Scavenger receptors (SRs)

SRs are heterogeneous types of receptors which are expressed on macrophages and macrophage derived foam cells in atherosclerotic lesions, and are important for these cells to remove lipoproteins deposited in the lesions.

SRs are defined as receptors binding to chemically modified lipoproteins such as acetylated LDL (AcLDL), Ox-LDL and often many other types of ligands. They have heterogeneous molecular structures, and consist of various types. These receptors are divided into classes A, B, C, D, E, F, and G and different types of receptors are members of each class (23).

7.1.1. SRs: classA

Class A receptors include type I, type II, and type III macrophage scavenger receptor (MSR), and MARCO (macrophage receptor with collagenous structure). These receptors are generally called macrophage scavenger receptor class A (MSR-A). They possess a collagenous domain required for ligand recognition and are expressed on macrophages.

(168;169). MSR-A I,II are expressed on the cell membrane of macrophages. Their binding properties are currently considered identical.

The C-terminal type-specific domain in MSR-A I is called the scavenger receptor “cysteine-rich” domain (SRCR) which is not predictive of SR activity; the selective upregulation of this receptor accomplishes the uptake of modified LDL during differentiation of monocytes into macrophages, and its expression is important for foam cell formation (170). MSR-A II is also important for the uptake of modified LDL by macrophages (171). MSR-A III is localized in cytoplasmic vesicles and is not expressed on the cell surface. Thus, this receptor is unable to bind to any extracellular ligands (172). In the trans-Golgi system, MSR-A I,II are packed into secretory vesicles, and the vesicles are transported into the cell periphery of macrophages, thus recycling MSR-A I,II to the cell membrane for reutilization (173).

A number of different biological roles for the SR-A are suggested. These include the endocytosis of modified lipoproteins and its association with vascular disease, the adhesion of macrophages to the substratum and other populations of cells, the binding and ingestion of microbes, the detoxification of pathogen-specific components and the phagocytosis of apoptotic or unwanted host cells (174).

However, the development of atherosclerosis was not completely inhibited by MSR-A I, II deficiency, suggesting that SRs other than MSR-A I,II, such as MARCO, CD36, and macrosialin/CD68, are implicated in the uptake of Ox-LDL by macrophages and in the transformation of the macrophages into foam cells during atherogenesis.

MARCO is a 210-kDa membrane glycoprotein consisting of molecular trimeric structures similar to those of MSR-A I,II, and III. It has an extremely long collagen like domain and a short α-helical coiled coil domain (175). Because of these molecular structures, the MARCO receptor is unable to dissociate from ligands within endosomes, and MARCO-ligand complexes are directly transported into lysosomes without receptor-ligand dissociation.

The SR cystein rich CD163 is a macrophage-restricted endocytic receptor for haemoglobin-haptoglobin complexes.

7.1.2. SRs: class B

CD36 and SR-BI (scavenger receptor type BI) belong to class B of SRs. CD36 is a double spanning SR with a very different structure from SR-A. CD36 is an 88-kDa glycoprotein expressed on monocytes/macrophages, platelets, and endothelial cells, and in adipose tissue; it binds to various ligands such as fatty acids, anionic phospholipids, collagen, thrombospondin, and Ox-LDL (36). CD36 was shown to function as an Ox-LDL receptor in macrophages (160) and a fatty acid transporter in adipocytes (176). In atherosclerotic lesions of human aorta, the expression of CD36 predominates in macrophage-derived foam cells compared to non-loaded macrophages and is distinct from the expression of MSR-A I,II suggesting a different role of these two receptor types (177). CD36 also plays a role in macrophage fatty acid metabolism, adhesion, and phagocytosis of apoptotic neutrophils (36).

SR-BI is a 509-amino-acid-long member of the CD36 superfamily of proteins with two transmembrane domains like CD36 but a quite different function. SRB-I and CD36 are fatty acylated proteins that cluster in caveola-like cholesterol-rich lipid domains in cultured cells (36). SR-BI is regarded as an HDL receptor, and mediates the selective uptake of HDL cholesterol by hepatocytes and steroidogenic cells (52). SR-BI can also function as a LDL receptor (binding and selective uptake). Although HDL does not bind as tightly as LDL, it binds preferentially when both ligands are present. CD36 can also bind HDL and LDL, but it cannot efficiently mediate CE uptake (178). The tissue distribution of SR-BI is that expected for an HDL receptor. It is highly expressed in liver and steroidogenic tissues, precisely those tissues that exhibit the highest levels of selective uptake of HDL-CE. In macrophages in atherosclerotic plaques, SR-BI is also present (178). The expression of SR-BI is coordinately regulated with cholesterol metabolism. Its expression in steroidogenic cells is regulated via the cAMP/protein kinase A signal transduction pathway that includes transcription factors such as CCAAT/enhancer-binding proteins (C/EBPs) and steroidogenic factor-1 (SF-1). The transcriptional regulation of SR-BI appears to be due to SR-BI promoter binding sites for a number of transcription factors including C/EBP, SF-1, and sterol regulatory element binding protein-1 (SREBP-1) (179).

SR-BI facilitates the cellular selective uptake of cholesterol (primarily in the form of CE) from the hydrophobic cores of lipoproteins, but not the apolipoprotein at the lipoprotein´s surface.

It does not involve the sequential internalization of the intact lipoprotein particle and its subsequent degradation which is the case in the uptake of LDL via the LDLR (Fig. 2). (168).

The detailed molecular mechanism underlying SR-BI-mediated selective lipid uptake has not yet been elucidated. In addition SR-BI can also mediate the bidirectional flux of unesterified cholesterol and phospholipids between HDL and cells.

Hepatic SR-BI mediates “reverse cholesterol transport” which implicates the transfer of cholesterol from plasma HDL to the bile for excretion. In atherosclerotic lesions of apoE-deficient mice, SR-BI is expressed in macrophages, and the expression is increased by peroxisome proliferator-activated receptors (PPARs), suggesting a contribution of SR-BI to the uptake of OxLDL by macrophages in loco (180).

Thus, SR-BI plays a key role in controlling the structure and amount of cholesterol in plasma HDL, steroidogenic and hepatic uptake of HDL cholesterol, and the use of HDL cholesterol for biliary cholesterol secretion.

7.1.3. SRs: classes D through G

CD68/macrosialin, classified as a class D receptor, is a member of the LAMP (lysosomal-associated membrane protein) family expressed on the endolysosomal compartments and partly on the cell surface of macrophages (181). It is demonstrated in macrophages and macrophage-derived foam cells in human and murine atherosclerotic lesions and was able to bind Ox-LDL in vitro (182;183). Lectin-like Ox-LDL receptor (LOX-1) and SR expressed by endothelial cells (SREC) are expressed on vascular endothelial cells and are classified as class E and class F, respectively (184;185). LOX-1 is also expressed on macrophages in humans and mice (185). It mediates endocytic uptake and subsequent lysosomal degradation of Ox-LDL. Binding of Ox-LDL to this receptor induces several cellular events such as activation of NFkB (186), upregulation of MCP-1 (187) and reduction in intracellular nitric oxide (186). Other ligands for LOX-1 include polyanionic compounds, aged/apoptotic cells (188), activated platelets (189) and bacteria (190). In addition, two other distinct novel SRs, SR for phosphatidylserine (PS) and Ox-LDL (PSOX, SR-G class) and PS receptor (PSR), have been identified (191;192). SR-PSOX recognizes PS and Ox-LDL and is predominantly expressed in lipidladen macrophages of human atherosclerotic lesions. This receptor does not share any structural homology with other Ox-LDL receptors. PSR is expressed not only in macrophages but also in fibroblasts and epithelial cells and is involved in the phagocytosis of apoptotic cells (192).

7.2. Uptake of lipoproteins by opsonin receptors including Fcg- and complement