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Chemokine receptors: Introduction
GENERAL
Chemokines (chemotactic cytokines) comprise a family of related proteins defined by structural criteria including overall amino acid sequence homology, length, conserved cysteine motifs and a common fold. Almost all chemokines are ~70-80 amino acids in length and have at least four conserved cysteines. Together they are differentially produced by virtually all cell types and coordinate leukocyte trafficking under homeostatic and inflammatory conditions. Additional activities possessed by subsets of chemokines include but are not limited to direct antimicrobial activity, HIV inhibitory activity, angiogenic or angiostatic activity, tumour-promoting or tumour-inhibiting activity, apoptosis or mitogenic activity, and the ability to modulate gene expression, T cell differentiation and phagocyte activation. Chemokines act by binding to 7-transmembrane domain, G protein-coupled receptors. There are 18 human chemokine receptors [12,17,23,25] and over fifty distinct chemokines [24]. A signalling function has still not been demonstrated for Duffy, D6, and CCX CKR, which are all 7TM proteins that bind large overlapping subsets of chemokines.
CLASSIFICATION
The receptor nomenclature system is based on the observation that ligand selectivity of promiscuous chemokine receptors is restricted by chemokine class. The four main classes are named CC, CXC, CX3C and C, according to the number and spacing of conserved cysteines. Most chemokines are divided between the CC and CXC classes. There are only two known C chemokines, and one known CX3C chemokine. Several CC chemokines with six cysteines have been discovered, defining a structural subclass relative to the more numerous group of CC chemokines with four cysteines. The CXC class can also be divided into two subclasses, ELR+ and ELR-, depending on whether the tripeptide signature glu-leu-arg is found N-terminal to the first cysteine.
There are at present ten human chemokine receptors that are highly selective for one main high affinity (Kd ~ 1 nM) endogenous chemokine ligand (monogamous receptors): CXCR1, CXCR4, CXCR5, CXCR6, CCR6, CCR8, CCR9, CCR10, XCR1 and CX3CR1. The other eight chemokine receptors are typically highly promiscuous.
FUNCTIONAL ROLE
The chief functions for chemokine receptors are differential regulation of leukocyte trafficking in hematopoiesis and in innate and adaptive immunity. It has become clearer that chemokines and their receptors can be usefully subclassified into homeostatic leukocyte homing molecules (CXCR4, CXCR5, CCR7, CCR9) versus inflammatory/inducible molecules (CXCR1, CXCR2, CXCR3, CCR1-6, CX3CR1), and substantial progress has been made, in part through the study of knock-out mice, in identifying specific phenotypes in development and disease. Phenotypes are concentrated in hematopoietic development, innate and adaptive immune responses and susceptibility to infectious agents [8]. Chemokine receptors preferentially expressed on important functional subsets of dendritic cells, monocytes and lymphocytes, including Th1 and Th2 lymphocyte subsets and Langerhans cells, have been defined [7,15].
PROBLEMS IN PHARMACOLOGICAL CLASSIFICATION
The classification of chemokine receptors, which is based on primary structure and ligand specificity, is clear and has not presented significant problems. However, correlation with native receptors has been difficult in some cases, particularly for CXCR1, CCR1 and CCR5, due to the lack of selective ligands - especially antagonists - and overlapping leukocyte distribution.
A second problem in classification relates to important differences that have been noted among different mammalian species in chemokine and receptor repertoire, pharmacology and biology. At the extreme, there may not even be a species orthologue for a given chemokine, as for interleukin-8 which is missing from the mouse. In addition, because chemokine ligands are relatively large proteins whose sequences are highly divergent phylogenetically, in some cases they do not signal across species barriers.
SURPRISES
Interesting non-chemokine endogenous agonists and HIV-encoded agonists have been identified for chemokine receptors, including HIV gp120 (CXCR4, CCR5) [20], HIV tat (CCR2) [1], a secreted ELR+ module of tyrosyl tRNA synthetase (CXCR1) [19] and human beta defensin 2 (CCR6) [22]. Also chemokines have been identified that act as agonists at one receptor but as antagonists at another (MCP-3, eotaxin) [4,21]. Chemokine receptor-expression has been detected in numerous non-hematopoietic cells, and roles in novel functional areas including development, angiogenesis and apoptosis have been proposed. CXCR4 has shown the broadest activity, although this is an extraordinary, possibly even unique, type of chemokine receptor. It is unusually highly conserved phylogenetically, and its distribution is unusually broad. It has been linked to cardiac, cerebellar and gastric vasculature development, in addition to hematopoiesis, and is essential for life. CXCR4 may also mediate neuronal apoptosis in response to HIV gp120 [11].
VIRAL ANTI-CHEMOKINES AND CHEMOKINE RECEPTORS
Although NC-IUPHAR classifications place emphasis on human receptors, it is important to point out that herpesvirus-encoded 7TM chemokine receptors have also been identified, including US28 of human cytomegalovirus, ECRF3 of Herpesvirus saimiri, ORF74 of HHV8, E1 of equine herpesvirus 2 and U12 of HHV6 (reviewed in [14]). Examples of herpesvirus and poxvirus chemokine homologues and secreted chemokine binding proteins are also known [13]. Current concepts of how these proteins function include immune evasion (MC148R of Molluscum contagiosum virus; US28 of human cytomegalovirus; myxoma T7 protein), target cell trafficking (US28), angiogenesis (vMIP-II of HHV8) and oncogenesis (ORF74 of HHV8). The existence of broadly specific viral anti-chemokines testifies powerfully to the importance of the chemokine signalling system in orchestrating appropriate immune responses to microbial challenge, and supports the hypothesis that blocking chemokine receptors may be effective in the treatment of immunologically mediated disease.
HIV-1-AIDS is a major disease indication for the chemokine receptor CCR5 [3]. HIV-1 can exploit CCR5 and several other chemokine receptors and related receptors as co-receptors with CD4 for cell entry, but, as revealed by discovery and study of the disease-modifying mutation CCR5Δ32, CCR5 is the most important of these for HIV transmission. The discovery of HIV co-receptors has explained many but not all aspects of HIV cytotropism, and has permitted a new, molecular classification scheme for HIV strains based on usage of CCR5 and/or CXCR4 (designated R5, X4 or R5/X4 strains) [2]. In vivo roles of other HIV-1 co-receptors are not yet clear.
In strong analogy to HIV, the malaria-causing protozoan Plasmodium vivax uses the non-signalling chemokine binding protein Duffy as its cell entry receptor on erythrocytes, and individuals lacking Duffy due to a defective allele fixed in African populations are resistant to P. vivax infection [14].
FUTURE PROSPECTS
Immunologically mediated inflammatory disease indications have been suggested for chemokine receptors from animal models, but selection of targets is still somewhat speculative. Interesting possibilities have been identified recently for inflammatory or inducible chemokine receptors, including cardiac allograft rejection (CCR1) [10], glomerulonephritis (CX3CR1, CCR1) [9,18], and atherosclerosis (CXCR2 and CCR2) [5-6]. Knockout mouse experiments have blunted the argument that the chemokine system is too redundant to target just one molecule in disease. However, it remains to be seen whether this holds in established disease.
In this regard, potent, selective and deliverable blocking agents will be needed. The has been substantial progress in identifying small molecule antagonists to chemokine receptors and several are now being evaluated in clinical trials.
In the data tables that follow, unless otherwise specified, the information given is for human receptors, chemokines, tissues and cell types, and receptor distribution pattern is based on studies with receptor-specific antibody and/or DNA probes. Emphasis is placed on antagonists that have been described in peer-reviewed scientific literature. The reference list is meant to be illustrative, not comprehensive, and, owing to space limitations, is focused on what in the author's judgment are key papers appearing since 1998. Additional references can be found in several recent reviews [3,8,14,16,24,26].
To cite this family introduction, please use the following:
Philip M. Murphy, Israel F. Charo, Richard Horuk, Kouji Matsushima, Joost J. Oppenheim.
Chemokine receptors, introductory chapter. Last modified on 28/01/2013. Accessed on 20/05/2013. IUPHAR database (IUPHAR-DB), http://www.iuphar-db.org/DATABASE/FamilyIntroductionForward?familyId=14.
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