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Scavenger receptors in atherosclerosis
During atherosclerosis, heightened oxidative stress in the artery wall gives rise to oxidized forms of low density lipoproteins (LDL) that provoke an inflammatory response. The macrophage, a major cellular effector of the innate immune response, recognizes these oxidized lipids through a family of pattern recognition receptors known as the scavenger receptors. Lesional macrophages express at least six classes (A-G) of structurally unrelated scavenger receptors that allow the unregulated uptake of oxidized or acetylated LDL (OxLDL, AcLDL) leading to cellular cholesterol accumulation (see diagram).1 These receptors are believed to play a prominent role in the conversion of subendothelial macrophages into cholesterol-laden “foam cells”. As cholesterol-laden macrophage foam cells are the primary component of the fatty streak, the earliest atherosclerotic lesion, lipid uptake by these pathways has long been considered a requisite and initiating event in the pathogenesis of atherosclerosis.
Genetic loss-of-function studies in mice have revealed substantial roles for SR-A, CD36, SR-BI, LOX-1 and CXCL16/SR-PSOX in the modulation of atherosclerotic lesion development.2-7 However, despite reductions in foam cell formation in Sra–/–, Cd36–/– and Cxcl16–/– macrophages in vitro, in vivo atherosclerosis studies have not uniformly shown a benefit to blocking these pattern recognition receptors, indicating that their roles in atherosclerosis are more complex than originally envisioned.2, 6 In addition to recognition and internalization of modified lipoproteins, scavenger receptors perform additional functions that can modulate atherosclerotic lesion progression, including (1) induction of macrophage apoptosis, (2) clearance of apoptotic cells and debris, and (3) activation of cellular signaling pathways regulating lipid metabolism and inflammation.1 Thus, these multi-functional receptors regulate numerous pathways that affect both the initiation and progression of atherosclerosis.
In addition to modified lipoproteins, scavenger receptors have been demonstrated to recognize and phagocytose other modified-self and non-self ligands, such as Gram negative and positive bacteria, apoptotic cells, anionic phospholipids and amyloid proteins.1 Through recognition of these diverse ligands, scavenger receptors are thought to contribute importantly to tissue homeostasis and host defense.
Focus on CD36 signaling cascades
In addition to modified ligand binding and clearance, the Class B SR can mediate signal transduction which regulates inflammatory responses in myeloid cells. Signaling cascades downstream of CD36 initiated by pathogen-derived ligands, oxidized LDL, amyloid peptides, and thrombospondin-1 (TSP-1) have been partially defined.8-15 CD36-mediated activation of Src and mitogen activated protein (MAP) kinase families appear to be ligand and cell type specific, leading to varied biological consequences including cell death, NFkBactivation, inflammatory gene expression, adhesion and migration. This difference in specificity has been proposed to arise from the interaction of CD36 with different coreceptors, including members of the Toll-like receptor (TLR) and integrin families and the integrin associated protein CD47. To date, the signaling responses downstream of CD36 engagement of apoptotic cells remains largely undefined.
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