Post-translational control of chemokines: a role for decoy receptors?
ABSTRACT It is well-established that chemokines play a critical role in the orchestration of inflammation and immunity. Interactions between chemokines and their receptors are essential for the homing of specific subsets of leukocytes to their functional microenvironments. They also influence other diverse biological processes such as development, leukocyte activation, Th1/Th2 polarisation, tumour metastasis, angiogenesis, and HIV pathogenesis. However, despite their importance, only now are we beginning to understand the complex regulation brought to bear on these molecules. In this review, we discuss a number of these key chemokine regulators that exert their influence once these proteins have been synthesised. We examine (i) chemokine storage, release, and presentation, (ii) protease regulation, (iii) viral manipulation of host chemokines, and (iv) natural mammalian receptor antagonists. Principally, the growing evidence for a role for decoy receptors in the chemokine system is discussed. In particular, the potential decoy function of the 'silent' pro-inflammatory chemokine receptor D6 is described alongside two other candidate decoy receptor molecules, DARC, and CCX-CKR. Dissecting the biological and pathological function of these chemokine controllers will lead to a deeper understanding of chemokine regulation, and may reveal novel strategies to therapeutically modify the chemokine system.
SourceAvailable from: PubMed Central[Show abstract] [Hide abstract]
ABSTRACT: Atherosclerosis is currently considered an inflammatory disease. Much attention has been focused on the potential role of inflammatory mediators as prognostic/diagnostic markers or therapeutic targets of atherosclerotic cardiovascular disease. CX3CL1 (or fractalkine) is a structurally and functionally unique chemokine with a well documented role in atherosclerosis. In its membrane bound form it promotes the firm adhesion of rolling leucocytes onto the vessel wall, while in its soluble form it serves as a potent chemoattractant for CX3CR1-expressing cells. Additionally, CX3CL1 exerts cytotoxic effects on the endothelium as well as anti-apoptotic and proliferative effects on vascular cells, affecting the context and stability of the atherosclerotic plaque. Studies on animal models have shown that the blockade of the CX3CL1/CX3CR1 pathway ameliorates the severity of atherosclerosis, while genetic epidemiology has confirmed that a genetically-defined less active CX3CL1/CX3CR1 pathway is associated with a reduced risk of atherosclerotic disease in humans. Although several studies support an important pathogenic role of CX3CL1/CX3CR1 in atherogenesis and plaque destabilization, this does not necessarily suggest that this pathway is a suitable therapeutic target or that CX3CL1 can serve as a prognostic/diagnostic biomarker. Further studies on the CX3CL1/CX3CR1 chemokine pathway are clearly warranted to justify the clinical relevance of its role in atherosclerosis.Acta Pharmacologica Sinica 08/2013; DOI:10.1038/aps.2013.92 · 2.50 Impact Factor