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Gene Review

CCR2  -  chemokine (C-C motif) receptor 2

Homo sapiens

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Disease relevance of CCR2

  • The role of CCR5 and CCR2 polymorphisms in HIV-1 transmission and disease progression [1].
  • Augmentation of monocyte CCR2 expression may underlie unexplained in vivo effects of GC as well as some of their actions on HIV infection [2].
  • However, the involved pathways are different, although in either case coupling of CCR2 to pertussis toxin-sensitive heterotrimeric G proteins is necessary [3].
  • The present study was designed to investigate the expression of CCR2 in tumor-associated macrophages (TAM) from ovarian cancer patients [4].
  • Roles of CCR2 and CXCR3 in the T cell-mediated response occurring during lupus flares [5].

High impact information on CCR2

  • A chemokine receptor CCR2 allele delays HIV-1 disease progression and is associated with a CCR5 promoter mutation [6].
  • A recent study showed that a conservative substitution (V64I) in the coding region of CCR2 also has a significant impact on disease progression, but not on HIV-1 transmission [6].
  • Here we focus on findings in the CCL2-CCR2 and CCL3-CCR5 ligand-receptor systems [7].
  • First, we examined whether prominent CCRs on different monocyte subsets, CCR2 or CX3CR1, mediated migration events upstream of the accumulation of monocyte-derived DCs in lymph nodes (LNs) [8].
  • In contrast, IL-2 augmented CCR2 expression and MCP-1 itself had no effect [9].

Chemical compound and disease context of CCR2


Biological context of CCR2


Anatomical context of CCR2

  • Consistent with these results, MCP-5 induced a calcium flux in human embryonic kidney (HEK)-293 cells transfected with human and murine CCR2, a CC chemokine receptor expressed on monocytes [16].
  • CCR2, the receptor for CCL2, was more frequently expressed by iNKT compared with natural killer and T cells from blood (P < 0.001) [17].
  • Differentiation of monocytes into macrophages also resulted in an increased secretion of MCP-1 that, at least in part, was responsible for the downmodulation of its receptor (CCR2) [18].
  • The loss of CCR2 mRNA expression in 7-day-cultured macrophages was associated with a strong reduction in the receptor expression at the plasma membrane, as well as in the monocyte chemotactic protein (MCP-1) binding, as compared with freshly isolated monocytes [18].
  • Using the monocyte cell line THP-1, we investigated the relative abilities of eotaxin and MCPs 1-4 to induce CCR2 signaling, employing assays of directed cell migration and intracellular calcium flux [19].

Associations of CCR2 with chemical compounds


Physical interactions of CCR2

  • Here we show that eotaxin-3 also binds to CCR2 on monocytes and CCR2-transfected cells [23].
  • This study shows that eotaxin also interacts with CCR2 and CCR5 and can, thus, affect the responses of monocytes, which express both receptors [24].
  • MCP-1 binds the chemokine receptor CCR2 [4].
  • CONCLUSION: These results suggest that CCR2A binds to CCR5 in the cytoplasm and down-modulates its surface expression [25].

Regulatory relationships of CCR2


Other interactions of CCR2

  • We show that, in the chemokine response, heterodimerization is also permitted between given receptor pairs, specifically between CCR2 and CCR5 [31].
  • Direct receptor binding experiments with the CysL24-51 peptide confirmed binding to cells transfected with CCR2 and CCR3 [32].
  • Eotaxin-3 is a natural antagonist for CCR2 and exerts a repulsive effect on human monocytes [23].
  • Eotaxin is a natural antagonist for CCR2 and an agonist for CCR5 [24].
  • RESULTS: Most normal PB monocytes expressed CCR1 (87%) and CCR2 (84%), but not CCRs 3, 4, 5, or 6 or CXCR3 [33].

Analytical, diagnostic and therapeutic context of CCR2


  1. The role of CCR5 and CCR2 polymorphisms in HIV-1 transmission and disease progression. Michael, N.L., Louie, L.G., Rohrbaugh, A.L., Schultz, K.A., Dayhoff, D.E., Wang, C.E., Sheppard, H.W. Nat. Med. (1997) [Pubmed]
  2. Up-regulation of CCR2 chemokine receptor expression and increased susceptibility to the multitropic HIV strain 89.6 in monocytes exposed to glucocorticoid hormones. Penton-Rol, G., Cota, M., Polentarutti, N., Luini, W., Bernasconi, S., Borsatti, A., Sica, A., LaRosa, G.J., Sozzani, S., Poli, G., Mantovani, A. J. Immunol. (1999) [Pubmed]
  3. Unusual chemokine receptor antagonism involving a mitogen-activated protein kinase pathway. Ogilvie, P., Thelen, S., Moepps, B., Gierschik, P., da Silva Campos, A.C., Baggiolini, M., Thelen, M. J. Immunol. (2004) [Pubmed]
  4. Defective expression of the monocyte chemotactic protein-1 receptor CCR2 in macrophages associated with human ovarian carcinoma. Sica, A., Saccani, A., Bottazzi, B., Bernasconi, S., Allavena, P., Gaetano, B., Fei, F., LaRosa, G., Scotton, C., Balkwill, F., Mantovani, A. J. Immunol. (2000) [Pubmed]
  5. Roles of CCR2 and CXCR3 in the T cell-mediated response occurring during lupus flares. Amoura, Z., Combadiere, C., Faure, S., Parizot, C., Miyara, M., Raphaël, D., Ghillani, P., Debre, P., Piette, J.C., Gorochov, G. Arthritis Rheum. (2003) [Pubmed]
  6. A chemokine receptor CCR2 allele delays HIV-1 disease progression and is associated with a CCR5 promoter mutation. Kostrikis, L.G., Huang, Y., Moore, J.P., Wolinsky, S.M., Zhang, L., Guo, Y., Deutsch, L., Phair, J., Neumann, A.U., Ho, D.D. Nat. Med. (1998) [Pubmed]
  7. Chemokines as regulators of T cell differentiation. Luther, S.A., Cyster, J.G. Nat. Immunol. (2001) [Pubmed]
  8. Role of CCR8 and other chemokine pathways in the migration of monocyte-derived dendritic cells to lymph nodes. Qu, C., Edwards, E.W., Tacke, F., Angeli, V., Llodrá, J., Sanchez-Schmitz, G., Garin, A., Haque, N.S., Peters, W., van Rooijen, N., Sanchez-Torres, C., Bromberg, J., Charo, I.F., Jung, S., Lira, S.A., Randolph, G.J. J. Exp. Med. (2004) [Pubmed]
  9. Bacterial lipopolysaccharide rapidly inhibits expression of C-C chemokine receptors in human monocytes. Sica, A., Saccani, A., Borsatti, A., Power, C.A., Wells, T.N., Luini, W., Polentarutti, N., Sozzani, S., Mantovani, A. J. Exp. Med. (1997) [Pubmed]
  10. The role of the C-C chemokine receptor 2 gene polymorphism V64I (CCR2-64I) in sarcoidosis in a Japanese population. Hizawa, N., Yamaguchi, E., Furuya, K., Jinushi, E., Ito, A., Kawakami, Y. Am. J. Respir. Crit. Care Med. (1999) [Pubmed]
  11. IL-13-induced chemokine responses in the lung: role of CCR2 in the pathogenesis of IL-13-induced inflammation and remodeling. Zhu, Z., Ma, B., Zheng, T., Homer, R.J., Lee, C.G., Charo, I.F., Noble, P., Elias, J.A. J. Immunol. (2002) [Pubmed]
  12. Role of CCR2 genotype in the clinical course of syncytium-inducing (SI) or non-SI human immunodeficiency virus type 1 infection and in the time to conversion to SI virus variants. van Rij, R.P., de Roda Husman, A.M., Brouwer, M., Goudsmit, J., Coutinho, R.A., Schuitemaker, H. J. Infect. Dis. (1998) [Pubmed]
  13. Chemokines in the MPTP model of Parkinson's disease: Absence of CCL2 and its receptor CCR2 does not protect against striatal neurodegeneration. Kalkonde, Y.V., Morgan, W.W., Sigala, J., Maffi, S.K., Condello, C., Kuziel, W., Ahuja, S.S., Ahuja, S.K. Brain Res. (2007) [Pubmed]
  14. The amino-terminal domain of the CCR2 chemokine receptor acts as coreceptor for HIV-1 infection. Frade, J.M., Llorente, M., Mellado, M., Alcamí, J., Gutiérrez-Ramos, J.C., Zaballos, A., Real, G., Martínez-A, C. J. Clin. Invest. (1997) [Pubmed]
  15. Redox regulation of chemokine receptor expression. Saccani, A., Saccani, S., Orlando, S., Sironi, M., Bernasconi, S., Ghezzi, P., Mantovani, A., Sica, A. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  16. Murine monocyte chemoattractant protein (MCP)-5: a novel CC chemokine that is a structural and functional homologue of human MCP-1. Sarafi, M.N., Garcia-Zepeda, E.A., MacLean, J.A., Charo, I.F., Luster, A.D. J. Exp. Med. (1997) [Pubmed]
  17. Natural killer T cells infiltrate neuroblastomas expressing the chemokine CCL2. Metelitsa, L.S., Wu, H.W., Wang, H., Yang, Y., Warsi, Z., Asgharzadeh, S., Groshen, S., Wilson, S.B., Seeger, R.C. J. Exp. Med. (2004) [Pubmed]
  18. Loss of CCR2 expression and functional response to monocyte chemotactic protein (MCP-1) during the differentiation of human monocytes: role of secreted MCP-1 in the regulation of the chemotactic response. Fantuzzi, L., Borghi, P., Ciolli, V., Pavlakis, G., Belardelli, F., Gessani, S. Blood (1999) [Pubmed]
  19. The CC chemokine eotaxin (CCL11) is a partial agonist of CC chemokine receptor 2b. Martinelli, R., Sabroe, I., LaRosa, G., Williams, T.J., Pease, J.E. J. Biol. Chem. (2001) [Pubmed]
  20. Coagulation cascade activation causes CC chemokine receptor-2 gene expression and mononuclear cell activation in hemodialysis patients. Pertosa, G., Simone, S., Soccio, M., Marrone, D., Gesualdo, L., Schena, F.P., Grandaliano, G. J. Am. Soc. Nephrol. (2005) [Pubmed]
  21. Identification of residues in the monocyte chemotactic protein-1 that contact the MCP-1 receptor, CCR2. Hemmerich, S., Paavola, C., Bloom, A., Bhakta, S., Freedman, R., Grunberger, D., Krstenansky, J., Lee, S., McCarley, D., Mulkins, M., Wong, B., Pease, J., Mizoue, L., Mirzadegan, T., Polsky, I., Thompson, K., Handel, T.M., Jarnagin, K. Biochemistry (1999) [Pubmed]
  22. Angiotensin AT1 receptor antagonist irbesartan decreases lesion size, chemokine expression, and macrophage accumulation in apolipoprotein E-deficient mice. Dol, F., Martin, G., Staels, B., Mares, A.M., Cazaubon, C., Nisato, D., Bidouard, J.P., Janiak, P., Schaeffer, P., Herbert, J.M. J. Cardiovasc. Pharmacol. (2001) [Pubmed]
  23. Eotaxin-3 is a natural antagonist for CCR2 and exerts a repulsive effect on human monocytes. Ogilvie, P., Paoletti, S., Clark-Lewis, I., Uguccioni, M. Blood (2003) [Pubmed]
  24. Eotaxin is a natural antagonist for CCR2 and an agonist for CCR5. Ogilvie, P., Bardi, G., Clark-Lewis, I., Baggiolini, M., Uguccioni, M. Blood (2001) [Pubmed]
  25. A CCR2-V64I polymorphism affects stability of CCR2A isoform. Nakayama, E.E., Tanaka, Y., Nagai, Y., Iwamoto, A., Shioda, T. AIDS (2004) [Pubmed]
  26. Monocyte chemoattractant protein-1-induced CCR2B receptor desensitization mediated by the G protein-coupled receptor kinase 2. Aragay, A.M., Mellado, M., Frade, J.M., Martin, A.M., Jimenez-Sainz, M.C., Martinez-A, C., Mayor, F. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  27. Induction of heme oxygenase-1 in monocytes suppresses angiotensin II-elicited chemotactic activity through inhibition of CCR2: role of bilirubin and carbon monoxide generated by the enzyme. Morita, T., Imai, T., Yamaguchi, T., Sugiyama, T., Katayama, S., Yoshino, G. Antioxid. Redox Signal. (2003) [Pubmed]
  28. The chemokine monocyte chemoattractant protein-1 induces functional responses through dimerization of its receptor CCR2. Rodríguez-Frade, J.M., Vila-Coro, A.J., de Ana, A.M., Albar, J.P., Martínez-A, C., Mellado, M. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  29. Expression of CCR2 on monocytes and macrophages in chronically inflamed skin in atopic dermatitis and psoriasis. Vestergaard, C., Just, H., Baumgartner Nielsen, J., Thestrup-Pedersen, K., Deleuran, M. Acta Derm. Venereol. (2004) [Pubmed]
  30. CD43 interacts with moesin and ezrin and regulates its redistribution to the uropods of T lymphocytes at the cell-cell contacts. Serrador, J.M., Nieto, M., Alonso-Lebrero, J.L., del Pozo, M.A., Calvo, J., Furthmayr, H., Schwartz-Albiez, R., Lozano, F., González-Amaro, R., Sánchez-Mateos, P., Sánchez-Madrid, F. Blood (1998) [Pubmed]
  31. Chemokine receptor homo- or heterodimerization activates distinct signaling pathways. Mellado, M., Rodríguez-Frade, J.M., Vila-Coro, A.J., Fernández, S., Martín de Ana, A., Jones, D.R., Torán, J.L., Martínez-A, C. EMBO J. (2001) [Pubmed]
  32. HIV-1 Tat protein mimicry of chemokines. Albini, A., Ferrini, S., Benelli, R., Sforzini, S., Giunciuglio, D., Aluigi, M.G., Proudfoot, A.E., Alouani, S., Wells, T.N., Mariani, G., Rabin, R.L., Farber, J.M., Noonan, D.M. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  33. Differential expression of chemokine receptors on peripheral blood, synovial fluid, and synovial tissue monocytes/macrophages in rheumatoid arthritis. Katschke, K.J., Rottman, J.B., Ruth, J.H., Qin, S., Wu, L., LaRosa, G., Ponath, P., Park, C.C., Pope, R.M., Koch, A.E. Arthritis Rheum. (2001) [Pubmed]
  34. CCR2 expressing CD4+ T lymphocytes are preferentially recruited to the ileum in Crohn's disease. Connor, S.J., Paraskevopoulos, N., Newman, R., Cuan, N., Hampartzoumian, T., Lloyd, A.R., Grimm, M.C. Gut (2004) [Pubmed]
  35. Expression of IL-8 during reperfusion of renal allografts is dependent on ischemic time. Araki, M., Fahmy, N., Zhou, L., Kumon, H., Krishnamurthi, V., Goldfarb, D., Modlin, C., Flechner, S., Novick, A.C., Fairchild, R.L. Transplantation (2006) [Pubmed]
  36. CCR2A and CCR2B, the two isoforms of the monocyte chemoattractant protein-1 receptor are up-regulated and expressed by different cell subsets in idiopathic inflammatory myopathies. Bartoli, C., Civatte, M., Pellissier, J.F., Figarella-Branger, D. Acta Neuropathol. (2001) [Pubmed]
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