Chemokines and their receptors in allergic disease

doi:10.1016/j.jaci.2006.06.010

Journal of Allergy and Clinical Immunology

Volume 118, Issue 2, August 2006, Pages 305-318

https://doi.org/10.1016/j.jaci.2006.06.010 Get rights and content

Mechanisms of chemoattraction underlie the spatial organization of the cells of the immune system under basal conditions and the localization of these cells to sites of inflammation. The chemokines, a family of around 50 small proteins, play a major role in these processes. Leukocytes are equipped with cell-surface sensors for chemokines. There are 19 such receptors that are differentially expressed on leukocytes: the repertoire of receptor expression depending on the type of leukocyte and its stage in maturation. From observations in animal models, clinical studies, in vitro cell biology, and molecular analysis, a working hypothesis has been established to explain the cellular interactions underlying allergic responses and the chemokines–chemokine receptors involved. Chemokines signal through G protein–coupled receptors that are used typically for sensory functions (eg, detection of olfactory signals in the nose). This type of receptor can be blocked selectively by small-molecule antagonists. This provides the opportunity for the development of therapeutic compounds designed to suppress the recruitment of particular leukocyte types in allergic reactions.

Section snippets

Chemokines

In human subjects, chemokines constitute a family of approximately 50 low-molecular-weight proteins that precisely coordinate leukocyte trafficking to lymphoid microenvironments and also regulate leukocyte recruitment to sites of inflammation.¹ Four chemokine groups have been defined on the basis of the arrangement of amino-terminal cysteine residues. The majority of chemokines are members of the CC or CXC classes, where the 2 N-terminal cysteines are adjacent or have a single amino acid

Chemokine receptors

As with many biological ligands, the effects of chemokines are mediated through cell-surface receptors of the G protein–coupled receptor (GPCR) superfamily, which is thought to make up almost 5% of the coding regions of the human genome.⁸ Chemokine receptors fall into the subfamily of class A, rhodopsin-like receptors, being approximately 350 amino acids long and with a distinctive motif of 7 hydrophobic regions, which, by analogy to rhodopsin, are thought to form transmembrane helices, leaving

Chemokine–chemokine receptor interactions and downstream signaling

Conserved between the majority of CC chemokine receptors (and class A GPCRs in general) is a DRY (aspartate-arginine-tyrosine) motif at the cytoplasmic end of the third transmembrane α-helix. This is analogous to the ERY motif of bovine rhodopsin, to date the only GPCR the crystal structure of which has been solved.¹⁷ This motif is thought to act as an ionic lock, holding GPCRs in an inactive state before their activation by ligand.¹⁸ On ligation, a conformation change in the GPCR is believed

Chemokines and their receptors in allergic inflammation

In the following sections we will address some of the chemokines and chemokine receptors implicated in the pathogenesis of allergic disease, discussing relevant in vitro and in vivo data and, where available, translation of this research into human disease. Although the availability of animal models of allergic disease has allowed us to dissect signaling pathways involved in leukocyte recruitment (indeed allowing the identification of some chemokines, such as CCL11), the physiologic differences

Chemokines acting on dendritic cells

Dendritic cells (DCs) are perceived as sentinels of the immune system, and as the most potent APCs of the immune system, the migration of activated DCs to lymph nodes after encounter with antigen is of paramount importance to the adaptive immune response. It therefore comes as no surprise that this migration is closely regulated at the molecular level by chemokines. Recruitment of immature DCs to inflamed tissues is mediated by a repertoire of receptors, including CCR2, CCR5, and CXCR4,

Chemokines and their receptors selective for T lymphocytes

As the principal orchestrators of adaptive immune responses, T lymphocytes have a critical requirement for directed migration to and from secondary lymphoid organs in addition to sites of inflammation. As is the case with DCs, migration to the former is controlled by the CCR7 ligands CCL19 and CCL21, and their absence results in the failure of naive T cells to home to lymph nodes.⁶⁰ Additionally, CCR7 appears to determine T-cell exit from peripheral tissues because T cells from mice deficient

Eosinophil-selective chemokines and their receptors

The characteristic accumulation of large numbers of eosinophils in allergic reactions suggests an important function, but the precise relationship between eosinophils and symptoms, particularly in asthma, has proved elusive. Some animal studies, in which IL-5 was neutralized with antibodies or the gene was deleted to suppress eosinophil production, suggested a strong link between activation of eosinophils in the lung and AHR.107, 108 However, IL-5 neutralization in asthmatic patients did not

Basophil-selective chemokines and their receptors

In an effort to understand the repertoire of chemokine receptors expressed by human basophils, Iikura et al¹³⁸ detected mRNA transcripts for CCR1, CCR2, CCR3, and CCR5, although only CCL2 and CCL11 induced in vitro migration, with CCL11 clearly the most potent chemokine. In keeping with this, CCL11 has also been reported to be a potent inducer of basophil migration in vivo in a humanized SCID mouse model grafted with autologous human skin.¹³⁹ Likewise, CCL5, a ligand for CCR1, CCR3, and CCR5

Mast cell–selective chemokines and their receptors

Mast cells characteristically express c-kit, and the ligand for this receptor, stem cell factor (SCF), induces their chemotaxis,¹⁵¹ in addition to other important effects, such as proliferation, differentiation, and inhibition of apoptosis. Several chemokine receptors have been identified on mast cells or mast cell lines, including CXCR2,¹²¹ CXCR3,¹⁵² CXCR4,121, 153 CCR1,¹⁵⁴ CCR3,121, 155 CCR4,¹⁵⁴ and CCR5,¹²¹ and their recognized chemokine ligands have been shown to be chemotactic for these

Blockade of chemokine receptors by small-molecule antagonists

A key point in turning our current understanding of leukocyte recruitment into a future therapy for the treatment of allergic disease is the question of which receptor or receptors to target. As a key effector of eosinophil migration in allergic inflammation, CCR3 was the major focus, with early in vitro and in vivo proof-of-principle studies suggesting that CCR3 blockade was feasible.160, 161, 162 Subsequent work by the pharmaceutical industry using high-throughput screens identified several

Summary

Our knowledge of the chemokine family has greatly enhanced the understanding of the mechanisms underlying allergic reactions. Small-molecule antagonists can now be designed to block particular chemokine receptors. Converting this knowledge into effective therapy for allergic diseases presents major challenges for the future. One important factor is the complexity of the chemoattraction mechanisms, particularly the number of different receptor types on a given cell and their plasticity, and the

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(Supported by an unrestricted educational grant from Genentech, Inc. and Novartis Pharmaceuticals Corporation)

Series editors: William T. Shearer, MD, PhD, Lanny J. Rosenwasser, MD, and Bruce S. Bochner, MD

Disclosure of potential conflict of interest: The authors have declared that they have no conflict of interest.

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Review and feature articleChemokines and their receptors in allergic disease

Section snippets

Chemokines

Chemokine receptors

Chemokine–chemokine receptor interactions and downstream signaling

Chemokines and their receptors in allergic inflammation

Chemokines acting on dendritic cells

Chemokines and their receptors selective for T lymphocytes

Eosinophil-selective chemokines and their receptors

Basophil-selective chemokines and their receptors

Mast cell–selective chemokines and their receptors

Blockade of chemokine receptors by small-molecule antagonists

Summary

Immunity

J Biol Chem

Mol Immunol

J Biol Chem

J Biol Chem

J Biol Chem

Cell

J Biol Chem

J Biol Chem

J Biol Chem

J Biol Chem

J Biol Chem

J Biol Chem

Cell

Blood

Blood

Biochem Biophys Res Commun

J Biol Chem

Cell

Immunity

Am J Pathol

J Allergy Clin Immunol

J Allergy Clin Immunol

Am J Pathol

J Biol Chem

J Allergy Clin Immunol

Lancet

Chemokines in innate and adaptive host defense: Basic chemokinese grammar for immune cells

Annu Rev Immunol

A new class of membrane-bound chemokine with a CX3C motif

Nature

Determination of the monomer-dimer equilibrium of interleukin-8 reveals it is a monomer at physiological concentrations

Biochemistry

A transmembrane CXC chemokine is a ligand for HIV-coreceptor Bonzo

Nat Immunol

The many roles of chemokines and chemokine receptors in inflammation

N Engl J Med

The G-protein-coupled receptors in the human genome form five main families. Phylogenetic analysis, paralogon groups, and fingerprints

Mol Pharmacol

International Union of Pharmacology. XXX. Update on chemokine receptor nomenclature

Pharmacol Rev

International union of pharmacology. XXII. Nomenclature for chemokine receptors

Pharmacol Rev

The promiscuous chemokine binding profile of the Duffy antigen/receptor for chemokines is primarily localized to sequences in the amino-terminal domain

J Biol Chem

Differential expression of chemokine receptors and chemotactic responsiveness of type 1 T helper cells (Th1s) and Th2s

J Exp Med

Flexible programs of chemokine receptor expression on human polarised T helper 1 and 2 lymphocytes

J Exp Med

CCR3 is essential for skin eosinophilia and airway hyperresponsiveness in a murine model of allergic skin inflammation

J Clin Invest

CCR3 is required for tissue eosinophilia and larval cytotoxicity after infection with Trichinella spiralis

J Immunol

Crystal structure of rhodopsin: a G protein-coupled receptor

Science

Alanine scanning mutagenesis of CCR3 reveals that the three intracellular loops are essential for functional receptor expression

Eur J Immunol

Sialylated O-glycans and sulfated tyrosines in the NH2-terminal domain of CC chemokine receptor 5 contribute to high affinity binding of chemokines

J Exp Med

Receptor-mediated activation of heterotrimeric G-proteins in living cells

Science

Potent inhibition of HIV-1 infectivity in macrophage and lymphocytes by a novel CCR5 antagonist

Science

Regulation of the receptor specificity and function of the chemokine RANTES (regulated on activation, normal T cell expressed and secreted) by dipeptidyl peptidase IV (CD26)-mediated cleavage

J Exp Med

CD26/dipeptidyl-peptidase IV down-regulates the eosinophil chemotactic potency, but not the anti-HIV activity of human eotaxin by affecting its interaction with CC chemokine receptor 3

J Immunol

Review and feature article
Chemokines and their receptors in allergic disease

A new class of membrane-bound chemokine with a CX₃C motif