Phosphocholine as a pattern recognition ligand for CD36

Abstract

We have previously shown that CD36 recognizes oxidation products of phospholipids on oxidized LDL (OxLDL) such as 1-palmitoyl-2-(5 -oxovaleroyl)-sn -glycero-3-phosphocholine (POVPC). The current study was designed to examine whether the phosphocholine (PC) headgroup in POVPC constitutes an obligatory binding target for CD36. To examine the contribution of PC in the binding of POVPC to CD36, we used well-defined synthetic oxidized phospholipids (OxPLs) cross-linked to BSA or to a hexapeptide. The OxPL adducts were then tested for their ability to bind to CD36-transfected cells and for their ability to inhibit OxLDL binding to CD36. Mounting evidence implicates oxidized low density lipoprotein (OxLDL) in the pathogenesis of atherosclerosis. The oxidative modifications are presumed to occur after the entry of plasma LDL into the intima and are catalyzed by the cellular constituents of the arterial wall. Although clearance of the highly cytotoxic OxLDL may protect the surrounding tissue from damage, the unregulated uptake of OxLDL by macrophages within the arterial wall leads to the formation of lipid-laden foam cells and the development of the fatty streak, the hallmark of early atherosclerotic lesions. The recognition and uptake of OxLDL by macrophages is mediated by specific cell surface scavenger receptors, including CD36, a class B scavenger receptor (1). CD36 is a heavily glycosylated protein with broad ligand specificity, a characteristic of pattern recognition receptors. It binds long-chain fatty acids (2), anionic phospholipids (3), ␤ -amyloid (4), advanced glycation end products (5), and OxLDL (1). It also functions in the recognition and removal of Plasmodium falciparum -infected erythrocytes (6) and apoptotic cells (7). It serves as the primary receptor for platelet adhesion to collagen (8) and may mediate the antiangiogenic activity of thrombospondin (9).Recent data derived from CD36-deficient mice support an important role of CD36 in foam cell formation and atherogenesis. A significant decrease in binding and degradation of OxLDL was observed in macrophages from null mice compared with those from control mice (10). Similarly, macrophages from CD36-deficient patients were less capable of binding and degrading OxLDL and accumulated less cholesteryl ester than macrophages from control subjects (11). The relative contribution of scavenger receptors in the uptake of OxLDL was further addressed in mice lacking both scavenger receptor A and CD36 (12). Binding and uptake studies demonstrated that scavenger receptor A and CD36 were the principal macrophage receptors responsible for the binding of OxLDL and the accumulation of cholesteryl ester derived from modified lipoproteins. Consistent with a principal pathogenic role of scavenger receptors in atherogenesis, the targeted disrup-

Protein targets of oxidized phospholipids in endothelial cells

“…The lipid-protein interaction was most likely covalent, because the endothelial cell proteins remained biotinylated throughout the denaturing conditions of SDS-PAGE; however, we cannot exclude the possibility that the lipids formed highaffinity, noncovalent interactions such as those described for platelet-activating factor, eicosanoids, and other lipid mediators. From the structures of oxidized lipids shown in Scheme 2, we would expect Schiff base formation for 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphatidyl-(N-biotinylethanolamine) (44) and Michael (39) and/or epoxide additions (45,46) for PEIPE-Nbiotin. 1-Palmitoyl-2-glutaroyl-sn-glycero-3-phosphatidyl-(Nbiotinylethanolamine) would most likely not participate in covalent interactions.…”

Tissue Plasminogen Activator (tPA) and Matrix Metalloproteinases in the Pathogenesis of Stroke: Therapeutic Strategies

“…1). Studies showed that oxidized phospholipids bearing the PC headgroup as a ligand on OxLDL mediate uptake by macrophage scavenging receptors such as CD36 [13]. The macrophage foam cells generate reactive oxygen species (ROS), produce TNF-α and IL-1, and MMP-9 that promote atherosclerosis, degrade the fibrous cap, and eventually lead to plaque rupture [14].…”

CD36 Is Differentially Expressed on B Cell Subsets during Development and in Responses to Antigen

“…CD36 binds multiple ligands including native and modified low density lipoproteins, oxidized phosphoryl choline (PC) epitope, anionic phospholipids, collagens, thrombospondin-1, and fibrillar ␤-amyloids (17,(21)(22)(23)(24)(25)(26)(27). A role for CD36 has also been suggested in the pathogenesis of Alzheimer's disease and atherosclerosis (18, 25, 28 -30).…”