15053339.
- Yamagami S, Tokuda Y, Ishii K, Tanaka H, Endo N (July 1994). "cDNA cloning and functional expression of a human monocyte chemoattractant protein 1 receptor". Biochemical and Biophysical Research Communications. 202 (2): 1156–62. doi:10.1006/bbrc.1994.2049. PMID 8048929.
- Charo IF, Myers SJ, Herman A, Franci C, Connolly AJ, Coughlin SR (March 1994). "Molecular cloning and functional expression of two monocyte chemoattractant protein 1 receptors reveals alternative splicing of the carboxyl-terminal tails". Proceedings of the National Academy of Sciences of the United States of America. 91 (7): 2752–6. doi:10.1073/pnas.91.7.2752. PMC 43448. PMID 8146186.
- Combadiere C, Ahuja SK, Van Damme J, Tiffany HL, Gao JL, Murphy PM (December 1995). "Monocyte chemoattractant protein-3 is a functional ligand for CC chemokine receptors 1 and 2B". The Journal of Biological Chemistry. 270 (50): 29671–5. doi:10.1074/jbc.270.50.29671. PMID 8530354.
- Samson M, Soularue P, Vassart G, Parmentier M (September 1996). "The genes encoding the human CC-chemokine receptors CC-CKR1 to CC-CKR5 (CMKBR1-CMKBR5) are clustered in the p21.3-p24 region of chromosome 3". Genomics. 36 (3): 522–6. doi:10.1006/geno.1996.0498. PMID 8884276.
- Wong LM, Myers SJ, Tsou CL, Gosling J, Arai H, Charo IF (January 1997). "Organization and differential expression of the human monocyte chemoattractant protein 1 receptor gene. Evidence for the role of the carboxyl-terminal tail in receptor trafficking". The Journal of Biological Chemistry. 272 (2): 1038–45. doi:10.1074/jbc.272.2.1038. PMID 8995400.
- Polentarutti N, Allavena P, Bianchi G, Giardina G, Basile A, Sozzani S, Mantovani A, Introna M (March 1997). "IL-2-regulated expression of the monocyte chemotactic protein-1 receptor (CCR2) in human NK cells: characterization of a predominant 3.4-kilobase transcript containing CCR2B and CCR2A sequences". Journal of Immunology. 158 (6): 2689–94. PMID 9058802.
- Gong X, Gong W, Kuhns DB, Ben-Baruch A, Howard OM, Wang JM (May 1997). "Monocyte chemotactic protein-2 (MCP-2) uses CCR1 and CCR2B as its functional receptors". The Journal of Biological Chemistry. 272 (18): 11682–5. doi:10.1074/jbc.272.18.11682. PMID 9115216.
- Daugherty BL, Springer MS (April 1997). "The beta-chemokine receptor genes CCR1 (CMKBR1), CCR2 (CMKBR2), and CCR3 (CMKBR3) cluster within 285 kb on human chromosome 3p21". Genomics. 41 (2): 294–5. doi:10.1006/geno.1997.4626. PMID 9143512.
- Berkhout TA, Sarau HM, Moores K, White JR, Elshourbagy N, Appelbaum E, Reape RJ, Brawner M, Makwana J, Foley JJ, Schmidt DB, Imburgia C, McNulty D, Matthews J, O'Donnell K, O'Shannessy D, Scott M, Groot PH, Macphee C (June 1997). "Cloning, in vitro expression, and functional characterization of a novel human CC chemokine of the monocyte chemotactic protein (MCP) family (MCP-4) that binds and signals through the CC chemokine receptor 2B". The Journal of Biological Chemistry. 272 (26): 16404–13. doi:10.1074/jbc.272.26.16404. PMID 9195948.
- Smith MW, Dean M, Carrington M, Winkler C, Huttley GA, Lomb DA, Goedert JJ, O'Brien TR, Jacobson LP, Kaslow R, Buchbinder S, Vittinghoff E, Vlahov D, Hoots K, Hilgartner MW, O'Brien SJ (August 1997). "Contrasting genetic influence of CCR2 and CCR5 variants on HIV-1 infection and disease progression. Hemophilia Growth and Development Study (HGDS), Multicenter AIDS Cohort Study (MACS), Multicenter Hemophilia Cohort Study (MHCS), San Francisco City Cohort (SFCC), ALIVE Study". Science. 277 (5328): 959–65. doi:10.1126/science.277.5328.959. PMID 9252328.
- Monteclaro FS, Charo IF (September 1997). "The amino-terminal domain of CCR2 is both necessary and sufficient for high affinity binding of monocyte chemoattractant protein 1. Receptor activation by a pseudo-tethered ligand". The Journal of Biological Chemistry. 272 (37): 23186–90. doi:10.1074/jbc.272.37.23186. PMID 9287323.
- Aragay AM, Mellado M, Frade JM, Martin AM, Jimenez-Sainz MC, Martinez-A C, Mayor F (March 1998). "Monocyte chemoattractant protein-1-induced CCR2B receptor desensitization mediated by the G protein-coupled receptor kinase 2". Proceedings of the National Academy of Sciences of the United States of America. 95 (6): 2985–90. doi:10.1073/pnas.95.6.2985. PMC 19681. PMID 9501202.
- Frade JM, Mellado M, del Real G, Gutierrez-Ramos JC, Lind P, Martinez-A C (December 1997). "Characterization of the CCR2 chemokine receptor: functional CCR2 receptor expression in B cells". Journal of Immunology. 159 (11): 5576–84. PMID 9548499.
- Mummidi S, Ahuja SS, Gonzalez E, Anderson SA, Santiago EN, Stephan KT, Craig FE, O'Connell P, Tryon V, Clark RA, Dolan MJ, Ahuja SK (July 1998). "Genealogy of the CCR5 locus and chemokine system gene variants associated with altered rates of HIV-1 disease progression". Nature Medicine. 4 (7): 786–93. doi:10.1038/nm0798-786. PMID 9662369.
- Human CCR2 genome location and CCR2 gene details page in the UCSC Genome Browser.
- "Chemokine Receptors: CCR2". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.
- CCR2+protein,+human at the US National Library of Medicine Medical Subject Headings (MeSH)
- description at Information Hyperlinked Over Proteins