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Gene Review

Ccr2  -  chemokine (C-C motif) receptor 2

Mus musculus

Synonyms: C-C CKR-2, C-C chemokine receptor type 2, CC-CKR-2, CCR-2, CCR2, ...
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Disease relevance of Ccr2


High impact information on Ccr2

  • Pax5-repressed genes are also reexpressed in plasma cells, which depend for normal function on Cd28 and Ccr2 reactivation [7].
  • Infection with the intracellular bacterial pathogen Listeria monocytogenes induces CCR2-dependent monocyte recruitment and activation, an essential response for host survival [8].
  • CD8 and CD4 T cell responses to L. monocytogenes antigens are preserved in CCR2-deficient mice, indicating that Tip-DCs are not essential for T cell priming [9].
  • We have identified a TNF/iNOS-producing (Tip)-DC subset in spleens of Listeria monocytogenes-infected mice that is absent from CCR2-deficient mice [9].
  • Ccr2(-/-) mice had fewer circulating Ly6C(hi) monocytes and, after infection with Listeria monocytogenes, accumulated activated monocytes in bone marrow [10].

Psychiatry related information on Ccr2

  • Alzheimer disease mice deficient in Ccr2 accumulated Abeta earlier and died prematurely, in a manner that correlated with Ccr2 gene dosage, indicating that absence of early microglial accumulation leads to decreased Abeta clearance and increased mortality [11].

Chemical compound and disease context of Ccr2


Biological context of Ccr2


Anatomical context of Ccr2

  • Wild-type choroidal macrophages degrade C5 and IgG in eye sections of Ccl2(-/-) or Ccr2(-/-) mice [4].
  • Ccr2 regulates the level of MCP-1/CCL2 in vitro and at inflammatory sites and controls T cell activation in response to alloantigen [18].
  • Additionally, T cells from CCR2(-/)- immunized mice showed decreased antigen-induced proliferation and production of IFN-gamma compared with wild-type immunized controls, suggesting that CCR2 enhances the T helper cell type 1 immune response in EAE [19].
  • The C-C motif chemokine receptor-2 (CCR2) regulates monocyte and macrophage recruitment and is necessary for macrophage-dependent inflammatory responses and the development of atherosclerosis [1].
  • Mice generated by gene targeting to lack CCR2 exhibit normal leukocyte rolling but have a pronounced defect in MCP-1-induced leukocyte firm adhesion to microvascular endothelium and reduced leukocyte extravasation [5].

Associations of Ccr2 with chemical compounds

  • Ethanol treatment (2.5 g/kg, i.p.) induced stronger conditioned taste aversion in Ccr2, Ccl2 or Ccl3 null mutant mice than in controls [20].
  • The CCR7 and CCR2 chemokine ligands are required for both T cell sequestration in LN and thymic T cell egress following FTY720 administration [21].
  • Wild-type mice treated with MC21 to block CCR2 function or with anti-Gr-1 to deplete neutrophils did not exhibit the vascular leakage that typically accompanies inflammation triggered by CCL2 and LPS in wild-type mice [22].
  • At days 14 and 21, lung remodelling and the hydroxyproline content of lung tissues were significantly reduced in CCR2-/- mice [13].
  • RESULTS: Estrogen and tamoxifen significantly decreased expression of CCR2 and, to a lesser extent, CXCR3 on murine monocytes [23].

Physical interactions of Ccr2

  • Evidence that MCP-1 levels are regulated by receptor binding and internalization was suggested by its rapid decline when added to WT macrophages at 37 degrees C but not 4 degrees C. These studies indicate that CCR2 plays an important role in regulating T cell responses and controlling the level of MCP-1 at inflammatory sites [18].
  • Lastly, CCL2-induced mØ transendothelial migration was blocked by treatment of WT BMEC with pertussis toxin, suggesting that CCR2 is functionally coupled to the inhibitory G protein Galphai, much as it is in other cell types [24].

Regulatory relationships of Ccr2


Other interactions of Ccr2

  • Supplementation of CCR2-/- mice with IFN-gamma normalized early thrombus resolution without increasing monocyte influx [28].
  • Already after 5 min of reperfusion, this increase was reduced significantly in Ccr1-/- and Ccr5-/- mice, whereas only in Ccr2-/- mice, was adherence attenuated significantly at 120 min after onset of reperfusion [2].
  • Early fibrinolysis was not impaired in CCR2-/- mice, but a significant reduction in both matrix metalloproteinase (MMP)-2 and MMP-9 activity was observed [28].
  • Differential role of CCR2 in islet and heart allograft rejection: tissue specificity of chemokine/chemokine receptor function in vivo [29].
  • CCR2 is required for monocyte recruitment in many inflammatory processes, as well as conferring Th1 lymphokine responses [28].

Analytical, diagnostic and therapeutic context of Ccr2

  • Mice deficient for the major MCP-1 receptor, CC chemokine receptor (CCR)2, did not develop EAE after active immunization but generated effector cells that could transfer the disease to naive wild-type recipients [30].
  • Furthermore, in contrast to the islet transplants, CCR2 deficiency offered only marginal prolongation of heart allograft survival [29].
  • In addition, CCR2-/- recipients had a reduced Th1 and increased Th2 alloresponse in the periphery (by ELISPOT analysis) as well as in the grafts (by RT-PCR) [29].
  • Three weeks after femoral artery ligation, LDI perfusion ratio of operated versus nonoperated distal hindlimb in BALB/c wild-type mice increased to 0.45+/-0.06 and in CCR2(-/-) animals only to 0.21+/-0.03 (P<0.01) [31].
  • A critical role for CCR2/MCP-1 interactions in the development of idiopathic pneumonia syndrome after allogeneic bone marrow transplantation [32].


  1. CCR2 modulates inflammatory and metabolic effects of high-fat feeding. Weisberg, S.P., Hunter, D., Huber, R., Lemieux, J., Slaymaker, S., Vaddi, K., Charo, I., Leibel, R.L., Ferrante, A.W. J. Clin. Invest. (2006) [Pubmed]
  2. Chemokine receptors Ccr1, Ccr2, and Ccr5 mediate neutrophil migration to postischemic tissue. Reichel, C.A., Khandoga, A., Anders, H.J., Schlöndorff, D., Luckow, B., Krombach, F. J. Leukoc. Biol. (2006) [Pubmed]
  3. CC chemokine receptor (CCR)-2 prevents arthritis development following infection by Mycobacterium avium. Quinones, M.P., Jimenez, F., Martinez, H., Estrada, C.A., Willmon, O., Dudley, M., Kuziel, W.A., Melby, P.C., Reddick, R.L., Ahuja, S.K., Ahuja, S.S. J. Mol. Med. (2006) [Pubmed]
  4. An animal model of age-related macular degeneration in senescent Ccl-2- or Ccr-2-deficient mice. Ambati, J., Anand, A., Fernandez, S., Sakurai, E., Lynn, B.C., Kuziel, W.A., Rollins, B.J., Ambati, B.K. Nat. Med. (2003) [Pubmed]
  5. Severe reduction in leukocyte adhesion and monocyte extravasation in mice deficient in CC chemokine receptor 2. Kuziel, W.A., Morgan, S.J., Dawson, T.C., Griffin, S., Smithies, O., Ley, K., Maeda, N. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  6. Lung-specific overexpression of CC chemokine ligand (CCL) 2 enhances the host defense to Streptococcus pneumoniae infection in mice: role of the CCL2-CCR2 axis. Winter, C., Taut, K., Srivastava, M., Länger, F., Mack, M., Briles, D.E., Paton, J.C., Maus, R., Welte, T., Gunn, M.D., Maus, U.A. J. Immunol. (2007) [Pubmed]
  7. Gene repression by Pax5 in B cells is essential for blood cell homeostasis and is reversed in plasma cells. Delogu, A., Schebesta, A., Sun, Q., Aschenbrenner, K., Perlot, T., Busslinger, M. Immunity (2006) [Pubmed]
  8. Sequential MyD88-independent and -dependent activation of innate immune responses to intracellular bacterial infection. Serbina, N.V., Kuziel, W., Flavell, R., Akira, S., Rollins, B., Pamer, E.G. Immunity (2003) [Pubmed]
  9. TNF/iNOS-producing dendritic cells mediate innate immune defense against bacterial infection. Serbina, N.V., Salazar-Mather, T.P., Biron, C.A., Kuziel, W.A., Pamer, E.G. Immunity (2003) [Pubmed]
  10. Monocyte emigration from bone marrow during bacterial infection requires signals mediated by chemokine receptor CCR2. Serbina, N.V., Pamer, E.G. Nat. Immunol. (2006) [Pubmed]
  11. Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease. El Khoury, J., Toft, M., Hickman, S.E., Means, T.K., Terada, K., Geula, C., Luster, A.D. Nat. Med. (2007) [Pubmed]
  12. Blockade of CCR2 ameliorates progressive fibrosis in kidney. Kitagawa, K., Wada, T., Furuichi, K., Hashimoto, H., Ishiwata, Y., Asano, M., Takeya, M., Kuziel, W.A., Matsushima, K., Mukaida, N., Yokoyama, H. Am. J. Pathol. (2004) [Pubmed]
  13. C-C chemokine receptor 2 (CCR2) deficiency improves bleomycin-induced pulmonary fibrosis by attenuation of both macrophage infiltration and production of macrophage-derived matrix metalloproteinases. Okuma, T., Terasaki, Y., Kaikita, K., Kobayashi, H., Kuziel, W.A., Kawasuji, M., Takeya, M. J. Pathol. (2004) [Pubmed]
  14. Monocyte chemoattractant protein-1 mediates cockroach allergen-induced bronchial hyperreactivity in normal but not CCR2-/- mice: the role of mast cells. Campbell, E.M., Charo, I.F., Kunkel, S.L., Strieter, R.M., Boring, L., Gosling, J., Lukacs, N.W. J. Immunol. (1999) [Pubmed]
  15. 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]
  16. Bone marrow-derived monocyte chemoattractant protein-1 receptor CCR2 is critical in angiotensin II-induced acceleration of atherosclerosis and aneurysm formation in hypercholesterolemic mice. Ishibashi, M., Egashira, K., Zhao, Q., Hiasa, K., Ohtani, K., Ihara, Y., Charo, I.F., Kura, S., Tsuzuki, T., Takeshita, A., Sunagawa, K. Arterioscler. Thromb. Vasc. Biol. (2004) [Pubmed]
  17. Molecular cloning and functional expression of murine JE (monocyte chemoattractant protein 1) and murine macrophage inflammatory protein 1alpha receptors: evidence for two closely linked C-C chemokine receptors on chromosome 9. Boring, L., Gosling, J., Monteclaro, F.S., Lusis, A.J., Tsou, C.L., Charo, I.F. J. Biol. Chem. (1996) [Pubmed]
  18. Ccr2 regulates the level of MCP-1/CCL2 in vitro and at inflammatory sites and controls T cell activation in response to alloantigen. Tylaska, L.A., Boring, L., Weng, W., Aiello, R., Charo, I.F., Rollins, B.J., Gladue, R.P. Cytokine (2002) [Pubmed]
  19. Resistance to experimental autoimmune encephalomyelitis in mice lacking the CC chemokine receptor (CCR)2. Izikson, L., Klein, R.S., Charo, I.F., Weiner, H.L., Luster, A.D. J. Exp. Med. (2000) [Pubmed]
  20. Perturbation of chemokine networks by gene deletion alters the reinforcing actions of ethanol. Blednov, Y.A., Bergeson, S.E., Walker, D., Ferreira, V.M., Kuziel, W.A., Harris, R.A. Behav. Brain Res. (2005) [Pubmed]
  21. FTY720-enhanced T cell homing is dependent on CCR2, CCR5, CCR7, and CXCR4: evidence for distinct chemokine compartments. Yopp, A.C., Fu, S., Honig, S.M., Randolph, G.J., Ding, Y., Krieger, N.R., Bromberg, J.S. J. Immunol. (2004) [Pubmed]
  22. The role of CC chemokine receptor 2 in alveolar monocyte and neutrophil immigration in intact mice. Maus, U., von Grote, K., Kuziel, W.A., Mack, M., Miller, E.J., Cihak, J., Stangassinger, M., Maus, R., Schlöndorff, D., Seeger, W., Lohmeyer, J. Am. J. Respir. Crit. Care Med. (2002) [Pubmed]
  23. Estrogen decreases expression of chemokine receptors, and suppresses chemokine bioactivity in murine monocytes. Janis, K., Hoeltke, J., Nazareth, M., Fanti, P., Poppenberg, K., Aronica, S.M. Am. J. Reprod. Immunol. (2004) [Pubmed]
  24. CCR2 expression by brain microvascular endothelial cells is critical for macrophage transendothelial migration in response to CCL2. Dzenko, K.A., Song, L., Ge, S., Kuziel, W.A., Pachter, J.S. Microvasc. Res. (2005) [Pubmed]
  25. The chemokine receptor CCR2 is involved in macrophage recruitment to the injured peripheral nervous system. Siebert, H., Sachse, A., Kuziel, W.A., Maeda, N., Brück, W. J. Neuroimmunol. (2000) [Pubmed]
  26. Targeted deletion of CC chemokine receptor 2 attenuates left ventricular remodeling after experimental myocardial infarction. Kaikita, K., Hayasaki, T., Okuma, T., Kuziel, W.A., Ogawa, H., Takeya, M. Am. J. Pathol. (2004) [Pubmed]
  27. CCR2 is required for CD8-induced graft-versus-host disease. Terwey, T.H., Kim, T.D., Kochman, A.A., Hubbard, V.M., Lu, S., Zakrzewski, J.L., Ramirez-Montagut, T., Eng, J.M., Muriglan, S.J., Heller, G., Murphy, G.F., Liu, C., Budak-Alpdogan, T., Alpdogan, O., van den Brink, M.R. Blood (2005) [Pubmed]
  28. Targeted deletion of CCR2 impairs deep vein thombosis resolution in a mouse model. Henke, P.K., Pearce, C.G., Moaveni, D.M., Moore, A.J., Lynch, E.M., Longo, C., Varma, M., Dewyer, N.A., Deatrick, K.B., Upchurch, G.R., Wakefield, T.W., Hogaboam, C., Kunkel, S.L. J. Immunol. (2006) [Pubmed]
  29. Differential role of CCR2 in islet and heart allograft rejection: tissue specificity of chemokine/chemokine receptor function in vivo. Abdi, R., Means, T.K., Ito, T., Smith, R.N., Najafian, N., Jurewicz, M., Tchipachvili, V., Charo, I., Auchincloss, H., Sayegh, M.H., Luster, A.D. J. Immunol. (2004) [Pubmed]
  30. Absence of monocyte chemoattractant protein 1 in mice leads to decreased local macrophage recruitment and antigen-specific T helper cell type 1 immune response in experimental autoimmune encephalomyelitis. Huang, D.R., Wang, J., Kivisakk, P., Rollins, B.J., Ransohoff, R.M. J. Exp. Med. (2001) [Pubmed]
  31. Collateral artery growth (arteriogenesis) after experimental arterial occlusion is impaired in mice lacking CC-chemokine receptor-2. Heil, M., Ziegelhoeffer, T., Wagner, S., Fernández, B., Helisch, A., Martin, S., Tribulova, S., Kuziel, W.A., Bachmann, G., Schaper, W. Circ. Res. (2004) [Pubmed]
  32. A critical role for CCR2/MCP-1 interactions in the development of idiopathic pneumonia syndrome after allogeneic bone marrow transplantation. Hildebrandt, G.C., Duffner, U.A., Olkiewicz, K.M., Corrion, L.A., Willmarth, N.E., Williams, D.L., Clouthier, S.G., Hogaboam, C.M., Reddy, P.R., Moore, B.B., Kuziel, W.A., Liu, C., Yanik, G., Cooke, K.R. Blood (2004) [Pubmed]
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