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

• Published in: Cell reports (Cambridge) 2016-03, Vol.14 (12), p.2859-2871
• Main Authors: Wong, Harikesh S., Jaumouillé, Valentin, Freeman, Spencer A., Doodnauth, Sasha A., Schlam, Daniel, Canton, Johnathan, Mukovozov, Ilya M., Saric, Amra, Grinstein, Sergio, Robinson, Lisa A.
• Format: Article
• Language: English
• Subjects: Actin Cytoskeleton - drug effects; Animals; CD36 Antigens - deficiency; CD36 Antigens - genetics; CD36 Antigens - metabolism; Chemokine CCL2 - metabolism; Chemokine CX3CL1 - metabolism; Chemokine CXCL12 - metabolism; Chemokines - metabolism; Foam Cells - cytology; Foam Cells - metabolism; HeLa Cells; Humans; Lipoproteins, LDL - toxicity; Macrophages - cytology; Macrophages - drug effects; Macrophages - metabolism; Mice; Mice, Knockout; Microscopy, Confocal; Protein Binding; RAW 264.7 Cells; Signal Transduction - drug effects; Transfection
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2016.02.071

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. [Display omitted] •Chemokines enhance CD36 clustering by activating integrins•Integrin signaling promotes CD36 clustering by altering cortical actin architecture•Larger clusters of CD36 are primed for the engagement of multivalent oxLDL•Prolonged exposure of macrophages to chemokines accelerates foam cell formation The mechanisms that regulate the uptake of oxLDL by macrophages remain poorly defined. Wong et al. discovered a feedforward mechanism whereby the activation of integrins by chemokines remodels the cortical actin cytoskeleton to promote clustering of CD36, which subsequently enhances the engagement of oxLDL.