© 2002 American Thoracic Society
Stalking the ChemokineDivision of Biomedical Sciences Imperial College Faculty of Medicine London, United Kingdom Our survival depends on an army of different types of defense cells specialized for diverse functions. The initial localization of these cell types and their recruitment to sites of potential danger depends on soluble chemical signals liberated at the intended site of assembly and the appropriate receptor on the surface of the particular defensive cell. Inappropriate or overexuberant recruitment of these cells results in inflammatory disease. The initial ripples of understanding about the mechanisms underlying this system were apparent in the second half of the 1980s with the discovery of the first chemokines (chemotactic cytokines). Now, approximately 50 are recognized. The complexity of this system is emphasized by the fact that they signal through approximately 20 7-transmembrane G-protein–coupled receptors and that different types of leukocytes display typically several types of receptor. Moreover, chemokines are often able to signal via several different receptors and can act in a combinatorial fashion. Chemokines are best known for their ability to recruit leukocytes from the blood stream by stimulating cytoskeletal changes in the cell and an upregulation of their integrin adhesion molecules. The integrins engage complementary receptors on endothelial cells of small blood vessels, resulting in firm attachment followed by migration through the vessel wall into the tissue. Chemokines can be synthesized by many different cell types, given the appropriate stimulus. It is thought that they bind to glycosaminoglycans on the luminal surface of endothelial cells and present the chemokine to its receptor on the leukocyte surface as the cell rolls along the vessel wall. What could be more natural, therefore, than for one such chemokine to shortcut this process and be synthesized with its own stalk for presentation on endothelial or other cells? Accordingly, two papers were published in 1997 describing such a molecule, variously described as neurotactin (1) or fractalkine (2), and having a chemokine attached to a mucin stalk. Hitherto, all known chemokines were soluble and had two disulphide bonds: the two cysteines near the N-terminus defining two major families, CC chemokines having adjacent cysteines, and CXC chemokines having one interposed amino acid. Fractalkine was an exception in having three interposed amino acids and is known as CX3CL in the new nomenclature of chemokine ligands (3). Other exceptions from the main two families are lymphotactin (XCL1), having a single disulphide bond, and newer family members, such as 6Ckine (CCL21), having three disulphide bonds. The receptor for fractalkine (CX3CR) was identified and found to be expressed on monocytes, T cells, mast cells, and natural killer cells (4, 5). Evidence was obtained that the mucin component functions as a stalk to facilitate presentation, rather than confer other properties to the molecule (6). Further interest was sparked by the observation that fractalkine could act not only as a stimulatory molecule of its receptor CX3CR but also as an adhesion molecule attaching to the same receptor and providing adherence independently of integrins (7, 8). Because of its celebrity status as a unique chemokine with special properties, much attention has been focused on the stalked chemokine with respect to its role in disease, and indeed animal models have suggested a role in inflammatory conditions, for example, of the kidney (9). Therefore, the article in this issue of AJRCCM (pp. 1419–1425) by Balabanian and colleagues (10) is timely. Balabanian and colleagues (10) show, first, that patients with pulmonary arterial hypertension (PAH) have increased expression of fractalkine receptor on their circulating T lymphocytes: CD4+ and CD8+, CD45RO+ memory, and CD45RO- naive all showed increased expression. This was backed up by increased functional responses to fractalkine in all but the CD45RO-/CD8+ cells, as measured by actin polymerization. Second, the authors demonstrate that levels of circulating soluble fractalkine are increased fivefold in PAH patients when compared with control subjects. It is known that the chemokine, together with its stalk, can be cleaved near the cell membrane by an enzyme, TACE, to yield a soluble form (11, 12). Third, the article goes on to show that the expression of fractalkine gene is higher in biopsies of lungs from PAH patients when compared with samples from control subjects, measured by reverse transcriptase-polymerase chain reaction. In situ hybridization experiments demonstrated fractalkine mRNA in pulmonary artery endothelial cells, and fractalkine protein was observed using immunohistochemistry in both PAH patients and control subjects. From these results, the authors conclude that fractalkine may have an important role in PAH. The increase in fractalkine mRNA seen in biopsies from PAH patients may be reflected in an elevation of expression of fractalkine protein on pulmonary endothelial cells over constitutive levels. This, combined with increased expression of fractalkine receptor on circulating inflammatory cells, particularly CD4+ T lymphocytes, may induce increased numbers of these cells to accumulate in the arterial wall. These cells may make an important contribution to the inflammatory events observed in the pulmonary arterial wall in PAH patients. The increased levels of circulating soluble fractalkine seen in PAH patients may be a consequence of increased production in the lung and/or increased cleavage of the cell-bound form by TACE. One note of caution is that the antibody used to detect fractalkine expression on pulmonary endothelial cells in this study (by inference from citation of their previously published methods) has been reported to cross-react with CD84 (13), which is expressed on endothelial cells. Other studies, using antibodies that do not cross-react, have not shown fractalkine expression on endothelial cells in normal or diseased tissues, except in the rheumatoid joint. Thus, sources of fractalkine, other than endothelial cells, may be important in vivo, raising the possibility that soluble fractalkine may have a significant role in recruiting cells across the endothelium. Molecular biology has thrown many tantalizing molecules into the scientific arena. Laboratory scientists are skilled at weaving these molecules into elaborate mechanisms. Thus it is with fractalkine, and articles such as that of Balabanian and colleagues provide an essential test of the durability of such putative mechanisms in the context of disease. REFERENCES
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