CC chemokine receptors explained

CC chemokine receptors (or beta chemokine receptors) are integral membrane proteins that specifically bind and respond to cytokines of the CC chemokine family. They represent one subfamily of chemokine receptors, a large family of G protein-linked receptors that are known as seven transmembrane (7-TM) proteins since they span the cell membrane seven times. To date, ten true members of the CC chemokine receptor subfamily have been described. These are named CCR1 to CCR10 according to the IUIS/WHO Subcommittee on Chemokine Nomenclature.

Mechanism

The CC chemokine receptors all work by activating the G protein Gi.[1]

Types

Overview table

Receptor Ligands
CCR1CCL4, CCL5, CCL6, CCL14, CCL15, CCL16, CCL23
CCR2CCL2, CCL8, CCL16
CCR3CCL11, CCL26, CCL7, CCL13, CCL15, CCL24, CCL5, CCL28, CCL18
CCR4CCL3, CCL5, CCL17, CCL22
CCR5CCL3, CCL4, CCL5, CCL8, CCL11, CCL13, CCL14, CCL16
CCR6CCL20
CCR7CCL19, CCL21
CCR8CCL1, CCL16
CCR9CCL25
CCR10CCL27, CCL28
CCR11CCL19, CCL21, CCL25

CCR1

CCR1 was the first CC chemokine receptor identified and binds multiple inflammatory/inducible (see inducible gene) CC chemokines (including CCL4, CCL5, CCL6, CCL14, CCL15, CCL16 and CCL23).[2] [3] [4] In humans, this receptor can be found on peripheral blood lymphocytes and monocytes. There is some suggestion that this chemokine receptor is restricted to memory T-cells within the lymphocyte pool. This receptor is also designated cluster of differentiation marker CD191.

CCR2

CCR2 can interact with CCL2, CCL8 and CCL16 and has been identified on the surface of monocytes, activated memory T cells, B cells, and basophils in humans, and also in peritoneal macrophages in mice.[4] [5] CCR2 is also designated CD192.

CCR3

CCR3 is a receptor for multiple inflammatory/inducible CC chemokines, including CCL11, CCL26, CCL7, CCL13, CCL15, CCL24 and CCL5 that attract eosinophils, and CCL28 that attracts B and T lymphocytes to mucosal tissues.[3] [6] [7] [8] [9] It is most highly expressed in both eosinophils and basophils, but can also be found in Th1 and Th2 cells and airway epithelial cells. Thus CCR3 plays a role in allergic reactions. CCR3 is also known as CD193.

CCR4

CCR4 is expressed on Th2 T lymphocytes and is up-regulated by T cell receptor activation. However, some reports suggest a role for this receptor also in trafficking of dendritic cells. The CC chemokines CCL3, CCL5, CCL17 and CCL22 signal through this receptor.[10] [11]

CCR5

CCR5 is expressed on several cell types including peripheral blood-derived dendritic cells, CD34+ hematopoietic progenitor cells and certain activated/memory Th1 lymphocytes. This receptor is well defined as a major coreceptor implicated in susceptibility to HIV-1 infection and disease. This receptor has several CC chemokine ligands including CCL2, CCL3, CCL4, CCL5, CCL11, CCL13, CCL14 and CCL16.[4] [5] [12] [13]

CCR6

CCR6, a receptor for CCL20, is expressed on unactivated memory T-cells and some dendritic cells. CCR6 is also expressed on Th17 cells.[14] CCR6 is down-regulated in activated T-cells.[15]

CCR7

CCR7 is a highly important receptor with a role in trafficking of B and T lymphocytes and dendritic cells to and across high endothelial venules and positioning those cells correctly in T cell zones of secondary lymphoid organs. Its ligands include the related chemokines CCL19 and CCL21, (previously called ELC and SLC).[16]

CCR8

CCR8 is associated with Th2 lymphocytes and is therefore found predominantly in the thymus (in humans) although some expression can be found in the brain, spleen, lymph node, and monocytes at the nucleotide level. The ligands for this receptor are CCL1 and CCL16[17]

CCR9

CCR9 was previously called orphan receptor GPR 9-6 and is very highly expressed in thymus (on both immature and mature T-cells) while low in lymph nodes and spleen. CCR9 is also abundant in the gut, with its expression associated with T cells of the intestine. The specific ligand of this receptor is CCL25[18] To note, the chemokine binding protein D6 had previously been named CCR9, but this molecule is a scavenger receptor not a true (signaling) chemokine receptor.

CCR10

CCR10 is receptor for CCL27 and CCL28 that was originally called orphan receptor GPR2.[8] [19] [20] [21] CCR10 has been implicated in inflammation of the skin, and has been shown to recruit regulatory T cells (Tregs) to mucosal layers.

CCR11

This molecule was originally designated CCR11 due to its ability to bind several CC chemokines (including CCL19, CCL21 and CCL25) and its structural similarity to chemokine receptors. However, due to the inability of this molecule (also known as CCRL1 and CCX CKR) to generate a signal following ligand interaction, it has been suggested that it is a scavenger receptor for chemokines and not a bona fide chemokine receptor. Thus CCRL1 should not be called CCR11 under the guidelines of the IUIS/WHO Subcommittee on Chemokine Nomenclature.

External links

Notes and References

  1. http://senselab.med.yale.edu/NeuronDB/receptors2.aspx#Chemokine%20receptors,CC senselab
  2. Ma B, Zhu Z, Homer RJ, Gerard C, Strieter R, Elias JA . The C10/CCL6 chemokine and CCR1 play critical roles in the pathogenesis of IL-13-induced inflammation and remodeling . Journal of Immunology . 172 . 3 . 1872–81 . February 2004 . 14734772 . 10.4049/jimmunol.172.3.1872 . free .
  3. Youn BS, Zhang SM, Lee EK, Park DH, Broxmeyer HE, Murphy PM, Locati M, Pease JE, Kim KK, Antol K, Kwon BS . 6 . Molecular cloning of leukotactin-1: a novel human beta-chemokine, a chemoattractant for neutrophils, monocytes, and lymphocytes, and a potent agonist at CC chemokine receptors 1 and 3 . Journal of Immunology . 159 . 11 . 5201–5 . December 1997 . 10.4049/jimmunol.159.11.5201 . 9548457 . 20622216 .
  4. Nomiyama H, Hieshima K, Nakayama T, Sakaguchi T, Fujisawa R, Tanase S, Nishiura H, Matsuno K, Takamori H, Tabira Y, Yamamoto T, Miura R, Yoshie O . 6 . Human CC chemokine liver-expressed chemokine/CCL16 is a functional ligand for CCR1, CCR2 and CCR5, and constitutively expressed by hepatocytes . International Immunology . 13 . 8 . 1021–9 . August 2001 . 11470772 . 10.1093/intimm/13.8.1021 . free .
  5. Ogilvie P, Bardi G, Clark-Lewis I, Baggiolini M, Uguccioni M . Eotaxin is a natural antagonist for CCR2 and an agonist for CCR5 . Blood . 97 . 7 . 1920–4 . April 2001 . 11264152 . 10.1182/blood.v97.7.1920 .
  6. Kitaura M, Suzuki N, Imai T, Takagi S, Suzuki R, Nakajima T, Hirai K, Nomiyama H, Yoshie O . 6 . Molecular cloning of a novel human CC chemokine (Eotaxin-3) that is a functional ligand of CC chemokine receptor 3 . The Journal of Biological Chemistry . 274 . 39 . 27975–80 . September 1999 . 10488147 . 10.1074/jbc.274.39.27975 . free .
  7. Kitaura M, Nakajima T, Imai T, Harada S, Combadiere C, Tiffany HL, Murphy PM, Yoshie O . 6 . Molecular cloning of human eotaxin, an eosinophil-selective CC chemokine, and identification of a specific eosinophil eotaxin receptor, CC chemokine receptor 3 . The Journal of Biological Chemistry . 271 . 13 . 7725–30 . March 1996 . 8631813 . 10.1074/jbc.271.13.7725 . free .
  8. Pan J, Kunkel EJ, Gosslar U, Lazarus N, Langdon P, Broadwell K, Vierra MA, Genovese MC, Butcher EC, Soler D . 6 . A novel chemokine ligand for CCR10 and CCR3 expressed by epithelial cells in mucosal tissues . Journal of Immunology . 165 . 6 . 2943–9 . September 2000 . 10975800 . 10.4049/jimmunol.165.6.2943 . free .
  9. White JR, Imburgia C, Dul E, Appelbaum E, O'Donnell K, O'Shannessy DJ, Brawner M, Fornwald J, Adamou J, Elshourbagy NA, Kaiser K, Foley JJ, Schmidt DB, Johanson K, Macphee C, Moores K, McNulty D, Scott GF, Schleimer RP, Sarau HM . 6 . Cloning and functional characterization of a novel human CC chemokine that binds to the CCR3 receptor and activates human eosinophils . Journal of Leukocyte Biology . 62 . 5 . 667–75 . November 1997 . 9365122 . 10.1002/jlb.62.5.667 . 12197497 .
  10. Imai T, Baba M, Nishimura M, Kakizaki M, Takagi S, Yoshie O . The T cell-directed CC chemokine TARC is a highly specific biological ligand for CC chemokine receptor 4 . The Journal of Biological Chemistry . 272 . 23 . 15036–42 . June 1997 . 9169480 . 10.1074/jbc.272.23.15036 . free .
  11. Imai T, Chantry D, Raport CJ, Wood CL, Nishimura M, Godiska R, Yoshie O, Gray PW . 6 . Macrophage-derived chemokine is a functional ligand for the CC chemokine receptor 4 . The Journal of Biological Chemistry . 273 . 3 . 1764–8 . January 1998 . 9430724 . 10.1074/jbc.273.3.1764 . free .
  12. Gong W, Howard OM, Turpin JA, Grimm MC, Ueda H, Gray PW, Raport CJ, Oppenheim JJ, Wang JM . 6 . Monocyte chemotactic protein-2 activates CCR5 and blocks CD4/CCR5-mediated HIV-1 entry/replication . The Journal of Biological Chemistry . 273 . 8 . 4289–92 . February 1998 . 9468473 . 10.1074/jbc.273.8.4289 . free .
  13. Blanpain C, Migeotte I, Lee B, Vakili J, Doranz BJ, Govaerts C, Vassart G, Doms RW, Parmentier M . 6 . CCR5 binds multiple CC-chemokines: MCP-3 acts as a natural antagonist . Blood . 94 . 6 . 1899–905 . September 1999 . 10477718 . 10.1182/blood.V94.6.1899.
  14. Acosta-Rodriguez EV, Rivino L, Geginat J, Jarrossay D, Gattorno M, Lanzavecchia A, Sallusto F, Napolitani G . 6 . Surface phenotype and antigenic specificity of human interleukin 17-producing T helper memory cells . Nature Immunology . 8 . 6 . 639–46 . June 2007 . 17486092 . 10.1038/ni1467 . 21824460 .
  15. Baba M, Imai T, Nishimura M, Kakizaki M, Takagi S, Hieshima K, Nomiyama H, Yoshie O . 6 . Identification of CCR6, the specific receptor for a novel lymphocyte-directed CC chemokine LARC . The Journal of Biological Chemistry . 272 . 23 . 14893–8 . June 1997 . 9169459 . 10.1074/jbc.272.23.14893 . free .
  16. Yoshida R, Imai T, Hieshima K, Kusuda J, Baba M, Kitaura M, Nishimura M, Kakizaki M, Nomiyama H, Yoshie O . 6 . Molecular cloning of a novel human CC chemokine EBI1-ligand chemokine that is a specific functional ligand for EBI1, CCR7 . The Journal of Biological Chemistry . 272 . 21 . 13803–9 . May 1997 . 9153236 . 10.1074/jbc.272.21.13803 . free .
  17. Roos RS, Loetscher M, Legler DF, Clark-Lewis I, Baggiolini M, Moser B . Identification of CCR8, the receptor for the human CC chemokine I-309 . The Journal of Biological Chemistry . 272 . 28 . 17251–4 . July 1997 . 9211859 . 10.1074/jbc.272.28.17251 . free .
  18. Zaballos A, Gutiérrez J, Varona R, Ardavín C, Márquez G . Cutting edge: identification of the orphan chemokine receptor GPR-9-6 as CCR9, the receptor for the chemokine TECK . Journal of Immunology . 162 . 10 . 5671–5 . May 1999 . 10.4049/jimmunol.162.10.5671 . 10229797 . 21522407 . free .
  19. Gosling J, Dairaghi DJ, Wang Y, Hanley M, Talbot D, Miao Z, Schall TJ . Cutting edge: identification of a novel chemokine receptor that binds dendritic cell- and T cell-active chemokines including ELC, SLC, and TECK . Journal of Immunology . 164 . 6 . 2851–6 . March 2000 . 10706668 . 10.4049/jimmunol.164.6.2851 . free .
  20. Homey B, Wang W, Soto H, Buchanan ME, Wiesenborn A, Catron D, Müller A, McClanahan TK, Dieu-Nosjean MC, Orozco R, Ruzicka T, Lehmann P, Oldham E, Zlotnik A . 6 . Cutting edge: the orphan chemokine receptor G protein-coupled receptor-2 (GPR-2, CCR10) binds the skin-associated chemokine CCL27 (CTACK/ALP/ILC) . Journal of Immunology . 164 . 7 . 3465–70 . April 2000 . 10725697 . 10.4049/jimmunol.164.7.3465 . free .
  21. Wang W, Soto H, Oldham ER, Buchanan ME, Homey B, Catron D, Jenkins N, Copeland NG, Gilbert DJ, Nguyen N, Abrams J, Kershenovich D, Smith K, McClanahan T, Vicari AP, Zlotnik A . 6 . Identification of a novel chemokine (CCL28), which binds CCR10 (GPR2) . The Journal of Biological Chemistry . 275 . 29 . 22313–23 . July 2000 . 10781587 . 10.1074/jbc.M001461200 . free .

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