Fractalkine: A Cellular Link Between Adipose Tissue Inflammation and Vascular Pathologies

It is hard to imagine, given the wealth of new data reported over the recent past, that adipose tissue at one time was primarily considered as a passive reservoir for energy deposition and storage. However, research beginning in the early 1990s on the role of tumor necrosis factor (TNF)-a ushered in a new era of investigation, and since that time, there has been an incredibly rapid and substantive increase in our understanding of underlying physiologic systems and molecular pathways linking obesity, inflammation, and insulin action (1,2). Specifically, our understanding of the link between obesity and carbohydrate metabolism has been significantly enhanced with the elucidation of key regulators of energy balance and cellular insulin signaling that are complex and highly integrated (3–6). We now readily accept adipose tissue as a key endocrine organ regulating processes throughout the body with its significant number of adipocyte secretions. What now appears to be emerging is the elucidation of cellular pathways that are operative at not only the level of the adipocyte, but appear in common with those reported in vascular tissue. Such a cellular mechanism that may link pathophysiologic processes between adipose and vascular tissue is the fractalkine chemokine system as reported in this issue of Diabetes by Shah et al. (7). Specifically, Shah et al. provide interesting data that suggest that fractalkine (CX3CL1), a chemokine whose source is the endothelium and is postulated to play a role in atherogenesis, is also expressed in obese adipose tissue and plays a role in monocyte adhesion processes. These data provide an intriguing molecular link between obesity-related metabolic dysfunction and cardiovascular disease (CVD) in humans. Fractalkine, a chemokine that signals through a single known receptor (CX3CR1), has received considerable interest in relation to the contribution to atheroscleroisis. It has been described as a multidomain protein of exceptionally large size, i.e., 95 kDa, and is expressed on numerous cells, but more importantly, on activated endothelial, smooth muscle cells, and macrophages (8,9). In addition to its large size, another feature that is different from other members of the cytokine family is the presence of a transmembrane anchor, and as such, fractalkine is capable of mediating adhesion of cells expressing the G protein–coupled receptor CX3CR1. The expression of fractalkine has reportedly been enhanced by inflammatory stimuli, i.e., TNF-a, interferon (IFN)-g and lipopolysaccharide (9). It is also reported that a soluble form can be released from its membrane form by extracellular cleavage and then act as a classical chemoattractant for leukocytes and also smooth muscle cells expressing the receptor, i.e., CX3CR1 (8,9). Recently, elegant studies in primary smooth muscle cell lines demonstrated that CX3CL1 may have novel functions in regard to antiapotosis and proliferation, and as such, have important implications for vascular pathologies where the balance of smooth muscle cell proliferation and apotosis plays a critical role in determining plaque stability and vessel stenosis (9). The chemokine family in general and fractalkine in particular are postulated to contribute significantly to the pathogenesis of CVD as leukocyte recruitment plays a role at all stages of CVD progression from early plaque formation to plaque rupture (10). The pathways by which fractalkine may participate in the modulation of adhesion processes at the cellular level are outlined schematically in Fig. 1 (11). As demonstrated in the figure, fractalkine may enhance leukocyte migration from the circulation into the tissue by enhancing the tethering (transient, selectinmediated binding), triggering (activation of integrins by chemokines), adhesion, and finally migration through the endothelial layer. As such, enhancing or inhibiting any of these steps can either promote or attenuate atherogenic processes, respectively. In this regard, a preclinical study in mice evaluated anti-inflammatory therapy in the form of aspirin and plaque severity. Interestingly, anti-inflammatory treatment improved the atherosclerotic lesion as assessed by pathology image analysis. Such therapy also reportedly suppressed the fractalkine expression as assessed by both RT-PCR and immunohistochemical analysis, suggesting a cause and effect (12). However, the clinical relevance in humans has been suggested by recent studies evaluating lesion extent and characteristics and the association to specific markers of the fractalkine-CX3CR1 chemokine system. Specifically, Ikejima et al. (10) demonstrated that plasma levels of fractalkine were significantly increased in patients with unstable angina pectoris with plaque rupture compared with patients with unstable angina pectoris without plaque rupture and patients with stable angina pectoris. In addition, they demonstrated that CX3CR1-expressing mononuclear cells were independent predictors of the presence of the plaque rupture (10). Other studies have suggested that fractalkine is increased in patients with coronary heart disease, but the beneficial effect of optimized anti-inflammatory therapy, i.e., statins, ACE inhibitors and ARBs, as part of coronary artery rehabilitation, may reduce the levels to those of control subjects (8). Additional studies in humans have evaluated polymorphisms of fractalkine that are postulated to alter ligand receptor affinity, and as such, potentially influence a patient’s From the Joint Program on Diabetes, Endocrinology, and Metabolism, Louisiana State University Health Sciences Center School of Medicine, New Orleans, Louisiana, and the Pennington Biomedical Research Center, Baton Rouge, Louisiana. Corresponding author: William T. Cefalu, [email protected]. DOI: 10.2337/db11-0239 2011 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by -nc-nd/3.0/ for details. See accompanying original article, p. 1512.