Alternative titles; symbols
HGNC Approved Gene Symbol: CX3CL1
Cytogenetic location: 16q21 Genomic coordinates (GRCh38): 16:57,372,490-57,385,044 (from NCBI)
Chemokines are small secreted proteins that stimulate the directional migration of leukocytes and mediate inflammation. During screening of a murine choroid plexus cDNA library, Pan et al. (1997) identified a new chemokine, which they designated neurotactin. Unlike other chemokines, neurotactin has a unique cysteine pattern, Cys-X-X-X-Cys, and is predicted to be a type 1 membrane protein. Full-length recombinant neurotactin was identified on the surface of transfected cultured cells. Recombinant neurotactin containing the chemokine domain was chemotactic for neutrophils both in vitro and in vivo. Neurotactin mRNA was predominantly expressed in normal murine brain and its protein expression in activated brain microglia was upregulated in mice with experimental autoimmune encephalomyelitis, as well as in mice treated with lipopolysaccharide.
Bazan et al. (1997) also reported the identification and characterization of a fourth human chemokine type, derived from nonhematopoietic cells and bearing the new CX3C fingerprint. They termed the gene fractalkine. The polypeptide chain of human fractalkine was predicted to be part of a 373-amino acid protein that carries the chemokine domain on top of an extended mucin-like stalk. This molecule can exist in 2 forms: as membrane-anchored or as a shed 95-kD glycoprotein. The soluble fractalkine has potent chemoattractant activity for T cells and monocytes, and the cell surface-bound protein, which is induced on activated primary endothelial cells, promotes strong adhesion of those leukocytes.
Imai et al. (1997) identified a 7-transmembrane high-affinity receptor (CX3CR1; 601470) for fractalkine and showed that it mediates both the adhesive and migratory functions of fractalkine.
The structure, biochemical features, tissue distribution, and chromosomal localization of fractalkine indicated to Bazan et al. (1997) that it represents a unique class of chemokine that may constitute part of the molecular control of leukocyte traffic at the endothelium.
By expressing wildtype p53 (191170) in p53-defective cells followed by differential display analysis, Shiraishi et al. (2000) detected induction of CX3CL1. Electrophoretic mobility shift analysis showed that p53 binds to the fractalkine promoter at a predicted site. Heterogeneous luciferase reporter analysis confirmed the p53-dependent transcriptional activity. Shiraishi et al. (2000) proposed that intact p53, in addition to inducing apoptosis, may thus eliminate dangerous cells by inducing fractalkine, attracting natural killer cells that could lyse the transformed cell.
Using mouse and human cells and DNA constructs, Garton et al. (2001) provided evidence that TACE (ADAM17; 603639) is the protease responsible for phorbol ester-stimulated release of membrane-bound fractalkine from the surface of endothelial cells and fibroblasts. TACE was not required for constitutive fractalkine shedding. Fractalkine cleavage did not rely on a specific TACE-sensitive amino acid sequence, but showed relaxed sequence specificity and apparent recognition by TACE of the structure of the juxtamembrane stalk region of membrane-bound fractalkine.
Using specific metalloprotease inhibitors and overexpression studies, Hundhausen et al. (2003) determined that basal shedding of CX3CL1 from human leukemia and bladder carcinoma cell membranes was mediated by ADAM10 (602192), whereas phorbol ester-stimulated CX3CL1 shedding was mediated by TACE. Mouse embryo fibroblasts deficient in Adam10 showed reduced basal Cx3cl1 shedding in comparison with wildtype fibroblasts, but stimulated Cx3cl1 shedding was not affected. Inhibition of CX3CL1 cleavage increased the adhesive properties of an adherent CX3CL1-expressing human bladder carcinoma cell line and prevented deadhesion of attached monocytic leukemia cells. Hundhausen et al. (2003) concluded that constitutive cleavage of CX3CL1 by ADAM10 may regulate recruitment of monocytic cells to CX3CL1-expressing cell layers.
Tripp et al. (2001) showed that the G glycoprotein of respiratory syncytial virus (RSV) shares a heparin-binding domain and a CX3C chemokine motif with CX3CL1. Binding analysis indicated that RSV can use CX3CR1 as a receptor. G glycoprotein binding mimics fractalkine binding and induces leukocyte chemotaxis. Tripp et al. (2001) concluded that RSV G glycoprotein uses its similarities with CX3C to facilitate infection and to modify the immune response.
By immunocytochemical analysis, Lucas et al. (2003) investigated the expression of fractalkine and its receptor CX3CR1 in human coronary artery plaques. A subset of mononuclear cells expressed high levels of fractalkine in atherosclerotic plaques, and smooth muscle cells within the neointima expressed CX3CR1. There was a positive correlation between the number of fractalkine-expressing cells and the number of CX3CR1-positive cells in 15 plaques (r = 0.70). Cultured vascular smooth muscle cells expressing CX3CR1 underwent chemotaxis toward a fractalkine source, and chemotaxis was inhibited by G-protein inactivation. Lucas et al. (2003) concluded that fractalkine can act as a mediator of smooth muscle cell migration in human atherosclerosis, rather than mediate inflammatory cell recruitment.
Hannan et al. (2004) hypothesized that leukocyte migration is induced indirectly by progesterone-regulated chemokines. The chemotactic membrane-bound adhesion factor fractalkine (CX3CL1) and its receptor CX3CR1 were assessed by immunohistochemistry in endometrial samples across the menstrual cycle, in early pregnancy, and in women using progestin-only contraceptives. CX3CL1 was localized predominantly to glandular epithelial and decidualized stromal cells, with the highest staining intensity in the secretory phase and early pregnancy. CX3CR1 was similarly colocalized to the glandular epithelium and decidualized stromal cells, with the highest expression in the secretory phase. CX3CR1-positive leukocytes (macrophages and neutrophils) were in greatest abundance during the menstrual phase. In the endometrium of women using progestin-only contraceptives, immunoreactive CX3CL1 was markedly reduced in the glandular epithelium, but was increased in decidualized stroma and infiltrating leukocytes. The authors concluded that these findings support a number of roles for CX3CL1 in the endometrium, in the secretory phase, in early pregnancy, and when influenced by progestin-only contraceptives.
Schistosoma species (see 181460) are helminth parasites that are adept at manipulating the host immune system to allow tolerance of chronic worm infections without overt morbidity. This modulation of immunity by schistosomes prevents a range of immune-mediated diseases, including allergies and autoimmunity. Smith et al. (2005) identified a molecule produced by Schistosoma eggs, termed S. mansoni chemokine-binding protein (smCKBP), that bound several chemokines, including CX3CL1. SmCKBP blocked interaction of these chemokines with their receptors and thereby inhibited induction of inflammation. Smith et al. (2005) proposed that since smCKBP is unrelated to host proteins, it may have potential as an antiinflammatory agent.
Crystal Structure
Burg et al. (2015) reported the crystal structure at 2.9-angstrom resolution of the human cytomegalovirus G protein-coupled receptor US28 in complex with the chemokine domain of human CX3CL1. The globular body of CX3CL1 is perched on top of the US28 extracellular vestibule, whereas its amino terminus projects into the central core of US28.
Pan et al. (1997) found that both human and murine neurotactin genes are located on different chromosomes from other chemokines. Using a panel of backcross progeny of C57BL/6J Mus musculus and Mus spretus mice, they mapped the murine neurotactin gene to the long arm of chromosome 8. The human neurotactin gene was localized by radiation hybrid mapping to the syntenic region of 16q. The results supported the notion that neurotactin represents a new class of chemokine, which the authors referred to as the delta-chemokine family.
By somatic cell hybridization and PCR on genomic DNAs, Bazan et al. (1997) mapped the fractalkine gene to chromosome 16.
Nomiyama et al. (1998) showed that the SCYD1 gene is clustered with the SCYA22 gene (602957) and the SCYA17 gene (601520) on 16q13. The mapping was achieved by analyzing somatic cell hybrids containing various portions of human chromosome 16 with PCR. To determine further whether these genes are closely adjacent to each other, Kim et al. (1996) searched the California Institute of Technology BAC library of average 130-kb insert size. At least 2 clones were found that contained all 3 genes, suggesting that they are located within a short segment, probably 200 kb or less. This supported their close evolutionary relationship.
Lesnik et al. (2003) found prominent expression of fractalkine in smooth muscle cells underlying macrophages in atherosclerotic plaques from apoE (107741)-null mice fed a high-fat diet. However, fractalkine was not strongly expressed within the macrophages themselves, indicating that macrophages were not the primary source of the cytokine. Compared to the apoE-null mice, mice doubly null for apoE and the fractalkine receptor Cx3cr1 showed a significant reduction in aortic atherosclerotic plaque lesion formation and lesion progression after being fed a high-fat diet. In addition, there was a significant reduction in numbers of macrophages within the plaques in mice doubly null for apoE and Cx3cr1 compared to apoE-null mice. Lesnik et al. (2003) concluded that fractalkine recruits monocytes and macrophages to the vessel wall and plays a role in the formation of atherosclerotic lesions.
Bazan, J. F., Bacon, K. B., Hardiman, G., Wang, W., Soo, K., Rossi, D., Greaves, D. R., Zlotnik, A., Schall, T. J. A new class of membrane-bound chemokine with a CX3C motif. Nature 385: 640-644, 1997. [PubMed: 9024663] [Full Text: https://doi.org/10.1038/385640a0]
Burg, J. S., Ingram, J. R., Venkatakrishnan, A. J., Jude, K. M., Dukkipati, A., Feinberg, E. N., Angelini, A., Waghray, D., Dror, R. O., Ploegh, H. L., Garcia, K. C. Structural basis for chemokine recognition and activation of a viral G protein-coupled receptor. Science 347: 1113-1117, 2015. [PubMed: 25745166] [Full Text: https://doi.org/10.1126/science.aaa5026]
Garton, K. J., Gough, P. J., Blobel, C. P., Murphy, G., Greaves, D. R., Dempsey, P. J., Raines, E. W. Tumor necrosis factor-alpha-converting enzyme (ADAM17) mediates the cleavage and shedding of fractalkine (CX3CL1). J. Biol. Chem. 276: 37993-38001, 2001. [PubMed: 11495925] [Full Text: https://doi.org/10.1074/jbc.M106434200]
Hannan, N. J., Jones, R. L., Critchley, H. O. D., Kovacs, G. J., Rogers, P. A. W., Affandi, B., Salamonsen, L. A. Coexpression of fractalkine and its receptor in normal human endometrium and in endometrium from users of progestin-only contraception supports a role of fractalkine in leukocyte recruitment and endometrial remodeling. J. Clin. Endocr. Metab. 89: 6119-6129, 2004. [PubMed: 15579768] [Full Text: https://doi.org/10.1210/jc.2003-031379]
Hundhausen, C., Misztela, D., Berkhout, T. A., Broadway, N., Saftig, P., Reiss, K., Hartmann, D., Fahrenholz, F., Postina, R., Matthews, V., Kallen, K.-J., Rose-John, S., Ludwig, A. The disintegrin-like metalloproteinase ADAM10 is involved in constitutive cleavage of CX3CL1 (fractalkine) and regulates CX3CL1-mediated cell-cell adhesion. Blood 102: 1186-1195, 2003. [PubMed: 12714508] [Full Text: https://doi.org/10.1182/blood-2002-12-3775]
Imai, T., Hieshima, K., Haskell, C., Baba, M., Nagira, M., Nishimura, M., Kakizaki, M., Takagi, S., Nomiyama, H., Schall, T. J., Yoshie, O. Identification and molecular characterization of fractalkine receptor CX3CR1, which mediates both leukocyte migration and adhesion. Cell 91: 521-530, 1997. [PubMed: 9390561] [Full Text: https://doi.org/10.1016/s0092-8674(00)80438-9]
Kim, U. J., Birren, B. W., Slepak, T., Mancino, V., Boysen, C., Kang, H. L., Simon, M. I., Shizuya, H. Construction and characterization of a human bacterial artificial chromosome library. Genomics 34: 213-218, 1996. [PubMed: 8661051] [Full Text: https://doi.org/10.1006/geno.1996.0268]
Lesnik, P., Haskell, C. A., Charo, I. F. Decreased atherosclerosis in CX3CR1-/- mice reveals a role for fractalkine in atherogenesis. J. Clin. Invest. 111: 333-340, 2003. [PubMed: 12569158] [Full Text: https://doi.org/10.1172/JCI15555]
Lucas, A. D., Bursill, C., Guzik, T. J., Sadowski, J., Channon, K. M., Greaves, D. R. Smooth muscle cells in human atherosclerotic plaques express the fractalkine receptor CX3CR1 and undergo chemotaxis to the CX3C chemokine fractalkine (CX3CL1). Circulation 108: 2498-2504, 2003. [PubMed: 14581400] [Full Text: https://doi.org/10.1161/01.CIR.0000097119.57756.EF]
Nomiyama, H., Imai, T., Kusuda, J., Miura, R., Callen, D. F., Yoshie, O. Human chemokines fractalkine (SCYD1), MDC (SCYA22) and TARC (SCYA17) are clustered on chromosome 16q13. Cytogenet. Cell Genet. 81: 10-11, 1998. [PubMed: 9691168] [Full Text: https://doi.org/10.1159/000015000]
Pan, Y., Lloyd, C., Zhou, H., Dolich, S., Deeds, J., Gonzalo, J.-A., Vath, J., Gosselin, M., Ma, J., Dussault, B., Woolf, E., Alperin, G., Culpepper, J., Gutierrez-Ramos, J. C., Gearing, D. Neurotactin, a membrane-anchored chemokine upregulated in brain inflammation. Nature 387: 611-617, 1997. Note: Erratum: Nature 389: 100 only, 1997. [PubMed: 9177350] [Full Text: https://doi.org/10.1038/42491]
Shiraishi, K., Fukuda, S., Mori, T., Matsuda, K., Yamaguchi, T., Tanikawa, C., Ogawa, M., Nakamura, Y., Arakawa, H. Identification of fractalkine, a CX3C-type chemokine, as a direct target of p53. Cancer Res. 60: 3722-3726, 2000. [PubMed: 10919640]
Smith, P., Fallon, R. E., Mangan, N. E., Walsh, C. M., Saraiva, M., Sayers, J. R., McKenzie, A. N. J., Alcami, A., Fallon, P. G. Schistosoma mansoni secretes a chemokine binding protein with antiinflammatory activity. J. Exp. Med. 202: 1319-1325, 2005. [PubMed: 16301741] [Full Text: https://doi.org/10.1084/jem.20050955]
Tripp, R. A., Jones, L. P., Haynes, L. M., Zheng, H., Murphy, P. M., Anderson, L. J. CX3C chemokine mimicry by respiratory syncytial virus G glycoprotein. Nature Immun. 2: 732-738, 2001. [PubMed: 11477410] [Full Text: https://doi.org/10.1038/90675]