Oxidized LDL Phagocytosis During Foam Cell Formation in Atherosclerotic Plaques Relies on a PLD2–CD36 Functional Interdependence
The uptake of cholesterol carried by low‐density lipoprotein (LDL) is tightly controlled in the body. Macrophages are not well suited to counteract the cellular consequences of excess cholesterol leading to their transformation into “foam cells,” an early step in vascular plaque formation. We have uncovered and characterized a novel mechanism involving phospholipase D (PLD) in foam cell formation. Utilizing bone marrow‐derived macrophages from genetically PLD deficient mice, we demonstrate that PLD2 (but not PLD1)‐null macrophages cannot fully phagocytose aggregated oxidized LDL (Agg‐Ox‐LDL), which was phenocopied with a PLD2‐selective inhibitor. We also report a role for PLD2 in coupling Agg‐oxLDL phagocytosis with WASP, Grb2, and Actin. Further, the clearance of LDL particles is mediated by both CD36 and PLD2, via mutual dependence on each other. In the absence of PLD2, CD36 does not engage in Agg‐Ox‐LDL removal and when CD36 is blocked, PLD2 cannot form protein–protein heterocomplexes with WASP or Actin. These results translated into humans using a GEO database of microarray expression data from atheroma plaques versus normal adjacent carotid tissue and observed higher values for NFkB, PLD2 (but not PLD1), WASP, and Grb2 in the atheroma plaques. Human atherectomy specimens confirmed high presence of PLD2 (mRNA and protein) as well as phospho‐WASP in diseased arteries. Thus, PLD2 interacts in macrophages with Actin, Grb2, and WASP during phagocytosis of Agg‐Ox‐LDL in the presence of CD36 during their transformation into “foam cells.” Thus, this study provides new molecular targets to counteract vascular plaque formation and atherogenesis.
Henkels, K. M.,
Wrenshall, L. E.,
Frohman, M. A.,
& Gomez-Cambronero, J.
(2018). Oxidized LDL Phagocytosis During Foam Cell Formation in Atherosclerotic Plaques Relies on a PLD2–CD36 Functional Interdependence. Journal of Leukocyte Biology, 103 (3), 867-883.