Treatments in Respiratory Medicine

, Volume 5, Issue 3, pp 159–166

Chemokine Receptors

Therapeutic Potential in Asthma
Leading Article

Abstract

Leukocyte infiltration of the lung is a characteristic feature of allergic asthma and it is thought that these cells are selectively recruited by chemokines. Extensive research has confirmed that chemokine receptors are expressed on the main cell types involved in asthma, including eosinophils, T helper type 2 cells, mast cells and even neutrophils. Moreover, animal experiments have outlined a functional role for these receptors and their ligands. Chemokines signal via seven-transmembrane spanning G-protein coupled receptors, which are favored targets of the pharmaceutical industry due to the possibility of designing small-molecule inhibitors. In fact, this family represents the first group of cytokines where small-molecule inhibitors have been designed. However, the search for efficient antagonists of chemokine/chemokine receptors has not been easy; a particular feature of the chemokine system is the number of molecules with overlapping functions and binding specificities, as well as the difficulty in reconciling the in vivo biologic functional validation of chemokines in rodent models with the development of antagonists which bind the human receptor, because of the lack of species cross-reactivity. The chemokines and their receptors that are active during allergic reactions are reviewed. Possible points of interaction that may be a target for development of new therapies, as well as the progress to date in developing inhibitors of key chemokine receptors for asthma therapy, are also discussed.

References

  1. 1.
    Thelen M. Dancing to the tune of chemokines. Nat Immunol 2001; 2: 129–34PubMedCrossRefGoogle Scholar
  2. 2.
    Alcami A, Koszinowski UH. Viral mechanisms of immune evasion. Mol Med Today 2000; 6: 365–72PubMedCrossRefGoogle Scholar
  3. 3.
    Ying S, Robinson DS, Meng Q, et al. C-C chemokines in allergen-induced latephase cutaneous responses in atopic subjects: association of eotaxin with early 6-hour eosinophils, and of eotaxin-2 and monocyte chemoattractant protein-4 with the later 24-hour tissue eosinophilia, and relationship to basophils and other C- C chemokines (monocyte chemoattractant protein-3 and RANTES). J Immunol 1999; 163: 3976–84PubMedGoogle Scholar
  4. 4.
    Robinson DS, Hamid Q, Ying S, et al. Predominant Th2-like bronchoalveolar T-lymphocyte population in atopic asthma. N Engl J Med 1992; 326: 298–304PubMedCrossRefGoogle Scholar
  5. 5.
    Gonzalo JA, Lloyd CM, Wen D, et al. The coordinated action of CC chemokines in the lung orchestrates allergic inflammation and airways hyperresponsiveness. J Exp Med 1998; 188: 157–67PubMedCrossRefGoogle Scholar
  6. 6.
    Coyle AJ, Lloyd C, Tian J, et al. Crucial role of the interleukin 1 receptor family member T1/ST2 in T helper cell type 2-mediated lung mucosal immune responses. J Exp Med 1999; 190: 895–902PubMedCrossRefGoogle Scholar
  7. 7.
    Brightling CE, Bradding P, Symon FA, et al. Mast-cell infiltration of airway smooth muscle in asthma. N Engl J Med 2002; 346: 1699–705PubMedCrossRefGoogle Scholar
  8. 8.
    Tillie-Leblond I, Gosset P, Tonnel AB. Inflammatory events in severe acute asthma. Allergy 2005; 60: 23–9PubMedCrossRefGoogle Scholar
  9. 9.
    Lloyd C. Chemokines in allergic lung inflammation. Immunology 2002; 105: 144–54PubMedCrossRefGoogle Scholar
  10. 10.
    D’Ambrosio D. Targeting chemoattractant receptors in allergic inflammation. Curr Drug Targets Inflamm Allergy 2005; 4: 163–7PubMedCrossRefGoogle Scholar
  11. 11.
    Palframan RT, Collins PD, Severs NJ, et al. Mechanisms of acute eosinophil mobilization from the bone marrow stimulated by interleukin 5: the role of specific adhesion molecules and phosphatidylinositol 3-kinase. J Exp Med 1998; 188: 1621–32PubMedCrossRefGoogle Scholar
  12. 12.
    Gu L, Tseng S, Horner RM, et al. Control of TH2 polarization by the chemokine monocyte chemoattractant protein-1. Nature 2000; 404: 407–11PubMedCrossRefGoogle Scholar
  13. 13.
    Jamieson T, Cook DN, Nibbs RJB, et al. The chemokine receptor D6 limits the inflammatory response in vivo. Nat Immunol 2005; 6: 403–11PubMedCrossRefGoogle Scholar
  14. 14.
    Miller AL, Bowlin TL, Lukacs NW. Respiratory syncytial virus-induced chemokine production: linking viral replication to chemokine production in vitro and in vivo. J Infect Dis 2004; 189: 1419–30PubMedCrossRefGoogle Scholar
  15. 15.
    Openshaw PJM, Tregoning JS. Immune responses and disease enhancement during respiratory syncytial virus infection. Clin Microbiol Rev 2005; 18: 541–55PubMedCrossRefGoogle Scholar
  16. 16.
    Miller AL, Strieter RM, Gruber AD, et al. CXCR2 Regulates respiratory syncytial virus-induced airway hyperreactivity and mucus overproduction. J Immunol 2003; 170: 3348–56PubMedGoogle Scholar
  17. 17.
    Lamblin C, Gosset P, Tillie-Leblond I, et al. Bronchial neutrophilia in patients with noninfectious status asthmaticus. Am J Respir Crit Care Med 1998; 157: 394–402PubMedCrossRefGoogle Scholar
  18. 18.
    Schuh JM, Blease K, Hogaboam CM. CXCR2 is necessary for the development and persistence of chronic fungal asthma in mice. J Immunol 2002; 168: 1447–56PubMedGoogle Scholar
  19. 19.
    Ponath PD, Qin S, Post TW, et al. Molecular cloning and characterization of a human eotaxin receptor expressed selectively on eosinophils. J Exp Med 1996; 183: 2437–48PubMedCrossRefGoogle Scholar
  20. 20.
    Daugherty BL, Siciliano SJ, DeMartino J, et al. Cloning, expression and characterization of the human eosinophil eotaxin receptor. J Exp Med 1996; 183: 2349–54PubMedCrossRefGoogle Scholar
  21. 21.
    Sallusto F, Lenig D, Mackay CR, et al. Flexible programs of chemokine receptor expression on human polarised T helper 1 and 2 lymphocytes. J Exp Med 1998; 187: 875–83PubMedCrossRefGoogle Scholar
  22. 22.
    Teran LM, Davies DE. The chemokines: their potential role in allergic inflammation. Clin Exp Allergy 1996; 26: 1005–19PubMedCrossRefGoogle Scholar
  23. 23.
    Sabroe I, Peck MJ, Jan Van Keulen B, et al. A small molecule antagonist of the chemokine receptors CCR1 and CCR3: potent inhibition of eosinophil function and CCR3-mediated HIV-1 entry. J Biol Chem 2000; 275: 25985–92PubMedCrossRefGoogle Scholar
  24. 24.
    De Lucca GV, Kim UT, Vargo BJ, et al. Discovery of CC chemokine receptor-3 (CCR3) antagonists with picomolar potency. J Med Chem 2005; 48: 2194–211PubMedCrossRefGoogle Scholar
  25. 25.
    Zhang L, Soares MP, Guan Y, et al. Functional expression and characterization of macaque C-C chemokine receptor 3 (CCR3) and generation of potent antagonistic anti-macaque CCR3 monoclonal antibodies. J Biol Chem 2002; 277: 33799–810PubMedCrossRefGoogle Scholar
  26. 26.
    Leckie MJ, ten Brinke A, Khan J, et al. Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyper-responsiveness, and the late asthmatic response. Lancet 2000; 356: 2144–8PubMedCrossRefGoogle Scholar
  27. 27.
    Humbles AA, Lloyd CM, McMillan SJ, et al. A critical role for eosinophils in allergic airways remodeling. Science 2004; 305: 1776–9PubMedCrossRefGoogle Scholar
  28. 28.
    Flood-Page P, Menzies-Gow A, Phipps S, et al. Anti-IL-5 treatment reduces deposition of ECM proteins in the bronchial subepithelial basement membrane of mild atopic asthmatics. J Clin Invest 2003; 112: 1029–36PubMedGoogle Scholar
  29. 29.
    Gonzalo JA, Pan Y, Lloyd CM, et al. Mouse monocyte-derived chemokine is involved in airway hyperreactivity and lung inflammation. J Immunol 1999; 163: 403–11PubMedGoogle Scholar
  30. 30.
    Kawasaki S, Takizawa H, Yoneyama H, et al. Intervention of thymus and activation-regulated chemokine attenuates the development of allergic airway inflammation and hyperresponsiveness in mice. J Immunol 2001; 166: 2055–62PubMedGoogle Scholar
  31. 31.
    Chvatchko Y, Hoogewerf AJ, Meyer A, et al. A key role for CC chemokine receptor 4 in lipopolysaccharide-induced endotoxic shock. J Exp Med 2000; 191: 1755–64PubMedCrossRefGoogle Scholar
  32. 32.
    Pilette C, Francis JN, Till SJ, et al. CCR4 ligands are up-regulated in the airways of atopic asthmatics after segmental allergen challenge. Eur Respir J 2004; 23: 876–84PubMedCrossRefGoogle Scholar
  33. 33.
    Purandare AV, Gao A, Wan H, et al. Identification of chemokine receptor CCR4 antagonist. Bioorg Med Chem Lett 2005; 15: 2669–72PubMedCrossRefGoogle Scholar
  34. 34.
    Newhouse B, Allen S, Fauber B, et al. Racemic and chiral lactams as potent, selective and functionally active CCR4 antagonists. Bioorg Med Chem Lett 2004; 14: 5537–42PubMedCrossRefGoogle Scholar
  35. 35.
    Chensue SW, Lukacs NW, Yang TY, et al. Aberrant in vivo T helper type 2 cell response and impaired eosinophil recruitment in cc chemokine receptor 8 knockout mice. J Exp Med 2001; 193: 573–84PubMedCrossRefGoogle Scholar
  36. 36.
    Goya I, Villares R, Zaballos A, et al. Absence of CCR8 does not impair the response to ovalbumin-induced allergic airway disease. J Immunol 2003; 170: 2138–46PubMedGoogle Scholar
  37. 37.
    Chung CD, Kuo F, Kumer J, et al. CCR8 is not essential for the development of inflammation in a mouse model of allergic airway disease. J Immunol 2003; 170: 581–7PubMedGoogle Scholar
  38. 38.
    Bochner BS, Hudson SA, Xiao HQ, et al. Release of both CCR4-active and CXCR3-active chemokines during human allergic pulmonary late-phase reactions. J Allergy Clin Immunol 2003; 112: 930–4PubMedCrossRefGoogle Scholar
  39. 39.
    Liu L, Jarjour NN, Busse WW, et al. Enhanced generation of helper T type 1 and 2 chemokines in allergen-induced asthma. Am J Respir Crit Care Med 2004; 169: 1118–24PubMedCrossRefGoogle Scholar
  40. 40.
    Brightling CE, Ammit AJ, Kaur D, et al. The CXCL10/CXCR3 axis mediates human lung mast cell migration to asthmatic airway smooth muscle. Am J Respir Crit Care Med 2005; 171: 1103–8PubMedCrossRefGoogle Scholar
  41. 41.
    Heise CE, Pahuja A, Hudson SC, et al. Pharmacologic characterization of CXC chemokine receptor 3 ligands and a small molecule antagonist. J Pharmacol Exp Ther 2005; 313: 1263–71PubMedCrossRefGoogle Scholar
  42. 42.
    Gonzalo JA, Lloyd CM, Peled A, et al. Critical involvement of the chemotactic axis CXCR4/stromal cell-derived factor-1 alpha in the inflammatory component of allergic airway disease. J Immunol 2000; 165: 499–508PubMedGoogle Scholar
  43. 43.
    Lukacs NW, Berlin A, Schols D, et al. AMD3100, a CxCR4 antagonist, attenuates allergic lung inflammation and airway hyperreactivity. Am J Pathol 2002; 160: 1353–60PubMedCrossRefGoogle Scholar
  44. 44.
    Proudfoot AE, Power CA, Hoogewerf AJ, et al. Extension of recombinant human RANTES by the retention of the initiating methionine produces a potent antagonist. J Biol Chem 1996; 271: 2599–603PubMedCrossRefGoogle Scholar
  45. 45.
    Chvatchko Y, Proudfoot AEI, Buser R, et al. Inhibition of airway inflammation by amino-terminally modified RANTES/CC chemokine ligand 5 analogues is not mediated through CCR3. J Immunol 2003; 171: 5498–506PubMedGoogle Scholar
  46. 46.
    Simmons G, Clapham PR, Picard L, et al. Potent inhibition of HIV-1 infectivity in macrophage and lymphocytes by a novel CCR5 antagonist. Science 1997; 276: 276–9PubMedCrossRefGoogle Scholar
  47. 47.
    Nibbs RJ, Salcedo TW, Campbell JD, et al. C-C chemokine receptor 3 antagonism by the beta-chemokine macrophage inflammatory protein 4, a property strongly enhanced by an amino-terminal alanine-methionine swap. J Immunol 2000 Feb 1; 164(3): 1488–97PubMedGoogle Scholar
  48. 48.
    Eisner J, Petering H, Hochstetter R, et al. The CC chemokine antagonist Met-RANTES inhibits eosinophil effector functions through the chemokine receptors CCR1 and CCR3. Eur J Immunol 1997; 27: 2892–8CrossRefGoogle Scholar
  49. 49.
    Eisner J, Mack M, Bruhl H, et al. Differential activation of CC chemokine receptors by AOP-RANTES. J Biol Chem 2000; 275: 7787–94CrossRefGoogle Scholar
  50. 50.
    Homey B, Zlotnik A. Chemokines in allergy. Curr Opin Immunol 1999; 11: 626–34PubMedCrossRefGoogle Scholar
  51. 51.
    Heath H, Qin S, Wu L, et al. Chemokine receptor usage by human eosinophils: the importance of CCR3 demonstrated using an antagonistic monoclonal antibody. J Clin Invest 1997; 99: 178–84PubMedCrossRefGoogle Scholar
  52. 52.
    Justice JP, Borchers MT, Crosby JR, et al. Ablation of eosinophils leads to a reduction of allergen-induced pulmonary pathology. Am J Physiol Lung Cell Mol Physiol 2003; 284: LI 69–78Google Scholar
  53. 53.
    Ding C, Li J, Zhang X. Bertilimumab Cambridge Antibody Technology Group. Curr Opin Investig Drugs 2004; 5: 1213–8PubMedGoogle Scholar
  54. 54.
    Boshoff C, Endo Y, Collins PD, et al. Angiogenic and HIV-inhibitory functions of KSHV-encoded chemokines. Science 1997; 278: 290–4PubMedCrossRefGoogle Scholar
  55. 55.
    Sozzani S, Allavena P, Vecchi A, et al. Chemokine receptors: interaction with HIV-1 and viral-encoded chemokines. Pharm Acta Helv 2000; 74: 305–12PubMedCrossRefGoogle Scholar
  56. 56.
    Gao JL, Murphy PM. Human cytomegalovirus open reading frame US28 encodes a functional beta chemokine receptor. J Biol Chem 1994; 269: 28539–42PubMedGoogle Scholar
  57. 57.
    Johnson Z, Kosco-Vilbois MH, Herren S, et al. Interference with heparin binding and oligomerization creates a novel anti-inflammatory strategy targeting the chemokine system. J Immunol 2004; 173: 5776–85PubMedGoogle Scholar
  58. 58.
    Johnson Z, Schwarz M, Power CA, et al. Multi-faceted strategies to combat disease by interference with the chemokine system. Trends Immunol 2005; 26: 268–74PubMedCrossRefGoogle Scholar
  59. 59.
    Wymann MP, Bjorklof K, Calvez R, et al. Phosphoinositide 3-kinase gamma: a key modulator in inflammation and allergy. Biochem Soc Trans 2003; 31: 275–80PubMedCrossRefGoogle Scholar
  60. 60.
    Wymann MP, Marone R. Phosphoinositide 3-kinase in disease: timing, location, and scaffolding. Curr Opin Cell Biol 2005; 17: 141–9PubMedCrossRefGoogle Scholar
  61. 61.
    Ward SG, Finan P. Isoform-specific phosphoinositide 3-kinase inhibitors as therapeutic agents. Curr Opin Pharmacol 2003; 3: 426–34PubMedCrossRefGoogle Scholar
  62. 62.
    Barnes PJ. New drugs for asthma. Nat Rev Drug Discov 2004; 3: 831–44PubMedCrossRefGoogle Scholar
  63. 63.
    Kumar S, Boehm J, Lee JC. P38 map kinases: key signalling molecules as therapeutic targets for inflammatory diseases. Nat Rev Drug Discov 2003; 2: 717–26PubMedCrossRefGoogle Scholar
  64. 64.
    Scandella E, Men Y, Gillessen S, et al. Prostaglandin E2 is a key factor for CCR7 surface expression and migration of monocyte-derived dendritic cells. Blood 2002; 100: 1354–61PubMedCrossRefGoogle Scholar
  65. 65.
    Wong M, Uddin S, Majchrzak B, et al. RANTES activates Jak2 and Jak3 to regulate engagement of multiple signaling pathways in T cells. J Biol Chem 2001; 276: 11427–31PubMedCrossRefGoogle Scholar
  66. 66.
    Roshak AK, Callahan JF, Blake SM. Small-molecule inhibitors of NF-[kappa]B for the treatment of inflammatory joint disease. Curr Opin Pharmacol 2002; 2: 316–21PubMedCrossRefGoogle Scholar
  67. 67.
    Gutierrez-Ramos JC, Lloyd C, Kapsenberg ML, et al. Non-redundant functional groups of chemokines operate in a coordinate manner during the inflammatory response in the lung. Immunol Rev 2000; 177: 31–42PubMedCrossRefGoogle Scholar

Copyright information

© adis data information BV 2006

Authors and Affiliations

  1. 1.Leukocyte Biology Section, NHLI, Sir Alexander Fleming Building, Faculty of MedicineImperial CollegeLondonEngland
  2. 2.Novartis Institutes for Biomedical ResearchHorshamEngland

Personalised recommendations