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Vol. 52, Issue 1, 145-176, March 2000
Laboratory of Host Defenses, National Institute of Allergy and
Infectious Diseases, National Institutes of Health, Bethesda, Maryland
(P.M.M.); Theodor-Kocher Institute, Bern, Switzerland (M.B.); Gladstone
Institute of Cardiovascular Disease, San Francisco, California
(I.F.C.); Genentech, Inc., South San Francisco, California (C.A.H.);
Department of Immunology, Berlex Biosciences, Richmond, California
(R.H.); Department of Molecular Preventive Medicine, School of
Medicine, University of Tokyo, Bunkyoku, Tokyo, Japan (K.M.);
Laboratory of Parasitic Diseases, National Institute of Allergy and
Infectious Diseases, National Institutes of Health, Bethesda, Maryland
(L.H.M.); Laboratory of Molecular Immunoregulation, Division of Basic
Science, National Cancer Institute-Frederick Cancer Research and
Development Center, Frederick, Maryland (J.J.O.); and Serono
Pharmaceutical Research Institute, Plan-les-Ouates, Geneva, Switzerland
(C.A.P.)
I. Overview
II. Introduction
A. Historical Background
B. Chemokine Classification
C. Chemokine Receptor Classification and Nomenclature
D. Chemokine Receptor Structure
E. Chemokine Receptor Specificity for Ligands and Leukocytes
III. CXC Chemokine Receptor Subtypes
A. CXCR1 and CXCR2
B. CXCR3
C. CXCR4
D. CXCR5
IV. CC Chemokine Receptor Subtypes
A. CCR1
B. CCR2
C. CCR3
D. CCR4
E. CCR5
F. CCR6
G. CCR7
H. CCR8
I. CCR9
J. CCR10
K. CCR11
V. CX3C Chemokine Receptor Subtypes
A. CX3CR1
VI. Chemokine Receptor Subtypes
A. XCR1
VII. Chemokine Binding Proteins
A. Duffy
B. D6
VIII. Virus-Encoded Chemokine Receptors
A. ECRF3
B. US28
C. KSHV GPCR
D. UL12
E. E1
IX. Conclusions
Acknowledgments
References
Chemokine receptors comprise a large family of seven transmembrane domain G protein-coupled receptors differentially expressed in diverse cell types. Biological activities have been most clearly defined in leukocytes, where chemokines coordinate development, differentiation, anatomic distribution, trafficking, and effector functions and thereby regulate innate and adaptive immune responses. Pharmacological analysis of chemokine receptors is at an early stage of development. Disease indications have been established in human immunodeficiency virus/acquired immune deficiency syndrome and in Plasmodium vivax malaria, due to exploitation of CCR5 and Duffy, respectively, by the pathogen for cell entry. Additional indications are emerging among inflammatory and immunologically mediated diseases, but selection of targets in this area still remains somewhat speculative. Small molecule antagonists with nanomolar affinity have been reported for 7 of the 18 known chemokine receptors but have not yet been studied in clinical trials. Virally encoded chemokine receptors, as well as chemokine agonists and antagonists, and chemokine scavengers have been identified in medically important poxviruses and herpesviruses, again underscoring the importance of the chemokine system in microbial pathogenesis and possibly identifying specific strategies for modulating chemokine action therapeutically. The purpose of this review is to update current concepts of the biology and pharmacology of the chemokine system, to summarize key information about each chemokine receptor, and to describe a widely accepted receptor nomenclature system, ratified by the International Union of Pharmacology, that is facilitating clear communication in this area.
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M. M. Rosenkilde, R. David, I. Oerlecke, T. Benned-Jensen, U. Geumann, A. G. Beck-Sickinger, and T. W. Schwartz Conformational Constraining of Inactive and Active States of a Seven Transmembrane Receptor by Metal Ion Site Engineering in the Extracellular End of Transmembrane Segment V Mol. Pharmacol., December 1, 2006; 70(6): 1892 - 1901. [Abstract] [Full Text] [PDF]
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D. Verzijl, L. Pardo, M. van Dijk, Y. K. Gruijthuijsen, A. Jongejan, H. Timmerman, J. Nicholas, M. Schwarz, P. M. Murphy, R. Leurs, et al. Helix 8 of the Viral Chemokine Receptor ORF74 Directs Chemokine Binding J. Biol. Chem., November 17, 2006; 281(46): 35327 - 35335. [Abstract] [Full Text] [PDF]
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 J. Maatta, M. Lehto, M. Leino, S. Tillander, R. Haapakoski, M.-L. Majuri, H. Wolff, S. Rautio, I. Welling, K. Husgafvel-Pursiainen, et al. Mechanisms of Particle-Induced Pulmonary Inflammation in a Mouse Model: Exposure to Wood Dust Toxicol. Sci., September 1, 2006; 93(1): 96 - 104. [Abstract] [Full Text] [PDF]
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I. von Luettichau, M. Nathrath, S. Burdach, R. Huss, S. Segerer, and P. J. Nelson Mononuclear Infiltrates in Osteosarcoma and Chemokine Receptor Expression Clin. Cancer Res., September 1, 2006; 12(17): 5253 - 5254. [Full Text] [PDF]
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G. Frascaroli, S. Varani, B. Moepps, C. Sinzger, M. P. Landini, and T. Mertens Human cytomegalovirus subverts the functions of monocytes, impairing chemokine-mediated migration and leukocyte recruitment. J. Virol., August 1, 2006; 80(15): 7578 - 7589. [Abstract] [Full Text] [PDF]
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M.-F. Hsieh, S.-L. Lai, J.-P. Chen, J.-M. Sung, Y.-L. Lin, B. A. Wu-Hsieh, C. Gerard, A. Luster, and F. Liao Both CXCR3 and CXCL10/IFN-Inducible Protein 10 Are Required for Resistance to Primary Infection by Dengue Virus J. Immunol., August 1, 2006; 177(3): 1855 - 1863. [Abstract] [Full Text] [PDF]
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 N. Michel, K. Ganter, S. Venzke, J. Bitzegeio, O. T. Fackler, and O. T. Keppler The Nef Protein of Human Immunodeficiency Virus Is a Broad-Spectrum Modulator of Chemokine Receptor Cell Surface Levels That Acts Independently of Classical Motifs for Receptor Endocytosis and G{alpha}i Signaling Mol. Biol. Cell, August 1, 2006; 17(8): 3578 - 3590. [Abstract] [Full Text] [PDF]
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 Y.-J. Na, S.-H. Yang, D.-W. Baek, D.-H. Lee, K.-H. Kim, Y.-M. Choi, S.-T. Oh, Y.-S. Hong, J.-Y. Kwak, and K.-S. Lee Effects of peritoneal fluid from endometriosis patients on the release of vascular endothelial growth factor by neutrophils and monocytes Hum. Reprod., July 1, 2006; 21(7): 1846 - 1855. [Abstract] [Full Text] [PDF]
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M. Dagan-Berger, R. Feniger-Barish, S. Avniel, H. Wald, E. Galun, V. Grabovsky, R. Alon, A. Nagler, A. Ben-Baruch, and A. Peled Role of CXCR3 carboxyl terminus and third intracellular loop in receptor-mediated migration, adhesion and internalization in response to CXCL11 Blood, May 15, 2006; 107(10): 3821 - 3831. [Abstract] [Full Text] [PDF]
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M. M. Rosenkilde, T. Benned-Jensen, H. Andersen, P. J. Holst, T. N. Kledal, H. R. Luttichau, J. K. Larsen, J. P. Christensen, and T. W. Schwartz Molecular Pharmacological Phenotyping of EBI2: AN ORPHAN SEVEN-TRANSMEMBRANE RECEPTOR WITH CONSTITUTIVE ACTIVITY J. Biol. Chem., May 12, 2006; 281(19): 13199 - 13208. [Abstract] [Full Text] [PDF]
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U. Hoffmann, S. Segerer, P. Rummele, B. Kruger, M. Pietrzyk, F. Hofstadter, B. Banas, and B. K. Kramer Expression of the chemokine receptor CXCR3 in human renal allografts--a prospective study Nephrol. Dial. Transplant., May 1, 2006; 21(5): 1373 - 1381. [Abstract] [Full Text] [PDF]
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 A. Gulati, M. Sacchetti, S. Bonini, and R. Dana Chemokine Receptor CCR5 Expression in Conjunctival Epithelium of Patients With Dry Eye Syndrome. Arch Ophthalmol, May 1, 2006; 124(5): 710 - 716. [Abstract] [Full Text] [PDF]
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J.-Y. Springael, P. N. Le Minh, E. Urizar, S. Costagliola, G. Vassart, and M. Parmentier Allosteric Modulation of Binding Properties between Units of Chemokine Receptor Homo- and Hetero-Oligomers Mol. Pharmacol., May 1, 2006; 69(5): 1652 - 1661. [Abstract] [Full Text] [PDF]
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V. Chabot, P. Reverdiau, S. Iochmann, A. Rico, D. Senecal, C. Goupille, P.-Y. Sizaret, and L. Sensebe CCL5-enhanced human immature dendritic cell migration through the basement membrane in vitro depends on matrix metalloproteinase-9 J. Leukoc. Biol., April 1, 2006; 79(4): 767 - 778. [Abstract] [Full Text] [PDF]
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S. Infantino, B. Moepps, and M. Thelen Expression and Regulation of the Orphan Receptor RDC1 and Its Putative Ligand in Human Dendritic and B Cells J. Immunol., February 15, 2006; 176(4): 2197 - 2207. [Abstract] [Full Text] [PDF]
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K. Ottersbach, J. Mclean, N. W. Isaacs, and G. J. Graham A310 helical turn is essential for the proliferation-inhibiting properties of macrophage inflammatory protein-1 alpha (CCL3) Blood, February 15, 2006; 107(4): 1284 - 1291. [Abstract] [Full Text] [PDF]
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 I. F. Charo and R. M. Ransohoff The Many Roles of Chemokines and Chemokine Receptors in Inflammation N. Engl. J. Med., February 9, 2006; 354(6): 610 - 621. [Full Text] [PDF]
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U. Panzer, O. M. Steinmetz, R. R. Reinking, T. N. Meyer, S. Fehr, A. Schneider, G. Zahner, G. Wolf, U. Helmchen, P. Schaerli, et al. Compartment-Specific Expression and Function of the Chemokine IP-10/CXCL10 in a Model of Renal Endothelial Microvascular Injury J. Am. Soc. Nephrol., February 1, 2006; 17(2): 454 - 464. [Abstract] [Full Text] [PDF]
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 M. Notohamiprodjo, R. Djafarzadeh, A. Mojaat, I. von Luttichau, H.-J. Grone, and P. J. Nelson Generation of GPI-linked CCL5 based chemokine receptor antagonists for the suppression of acute vascular damage during allograft transplantation Protein Eng. Des. Sel., January 1, 2006; 19(1): 27 - 35. [Abstract] [Full Text] [PDF]
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C. A. Reichel, A. Khandoga, H.-J. Anders, D. Schlondorff, B. Luckow, and F. Krombach Chemokine receptors Ccr1, Ccr2, and Ccr5 mediate neutrophil migration to postischemic tissue J. Leukoc. Biol., January 1, 2006; 79(1): 114 - 122. [Abstract] [Full Text] [PDF]
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D. R. Dewin, J. Catusse, and U. A. Gompels Identification and Characterization of U83A Viral Chemokine, a Broad and Potent {beta}-Chemokine Agonist for Human CCRs with Unique Selectivity and Inhibition by Spliced Isoform J. Immunol., January 1, 2006; 176(1): 544 - 556. [Abstract] [Full Text] [PDF]
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D. Porath, C. Riegger, J. Drewe, and J. Schwager Epigallocatechin-3-gallate Impairs Chemokine Production in Human Colon Epithelial Cell Lines J. Pharmacol. Exp. Ther., December 1, 2005; 315(3): 1172 - 1180. [Abstract] [Full Text] [PDF]
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C.-Y. Kao, F. Huang, Y. Chen, P. Thai, S. Wachi, C. Kim, L. Tam, and R. Wu Up-Regulation of CC Chemokine Ligand 20 Expression in Human Airway Epithelium by IL-17 through a JAK-Independent but MEK/NF-{kappa}B-Dependent Signaling Pathway J. Immunol., November 15, 2005; 175(10): 6676 - 6685. [Abstract] [Full Text] [PDF]
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J. A. Belperio, M. P. Keane, M. D. Burdick, B. N. Gomperts, Y. Y. Xue, K. Hong, J. Mestas, D. Zisman, A. Ardehali, R. Saggar, et al. CXCR2/CXCR2 Ligand Biology during Lung Transplant Ischemia-Reperfusion Injury J. Immunol., November 15, 2005; 175(10): 6931 - 6939. [Abstract] [Full Text] [PDF]
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 L. Farkas, M.-C. Hahn, M. Schmoczer, N. Jentsch, K. Kratzel, M. Pfeifer, and C. Schulz Expression of CXC Chemokine Receptors 1 and 2 in Human Bronchial Epithelial Cells Chest, November 1, 2005; 128(5): 3724 - 3734. [Abstract] [Full Text] [PDF]
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 E. Dimitriadis, C.A. White, R.L. Jones, and L.A. Salamonsen Cytokines, chemokines and growth factors in endometrium related to implantation Hum. Reprod. Update, November 1, 2005; 11(6): 613 - 630. [Abstract] [Full Text] [PDF]
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C. A. Wysocki, Q. Jiang, A. Panoskaltsis-Mortari, P. A. Taylor, K. P. McKinnon, L. Su, B. R. Blazar, and J. S. Serody Critical role for CCR5 in the function of donor CD4+CD25+ regulatory T cells during acute graft-versus-host disease Blood, November 1, 2005; 106(9): 3300 - 3307. [Abstract] [Full Text] [PDF]
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K. Balabanian, B. Lagane, S. Infantino, K. Y. C. Chow, J. Harriague, B. Moepps, F. Arenzana-Seisdedos, M. Thelen, and F. Bachelerie The Chemokine SDF-1/CXCL12 Binds to and Signals through the Orphan Receptor RDC1 in T Lymphocytes J. Biol. Chem., October 21, 2005; 280(42): 35760 - 35766. [Abstract] [Full Text] [PDF]
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Y. Su, S. K. Raghuwanshi, Y. Yu, L. B. Nanney, R. M. Richardson, and A. Richmond Altered CXCR2 Signaling in {beta}-Arrestin-2-Deficient Mouse Models J. Immunol., October 15, 2005; 175(8): 5396 - 5402. [Abstract] [Full Text] [PDF]
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R. W. DePaolo, R. Lathan, B. J. Rollins, and W. J. Karpus The Chemokine CCL2 Is Required for Control of Murine Gastric Salmonella enterica Infection Infect. Immun., October 1, 2005; 73(10): 6514 - 6522. [Abstract] [Full Text] [PDF]
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A. Takeuchi, Y. Usui, M. Takeuchi, T. Hattori, T. Kezuka, J. Suzuki, Y. Okunuki, T. Iwasaki, M. Haino, K. Matsushima, et al. CCR5-Deficient Mice Develop Experimental Autoimmune Uveoretinitis in the Context of a Deviant Effector Response Invest. Ophthalmol. Vis. Sci., October 1, 2005; 46(10): 3753 - 3760. [Abstract] [Full Text] [PDF]
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 N. Wettschureck and S. Offermanns Mammalian G Proteins and Their Cell Type Specific Functions Physiol Rev, October 1, 2005; 85(4): 1159 - 1204. [Abstract] [Full Text] [PDF]
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R. Sano, A. Tessitore, A. Ingrassia, and A. d'Azzo Chemokine-induced recruitment of genetically modified bone marrow cells into the CNS of GM1-gangliosidosis mice corrects neuronal pathology Blood, October 1, 2005; 106(7): 2259 - 2268. [Abstract] [Full Text] [PDF]
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 B. R Blazar and W. J Murphy Bone marrow transplantation and approaches to avoid graft-versus-host disease (GVHD) Phil Trans R Soc B, September 29, 2005; 360(1461): 1747 - 1767. [Abstract] [Full Text] [PDF]
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T. Kikuchi, S. Andarini, H. Xin, K. Gomi, Y. Tokue, Y. Saijo, T. Honjo, A. Watanabe, and T. Nukiwa Involvement of Fractalkine/CX3CL1 Expression by Dendritic Cells in the Enhancement of Host Immunity against Legionella pneumophila Infect. Immun., September 1, 2005; 73(9): 5350 - 5357. [Abstract] [Full Text] [PDF]
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 A. A. Maghazachi Insights into Seven and Single Transmembrane-Spanning Domain Receptors and Their Signaling Pathways in Human Natural Killer Cells Pharmacol. Rev., September 1, 2005; 57(3): 339 - 357. [Abstract] [Full Text] [PDF]
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S. M. Curbishley, B. Eksteen, R. P. Gladue, P. Lalor, and D. H. Adams CXCR3 Activation Promotes Lymphocyte Transendothelial Migration across Human Hepatic Endothelium under Fluid Flow Am. J. Pathol., September 1, 2005; 167(3): 887 - 899. [Abstract] [Full Text] [PDF]
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E. K. de Jong, I. M. Dijkstra, M. Hensens, N. Brouwer, M. van Amerongen, R. S. B. Liem, H. W. G. M. Boddeke, and K. Biber Vesicle-Mediated Transport and Release of CCL21 in Endangered Neurons: A Possible Explanation for Microglia Activation Remote from a Primary Lesion J. Neurosci., August 17, 2005; 25(33): 7548 - 7557. [Abstract] [Full Text] [PDF]
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 O. Quehenberger Thematic Review Series: The Immune System and Atherogenesis. Molecular mechanisms regulating monocyte recruitment in atherosclerosis J. Lipid Res., August 1, 2005; 46(8): 1582 - 1590. [Abstract] [Full Text] [PDF]
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