Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi


  • Paula A. Pino
  • Astrid E. CardonaEmail author
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_600


Historical Background

Human CX3CL1 was first cloned in 1997 and the mouse homolog in 1998. CX3CL1 is a relatively large protein consisting of an amino-terminal domain, a mucin-like stalk attached to a transmembrane region that connects the molecule to the plasma membrane, followed by the intracellular domain. CX3CL1 is biologically active either as a membrane-bound protein or as a soluble protein upon proteolytic cleavage from cell membranes. CX3CL1 actions are mediated through interaction with its unique G-protein coupled receptor CX3CR1 (previously called chemokine receptor CKRBRL1, RBS11, or V28). Both CX3CL1 and CX3CR1 are highly abundant in central nervous system (CNS) tissues; CX3CL1 is produced by neurons and CX3CR1 is present on microglial cells. In the periphery, CX3CL1 is produced mostly by endothelial cells and CX3CR1 is expressed on peripheral leukocytes. CX3CL1 plays a role in chemotaxis, cell adhesion, and cellular activation. Notably,...

This is a preview of subscription content, log in to check access.


  1. Auffray C, Sieweke MH, Geissmann F. Blood monocytes: development, heterogeneity, and relationship with dendritic cells. Annu Rev Immunol. 2009;27:669–92.PubMedCrossRefGoogle Scholar
  2. Cardona A, Pioro EP, Sasse ME, Kostenko V, Cardona SM, Dijkstra IM, et al. Control of microglial neurotoxicity by the fractalkine receptor. Nat Neurosci. 2006;9(7):917–24.PubMedCrossRefGoogle Scholar
  3. Carson MJ, Reilly CR, Sutcliffe JG, Lo D. Mature microglia resemble immature antigen-presenting cells. Glia. 1998;22(1):72–85.PubMedCrossRefGoogle Scholar
  4. Chan CC, Tuo J, Bojanowski CM, Csaky KG, Green WR. Detection of CX3CR1 single nucleotide polymorphism and expression on archived eyes with age-related macular degeneration. Histol Histopathol. 2005;20(3):857–63.PubMedPubMedCentralGoogle Scholar
  5. Chastain EM, Duncan DS, Rodgers JM, Miller SD. The role of antigen presenting cells in multiple sclerosis. Biochim Biophys Acta. 2011;1812(2):265–74.PubMedCrossRefGoogle Scholar
  6. Chen CJ, Kono H, Golenbock D, Reed G, Akira S, Rock KL. Identification of a key pathway required for the sterile inflammatory response triggered by dying cells. Nat Med. 2007;13(7):851–6.PubMedCrossRefGoogle Scholar
  7. Fuller AD, Van Eldik LJ. MFG-E8 regulates microglial phagocytosis of apoptotic neurons. J Neuroimmune Pharmacol. 2008;3(4):246–56.PubMedPubMedCentralCrossRefGoogle Scholar
  8. Garton KJ, Gough PJ, Blobel CP, Murphy G, Greaves DR, Dempsey PJ, et al. Tumor necrosis factor-alpha-converting enzyme (ADAM17) mediates the cleavage and shedding of fractalkine (CX3CL1). J Biol Chem. 2001;276(41):37993–8001.PubMedPubMedCentralGoogle Scholar
  9. Geissmann F, Auffray C, Palframan R, Wirrig C, Ciocca A, Campisi L, et al. Blood monocytes: distinct subsets, how they relate to dendritic cells, and their possible roles in the regulation of T-cell responses. Immunol Cell Biol. 2008;86(5):398–408.PubMedCrossRefGoogle Scholar
  10. Gough PJ, Garton KJ, Wille PT, Rychlewski M, Dempsey PJ, Raines EW. A disintegrin and metalloproteinase 10-mediated cleavage and shedding regulates the cell surface expression of CXC chemokine ligand 16. J Immunol. 2004;172(6):3678–85.PubMedCrossRefGoogle Scholar
  11. Green SR, Han KH, Chen Y, Almazan F, Charo IF, Miller YI, et al. The CC chemokine MCP-1 stimulates surface expression of CX3CR1 and enhances the adhesion of monocytes to fractalkine/CX3CL1 via p38 MAPK. J Immunol. 2006;176(12):7412–20.PubMedCrossRefGoogle Scholar
  12. Hamann I, Unterwalder N, Cardona AE, Meisel C, Zipp F, Ransohoff RM, et al. Analyses of phenotypic and functional characteristics of CX3CR1-expressing natural killer cells. Immunology. 2011;133(1):62–73.PubMedPubMedCentralCrossRefGoogle Scholar
  13. Hiroyama T, Iwama A, Nakamura Y, Nakauchi H. Fractalkine shares signal sequence with TARC: gene structures and expression profiles of two chemokine genes. Genomics. 2001;75(1–3):3–5.PubMedCrossRefGoogle Scholar
  14. Huang D, Shi FD, Jung S, Pien GC, Wang J, Salazar-Mather TP, et al. The neuronal chemokine CX3CL1/fractalkine selectively recruits NK cells that modify experimental autoimmune encephalomyelitis within the central nervous system. FASEB J. 2006;20(7):896–905.PubMedCrossRefGoogle Scholar
  15. Hurst LA, Bunning RA, Couraud PO, Romero IA, Weksler BB, Sharrack B, et al. Expression of ADAM-17, TIMP-3 and fractalkine in the human adult brain endothelial cell line, hCMEC/D3, following pro-inflammatory cytokine treatment. J Neuroimmunol. 2009;210(1–2):108–12.PubMedCrossRefGoogle Scholar
  16. Infante-Duarte C, Weber A, Kratzschmar J, Prozorovski T, Pikol S, Hamann I, et al. Frequency of blood CX3CR1-positive natural killer cells correlates with disease activity in multiple sclerosis patients. FASEB J. 2005;19(13):1902–4.PubMedCrossRefGoogle Scholar
  17. Jung S, Aliberti J, Graemmel P, Sunshine MJ, Kreutzberg GW, Sher A, et al. Analysis of fractalkine receptor CX(3)CR1 function by targeted deletion and green fluorescent protein reporter gene insertion. Mol Cell Biol. 2000;20(11):4106–14.PubMedPubMedCentralCrossRefGoogle Scholar
  18. Klosowska K, Volin MV, Huynh N, Chong KK, Halloran MM, Woods JM. Fractalkine functions as a chemoattractant for osteoarthritis synovial fibroblasts and stimulates phosphorylation of mitogen-activated protein kinases and Akt. Clin Exp Immunol. 2009;156(2):312–9.PubMedPubMedCentralCrossRefGoogle Scholar
  19. Lavergne E, Combadiere B, Bonduelle O, Iga M, Gao JL, Maho M, et al. Fractalkine mediates natural killer-dependent antitumor responses in vivo. Cancer Res. 2003;63(21):7468–74.PubMedPubMedCentralGoogle Scholar
  20. Lee SJ, Namkoong S, Kim YM, Kim CK, Lee H, Ha KS, et al. Fractalkine stimulates angiogenesis by activating the Raf-1/MEK/ERK- and PI3K/Akt/eNOS-dependent signal pathways. Am J Physiol Heart Circ Physiol. 2006;291(6):H2836–46.PubMedCrossRefGoogle Scholar
  21. Lee S, Varvel N, Konerth M, Xu G, Cardona AE, Ransohoff RM, et al. CX3CR1 deficiency alters microglial activation and reduces beta-amyloid deposition in two Alzheimer’s disease models. Am J Pathol. 2010;177:2549–62.PubMedPubMedCentralCrossRefGoogle Scholar
  22. Lyszkiewicz M, Witzlau K, Pommerencke J, Krueger A. Chemokine receptor CX3CR1 promotes dendritic cell development under steady-state conditions. Eur J Immunol. 2011;41(4):1256–65.PubMedCrossRefGoogle Scholar
  23. Marchesi F, Locatelli M, Solinas G, Erreni M, Allavena P, Mantovani A. Role of CX3CR1/CX3CL1 axis in primary and secondary involvement of the nervous system by cancer. J Neuroimmunol. 2010;224(1–2):39–44.PubMedCrossRefGoogle Scholar
  24. McDermott DH, Halcox JP, Schenke WH, Waclawiw MA, Merrell MN, Epstein N, et al. Association between polymorphism in the chemokine receptor CX3CR1 and coronary vascular endothelial dysfunction and atherosclerosis. Circ Res. 2001;89(5):401–7.PubMedCrossRefGoogle Scholar
  25. McDermott DH, Fong AM, Yang Q, Sechler JM, Cupples LA, Merrell MN, et al. Chemokine receptor mutant CX3CR1-M280 has impaired adhesive function and correlates with protection from cardiovascular disease in humans. J Clin Invest. 2003;111(8):1241–50.PubMedPubMedCentralCrossRefGoogle Scholar
  26. Mizuno T, Kawanokuchi J, Numata K, Suzumura A. Production and neuroprotective functions of fractalkine in the central nervous system. Brain Res. 2003;979(1–2):65–70.PubMedCrossRefGoogle Scholar
  27. Mizutani M, Pino A, Saederup N, Charo I, Ransohoff RM, Cardona AE. The fractalkine receptor but not CCR2 is present on microglia from embryonic development throughout adulthood. J Immunol. 2011. (in press).Google Scholar
  28. Moatti D, Faure S, Fumeron F, Amara M, Seknadji P, McDermott DH, et al. Polymorphism in the fractalkine receptor CX3CR1 as a genetic risk factor for coronary artery disease. Blood. 2001;97(7):1925–8.PubMedCrossRefGoogle Scholar
  29. Nassar BA, Nanji AA, Ransom TP, Rockwood K, Kirkland SA, Macpherson K, et al. Role of the fractalkine receptor CX3CR1 polymorphisms V249I and T280M as risk factors for early-onset coronary artery disease in patients with no classic risk factors. Scand J Clin Lab Invest. 2008;68(4):286–91.PubMedCrossRefGoogle Scholar
  30. Nimmerjahn A, Kirchhoff F, Helmchen F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science. 2005;308(5726):1314–8.CrossRefGoogle Scholar
  31. Noda M, Doi Y, Liang J, Kawanokuchi J, Sonobe Y, Takeuchi H, et al. Fractalkine attenuates excito-neurotoxicity via microglial clearance of damaged neurons and antioxidant enzyme heme oxygenase-1 expression. J Biol Chem. 2011;286(3):2308–19.PubMedCrossRefGoogle Scholar
  32. Neumann H, Kotter MR, Franklin JM. Debris clearance by microglia: an essential link between degeneration and regeneration. Brain. 2009;132(Pt2):288–95.PubMedPubMedCentralGoogle Scholar
  33. Pallandre JR, Krzewski K, Bedel R, Ryffel B, Caignard A, Rohrlich PS, et al. Dendritic cell and natural killer cell cross-talk: a pivotal role of CX3CL1 in NK cytoskeleton organization and activation. Blood. 2008;112(12):4420–4.PubMedPubMedCentralCrossRefGoogle Scholar
  34. Saederup N, Cardona AE, Croft K, Mizutani M, Cotleur AC, Tsou CL, et al. Selective chemokine receptor usage by central nervous system myeloid cells in CCR2-red fluorescent protein knock-in mice. PLoS One. 2010;5(10):e13693.PubMedPubMedCentralCrossRefGoogle Scholar
  35. Savarin-Vuaillat C, Ransohoff RM. Chemokines and chemokine receptors in neurological disease: raise, retain, or reduce? Neurotherapeutics. 2007;4(4):590–601.PubMedCrossRefGoogle Scholar
  36. Sunnemark D, Eltayeb S, Nilsson M, Wallstrom E, Lassmann H, Olsson T, et al. CX3CL1 (fractalkine) and CX3CR1 expression in myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis: kinetics and cellular origin. J Neuroinflamm. 2005;2:17.CrossRefGoogle Scholar
  37. Truman LA, Ford CA, Pasikowska M, Pound JD, Wilkinson SJ, Dumitriu IE, et al. CX3CL1/fractalkine is released from apoptotic lymphocytes to stimulate macrophage chemotaxis. Blood. 2008;112(13):5026–36.PubMedCrossRefGoogle Scholar
  38. Williams K, Ulvestad E, Waage A, Antel JP, McLaurin J. Activation of adult human derived microglia by myelin phagocytosis in vitro. J Neurosci Res. 1994;38(4):433–43.PubMedCrossRefGoogle Scholar
  39. Xun CQ, Thompson JS, Jennings CD, Brown SA, Widmer MB. Effect of total body irradiation, busulfan-cyclophosphamide, or cyclophosphamide conditioning on inflammatory cytokine release and development of acute and chronic graft-versus-host disease in H-2-incompatible transplanted SCID mice. Blood. 1994;83(8):2360–7.PubMedPubMedCentralGoogle Scholar
  40. Yajima N, Kasama T, Isozaki T, Odai T, Matsunawa M, Negishi M, et al. Elevated levels of soluble fractalkine in active systemic lupus erythematosus: potential involvement in neuropsychiatric manifestations. Arthritis Rheum. 2005;52(6):1670–5.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of Biology and South Texas Center for Emerging Infectious DiseasesThe University of Texas at San AntonioSan AntonioUSA