Trends in Pharmacological Sciences
ReviewChemokine receptors as therapeutic targets in chronic obstructive pulmonary disease
Section snippets
Chronic obstructive pulmonary disease and chemokines
Chronic obstructive pulmonary disease (COPD) is a major and increasing global health problem that is the fourth commonest cause of death in developed countries and that is predicted to become the fifth commonest cause of chronic disability in the world during the next 15 years [1]. The prevalence of COPD is increasing with the rise in cigarette smoking. COPD is characterized by progressive airflow limitation, resulting in shortness of breath on exertion and, eventually, death from respiratory
CXCR1 and CXCR2
CXCL8 (IL-8) has long been implicated as a mediator of neutrophilic inflammation in COPD. It activates the chemokine receptors CXCR1 and CXCR2, which are also activated by other related CXC chemokines. CXCL8 concentrations are markedly increased in the induced sputum of patients with COPD, including those with α1-antitrypsin deficiency, and correlate with the increased neutrophil accumulation 10, 11, 12. The concentrations of CXCL8 in induced sputum are further increased during acute
CXCR3
The mechanisms by which CD8+, and to a lesser extent CD4+ cells, accumulate in the airways and lungs of patients with COPD are unknown. However, T-cell homing depends on initial activation followed by adhesion and chemotaxis. T cells in the peripheral airways of COPD patients show increased expression of CXCR3 34, 35, which is activated by three chemokines: CXCL9 [monokine induced by interferon (IFN)-γ], CXCL10 (IFN-γ-inducible protein of 10 kDa) and CXCL11 (IFN-inducible T-cell-α
Other CXC receptors
CXCR4 and CXCR5 bind to CXCL12 (stromal-cell-derived factor-1) and CXCL13 (B-cell-attracting chemokine-1), respectively [44]. CXCR4 is expressed by T cells, monocytes, immature B cells and airway epithelial cells following stimulation, although a role for CXCR4 in COPD is unknown. The selective CXCR4 antagonist AMD3100 inhibits allergic inflammation in mice [45] but its potential in COPD remains unexplored. CXCL13 is the most efficacious B-cell chemoattractant [46]; however, the role of it and
CCR1
CCL3 [macrophage inflammatory protein (MIP)-1α] is released by macrophages and has chemotactic activity for monocytes and neutrophils via the activation of CCR1. However, CCL3 concentrations are not increased in the BAL fluid of smokers with or without chronic bronchitis, whereas concentrations of the related chemokine CCL4 (MIP-1β) are increased in patients with chronic bronchitis but not in asymptomatic smokers [49]. CCL5 (released by activated normal T cells expressed and secreted) is also a
CCR2
CCL2 (monocyte chemotactic protein-1) is a CC chemokine that activates CCR2 on monocytes and T cells [51]. CCR2 might have a role in COPD because CCL2 levels are increased in the sputum, BAL fluid and lungs of patients with COPD; furthermore, CCL2 is also expressed by alveolar macrophages, T cells and epithelial cells 16, 49, 52 and by type II pneumocytes in culture following stimulation with LPS [53]. CCR2 is downregulated by toll-like receptor (TLR)-2, TLR-4 and other inflammatory receptors,
CCR3
The concentration of eosinophils is increased in COPD airways and lungs, although these cells are not the predominant inflammatory cells as in asthma. There is a small increase in eosinophil concentration during exacerbations of chronic bronchitis 10, 57, 58. CCL5 also activates CCR3, is strongly expressed in airway epithelial cells of patients with exacerbations of chronic bronchitis [59] and is elevated in sputum [50]. Several small-molecule CCR3 antagonists are now in development for
Other CC receptors
CCR4 and CCR8 are selectively expressed on Th2 cells and are activated by CCL22 (macrophage-derived chemokine) and CCL17 (thymus- and activation-dependent chemokine), respectively [61]. However, Th2 cells are not prominent in COPD, so these receptors are unlikely to be relevant.
CCR5 is activated by CCL3, CCL4 and CCL5, levels of all of which are elevated in COPD. Numbers of T cells expressing CCR5 are increased in the airways of mild–moderate-COPD patients but are reduced in severe disease 35,
CX3CR
The unique CX3C chemokine CX3CL1 (fractalkine), which is tethered to cell surfaces, undergoes increased expression in human airway epithelial cells after stimulation with IFN-γ and might be involved in the recruitment and adhesion of monocytes, T cells and natural killer cells to epithelial surfaces [67] and to airway smooth muscle [68]. It is unknown whether levels of fractalkine or its receptor, CX3CR1, are increased in COPD, although fractalkine has recently been implicated in dendritic cell
Therapeutic perspectives
Many new approaches to the treatment of inflammation in COPD are under investigation [2]. Chemokine-receptor antagonists are an attractive approach to COPD therapy because chemokines have a crucial role in the recruitment of key inflammatory cells, including macrophages (and monocytes), neutrophils and T cells. However, there is considerable redundancy in the system, so blocking a specific chemokine receptor might not inhibit the chemotactic response because other chemokine receptors and other
Glossary
- CD4+
- a subset of T cells that predominantly helps or induces immune responses.
- CD8+
- a subset of T cells that is predominantly cytotoxic.
- Tc1
- a subset of cytotoxic lymphocytes.
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