Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Chemokine Receptor CCR1

  • Richard Horuk
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_406

Synonyms

 CCR-1;  CD191;  CC-CKR-1;  CKR1;  CMKBR1;  HM145;  MIP1aR

Definition

Chemokines represent a large group of chemotactic proteins, with more than 50 members that regulate the trafficking and activation of immune cells. They mediate their activity by binding to cell surface chemokine receptors that belong to the G-protein coupled receptor (GPCR) superfamily. CCR1 is a chemokine receptor that responds to a large number of CC chemokines including CCL3 (MIP-1alpha), CCL5 (RANTES), CCL7 (MCP-3), CCL9 (MIP-1gamma), CCL15 (MIP1 delta), CCL23 (MIP-3), and with low affinity to CCL4 (MIP-1 beta) and CCL8 (MCP-2).

Structure and Functions

Human CCR1 is a serpentine protein comprising of 355 amino acids with three potential glycosylation sites and the characteristic seven membrane spanning architecture typical of GPCR’s (Fig. 1). The receptor has a consensus site for tyrosine sulfation, which affects the affinity and binding of some chemokine receptors to their ligand(s) and has been...
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References

  1. Carson KG, Jaffee BD, Harriman GB. CCR1 antagonists. Annu Rep Med Chem. 2004;39:149–58.Google Scholar
  2. Cavallaro CL, Briceno S, Chen J, Cvijic ME, Davies P, Hynes J, Liu R-Q, Mandlekar S, Rose AV, Tebben AJ, Van Kirk K, Watson A, Wu H, Yang G, Carter PH. Discovery and lead optimization of a novel series of CC chemokine receptor 1 (CCR1)-selective piperidine antagonists via parallel synthesis. J Med Chem. 2012;55:9643–53.PubMedCrossRefGoogle Scholar
  3. Dairaghi DJ, Zhang P, Wang Y, Seitz LC, Johnson DA, Miao S, Ertl LS, Zeng Y, Powers JP, Pennell AM, Bekker P, Schall TJ, Jaen JC. Pharmacokinetic and pharmacodynamic evaluation of the novel CCR1 antagonist CCX354 in healthy human subjects: implications for selection of clinical dose. Clin Pharmacol Ther. 2011;89:726–34.PubMedCrossRefGoogle Scholar
  4. Domachowske JB, Bonville CA, Gao JL, Murphy PM, Easton AJ, Rosenberg HF. The chemokine macrophage-inflammatory protein-1 alpha and its receptor CCR1 control pulmonary inflammation and antiviral host defense in paramyxovirus infection. J Immunol. 2000;165:2677–82.PubMedCrossRefGoogle Scholar
  5. Futamatsu H, Suzuki J, Koga N, Adachi S, Kosuge H, Maejima Y, Haga T, Hirao K, Horuk R, Isobe M. A CCR1 antagonist prevents the development of experimental autoimmune myocarditis in association with T cell inactivation. J Mol Cell Cardiol. 2006;40:853–61.PubMedCrossRefGoogle Scholar
  6. Gao JL, Kuhns DB, Tiffany HL, McDermott D, Li X, Francke U, Murphy PM. Structure and functional expression of the human macrophage inflammatory protein 1 alpha/RANTES receptor. J Exp Med. 1993;177:1421–7.PubMedCrossRefGoogle Scholar
  7. Gao JL, Wynn TA, Chang Y, Lee EJ, Broxmeyer HE, Cooper S, Tiffany HL, Westphal H, Kwon-Chung J, Murphy PM. Impaired host defense, hematopoiesis, granulomatous inflammation and type 1-type 2 cytokine balance in mice lacking CC chemokine receptor 1. J Exp Med. 1997;185:1959–68.PubMedPubMedCentralCrossRefGoogle Scholar
  8. Gardner DS, Santella 3rd JB, Duncia JV, Carter PH, Dhar TG, Wu H, Guo W, Cavallaro C, Van Kirk K, Yarde M, Briceno SW, Grafstrom RR, Liu R, Patel SR, Tebben AJ, Camac D, Khan J, Watson A, Yang G, Rose A, Foster WR, Cvijic ME, Davies P, Hynes Jr J. The discovery of BMS-457, a potent and selective CCR1 antagonist. Bioorg Med Chem Lett. 2013;23:3833–40.PubMedCrossRefGoogle Scholar
  9. Gerard C, Frossard JL, Bhatia M, Saluja A, Gerard NP, Lu B, Steer M. Targeted disruption of the beta-chemokine receptor CCR1 protects against pancreatitis-associated lung injury. J Clin Invest. 1997;100:2022–7.PubMedPubMedCentralCrossRefGoogle Scholar
  10. Gladue RP, Brown MF, Zwillich SH. CCR1 antagonists: what have we learned from clinical trials. Curr Top Med Chem. 2010;10:1268–77.PubMedCrossRefGoogle Scholar
  11. Gladue RP, Cole SH, Roach ML, Tylaska LA, Nelson RT, Shepard RM, McNeish JD, Ogborne KT, Neote KS. The human specific CCR1 antagonist CP-481,715 inhibits cell infiltration and inflammatory responses in human CCR1 transgenic mice. J Immunol. 2006;176:3141–8.PubMedCrossRefGoogle Scholar
  12. Hickey MJ, Held KS, Baum E, Gao JL, Murphy PM, Lane TE. CCR1 deficiency increases susceptibility to fatal coronavirus infection of the central nervous system. Viral Immunol. 2007;20:599–608.PubMedCrossRefGoogle Scholar
  13. Horuk R. Chemokine receptor antagonists: overcoming developmental hurdles. Nat Rev Drug Discov. 2009;8:23–33.PubMedCrossRefGoogle Scholar
  14. Karpus WJ, Lukacs NW, McRae BL, Strieter RM, Kunkel SL, Miller SD. An important role for the chemokine macrophage inflammatory protein-1 alpha in the pathogenesis of the T cell-mediated autoimmune disease, experimental autoimmune encephalomyelitis. J Immunol. 1995;155:5003–10.PubMedPubMedCentralGoogle Scholar
  15. Kerstjens HA, Bjermer L, Eriksson L, Dahlstrom K, Vestbo J. Tolerability and efficacy of inhaled AZD4818, a CCR1 antagonist, in moderate to severe COPD patients. Respir Med. 2010;104:1297–303.PubMedCrossRefGoogle Scholar
  16. Khan IA, Murphy PM, Casciotti L, Schwartzman JD, Collins J, Gao JL, Yeaman GR. Mice lacking the chemokine receptor CCR1 show increased susceptibility to Toxoplasma gondii infection. J Immunol. 2001;166:1930–7.PubMedCrossRefGoogle Scholar
  17. Kim IS, Jang SW, Sung HJ, Lee JS, Ko J. Differential CCR1-mediated chemotaxis signaling induced by human CC chemokine HCC-4/CCL16 in HOS cells. FEBS Lett. 2005;579:6044–8.PubMedCrossRefGoogle Scholar
  18. Kivitz A, Maciag P, Gulati P, Du S, Connolly SE, Davies P, Li X, Repsher T, Haggerty HG, Londei M. Lack of efficacy of CCR1 antagonist BMS-817399 in patients with moderate to severe rheumatoid arthritis: results of 12-week proof-of-concept study. Ann Rheum Dis. 2014;73(Suppl 2):215.CrossRefGoogle Scholar
  19. Ko J, Yun CY, Lee JS, Kim JH, Kim IS. p38 MAPK and ERK activation by 9-cis-retinoic acid induces chemokine receptors CCR1 and CCR2 expression in human monocytic THP-1 cells. Exp Mol Med. 2007;39:129–38.PubMedCrossRefGoogle Scholar
  20. Liehn EA, Merx MW, Postea O, Becher S, Djalali-Talab Y, Shagdarsuren E, Kelm M, Zernecke A, Weber C. CCR1 deficiency reduces inflammatory remodelling and preserves left ventricular function after myocardial infarction. J Cell Mol Med. 2008;12:496–506.PubMedCrossRefGoogle Scholar
  21. Liu J, Louie S, Hsu W, Yu KM, Nicholas Jr HB, Rosenquist GL. Tyrosine sulfation is prevalent in human chemokine receptors important in lung disease. Am J Respir Cell Mol Biol. 2008;38:738–43.PubMedPubMedCentralCrossRefGoogle Scholar
  22. Merritt JR, Gilchrist A. CCR1. Royal Soc Chem. 2012;26Google Scholar
  23. Murphy PM, Baggiolini M, Charo IF, Hebert CA, Horuk R, Matsushima K, Miller LH, Oppenheim JJ, Power CA. International union of pharmacology. XXII. Nomenclature for chemokine receptors. Pharmacol Rev. 2000;52:145–76.PubMedPubMedCentralGoogle Scholar
  24. Nardelli B, Tiffany HL, Bong GW, Yourey PA, Morahan DK, Li Y, Murphy PM, Alderson RF. Characterization of the signal transduction pathway activated in human monocytes and dendritic cells by MPIF-1, a specific ligand for CC chemokine receptor 1. J Immunol. 1999;162:435–44.PubMedPubMedCentralGoogle Scholar
  25. Neote K, DiGregorio D, Mak JY, Horuk R, Schall TJ. Molecular cloning, functional expression, and signaling characteristics of a C-C chemokine receptor. Cell. 1993;72:415–25.PubMedCrossRefGoogle Scholar
  26. Pease J, Horuk R. Chemokine receptor antagonists. J Med Chem. 2012;55:9363–92.PubMedCrossRefGoogle Scholar
  27. Pease JE, Horuk R. Chemokine receptor antagonists:Part 1. Exp Op Therap Pat. 2009;19:39–58.CrossRefGoogle Scholar
  28. Proof-of-Concept Study With BMS-817399 to Treat Moderate to Severe Rheumatoid Arthritis (RA). (2011). from http://clinicaltrials.gov/show/NCT01404585
  29. Richardson RM, Pridgen BC, Haribabu B, Snyderman R. Regulation of the human chemokine receptor CCR1. Cross-regulation by cxcr1 and cxcr2. J Biol Chem. 2000;275:9201–8.PubMedCrossRefGoogle Scholar
  30. Rottman JB, Slavin AJ, Silva R, Weiner HL, Gerard CG, Hancock WW. Leukocyte recruitment during onset of experimental allergic encephalomyelitis is CCR1 dependent. Eur J Immunol. 2000;30:2372–7.PubMedCrossRefGoogle Scholar
  31. Santella 3rd JB, Gardner DS, Duncia JV, Wu H, Dhar M, Cavallaro C, Tebben AJ, Carter PH, Barrish JC, Yarde M, Briceno SW, Cvijic ME, Grafstrom RR, Liu R, Patel SR, Watson AJ, Yang G, Rose AV, Vickery RD, Caceres-Cortes J, Caporuscio C, Camac DM, Khan JA, An Y, Foster WR, Davies P, Hynes Jr J. Discovery of the CCR1 antagonist, BMS-817399, for the treatment of rheumatoid arthritis. J Med Chem. 2014;57:7550–64.PubMedCrossRefGoogle Scholar
  32. Tak PP, Balanescu A, Tseluyko V, Bojin S, Drescher E, Dairaghi D, Miao S, Marchesin V, Jaen J, Bekker P, & Schall TJ. Safety and efficacy of oral chemokine receptor 1 antagonist CCX354-C in a phase 2 rheumatoid arthritis study. Paper presented at the American College of Rheumatology, Chicago. https://acr.confex.com/acr/2011/webprogram/Paper24548.html
  33. Tian Y, New DC, Yung LY, Allen RA, Slocombe PM, Twomey BM, Lee MM, Wong YH. Differential chemokine activation of CC chemokine receptor 1-regulated pathways: ligand selective activation of Galpha 14-coupled pathways. Eur J Immunol. 2004;34:785–95.PubMedCrossRefGoogle Scholar
  34. Trebst C, Sorensen TL, Kivisakk P, Cathcart MK, Hesselgesser J, Horuk R, Sellebjerg F, Lassmann H, Ransohoff RM. CCR1+/CCR5+ mononuclear phagocytes accumulate in the central nervous system of patients with multiple sclerosis. Am J Pathol. 2001;159:1701–10.PubMedPubMedCentralCrossRefGoogle Scholar
  35. Vergunst CE, Gerlag DM, von Moltke L, Karol M, Wyant T, Chi X, Matzkin E, Leach T, Tak PP. MLN3897 plus methotrexate in patients with rheumatoid arthritis: safety, efficacy, pharmacokinetics, and pharmacodynamics of an oral CCR1 antagonist in a phase IIa, double-blind, placebo-controlled, randomized, proof-of-concept study. Arthritis Rheum. 2009;60:3572–81.PubMedCrossRefGoogle Scholar
  36. Vroon A, Heijnen CJ, Lombardi MS, Cobelens PM, Mayor Jr F, Caron MG, Kavelaars A. Reduced GRK2 level in T cells potentiates chemotaxis and signaling in response to CCL4. J Leukoc Biol. 2004;75:901–9.PubMedPubMedCentralCrossRefGoogle Scholar
  37. Waldhoer M, Kledal TN, Farrell H, Schwartz TW. Murine cytomegalovirus (CMV) M33 and human CMV US28 receptors exhibit similar constitutive signaling activities. J Virol. 2002;76:8161–8.PubMedPubMedCentralCrossRefGoogle Scholar
  38. Zhang P, Dairaghi DJ, Jaen JC, Powers JP. Recent advances in the discovery and development of CCR1 antagonists. Annu Rep Med Chem. 2013;48:133–47.Google Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of PharmacologyUC DavisDavisUSA