title: Fractalkine promotes human monocyte survival via a reduction in oxidative stress.
abstract: OBJECTIVE
  The CX3C chemokine fractalkine (CX3CL1) has a critical role in the development of atherogenesis because apolipoprotein-E-deficient mice lacking CX3CL1 or its receptor CX3CR1 develop smaller plaques and polymorphisms in CX3CR1 are associated with altered risk of cardiovascular disease. CX3CR1 is found on numerous cell types involved in atherogenesis but seems to have a key role in monocyte function. We aimed to elucidate the role of CX3CL1 in human monocyte survival and determine the mechanism by which CX3CL1 spares monocytes from apoptosis.
  
  
  RESULTS
  Primary human monocytes were prepared from healthy donors and subjected to serum-starvation to induce spontaneous apoptosis. The addition of CX3CL1, but not other chemokines tested, promoted monocyte survival in a dose-dependent manner with full-length CX3CL1 (including the mucin stalk) having a more potent antiapoptotic effect than chemokine-domain CX3CL1. The prosurvival effect of CX3CL1 was evident in both monocyte subsets although nonclassical monocytes were more prone to spontaneous apoptosis. In addition, we found that the effect of CX3CL1 was independent of CX3CR1 genotype. Serum-starvation increased the level of intracellular reactive oxygen species, and this was reduced by the addition of CX3CL1. Inhibition of oxidative stress with an antioxidant prevented monocyte apoptosis, indicating that this is the dominant mechanism of cell death targeted by CX3CL1.
  
  
  CONCLUSIONS
  CX3CL1 has a substantial and highly reproducible antiapoptotic effect on human monocytes, via a mechanism involving a reduction in oxidative stress. This suggests that CX3CL1 is likely to play a key role in human atherogenesis and may provide a novel therapeutic target in cardiovascular disease.
authors.affiliation: From the Sir William Dunn School of Pathology (G.E.W., D.R.G.), Division of Cardiovascular Medicine, British Heart Foundation Centre of Research Excellence, John Radcliffe Hospital (E.M., K.M.C.), and Wellcome Trust Centre for Human Genetics (E.M., K.M.C.), University of Oxford, Oxford, United Kingdom.
authors.forename: Gemma E
authors.initials: GE
authors.lastname: White
authors.affiliation: From the Sir William Dunn School of Pathology (G.E.W., D.R.G.), Division of Cardiovascular Medicine, British Heart Foundation Centre of Research Excellence, John Radcliffe Hospital (E.M., K.M.C.), and Wellcome Trust Centre for Human Genetics (E.M., K.M.C.), University of Oxford, Oxford, United Kingdom.
authors.forename: Eileen
authors.initials: E
authors.lastname: McNeill
authors.affiliation: From the Sir William Dunn School of Pathology (G.E.W., D.R.G.), Division of Cardiovascular Medicine, British Heart Foundation Centre of Research Excellence, John Radcliffe Hospital (E.M., K.M.C.), and Wellcome Trust Centre for Human Genetics (E.M., K.M.C.), University of Oxford, Oxford, United Kingdom.
authors.forename: Keith M
authors.initials: KM
authors.lastname: Channon
authors.affiliation: From the Sir William Dunn School of Pathology (G.E.W., D.R.G.), Division of Cardiovascular Medicine, British Heart Foundation Centre of Research Excellence, John Radcliffe Hospital (E.M., K.M.C.), and Wellcome Trust Centre for Human Genetics (E.M., K.M.C.), University of Oxford, Oxford, United Kingdom. david.greaves@path.ox.ac.uk.
authors.forename: David R
authors.initials: DR
authors.lastname: Greaves
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D000073883:CX3C Chemokine Receptor 1; D002470:Cell Survival / Q000502:physiology*; D018932:Chemokine CCL2 / Q000378:metabolism; D054428:Chemokine CX3CL1 / Q000737:chemistry / Q000378:metabolism*; D002634:Chemotaxis, Leukocyte; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D051379:Mice; D009000:Monocytes / Q000145:classification / Q000166:cytology* / Q000378:metabolism*; D018384:Oxidative Stress; D017434:Protein Structure, Tertiary; D019707:Receptors, Chemokine / Q000378:metabolism
chemical_list: C111835:CCL2 protein, human; D000073883:CX3C Chemokine Receptor 1; C515538:CX3CL1 protein, human; C095235:CX3CR1 protein, human; C508606:CXCL8 protein, human; D018932:Chemokine CCL2; D054428:Chemokine CX3CL1; D016209:Interleukin-8; D019707:Receptors, Chemokine
keywords: apoptosis; chemokine CX3CL1; monocytes; oxidative stress