title: Chemokine Signaling Enhances CD36 Responsiveness toward Oxidized Low-Density Lipoproteins and Accelerates Foam Cell Formation.
abstract: Excessive uptake of oxidized low-density lipoproteins (oxLDL) by macrophages is a fundamental characteristic of atherosclerosis. However, signals regulating the engagement of these ligands remain elusive. Using single-molecule imaging, we discovered a mechanism whereby chemokine signaling enhanced binding of oxLDL to the scavenger receptor, CD36. By activating the Rap1-GTPase, chemokines promoted integrin-mediated adhesion of macrophages to the substratum. As a result, cells exhibited pronounced remodeling of the cortical actin cytoskeleton that increased CD36 clustering. Remarkably, CD36 clusters formed predominantly within actin-poor regions of the cortex, and these regions were primed to engage oxLDL. In accordance with enhanced ligand engagement, prolonged exposure of macrophages to chemokines amplified the accumulation of esterified cholesterol, thereby accentuating the foam cell phenotype. These findings imply that the activation of integrins by chemokine signaling exerts feedforward control over receptor clustering and effectively alters the threshold for cells to engage ligands.
authors.affiliation: Program in Cell Biology, The Hospital for Sick Children Research Institute, Toronto, ON M5G 1X8, Canada; Institute of Medical Science, University of Toronto, Toronto, ON M5S 2Z9, Canada.
authors.forename: Harikesh S
authors.initials: HS
authors.lastname: Wong
authors.affiliation: Program in Cell Biology, The Hospital for Sick Children Research Institute, Toronto, ON M5G 1X8, Canada.
authors.forename: Valentin
authors.initials: V
authors.lastname: Jaumouillé
authors.affiliation: Program in Cell Biology, The Hospital for Sick Children Research Institute, Toronto, ON M5G 1X8, Canada.
authors.forename: Spencer A
authors.initials: SA
authors.lastname: Freeman
authors.affiliation: Program in Cell Biology, The Hospital for Sick Children Research Institute, Toronto, ON M5G 1X8, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5S 2Z9, Canada.
authors.forename: Sasha A
authors.initials: SA
authors.lastname: Doodnauth
authors.affiliation: Program in Cell Biology, The Hospital for Sick Children Research Institute, Toronto, ON M5G 1X8, Canada; Institute of Medical Science, University of Toronto, Toronto, ON M5S 2Z9, Canada.
authors.forename: Daniel
authors.initials: D
authors.lastname: Schlam
authors.affiliation: Program in Cell Biology, The Hospital for Sick Children Research Institute, Toronto, ON M5G 1X8, Canada.
authors.forename: Johnathan
authors.initials: J
authors.lastname: Canton
authors.affiliation: Program in Cell Biology, The Hospital for Sick Children Research Institute, Toronto, ON M5G 1X8, Canada; Institute of Medical Science, University of Toronto, Toronto, ON M5S 2Z9, Canada.
authors.forename: Ilya M
authors.initials: IM
authors.lastname: Mukovozov
authors.affiliation: Department of Chemistry and Biology, Ryerson University, Toronto, ON M5B 2K3, Canada.
authors.forename: Amra
authors.initials: A
authors.lastname: Saric
authors.affiliation: Program in Cell Biology, The Hospital for Sick Children Research Institute, Toronto, ON M5G 1X8, Canada; Keenan Research Centre of the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, ON M5B 1T8, Canada.
authors.forename: Sergio
authors.initials: S
authors.lastname: Grinstein
authors.affiliation: Program in Cell Biology, The Hospital for Sick Children Research Institute, Toronto, ON M5G 1X8, Canada; Institute of Medical Science, University of Toronto, Toronto, ON M5S 2Z9, Canada; Department of Paediatrics, University of Toronto, Toronto, ON M5G 1X8, Canada. Electronic address: lisa.robinson@sickkids.ca.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Robinson
mesh_terms: D008841:Actin Cytoskeleton / Q000187:drug effects; D000818:Animals; D018955:CD36 Antigens / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018932:Chemokine CCL2 / Q000378:metabolism; D054428:Chemokine CX3CL1 / Q000378:metabolism; D054377:Chemokine CXCL12 / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism*; D005487:Foam Cells / Q000166:cytology / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008077:Lipoproteins, LDL / Q000633:toxicity*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D011485:Protein Binding; D000067996:RAW 264.7 Cells; D015398:Signal Transduction / Q000187:drug effects*; D014162:Transfection
chemical_list: D018955:CD36 Antigens; D018932:Chemokine CCL2; D054428:Chemokine CX3CL1; D054377:Chemokine CXCL12; D018925:Chemokines; D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein