Chemokines: established and novel targets in atherosclerosis.
Bottom Line: Targeting the chemokine system offers various entry points for a causative treatment of this widespread and chronic illness.Although this approach has encountered some setbacks, several innovative compounds are currently in an advanced stage of development.In this review, the current standing of this dynamic field is highlighted and the potential advantages and drawbacks of particular strategies are discussed.
Affiliation: Institute for Cardiovascular Prevention, Ludwig-Maximilians-University of Munich, Munich, Germany.Show MeSH
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Mentions: Chemokine signalling is initiated by binding to and activation of G protein-coupled seven-transmembrane receptors (Fig 1). Their classification is based on their specificity for the chemokine family members, for example CC-chemokine receptors (CCR) preferentially bind to CC-chemokines and CXCR analogously bind to CXC-chemokines. Activation of chemokine receptors occurs in a two-step fashion, in which the globular part of the chemokine ligand binds to the extracellular loops of the receptor and the flexible chemokine N-terminus subsequently enters a defined pocket between the transmembrane helices (Monteclaro & Charo, 1996). An interesting feature of chemokine receptors is their ability to form homo- and heterodimers, although the functional consequences of such interactions have been diverse (Kramp et al, 2011). For example, an enrichment of CCR5 and CXCR4 was observed in the immunological synapse between B and T cells, and the stimulation of T-cell responses relied on the presence of both receptors, which were found in a complex on T-cell membranes (Contento et al, 2008). However, in a similar study, a negative binding cooperativity was observed between the ligands for CXCR4, CCR2 and CCR5 (Sohy et al, 2009). The affinity of CXCR4 for its ligand CXCL12 was significantly reduced in the presence of CCR2 or CCR5 ligands, both in transfected cells as well as in naive CD4+ T lymphocytes. In a mouse air pouch model of leukocyte recruitment, addition of the CCR5 antagonist TAK779 strongly reduced the migration of leukocytes towards CXCL12 (Sohy et al, 2009). Although these studies indicate that chemokine receptors readily form heterodimers on the cell surface, the functional consequences of such interaction may vary depending on the physiologic context.
Affiliation: Institute for Cardiovascular Prevention, Ludwig-Maximilians-University of Munich, Munich, Germany.