Chemokine receptors: multifaceted therapeutic targets

Abstract

Chemokines and their receptors are involved in the pathogenesis of diseases ranging from asthma to AIDS. Chemokine receptors are G-protein-coupled serpentine receptors that present attractive tractable targets for the pharmaceutical industry. It is only ten years since the first chemokine receptor was discovered, and the rapidly expanding number of antagonists holds promise for new medicines to combat diseases that are currently incurable. Here, I focus on the rationale for developing antagonists of chemokine receptors for inflammatory disorders and AIDS, and the accumulating evidence that favours this strategy despite the apparent redundancy in the chemokine system.

Figure 1. Chemokine receptors and their ligands.

Chemokines are divided into subclasses on the basis of the spacing of the N-terminal cysteine residues. The receptors for the α (or CXC) subclass are shown in blue, the receptors for the β (or CC) subclass in red and the receptors for the minor subclasses (C and CX₃C) in green. The pairing of chemokines to their receptors has been carried out mainly by receptor-binding assays. Chemokines were initially named according to their function or from the cell type that produced them, giving rise to names such as monocyte chemoattractant protein 1 (MCP-1), stromal derived factor 1 (SDF-1) and mucosae-associated epithelial chemokine (MEC). The simultaneous identification by different laboratories of a chemokine sequence often resulted in several names, such as MIP-3α, LARC and exodus-1. In order to eliminate the confusion, a systematic nomenclature has recently been adopted. The abbreviations of the common names are as follows: BCA-1, B-cell-attracting chemokine 1; CTACK, cutaneous T-cell-attracting chemokine; ELC, Epstein–Barr-virus-induced gene 1 ligand chemokine; ENA78, epithelial-cell-derived neutrophil-activating peptide 78; GCP-2, granulocyte chemotactic protein 2; Gro, growth-regulated oncogene; IL-8, interleukin 8; IP-10, interferon-inducible protein 10; I-TAC, interferon-inducible T-cell α chemoattractant; MCP, monocyte chemoattractant protein; MDC, macrophage-derived chemokine; MEC, mucosae-associated epithelial chemokine; MIG, monokine induced by interferon γ; MIP, macrophage inflammatory protein; NAP-2, neutrophil-activating peptide 2; RANTES, regulated on activation, normal T-cell expressed and secreted; SDF-1, stromal-cell-derived factor 1; SLC, secondary lymphoid-tissue chemokine; TARC, thymus and activation-regulated chemokine; TECK, thymus-expressed chemokine.

Figure 2. Chemokine receptors can be expressed constitutively or inducibly.

Chemokines can be classified as constitutive (developmentally regulated) or inducible (inflammatory). This division should not be regarded as absolute but rather as a rule with some exceptions. For example, CCR6 is constitutively expressed in immature dendritic cells and in T cells, but it is downregulated as dendritic cells mature. However, it is upregulated in skin lesions. CCR8 is constitutively expressed in the thymus but is upregulated during T-cell activation and is a marker of T_H2 cells. Last, CCR7 is upregulated during the antigen recognition process, a requisite for immune surveillance, because it is upregulated as dendritic cells mature. The classification into 'specific' or 'shared' is defined by whether they bind a single or many ligands, respectively.

Figure 3. Chemokine receptors and disease.

The receptors classified as constitutive in Fig. 2 do not have a great role in inflammatory disorders, with the exception of CCR8. CCR8 is expressed constitutively in the thymus but is upregulated on T-helper type-2 (T_H2) cells. The only constitutive receptor involved in disease that has been described to date is the ubiquitous receptor CXCR4, which is one of the main HIV co-receptors and also plays a role in cancer metastasis. IBD, inflammatory bowel disease; MS, multiple sclerosis; RA, rhematoid arthritis.

Figure 4. Chemokines are central to the pathogenesis of multiple sclerosis (MS).

MS is an autoimmune disease associated with a T-helper type 1 phenotype. It is therefore believed that activated T cells have a crucial role. Chemokine receptors have been shown to be highly produced in brain samples from MS patients after autopsy^,. One of these receptors, CXCR3, is produced by activated T cells, so it might be responsible for the recruitment of auto-aggressive T cells. This hypothesis is further confirmed by the high level of the CXCR3 ligand CXCL10 in these lesion samples. Two CC chemokine receptors, CCR1 and CCR5, have also been observed, and these receptors are both produced on T cells and monocytes/macrophages. The accumulation of these cells is directly correlated with lesions in which demyelination occurs, followed by axonal loss, which ultimately leads to paralysis.