Amanda E. I. Proudfoot

Merck Serono (Switzerland)

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i-10 index

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Co-Authors

Timothy N. C. Wells

Medicines for Malaria Venture

112

Christopher Power

University of Alberta

Zoë Johnson

Roivant Sciences (Switzerland)

Frédéric Borlat

University of Geneva

Tracy M. Handel

University of Montana

Mark A. Payton

PsiOxus Therapeutics (United Kingdom)

Christine A. Power

Merck Serono (Switzerland)

Mauro M. Teixeira

Universidade Federal de Minas Gerais

Pierre Graber

Merck Serono (Switzerland)

Matthias Mack

Umicore (Belgium)

Cooperative Institutions

Weatherford College

147

Inserm

Merck Serono (Switzerland)

University of Geneva

Universidade Federal de Minas Gerais

Harvard University

Ludwig-Maximilians-Universität München

Merck Serono (Italy)

Centre National de la Recherche Scientifique

National Institutes of Health

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International Union of Basic and Clinical Pharmacology. LXXXIX. Update on the Extended Family of Chemokine Receptors and Introducing a New Nomenclature for Atypical Chemokine Receptors

Pharmacological Reviews (2013)

Françoise Bachelerie Adit Ben‐Baruch Amanda M. Burkhardt Christophe Combadière Joshua Μ. Farber

Sixteen years ago, the Nomenclature Committee of the International Union of Pharmacology approved a system for naming human seven-transmembrane (7TM) G protein-coupled chemokine receptors, the large family of leukocyte chemoattractant receptors that regulates immune system development and function, in large part by mediating leukocyte trafficking. This was announced in Pharmacological Reviews in a major overview of the first decade of research in this field [Murphy PM, Baggiolini M, Charo IF, Hébert CA, Horuk R, Matsushima K, Miller LH, Oppenheim JJ, and Power CA (2000) Pharmacol Rev 52:145–176]. Since then, several new receptors have been discovered, and major advances have been made for the others in many areas, including structural biology, signal transduction mechanisms, biology, and pharmacology. New and diverse roles have been identified in infection, immunity, inflammation, development, cancer, and other areas. The first two drugs acting at chemokine receptors have been approved by the U.S. Food and Drug Administration (FDA), maraviroc targeting CCR5 in human immunodeficiency virus (HIV)/AIDS, and plerixafor targeting CXCR4 for stem cell mobilization for transplantation in cancer, and other candidates are now undergoing pivotal clinical trials for diverse disease indications. In addition, a subfamily of atypical chemokine receptors has emerged that may signal through arrestins instead of G proteins to act as chemokine scavengers, and many microbial and invertebrate G protein-coupled chemokine receptors and soluble chemokine-binding proteins have been described. Here, we review this extended family of chemokine receptors and chemokine-binding proteins at the basic, translational, and clinical levels, including an update on drug development. We also introduce a new nomenclature for atypical chemokine receptors with the stem ACKR (atypical chemokine receptor) approved by the Nomenclature Committee of the International Union of Pharmacology and the Human Genome Nomenclature Committee.

CXC chemokine receptors

CCL21

CCL13

XCL2

CCR1

10.1124/pr.113.007724

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Citations (790)

Modulation of antibody-mediated glomerular injury in vivo by interleukin-6

Kidney International (1993)

Ayman Karkar Frederick W.K. Tam Amanda E. I. Proudfoot Anthony Meager Andrew J. Rees

Heterologous

Albuminuria

Nephrotoxicity

Nephritis

10.1038/ki.1993.338

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Citations (34)

Ticks produce highly selective chemokine binding proteins with antiinflammatory activity

The Journal of Experimental Medicine (2008)

Maud Déruaz Achim Frauenschuh Ana L. Alessandri João M. Dias Fernanda M. Coelho

Bloodsucking parasites such as ticks have evolved a wide variety of immunomodulatory proteins that are secreted in their saliva, allowing them to feed for long periods of time without being detected by the host immune system. One possible strategy used by ticks to evade the host immune response is to produce proteins that selectively bind and neutralize the chemokines that normally recruit cells of the innate immune system that protect the host from parasites. We have identified distinct cDNAs encoding novel chemokine binding proteins (CHPBs), which we have termed Evasins, using an expression cloning approach. These CHBPs have unusually stringent chemokine selectivity, differentiating them from broader spectrum viral CHBPs. Evasin-1 binds to CCL3, CCL4, and CCL18; Evasin-3 binds to CXCL8 and CXCL1; and Evasin-4 binds to CCL5 and CCL11. We report the characterization of Evasin-1 and -3, which are unrelated in primary sequence and tertiary structure, and reveal novel folds. Administration of recombinant Evasin-1 and -3 in animal models of disease demonstrates that they have potent antiinflammatory properties. These novel CHBPs designed by nature are even smaller than the recently described single-domain antibodies (Hollinger, P., and P.J. Hudson. 2005. Nat. Biotechnol. 23:1126–1136), and may be therapeutically useful as novel antiinflammatory agents in the future.

CCL5

CCL21

CXCL2

10.1084/jem.20072689

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Citations (205)

Up-regulation of CCR1 and CCR3 and induction of chemotaxis to CC chemokines by IFN-gamma in human neutrophils.

PubMed (1999)

Raffaella Bonecchi Nadia Polentarutti Walter Luini Alessandro Borsatti Sergio Bernasconi

Human neutrophils (polymorphonuclear leukocytes; PMN) respond to some CXC chemokines but do not migrate to CC chemokines. Recent work has shown that chemokine receptors can be modulated by inflammatory cytokines. In this study, the effect of IFN-gamma, a prototypic Th1 cytokine, on chemokine receptor expression in PMN was investigated. IFN-gamma caused a rapid (approximately 1 h) and concentration-dependent increase of CCR1 and CCR3 mRNA. The expression of CCR2, CCR5, and CXCR1-4 was not augmented. IFN-gamma-treated PMN, but not control cells, expressed specific binding sites for labeled monocyte-chemotactic protein (MCP)-3 and migrated to macrophage-inflammatory protein (MIP)-1alpha, RANTES, MCP-3, MIP-5/HCC2, and eotaxin. 7B11, a mAb for CCR3, inhibited the chemotactic response of IFN-gamma-treated PMN to eotaxin, and aminoxypentane-RANTES blocked PMN migration to RANTES. These results suggest that the selectivity of certain chemokines for their target cells may be altered by cytokines produced within an inflammatory context. Since PMN may play a role in orienting immunity toward Th1 responses, it is possible to speculate that IFN-gamma not only promotes Th1 differentiation directly, but also reorients the functional significance of Th2 effector cytokines by broadening the spectrum of their action to include PMN.

CCR3

CCR1

CCL13

Macrophage inflammatory protein

CXCL2

Monocyte

CCL7

CXC chemokine receptors

CC chemokine receptors

Proinflammatory cytokine

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Citations (207)

Purification of Recombinant Chemokines from E. coli

Humana Press eBooks (2003)

Amanda E. I. Proudfoot Frédéric Borlat

The majority of chemokines are highly basic, small proteins, with a molecular mass of around 8–10 kDa. Although they do not necessarily have a high level of homology at the primary sequence level, which can be as low as 20%, although it can also be as high as 90%, the three-dimensional structure of all the chemokines solved to date has shown that they have a superimposable monomeric fold. This fold is imposed on the family by the four cysteine motif that is common to the majority of the chemokines since they all form two disulfides between Cys-1 and 3, and Cys2 and 4, whether they belong to the α or CXC or β or CC subclass. Molecular modeling of the two chemokines that deviate from the motif, the C chemokine lymphotactin which lacks a disulfide, and the CX3C chemokine neurotactin or fraktalkine which has three amino acids between the first cysteine pair, both adopt the same fold. Modeling in fact shows that either one or three residues between the first two Cys can be adopted, but not two, probably explaining why examples of CX2C chemokines do not exist.

CX3CL1

10.1385/1-59259-058-6:75

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Citations (30)

The basic residue cluster 55KKWVR59 in CCL5 is required for in vivo biologic function

Molecular Immunology (2009)

Stephan Segerer Zoë Johnson Angelika Rek Thomas Baltus Philipp von Hundelshausen

CCL5

10.1016/j.molimm.2009.05.015

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Citations (17)

Chemokine receptors — the new frontier for AIDS research

Chemistry & Biology (1996)

Timothy N. C. Wells Amanda E. I. Proudfoot Christine A. Power Mark Marsh

Chemokine receptor CCR5

10.1016/s1074-5521(96)90126-x

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Citations (54)

Editorial: Chemokines – beyond chemotaxis

Cytokine (2018)

Amanda E. I. Proudfoot Tracy M. Handel Gerry Graham

10.1016/j.cyto.2018.04.036

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Citations (1)

Granzyme A is an interleukin 1 beta-converting enzyme.

The Journal of Experimental Medicine (1995)

Martin Irmler Sylvie Hertig H. Robson MacDonald Rémy Sadoul J. David Becherer

Apoptosis is critically dependent on the presence of the ced-3 gene in Caenorhabditis elegans, which encodes a protein homologous to the mammalian interleukin (IL)-1 beta-converting enzyme (ICE). Overexpression of ICE or ced-3 promotes apoptosis. Cytotoxic T lymphocyte-mediated rapid apoptosis is induced by the proteases granzyme A and B. ICE and granzyme B share the rare substrate site of aspartic acid, after which amino acid cleavage of precursor IL-1 beta (pIL-1 beta) occurs. Here we show that granzyme A, but not granzyme B, converts pIL-1 beta to its 17-kD mature form. Major cleavage occurs at Arg120, four amino acids downstream of the authentic processing site, Asp116. IL-1 beta generated by granzyme A is biologically active. When pIL-1 beta processing is monitored in lipopolysaccharide-activated macrophage target cells attacked by cytotoxic T lymphocytes, intracellular conversion precedes lysis. Prior granzyme inactivation blocks this processing. We conclude that the apoptosis-inducing granzyme A and ICE share at least one downstream target substrate, i.e., pIL-1 beta. This suggests that lymphocytes, by means of their own converting enzyme, could initiate a local inflammatory response independent of the presence of ICE.

Granzyme

Granzyme A

10.1084/jem.181.5.1917

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Citations (217)

The chemokine family. Potential therapeutic targets from allergy to HIV infection.

PubMed (1998)

Amanda E. I. Proudfoot

Basal trafficking and homing of leukocytes is controlled by a large subfamily of cytokines, the chemokines. The initiation and perpetuation of an inflammatory response is also mediated by the chemokines. The chemokine family acts through a sub-family of the seven transmembrane, G-protein-coupled receptor class. Despite the large number of chemokine proteins, several factors such as regulated expression of the ligands and their receptors, glycosoaminoglycan interactions and their signaling mechanisms introduce the required selectivity in vivo. Recently, chemokine receptors have been identified as an essential component for the infection of host cells by HIV. Chemokine receptors thus present an attractive therapeutic target for inflammatory disorders and HIV infection, and evidence for their validation using antibodies and receptor antagonists is discussed.

CCR1

CXC chemokine receptors

CXCL2

CCL13

CCR3

Chemokine receptor CCR5

CCL7

CCL21

CCR2

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Citations (14)