Format

Send to

Choose Destination
Cell Rep. 2016 Mar 29;14(12):2859-71. doi: 10.1016/j.celrep.2016.02.071. Epub 2016 Mar 17.

Chemokine Signaling Enhances CD36 Responsiveness toward Oxidized Low-Density Lipoproteins and Accelerates Foam Cell Formation.

Author information

1
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.
2
Program in Cell Biology, The Hospital for Sick Children Research Institute, Toronto, ON M5G 1X8, Canada.
3
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.
4
Department of Chemistry and Biology, Ryerson University, Toronto, ON M5B 2K3, Canada.
5
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.
6
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.

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.

PMID:
26997267
DOI:
10.1016/j.celrep.2016.02.071
[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center