Oxidized Phospholipids as Endogenous Pattern Recognition Ligands in Innate Immunity

Abstract

One of the major functions of the innate immune system is the surveillance of host tissues, identifying apoptotic and senescent cells for engulfment and orderly removal by macrophages (1, 2). Macrophage recognition of modified lipoproteins occurs via similar pathways of the innate immune system, involving shared scavenger receptors and molecular pattern recognition ligands (3–6). These critical homeostatic functions of the innate immune system are essential to a diverse array of physiological processes, ranging from embryonic development and tissue remodeling to resolution of inflammation (7, 8). Phagocytic cells express a broad range of receptors that participate in recognition and engulfment of apoptotic and senescent cells, including CD36, a prototypic member of the class B scavenger receptor family (9–14). CD36 recognizes pathogen-associated molecular patterns, including erythrocytes infected with Plasmodium falciparum (15, 16). It also recognizes oxidatively modified lipoproteins, leading to cholesterol accumulation and atherosclerotic plaque development in vivo (17, 18). Recent data support the notion that phospholipid oxidation within cell membranes and lipoproteins exposes similar molecular patterns recognized by CD36 and other receptors of innate immunity. Animal model studies with mice genetically engineered to lack functional CD36 confirm that this prototypic scavenger receptor participates in recognition and engulfment of apoptotic cells (19), senescent cells or cell fragments (20), and oxLDL2 in vivo (18, 21). This review will discuss recent discoveries regarding the structural nature of oxidized phospholipids that serve as high affinity ligands for CD36 in vivo. Also discussed will be the Lipid Whisker Model (22). A revision to the Fluid Mosaic Model (23), the Lipid Whisker Model focuses on phospholipid conformation within oxidized cell membranes and lipoproteins and is derived from recent studies demonstrating the generality of a conformational switch in the structure of many phospholipids within cell membranes that occurs following oxidation. The conformational switch, involving the protrusion of oxidized fatty acids from the hydrophobic membrane interior into the more polar aqueous compartment (22, 24), facilitates physical contact between pattern recognition receptor and molecular pattern ligand. This anatomic positioning of oxidized fatty acids of membrane phospholipids may also underlie the preferential selectivity of some phospholipases for oxidized fatty acids during membrane remodeling.