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Atherosclerosis is an inflammatory process that is strongly affected by chemokines that regulate the trafficking of inflammatory cells. A large amount of data from in vitro studies and murine models suggest an important role for chemokines in atherosclerosis. In man, genetic studies have revealed that specific polymorphisms in chemokine and chemokine receptor genes are associated with atherosclerotic diseases including coronary artery disease and carotid artery occlusive disease. Specifically, there are sound data supporting roles for the following receptors and their ligands: CCR2 and MCP-1 (CCL2); CX3CR1 and fractalkine (CX3CL1); CCR1, CCR5, and RANTES (CCL5); CXCR2 and IL-8 (CXCL8); CXCR6 and CXCL16; and CXCR3 and its ligands MIG (CXCL9), IP-10 (CXCL10) and I-TAC (CXCL11). These chemokines and their receptors participate in vascular inflammation via T-cell and monocyte chemoattraction, adhesion of monocytes to the vessel wall, and vascular smooth muscle cell migration and proliferation. Chemokines and chemokine receptors are being studied as potential therapeutic targets for the prevention or retardation of atherosclerotic disease. Although many of these therapies are promising, there are also limitations to specific chemokine-targeted therapy.

This chapter is an attempt to integrate recent studies concerning the role of chemokine receptors in the initiation, development, and maintenance of allergic lung diseases collectively referred to as asthma. The pathogenesis of asthma involves the coordinated trafficking of inflammatory cells to the lungs and draining lymph nodes, as well as the activation of these inflammatory cells. Chemokine receptors and their ligands play a prominent role in directing the inflammation associated with allergic lung disease. T lymphocyte-mediated immune responses can be broadly categorized as being type 1 or type 2, based on the cell types present and the associated cytokines produced. Allergic lung disease is a predominately type 2-mediated disease. The chemokine receptors CCR4, CCR6, and CCR8 serve to promote the recruitment of type 2 T (T helper 2; Th2) cells, whereas CXCR3 antagonizes type 2 and promotes type 1 T (T helper 1; Th1) cells. The pathophysiologic manifestations of asthma, including excessive mucus production, eosinophilia, and airway hyperreactivity, are dependent upon the trafficking and activation of eosinophils, mast cells, and goblet cells. Roles for chemokine receptors, including CCR4, CCR2, and CXCR4, in the trafficking and activation of these cell types during allergic lung disease are discussed. Finally, the incidence of allergic lung disease is increasing, and the costs associated with it are substantial. Chemokine receptor expression and use by inflammatory cells during allergic lung disease makes chemokine receptors an attractive therapeutic target. Implications for drug development are discussed in the context of experimental results.

There have been tremendous advances made toward our understanding of chemokine receptor biology over the past decade. Much of the research conducted in this area was fueled by discoveries that certain chemokine receptor ligands (chemokines) could specifically block human immunodeficiency virus type 1 (HIV-1) infection and that certain chemokine receptors were the long-sought coreceptors that, together with CD4, were required for the productive entry of HIV-1, HIV-2, and simian immuno-deficiency virus (SIV) isolates. In the current survey, along with the interactions of the HIV-1 envelope glycoprotein with chemokine receptors, we have focused on the relationship certain chemokine receptors have with particular cellular systems such as lipid rafts, chemokine receptor-mediated signaling, and the actin cytoskeleton; all of which appear to play roles in or influence the establishment of HIV-1 infection. We will also discuss the dichotomous effects that chemokines display at both entry and postentry levels of HIV-1 infection and their potential significance for HIV-1 pathogenesis and acquired immunodeficiency syndrome (AIDS).

Tissue fibrosis, which results in the destruction of normal organ function, is a leading cause of morbidity and mortality. Current strategies for treating fibrosis have been unsuccessful, largely because of the difficulty in distinguishing whether inflammatory or fibrogenic events sustain the progression of the disease. The causes of fibrosis are diverse regardless of the tissue involved, and the common features include the sequential recruitment of inflammatory cells, overproliferation of matrix-producing cells, and the overproduction of extracellular matrix. An excessive wound-healing response presumably represents disruption in this sequence thereby leading to a disturbance in the balance between tissue remodeling, matrix degradation, and permanent scarring. The mechanisms involved in pulmonary fibrosis also represent three sequential events characterized by an initial insult, inflammation, and tissue repair. Central to the progression of these events is the balance between a T helper 1 (Th1) and a T helper 2 (Th2) environment, in which Th2-specific signals have been shown to be immunomodulatory and profibrotic. However, the release of these Th2-specific cytokines and chemokines by both inflammatory and resident cells maintains the fibrotic response, consequently leading to fibrotic disease. Evidence from animal models and human studies have identified a number of Th1/Th2-associated chemokines and chemokine receptors as profibrotic or antifibrotic. Therefore, investigating the chemokines, chemokine receptors, and the cells that they impact is an attractive approach to identifying therapeutic targets in fibrosis.

Angiogenesis is the process of new blood vessel growth and is a critical biological process under both physiologic and pathologic conditions. Angiogenesis can occur under physiologic conditions that include embryogenesis and the ovarian/menstrual cycle. In contrast, pathologic angiogenesis is associated with chronic inflammation/chronic fibroproliferative disorders and tumorigenesis of cancer. Similarly, aberrant angiogenesis associated with chronic inflammation/fibroproliferative disorders is analogous to neovascularization of tumorigenesis of cancer. Net angiogenesis is determined by a balance in the expression of angiogenic compared with angiostatic factors. CXC chemokines are heparin-binding proteins that display unique disparate roles in the regulation of angiogenesis. Based on their structure, CXC chemokines can be divided into two groups that either promote or inhibit angiogenesis, and they are therefore uniquely placed to regulate net angiogenesis in both physiologic and pathologic conditions.

Many chemokine receptors have now been detected in a variety of malignancies. Considerable data now exist that two receptors, CXCR4 and CCR7, are widely expressed in epithelial cancers and contribute to the ability of some tumors to metastasize. Preclinical studies support a role for these receptors in mediating tumor cell migration, but other functions have also been identified including support of tumor cell proliferation in response to ligand stimulation. Less is known about the function of other chemokine receptors expressed in malignant cells, but it is likely that at least some of these also contribute to aggressive behavior. Although the specific role of each receptor is complex, it is becoming clear that these receptors may mediate metastasis to some, but not all, metastatic sites characteristic of each histologic type. Some of the site specificity is due to expression of the cognate ligand at the secondary site; however, other factors to be defined also contribute to chemokine receptor-determined metastatic patterns.

Actions of chemokines and the interaction with specific receptors within the central nervous system (CNS) surpass their original defined role of leukocyte recruitment to inflamed tissues. Chemokine receptor expression by resident CNS cells is crucial for normal brain development and architectural organization, neuronal protection during inflammatory and neurotoxic challenges, and, among many others, protective mechanisms during inflammatory conditions such as multiple sclerosis. The chemokine/chemokine receptor systems involved in such significant functions include CXCR4/CXCL12, CXCR2/CXCL1, and CX3CR1/CX3CL1. In this chapter, we discuss how these receptors might contribute to modulate communication within the CNS and with peripheral elements, and we also suggest potential mechanisms of action of fractalkine and the translation of these into the understanding of microglial function during neuro-inflammatory conditions.

In this chapter, we will give a perspective of in vitro assays used in drug discovery when targeting chemokine receptors. We outline the complexity of the chemokine system and give a historical perspective on the in vitro assays and types of assays used at different stages of discovery, followed by several examples of successes and failures in clinical trials. Finally, we discuss the rationale for continuing, after several failures, to target chemokine receptors and how screening may change with the increasing evidence of dimerization of chemokine receptors.