Scavenger receptor class B, type I: a promising immunotherapy target

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Scavenger receptor class B, type I: a promising immunotherapy target Scavenger receptor class B, type I (SR-BI) is a crucial molecule in lipid metabolism, since the interaction of high-density lipoproteins (HDLs) with SR-BI is involved in reverse cholesterol transport and cholesterol efflux. Recent findings also underscore a critical role of SR-BI in antimicrobial and immune responses. SR-BI is not only highly expressed in liver and steroidogenic glands, but also in endothelial cells, macrophages and dendritic cells. SR-BI mainly mediates anti-inflammatory responses, which may be altered by dysfunctional HDLs produced in several diseases. Moreover, SR-BI has been involved in the capture and cross-presentation of antigens from viruses, bacteria and parasites. It thus works as a pattern-recognition receptor that interacts with both damage-associated molecular patterns and pathogen-associated molecular patterns. These new findings in the microbiology and immunology fields present SR-BI as an unexplored therapeutic target that warrants further basic and applied research. KEYWORDS: atherosclerosis n diabetes mellitus n dysfunctional high-density lipoprotein n hepatitis C virus n high-density lipoprotein n lipopolysaccharide n Plasmodium sporozoites n rheumatoid arthritis n scavenger receptor class B, type I n serum amyloid A

Jessica Fioravanti1, José Medina-Echeverz1 & Pedro Berraondo†1 Division of Hepatology & Gene Therapy, Center for Applied Medical Research, University of Navarra, Pamplona, Navarra, Spain † Author for correspondence: [email protected] 1

Scavenger receptor class B, type I (SR-BI) is a 509-amino acid membrane glycoprotein, containing a large extracellular domain and two transmembrane domains, with short cytoplasmic amino- and carboxy-terminal domains [1,2] . The protein has an apparent molecular weight of 85 kDa since it is highly glycosylated and fatty acylated [3,4] . Its splicing variant SR-BII differs from SR-BI at the C-terminus, which is reported to confer an intracellular localization on SR-BII [5,6] . In SR-BII, 42 amino acids in the C-terminal cytoplasmic domain of SR-BI are replaced by 40 different residues [7] . Major sites of SR-BI expression are the liver and steroidogenic glands [8–11] . SR-BI is also present in other tissues and cells, including brain, intestine, endothelium and in several immune cell subsets, such as macrophages and dendritic cells (DCs) [9,12–14] . SR-BI is clustered in specialized plasma membrane domains, including caveolae [4,15,16] , microv illar channels and microvillar extensions [17–19] . SR-BI contains a PDZK1-binding motif (EAKL) in its carboxy-terminal region [20,21] . PDZK1deficient mice have greatly diminished surface expression of SR-BI in the liver, but not in steroidogenic tissues [22] , and a mutant form of SR-BI that lacks the carboxy-terminal residues required for the PDZK1 binding is not stably expressed on the surface of hepatocytes in vivo [20] . SR-BI can bind a variety of ligands

including high-density lipoproteins (HDLs), low-density lipoproteins (LDLs) and very-lowdensity lipoproteins (VLDLs). Nevertheless, it is best known as the first HDL receptor to have been identified [1,8,12,23,24] . Regarding HDLs, SR-BI binds both discoidal reconstituted HDLs [1,23,25,26] and spherical HDLs [23,25] . The dissociation constant of the complex is 1–5 µg protein/µl for reconstituted HDLs and 16 µg protein/µl for HDLs, with larger spherical HDLs binding more tightly than smaller HDLs. Competition experiments suggest that pre-bHDL and lipid-free apolipo protein A-I are poor ligands for SR-BI [25] . SR-BI mediates not only the selective uptake of cholesteryl esters and other lipids from HDLs and LDLs to cells [8,27–32] , but also bidirectional unesterified cholesterol movements [33,34] . SR-BI containing a C-terminal epitope tag has been purified from lysates of transfected cells and reconstituted into phospholipid/cholesterol liposomes. The reconstituted receptors displayed both high binding affinity and selective lipid uptake [35] . Thus, SR-BI does not require other proteins, specialized cellular structures or compartments for these activities. Alterations in SR-BI expression can profoundly influence several physiologic processes involving lipid homeostasis, such as biliary cholesterol secretion or female fertility [36,37] . Reverse cholesterol transport is known to be

10.2217/IMT.10.104 © 2011 Future Medicine Ltd

Immunotherapy (2011) 3(3), 395–406

ISSN 1750-743X

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an important mechanism allowing HDLs to prevent the accumulation of cholesterol in leukocytes and the formation of foam cells in the intima of vessel walls. The reverse cholesterol transfer is the process whereby excess cholesterol from the periphery is transported back to the liver for excretion [38] . During this process, the ATP-binding membrane cassette transporter A1 (ABCA1) mediates the efflux of excess cholesterol and phospholipids from peripheral cells, such as macrophages, to lipid-poor apolipoprotein A-I, forming nascent HDL particles. The HDL–cholesterol is further esterified in the circulation by lecithin–cholesterol acyltransferase (LCAT), and excreted after uptake by the liver either indirectly, through ‘cholesteryl ester transfer protein’-mediated transfer to apolipoprotein B containing lipoproteins, or directly, through SR-BI. The ATP-binding cassette subfamily group G member 1 transporter (ABCG1) works in concert with ABCA1 by effluxing cholesterol, mainly to spherical HDLs [39] . Experiments with transgenic animals suggest that disruption of one or more steps in reverse cholesterol transport results in accelerated atherosclerosis, whereas overexpression of pivotal proteins in reverse cholesterol transport, such as apolipoprotein A-I, LCAT and SR-BI, exerts atheroprotective effects [40–42] . Regarding SR-BI, hepatic overexpression of this receptor in the liver of transgenic animals [43] , or by adenovirus-mediated gene transfer [44] , demonstrated a strong anti-atherogenic potential. Besides, animals with dysfunctional SR-BI display enhanced arteriosclerosis combined with increased HDL concentrations [45,46] . Nevertheless, SR-BI, upon interaction with HDLs, also plays an important role in controlling chronic inflammatory processes. This anti-inflammatory function, observed in the steady state, can be disrupted by ligands that compete with HDLs in acute-phase responses or in pathogenic situations [47–51] . In this article, we analyze the literature that describes the role of SR-BI in microbiology and immunology to illustrate the important role of SR-BI as a pattern-recognition receptor.

SR-BI as a pattern-recognition receptor Pattern-recognition receptors are a class of innate immune response-expressed proteins that respond to pathogen-associated mole cular patterns (PAMPs) and endogenous stress signals termed danger-associated molecular patterns (DAMPs). 396

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SR-BI not only binds lipoproteins but can also bind and internalize other molecules such as negatively charged phospholipids [11,52] or anionic class A amphipathic a-helixes [53,54] . One or both of these motifs present inside the cell has been associated with bacterial and viral recognition by class B scavenger receptors [55] . In pattern-recognition receptors, ligand-receptor interaction does not require a high level of ligand stereospecificity, or a significantly smaller ligand than the receptor itself. In fact, SR-BI ligands are multimolecular complexes, where the hydrophobic portions are in the core, while the hydrophilic components of the ligands are exposed on the surface. This ‘micelle formation’ is characteristic of most SR-BI ligands such as HDLs, LDLs, liposomes, serum amyloid A (SAA) and lipopolysaccharide (LPS). A ‘lock and key’ mechanism has been proposed for SR-BI, where the ligand functions as the lock, while SR-BI, inserts some parts of the extracellular loop into the micelle–ligand complex, functioning as a key [56] .

Influence of SR-BI on Toll-like receptor signaling Since the first description of the uptake of Gram-negative and Gram-positive bacteria by SR-BI, this process has been postulated to be a mechanism for cytosolic recognition, ubiquitination and degradation of bacteria that could cooperate with Toll-like receptors (TLRs) to initiate an antimicrobial immune response [55] . This is the case of a SR-BI-related molecule, CD36, which has been reported as a cofactor for the TLR2/TLR6 and TLR4/TLR6 heterodimers and enhances TLR2 signaling [57,58] . However, SR-BI has been shown to downregulate TLR4- and TLR9-mediated inflammatory responses [59,60] . SR-BI binds and internalizes LPS, a TLR4 ligand [61] , and exerts a direct anti-inflammatory activity by suppressing TLR4-mediated NF-kB activation [59] . In this direct antiinflammatory effect, the reverse cholesterol transport mediated by SR-BI is probably playing an important role, although there still is no direct evidence. Indeed, studies on ABCA1 or ABCG1 knockout macrophages display an augmented TLR2-, TLR3- and TLR4-mediated inflammatory response and enhanced cholesterol accumulation [62,63] . In addition to this direct effect on TLR4 signaling, SR-BI also mediated other effects that protect against septic death. SR-BI binds and internalizes monomerized and HDL-associated LPS [61] . future science group

Scavenger receptor class B, type I: a promising immunotherapy target

Through this scavenger activity of SR-BI, the liver is a major organ of plasma clearance of LPS [64] . SR-BI is also involved in the correct function of the adrenal gland. SR-BI knockout mice do not properly produce corticosterone in response to LPS and these mice develop an exaggerated inf lammatory response to LPS-induced endotoxemia [64] . Regarding TLR9, SR-BI has been shown to bind TLR9 ligands in B cells. The result of this interaction is that calcium entry is triggered via phospholipase C g-1-mediated activation of transient receptor potential cation channel, subfamily C, member 3 (TRPC3) channels, leading to dampened cytokine production [60] . Altogether, SR-BI appears to be a receptor, which controls excessive inflammation that could be harmful for the host.

SR-BI as a receptor of hepatitis C virus & malaria Bacteria are not the only microorganisms that take advantage of the excellent properties of SR-BI to gain access to the host cells. By contrast, it seems to be a general mechanism, as viruses and parasites also use this receptor. It is well established that SR-BI plays an essential role in the entry of hepatitis C virus (HCV) and malaria but the list of microorganisms that interact with SR-BI during the infection process will probably continue to grow. It is likely that the mechanism employed by HCV and malaria may shed light to the compre hension of the mechanism of infection by other microorganisms. Hepatitis C virus infection is a major cause of chronic hepatitis, with more than 170 million humans chronically infected, with limited treatment options and no vaccine developed. HCV is a positive-stranded RNA enveloped virus, from the Flaviviridae family. Despite the obstacles to an efficient study in HCV infection, great progress has been made using replicon systems [65,66] , infectious HCV pseudo particles (HCVpp) containing functional E1–E2 envelope protein [67,68] and finally complete cell-culture systems (HCVcc) [69–71] that provide production of recombinant infectious HCV in tissue culture. The infection of hepatocytes can be explained as a multiple-stage process. Initially, several attachment molecules, such as LDL receptor, glycosaminoglycans and liver-specific intercellular adhesion molecule-3grabbing integrin, can promote cell infection by engaging virus interaction with hepatocytes [72,73] . Following the initial attachment future science group

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of the virus to the host cell surface, entry receptors induce the ingress of HCV particles across the cell plasma membrane by endocytosis. Here, CD81 (a member of the tetraspanin superf amily of type III transmembrane proteins) is crucial, mediating the entry of virions in hepatoc ytes [74] , since tetraspanins associate with both tetraspanin and nontetraspanin proteins in cholesterol-enriched microdomains, exerting an array of biological functions, including cell–cell adhesion, cell migration and proliferation [75] . Finally, following virus interaction and binding with CD81, the tight junction component, claudin-1, acts at a late stage of the entry process [68] . Another final cofactor, occludin, has been recently identified [76,77] . SR-BI plays also an essential role in the infection of hepatocytes by HCV. Heo et al. demonstrated that soluble CD81, SR-BI and HCV E1 could be physically associated via the HCV E2 glycoprotein [78] . Importantly, SRBImediated viral infection depends on its lipid exchange activity [79,80] . Consistently, HDLs enhance HCV infection, while small chemical inhibitors of SR-BI-dependent lipid transfer (BLT-2 and BLT-4) [80] , natural SR-BI ligands such as oxidized LDLs [81] or SR-BI antibodies (mouse monoclonal 3D5 and human C167) abolish HCV-stimulated infectivity by HDLs or serum [82] . This HDL-mediated enhancement of HCV binding to hepatocytes has been demonstrated in all the in vitro HCV model systems, such as HCVcc or HCVpp [83] . Recently, it has been proposed that SR-BI may be particularly important for HCV cell-to-cell transmission [84] . A more mechanistic insight into the interaction between SR-BI and CD81 has recently emerged from the study of malaria infection. Malaria is an infectious disease caused by the five species of the Plasmodium parasite. It remains a major cause of morbidity in tropical and subt ropical areas, with an estimated range of 350–500 million individuals displaying clinical manifestations every year [85] . In the human host, Plasmodium sporozoites first cause liver asymptomatic infection, while the parasite proliferates and changes from a motile sporozoite into thousands of merozoites that will initiate the clinical phase of infection after infecting red blood cells. The entry of sporozoites of Plasmodium falciparum and Plasmodium yoelii into hepatocytes is both CD81 [86–88] and SR-BI dependent [89] . Yalaoui et al. reported that SR-BI at the plasma membrane of hepatocytes acts by providing cholesterol, and thereby www.futuremedicine.com

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facilitating reorganizations in the hepatocyte membrane, rendering it highly permissive to the entry of Plasmodium sporozoites [90] . However, this membrane-associated cholesterol is not the only reason for raised malaria infection, since SR-BI activates the positioning of CD81, generating tetraspanin-enriched microdomains required for infection with malaria [87] .

Role of SR-BI on HCV adaptive immune responses The outcome of HCV infection is associated with a robust, long-lasting, HCV-specific CD4 + (helper) and CD8 + (cytotoxic) T-cell response [91,92] . In chronic hepatitis C, such responses are weak or absent. Efficient naive T-cell priming and expansion lean on antigen presentation and stimulation by DCs. These unique cells can exert their ability to crossover exogenous antigens to the endogenous pathway, reaching access to MHC class I-inducing CD8 + T-cell responses. This cross-presentation process originates cytotoxicity against viruses with restricted tissue tropism such as HCV [93] . Some groups have shown the presence of viral positive-strand HCV RNA and the replicative intermediate (negative-strand HCV RNA) in DCs from HCV-infected patients. These results suggest that DCs are permissive for HCV infection and, therefore, direct antigen presentation could be possible [94,95] . However, the viral load observed in DCs is extremely low compared with that in infected hepatocytes [96] and a recent study failed to demonstrate the infection of DCs by HCVcc [97] . Barth et al. proposed that HCV-LP and HCVcc-derived peptides can enter to the cross-presentation pathway through SR-BI. During the differentiation from monocytes to DCs, the expression of SR-BI continuously increases, reaching high levels of the receptor, comparable with those in human HepG2 hepatoma cells [98] . By contrast, cell-surface CD36 is expressed in large amounts in monocytes, DCs and human HepG2 cells [98] . This group demonstrated that SR-BI is required for the binding and uptake of HCV by human monocyte-derived DCs, which leads to trafficking through the MHC class I pathway and to efficient cross-presentation to HCV-specific CD8 + T cells. However, the same group reported in a later work that ex vivo-isolated human DCs present low levels of SR-BI expression, and HCV uptake by these ex vivo-isolated cells was SR-BI independent [99] . Therefore, these studies might suggest a novel mechanism mediated 398


by SR-BI in DCs to capture and process viral antigens, which may be crucial for an early immune response at early stages of HCV infection. However, the physiologic relevance of this pathway remains unclear. Following a study by Dreux et al., a particularly original feature, involving humoral response, arose. They demonstrated that HDLs protected HCVpp and HCVcc from neutralizing antibodies via a mechanism involving the biological activity of SR-BI, as lipid transport inhibition fully restored the potency of neutralizing antibodies (HCV E1–E2-targeted antibodies). This work highlights a link between neutralization and stimulation of cell entry in hepatocytes. The key viral element of this phenomenon is the high variable region 1 of HCV, while SR-BI might be enhancing HCV entry by facilitating membrane fusion events or modulating lipid membrane contents [100] .

Role of SR-BI in the anti‑inflammatory effect of HDLs Non-modified HDLs exert a direct anti- inflammatory activity on endothelial cells upon binding to SR-BI. This is one of the mechanisms involved in the anti-atherogenic properties of HDLs that have been demonstrated both in animal models and in humans [101–103] . Several groups have shown that HDLs inhibit the expression of cell surface adhesion molecules by activated endothelial cells in vitro. Both native HDLs and reconstituted HDLs containing only apolipoprotein A-I and phosphatidylcholine inhibit the cytokine-induced expression of VCAM-1, ICAM-1 and E-selectin by human umbilical vein endothelial cells in a concentration-dependent manner within the range of physiological HDL levels [104–106] . High density lipoprotein-induced inhibition of adhesion molecules expression is mediated by nitric oxide synthase (NOS) activation through both SR-BI and S1P receptors [107] . HDLs act as carrier of potent bioactive lipid mediators, including S1P, and stimulate AMPK activation through both S1P and SR-BI receptors. The HDL-induced activation of AMPK resulted in endothelial NOS activation through PI3K/Akt and in subsequent inhibition of expression of the adhesion molecule VCAM-1, thereby inhibiting monocyte adhesion to endothelial cells [108] . Thus, the anti-inflammatory activity of circulating HDLs represents a physiologic brake on excessive inflammation that could lead to diseases such as arteriosclerosis future science group


Role of SR-BI in the inflammatory effect of dysfunctional HDLs In the presence of glucose intolerance or diabetes, and under conditions of inf lammation, circulating HDLs can be modified by replacement or modification of its protein and lipid components. Under chronic hyperglycemia conditions, plasma proteins, such as apolipoprotein A-I, may become nonenzymatically glycated. Glycation of apolipoprotein A-I has been shown to impair its ability to promote ABCA1 stabilization and ABCA1-dependent cholesterol efflux, inhibition of adhesion molecule expression [109] , and activation of LCAT [110] . HDLs from diabetic patients’ plasma have a reduced ability to stimulate endothelial nitric oxide production, endothelial-dependent vasod ilatation and to promote endothelial progenitor cell-mediated repair [47] . High-density lipoproteins can also be modified by oxidation. These modifications reduce the ability of apolipoprotein A-I to promote cholesterol efflux via ABCA1 [49,111–113] . The mechanism of oxidation involves myeloperoxidase-generated products, such as hypochlorous acid and peroxynitrite, in atherosclerotic lesions [49,111,112,114] . Interestingly, oxidation of apolipoprotein A-I has also been observed in sera from patients with hepatocarcinoma. It is likely that this modification, proposed as a biomarker, can alter the function of HDLs in these patients [48] . Finally, modifications in the protein content of HDLs also produce dysfunctional HDLs. The analysis of the composition of HDLs in individuals with coronary artery disease by shotgun proteomics have identified complement-regulatory proteins, a diverse array of distinct serpins with serine-type endopeptidase inhibitor activity and many acute-phase response proteins [50] . One of the most important acute phase proteins associated with HDLs is SAA. It is a highly conserved acute-phase protein whose serum levels increase up to 1000-fold within hours of an inflammatory stimulus [115] . At normal serum levels, SA A associates with HDLs forming a heterogeneous HDL population, containing both SAA and apolipoprotein A-I [116] . However, during the inflammatory response, the SAA is dramatically elevated in serum (1–1000 µg/ml), displacing apolipoprotein A-I and saturating HDLs, and also resulting in high levels of free circulating SAA [117–120] . future science group

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Serum amyloid A induces the secretion of proinflammatory cytokines, such as TNF-a, IL-1b and IL-8, and acts as chemoattractant for human monocytes, neutrophils and T cells [121,122] . Serum amyloid A protein in lipid-free form or in reconstituted HDL particles binds with high affinity to SR-BI. In contrast to lipid-free apolipoprotein A-I, lipid-free SAA can inhibit HDL binding to SR-BI and selective cholesteryl ester uptake [123] . Finally, SA A, when attached to SR-BI expressed in a monocyte cell line, induces production of chemokines, activates extracellular signal-regulated kinases 1/2 and p38 MAPKs [124] . This proinflammatory role correlates negatively with rheumatoid arthritis. SAAmediated inflammatory effects can be downregulated by SR-BI antagonist mimetic peptides and a specific anti-SR-BI antibody [51] .

Potential drug targeting SR-BI Basic research about SR-BI biology has provided extensive pharmacologic tools that are candidates to become drugs for treatment of various diseases by modulation of SR-BI activity. The paradigms of these drugs are the natural ligands HDLs and oxidized LDLs, but the new drugs allow fine-tuning of SR-BI functions by blocking some functions while allowing others. These are discussed in the following sections. Reconstituted HDLs Incubation of apolipoprotein A-I with phospholipids leads to the formation of nanoparticles that resemble natural HDLs [125] . The product termed ETC-216 is composed of recombinant apolipoprotein A-I Milano, complexed with phospholipids, and has been tested in clinical trials. Nissen et al. examined the effects of five-weekly infusions of ETC-216 or placebo in a clinical trial for patients with established coronary artery disease [102] . The atherosclerotic lesions were evaluated at baseline and after treatment by intravascular ultrasound. ETC‑216 infusion significantly reduced atheroma volume compared to baseline, whereas no measurable change occurred in the placebo group. Eriksson et al. used synthetic HDLs containing recombinant pro-apolipoprotein A-I. After a single intravenous infusion, this strategy resulted in a 30% increase of fecal bile salt excretion and a 39% increase in neutral sterol excretion in four patients with heterozygous familial hypercholesterolemia, indicating that the synthetic HDL particles augmented reverse cholesterol transport [126] . Other studies have demonstrated that intravenous infusions of reconstituted www.futuremedicine.com

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HDLs, combining apolipoprotein A-I (or variants) with phospholipids, increased HDLs functionality, improved endothelial function, and lead out to a reduction in inflammatory and oxidant markers [127–133] . Thus, exogenous HDL administration to enhance and improve its functions may prevent or regress atherosclerotic plaques. Synthetic mimetic peptides of apolipoprotein A-I Apolipoprotein A-I is composed of a series of a-helix peptide regions. Segrest et al. designed several synthetic peptides mimicking this a-helix structural motif [134] . They discovered a peptide termed 18A that displayed many of the characteristics of apolipoprotein A-I a-helices and could bind lipids. This peptide possesses two phenylalanine residues on the hydrophobic face of the a-helix. The lipid affinity was improved by increasing the number of phenylalanine

Inflammation

SAA

LPS

SR-BI HDL

HCV

CpG

Modified apoA-1

Figure 1. Scavenger receptor class B, type I as a molecular switch to block or stimulate inflammation. In the steady state, interaction of ligands, such as HDLs, LPS or CpG with SR-BI, produce cell-mediated anti-inflammatory responses. However, in acute phase response or chronic inflammatory diseases, other ligands, such as SAA, HCV or oxidized or glycated apolipoprotein A-I (modified ApoA-I), can trigger a proinflammatory response upon binding to SR-BI. CPG: CpG oligodeoxynucleotides; HCV: Hepatitis C virus ; HDL: High-density lipoprotein; LPS: Lipopolysaccharide; SAA: Serum amyloid A; SR-BI: Scavenger receptor class B, type I.

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residues [135] . Another strategy to improve this peptide was the use of d-amino acids. Thus, the biological activity was retained while improving the pharmacokinetic profile owing to resistance to proteolytic degradation [136] . After several of these peptides demonstrated in vivo efficacy in mouse models of atherosclerosis [136–138] , one of them was tested in Phase I clinical trials. D-4F is a 18A-derivative made with d-amino acids that displays four phenylalanine residues in the hydrophobic face. It can be administered orally and has been shown to be highly effective in mouse models of atherosclerosis [136] . In humans, the bioavailability was low but HDLs from patients treated with the highest dose displayed an increased anti-inflammatory activity [139] . SR-BI monoclonal antibodies Catanese et al. [82] developed a panel of monoclonal antibodies against human SR-BI. Two of them, 3D5 and C167, are of great interest, since they prevented HDLs binding to SR-BI and inhibited SR-BI-mediated cholesterol efflux. Moreover, they are able to neutralize ex vivo infection by HCV [82] . Small molecules: lipid transport inhibitors (block lipid transport 1–5), glyburide & ITX5061 Lipid transport inhibitors are five chemical compounds discovered by Nieland et al. [140] . They inhibit both the efflux of cellular cholesterol to HDLs and the selective lipid uptake from HDLs mediated by SR-BI. Block lipid transport (BLT)-1 was particularly potent. However, although they work as lipid transport inhibitors, they also enhance HDL binding to SR-BI owing to an increased receptor affinity [140] . Later, glyburide, a sulfonylurea that inhibits the activities of ABC proteins, was shown to display BLT-like properties. It prevents SR-BI-mediated selective lipid uptake from, and cholesterol efflux to, HDLs. Moreover, it also enhances the affinity of HDLs binding to SR-BI [141] . ITX5061 was initially characterized as a p38 MAPK inhibitor molecule. However, recently, it was used to increase cholesterol associated with HDLs in humans and rodents. This effect was mediated by inhibition of SR-BI activity [142] . Another related compound, ITX7904, has been shown to inhibit SR-BI-mediated lipid transfer from HDLs without the simultaneous inhibition of p38 MAPK [143] . These small molecules could be useful as HCV entry inhibitors. ITX5061 and ITX7650 are able to inhibit both HCVcc and HCVpp infection of future science group


human hepatocytes and they are being tested in Phase I clinical trials as single agents for the treatment of chronic viral hepatitis [84,143] . Another potential application of these small molecules that block SR-BI-mediated lipid transfer, while allowing the binding of HDLs to the receptor, is the blockade of HDL anti-inflammatory activities. Cholesterol efflux has been shown to be required to initiate SR-BI-mediated signaling in endo thelial cells [144] . This signaling leads to the activation of endothelial NOS [145] , leading to nitric oxide-mediated inhibition of adhesion molecules expression [107] . Interestingly, BLT-1 has been shown to inhibit SR-BI-mediated signaling [146] . Thus, transient blockade of this anti-inflammatory pathway could be envisioned to potentiate immunotherapeutic treatments by increasing leukocyte trafficking through endothelium. However, animals deficient in SR-BI present complications, such as increased atherosclerosis [45,46] , infertility [36] and platelet abnormalities [147] . Therefore, long-term suppression of SR-BI function may produce severe adverse effects. Noteworthy, the first clinical trial in patients with ITX5061 displayed a good safety profile [143] . Further studies are required to definitively establish the safety of targeting SR-BI, but these early results in humans encourage the development of this strategy.

Conclusions & future perspective SR-BI is part of a diverse group of key molecules that maintain an adequate lipid balance in cells. The interaction of HDLs with this group of proteins, which includes SR-BI, leads to benefit for the treatment of coronary artery diseases, mediated by lipid exchange and by a direct anti-inflammatory activity. The interest of this approach has generated intensive research into drugs that emulate the properties of natural HDLs. Thus, clinical trials have been conducted with reconstituted HDLs and apolipoprotein A-I mimetic peptides with successful results. However, these clinical trials have not been extended to other diseases with a chronic inflammatory component in which dysfunctional HDL occurrence has been reported, such as rheumatoid arthritis, chronic kidney disease or diabetes mellitus. It is possible that the infusion of reconstituted HDLs with an intact anti-inflammatory capacity could reverse the adverse effects of dysfunctional HDLs present in these patients. Therefore, clinical trials in these diseases are feasible and desirable. In addition, it will be interesting to extend the analysis of the properties and composition of the future science group

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HDLs of patients in other chronic inflammatory diseases. It is possible that HDLs may contain important biomarkers and that the restoration of anti-inflammatory properties may be a new therapeutic target. However, the generation of dysfunctional HDLs is a physiological process that disrupts the anti-inflammatory role of HDLs in situations where an insult triggers an acute-phase response. Regarding immunotherapy, it may be interesting to reproduce this situation to trigger a greater response to treatment based on proinflammatory cytokines, anti-inflammatory cytokine inhibitors or to enhance prophylactic or therapeutic vaccines. SR-BI ligation downregulates signaling mediated by proinflammatory cytokines [104–107] and TLR-mediated signaling [59,60] . Thus, blockade of these activities may boost the effector immune responses stimulated by immunotherapy. It is possible that drugs that allow binding of HDLs to SR-BI while preventing the transport of lipids may be useful in this regard. Alternatively, HDLs reconstituted with proinflammatory components, such as glycated apolipoprotein A-I or SAA, may be envisioned to enhance the immune response. Concomitant administration of these modified HDLs with immunotherapy can temporarily block the antiinflammatory effects of endogenous HDLs, leading to a synergistic effect. Therefore, SR-BI is a molecular switch that can block or stimulate inflammation depending on the ligand (F igur e 1) . New immunotherapeutic therapies can take advantage of both activities. Progress in understanding the underlying mechanisms by which SR-BI can be anti- or proinflammatory will refine these therapeutic approaches. Financial & competing interests disclosure This work was supported by the agreement between Fundación para la Investigación Médica Aplicada and the ‘Unión Temporal de Empresas project Centro de Investigación Médica Aplicada’ and Red de Inmunoterapia INMUNONET-SOE1/P1/E014. Jessica Fioravanti and José Medina-Echeverz were supported by a fellowship of Spanish Fondo de Investigaciones Sanitarias. Pedro Berraondo was supported by a Miguel Servet contract from Instituto de Salud Carlos III, Fondo de Investigaciones Sanitarias. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript. www.futuremedicine.com

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Executive summary Scavenger receptor class B, type I (SR-BI) is a membrane glycoprotein that can bind to a broad range of ligands, including high-density lipoproteins (HDLs), lipopolysaccharide, CpG oligodeoxynucleotides, Gram-positive and Gram-negative bacteria, hepatitis C virus (HCV), Plasmodium sporozoites, serum amyloid A and dysfunctional HDLs. Upon binding of HDLs, SR-BI mediates reverse cholesterol transport in the liver and a direct anti-inflammatory effect on endothelial cells, which are crucial to prevent atherosclerosis. SR-BI downregulates Toll-like receptor (TLR)4 and TLR9 signaling and, thus, can promote infection by certain pathogens. SR-BI is an essential entry receptor for HCV in hepatocytes. Therefore, it represents a good molecular target for the development of anti‑HCV drugs. Modifications in the composition of HDLs or alterations in proteic or lipidic components of HDLs generate dysfunctional HDLs that exert proinflammatory activity upon binding to SR-BI. These dysfunctional HDLs are observed in acute-phase response or chronic inflammatory diseases such as rheumatoid arthritis, chronic kidney disease, diabetes mellitus or coronary artery disease. Both anti- and pro-inflammatory activities mediated by SR-BI can be useful in immunotherapy. Basic and applied research in this field will produce new drugs that will allow fine tuning of SR-BI functions. 9

Rigotti A, Trigatti B, Babitt J, Penman M, Xu S, Krieger M: Scavenger receptor BI – a cell surface receptor for high density lipoprotein. Curr. Opin. Lipidol. 8(3), 181–188 (1997).

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Cao G, Garcia CK, Wyne KL, Schultz RA, Parker KL, Hobbs HH: Structure and localization of the human gene encoding SR-BI/CLA-1. Evidence for transcriptional control by steroidogenic factor 1. J. Biol. Chem. 272(52), 33068–33076 (1997).

Bibliography Papers of special note have been highlighted as: n of interest 1

Acton SL, Scherer PE, Lodish HF, Krieger M: Expression cloning of SR-BI, a CD36-related class B scavenger receptor. J. Biol. Chem. 269(33), 21003–21009 (1994).

2

Calvo D, Vega MA: Identification, primary structure, and distribution of CLA-1, a novel member of the CD36/LIMPII gene family. J. Biol. Chem. 268(25), 18929–18935 (1993).

3

Calvo D, Gomez-Coronado D, Lasuncion MA, Vega MA: CLA-1 is an 85-kD plasma membrane glycoprotein that acts as a high-affinity receptor for both native (HDL, LDL, and VLDL) and modified (OxLDL and AcLDL) lipoproteins. Arterioscler. Thromb. Vasc. Biol. 17(11), 2341–2349 (1997).

4

Babitt J, Trigatti B, Rigotti A et al.: Murine SR-BI, a high density lipoprotein receptor that mediates selective lipid uptake, is N-glycosylated and fatty acylated and colocalizes with plasma membrane caveolae. J. Biol. Chem. 272(20), 13242–13249 (1997).

5

Eckhardt ER, Cai L, Sun B, Webb NR, Van Der Westhuyzen DR: High density lipoprotein uptake by scavenger receptor SR-BII. J. Biol. Chem. 279(14), 14372–14381 (2004).

6

Eckhardt ER, Cai L, Shetty S et al.: High density lipoprotein endocytosis by scavenger receptor SR-BII is clathrin-dependent and requires a carboxyl-terminal dileucine motif. J. Biol. Chem. 281(7), 4348–4353 (2006).

7

8

Webb NR, Connell PM, Graf GA et al.: SR-BII, an isoform of the scavenger receptor BI containing an alternate cytoplasmic tail, mediates lipid transfer between high density lipoprotein and cells. J. Biol. Chem. 273(24), 15241–15248 (1998). Acton S, Rigotti A, Landschulz KT, Xu S, Hobbs HH, Krieger M: Identification of scavenger receptor SR-BI as a high density lipoprotein receptor. Science (NY) 271(5248), 518–520 (1996).

402

11

Murao K, Terpstra V, Green SR, Kondratenko N, Steinberg D, Quehenberger O: Characterization of CLA-1, a human homologue of rodent scavenger receptor BI, as a receptor for high density lipoprotein and apoptotic thymocytes. J. Biol. Chem. 272(28), 17551–17557 (1997).

17

Reaven E, Nomoto A, Leers-Sucheta S, Temel R, Williams Dl, Azhar S: Expression and microvillar localization of scavenger receptor, class B, type I (a high density lipoprotein receptor) in luteinized and hormone-desensitized rat ovarian models. Endocrinology 139(6), 2847–2856 (1998).

18

Williams DL, Wong JS, Hamilton RL: SR-BI is required for microvillar channel formation and the localization of HDL particles to the surface of adrenocortical cells in vivo. J. Lipid Res. 43(4), 544–549 (2002).

19

Peng Y, Akmentin W, Connelly MA, Lund-Katz S, Phillips MC, Williams DL: Scavenger receptor BI (SR-BI) clustered on microvillar extensions suggests that this plasma membrane domain is a way station for cholesterol trafficking between cells and high-density lipoprotein. Mol. Biol. Cell 15(1), 384–396 (2004).

12 Krieger M: Charting the fate of the ‘good

cholesterol’: identification and characterization of the high-density lipoprotein receptor SR-BI. Annu. Rev. Biochem. 68, 523–558 (1999).

20 Silver DL: A carboxyl-terminal PDZ-

interacting domain of scavenger receptor B, type I is essential for cell surface expression in liver. J. Biol. Chem. 277(37), 34042–34047 (2002).

13 Husemann J, Silverstein SC: Expression of

scavenger receptor class B, type I, by astrocytes and vascular smooth muscle cells in normal adult mouse and human brain and in Alzheimer’s disease brain. Am. J. Pathol. 158(3), 825–832 (2001). 14

15

16

Srivastava RA: Scavenger receptor class B type I expression in murine brain and regulation by estrogen and dietary cholesterol. J. Neurol. Sci. 210(1–2), 11–18 (2003). Graf GA, Connell PM, van der Westhuyzen DR, Smart EJ: The class B, type I scavenger receptor promotes the selective uptake of high density lipoprotein cholesterol ethers into caveolae. J. Biol. Chem. 274(17), 12043–12048 (1999). Matveev S, Van Der Westhuyzen DR, Smart EJ: Co-expression of scavenger receptor-BI and caveolin-1 is associated with enhanced selective cholesteryl ester uptake in THP-1 macrophages. J. Lipid Res. 40(9), 1647–1654 (1999).


21

Ikemoto M, Arai H, Feng D et al.: Identification of a PDZ-domain-containing protein that interacts with the scavenger receptor class B type I. Proc. Natl Acad. Sci. USA 97(12), 6538–6543 (2000).

22 Kocher O, Yesilaltay A, Cirovic C, Pal R,

Rigotti A, Krieger M: Targeted disruption of the PDZK1 gene in mice causes tissue-specific depletion of the high density lipoprotein receptor scavenger receptor class B type I and altered lipoprotein metabolism. J. Biol. Chem. 278(52), 52820–52825 (2003). 23 Krieger M: Scavenger receptor class B type I is

a multiligand HDL receptor that influences diverse physiologic systems. J. Clin. Invest. 108(6), 793–797 (2001). 24 Calvo D, Gomez-Coronado D, Suarez Y,

Lasuncion MA, Vega MA: Human CD36 is a high affinity receptor for the native lipoproteins HDL, LDL, and VLDL. J. Lipid Res. 39(4), 777–788 (1998). future science group


25 Liadaki KN, Liu T, Xu S et al.: Binding of

high density lipoprotein (HDL) and discoidal reconstituted HDL to the HDL receptor scavenger receptor class B type I. Effect of lipid association and APOA-I mutations on receptor binding. J. Biol. Chem. 275(28), 21262–21271 (2000).

lipoproteins is dependent on lipoprotein binding to the receptor. J. Biol. Chem. 275(39), 29993–30001 (2000). 35

26 Xu S, Laccotripe M, Huang X, Rigotti A,

Zannis VI, Krieger M: Apolipoproteins of HDL can directly mediate binding to the scavenger receptor SR-BI, an HDL receptor that mediates selective lipid uptake. J. Lipid Res. 38(7), 1289–1298 (1997).

37 Mardones P, Quinones V, Amigo L et al.:

38 Lewis GF, Rader DJ: New insights into the

regulation of HDL metabolism and reverse cholesterol transport. Circ. Res. 96(12), 1221–1232 (2005).

31

Gu X, Lawrence R, Krieger M: Dissociation of the high density lipoprotein and low density lipoprotein binding activities of murine scavenger receptor class B type I (mSR-BI) using retrovirus library-based activity dissection. J. Biol. Chem. 275(13), 9120–9130 (2000).

40 Rubin EM, Krauss RM, Spangler EA,

34 Gu X, Kozarsky K, Krieger M: Scavenger

receptor class B, type I-mediated [3H] cholesterol efflux to high and low density

future science group

48 Fernandez-Irigoyen J, Santamaria E, Sesma L

et al.: Oxidation of specific methionine and tryptophan residues of apolipoprotein A-I in hepatocarcinogenesis. Proteomics 5(18), 4964–4972 (2005). n

41 Duverger N, Kruth H, Emmanuel F et al.:

Apolipoprotein A-I is a selective target for myeloperoxidase-catalyzed oxidation and functional impairment in subjects with cardiovascular disease. J. Clin. Invest. 114(4), 529–541 (2004). 50 Vaisar T, Pennathur S, Green PS et al.:

Shotgun proteomics implicates protease inhibition and complement activation in the antiinflammatory properties of HDL. J. Clin. Invest. 117(3), 746–756 (2007). 51

Mullan RH, Mccormick J, Connolly M, Bresnihan B, Veale DJ, Fearon U: A role for the high-density lipoprotein receptor SR-B1 in synovial inflammation via serum amyloid-A. Am. J. Pathol. 176(4), 1999–2008 (2010).

52

Nakagawa A, Shiratsuchi A, Tsuda K, Nakanishi Y: In vivo analysis of phagocytosis of apoptotic cells by testicular Sertoli cells. Mol. Reprod. Dev. 71(2), 166–177 (2005).

Inhibition of atherosclerosis development in cholesterol-fed human apolipoprotein A-Itransgenic rabbits. Circulation 94(4), 713–717 (1996). 42 Hoeg JM, Santamarina-Fojo S, Berard AM

et al.: Overexpression of lecithin:cholesterol acyltransferase in transgenic rabbits prevents diet-induced atherosclerosis. Proc. Natl Acad. Sci. USA 93(21), 11448–11453 (1996).

53 Bocharov AV, Baranova IN, Vishnyakova TG

43 Arai T, Wang N, Bezouevski M, Welch C,

et al.: Targeting of scavenger receptor class B type I by synthetic amphipathic a-helicalcontaining peptides blocks lipopolysaccharide (LPS) uptake and LPS-induced proinflammatory cytokine responses in THP-1 monocyte cells. J. Biol. Chem. 279(34), 36072–36082 (2004).

Tall AR: Decreased atherosclerosis in heterozygous low density lipoprotein receptor-deficient mice expressing the scavenger receptor BI transgene. J. Biol. Chem. 274(4), 2366–2371 (1999). 44 Kozarsky KF, Donahee MH, Glick JM,

Krieger M, Rader DJ: Gene transfer and hepatic overexpression of the HDL receptor SR-BI reduces atherosclerosis in the cholesterol-fed LDL receptor-deficient mouse. Arterioscler. Thromb. Vasc. Biol. 20(3), 721–727 (2000). 45

Rigotti A, Trigatti BL, Penman M, Rayburn H, Herz J, Krieger M: A targeted mutation in the murine gene encoding the high density lipoprotein (HDL) receptor scavenger receptor class B type I reveals its

www.futuremedicine.com

Proposes oxidized apolipoprotein A-I as a biomarker of hepatocarcinoma.

49 Zheng L, Nukuna B, Brennan ML et al.:

Verstuyft JG, Clift SM: Inhibition of early atherogenesis in transgenic mice by human apolipoprotein AI. Nature 353(6341), 265–267 (1991).

33 Ji Y, Jian B, Wang N et al.: Scavenger

receptor BI promotes high density lipoprotein-mediated cellular cholesterol efflux. J. Biol. Chem. 272(34), 20982–20985 (1997).

Endothelial-vasoprotective effects of high-density lipoprotein are impaired in patients with Type 2 diabetes mellitus but are improved after extended-release niacin therapy. Circulation 121(1), 110–122 (2010).

ABCA1 and ABCG1 synergize to mediate cholesterol export to ApoA-I. Arterioscler. Thromb. Vasc. Biol. 26(3), 534–540 (2006).

32 Gu X, Trigatti B, Xu S, Acton S, Babitt J,

Krieger M: The efficient cellular uptake of high density lipoprotein lipids via scavenger receptor class B type I requires not only receptor-mediated surface binding but also receptor-specific lipid transfer mediated by its extracellular domain. J. Biol. Chem. 273(41), 26338–26348 (1998).

47 Sorrentino SA, Besler C, Rohrer L et al.:

39 Gelissen IC, Harris M, Rye KA et al.:

30 Swarnakar S, Temel RE, Connelly MA,

Azhar S, Williams DL: Scavenger receptor class B, type I, mediates selective uptake of low density lipoprotein cholesteryl ester. J. Biol. Chem. 274(42), 29733–29739 (1999).

Increased LDL cholesterol and atherosclerosis in LDL receptor-deficient mice with attenuated expression of scavenger receptor B1. Arterioscler. Thromb. Vasc. Biol. 20(4), 1068–1073 (2000).

Hepatic cholesterol and bile acid metabolism and intestinal cholesterol absorption in scavenger receptor class B type I-deficient mice. J. Lipid Res. 42(2), 170–180 (2001).

29 Greene DJ, Skeggs JW, Morton RE: Elevated

triglyceride content diminishes the capacity of high density lipoprotein to deliver cholesteryl esters via the scavenger receptor class B type I (SR-BI). J. Biol. Chem. 276(7), 4804–4811 (2001).

46 Huszar D, Varban ML, Rinninger F et al.:

Abnormal lipoprotein metabolism and reversible female infertility in HDL receptor (SR-BI)-deficient mice. J. Clin. Invest. 108(11), 1717–1722 (2001).

28 Thuahnai ST, Lund-Katz S, Williams DL,

Phillips MC: Scavenger receptor class B, type I-mediated uptake of various lipids into cells. Influence of the nature of the donor particle interaction with the receptor. J. Biol. Chem. 276(47), 43801–43808 (2001).

key role in HDL metabolism. Proc. Natl Acad. Sci. USA 94(23), 12610–12615 (1997).

36 Miettinen HE, Rayburn H, Krieger M:

27 Urban S, Zieseniss S, Werder M, Hauser H,

Budzinski R, Engelmann B: Scavenger receptor BI transfers major lipoproteinassociated phospholipids into the cells. J. Biol. Chem. 275(43), 33409–33415 (2000).

Liu B, Krieger M: Highly purified scavenger receptor class B, type I reconstituted into phosphatidylcholine/cholesterol liposomes mediates high affinity high density lipoprotein binding and selective lipid uptake. J. Biol. Chem. 277(37), 34125–34135 (2002).

Review

54 Williams DL, De La Llera-Moya M,

Thuahnai ST et al.: Binding and cross-linking studies show that scavenger receptor BI interacts with multiple sites in apolipoprotein A-I and identify the class A amphipathic a-helix as a recognition motif. J. Biol. Chem. 275(25), 18897–18904 (2000). 55

Philips JA, Rubin EJ, Perrimon N: Drosophila RNAi screen reveals CD36 family member required for mycobacterial infection. Science (NY) 309(5738), 1251–1253 (2005).

403

Review n


Describes the role of scavenger receptor class B, type I (SR-BI) in mediating uptake of Mycobacterium fortuitum.

56 Vishnyakova TG, Kurlander R, Bocharov AV

et al.: CLA-1 and its splicing variant CLA-2 mediate bacterial adhesion and cytosolic bacterial invasion in mammalian cells. Proc. Natl Acad. Sci. USA 103(45), 16888–16893 (2006).

in glucocorticoid production and hepatic clearance. J. Clin. Invest. 118(1), 364–375 (2008). 65

Infectious hepatitis C virus pseudo-particles containing functional E1–E2 envelope protein complexes. J. Exp. Med. 197(5), 633–642 (2003). virus glycoproteins mediate pH-dependent cell entry of pseudotyped retroviral particles. Proc. Natl Acad. Sci. USA 100(12), 7271–7276 (2003). 69 Lindenbach BD, Evans MJ, Syder AJ et al.:

Describes the dual role of SR-BI in sepsis modulating inflammatory response in macrophages and facilitating lipopolysaccharide clearance.

70 Wakita T, Pietschmann T, Kato T et al.:

Freedman BD: Mechanism and regulatory function of CpG signaling via scavenger receptor B1 in primary B cells. J. Biol. Chem. 284(34), 22878–22887 (2009). 61

Vishnyakova TG, Bocharov AV, Baranova IN et al.: Binding and internalization of lipopolysaccharide by Cla-1, a human orthologue of rodent scavenger receptor B1. J. Biol. Chem. 278(25), 22771–22780 (2003).

Complete replication of hepatitis C virus in cell culture. Science (NY) 309(5734), 623–626 (2005). Production of infectious hepatitis C virus in tissue culture from a cloned viral genome. Nat. Med. 11(7), 791–796 (2005).

n

References [62] and [63] link cholesterol accumulation and inflammatory responses.

63 Yvan-Charvet L, Welch C, Pagler TA et al.:

Increased inflammatory gene expression in ABC transporter-deficient macrophages: free cholesterol accumulation, increased signaling via toll-like receptors, and neutrophil infiltration of atherosclerotic lesions. Circulation 118(18), 1837–1847 (2008). n

References [62] and [63] link cholesterol accumulation and inflammatory responses.

64 Cai L, Ji A, De Beer FC, Tannock LR,

van der Westhuyzen DR: SR-BI protects against endotoxemia in mice through its roles

404

n

Robust hepatitis C virus infection in vitro. Proc. Natl Acad. Sci. USA 102(26), 9294–9299 (2005).

Op De Beeck A, Dubuisson J, Vu-Dac N: High density lipoproteins facilitate hepatitis C virus entry through the scavenger receptor class B type I. J. Biol. Chem. 280(9), 7793–7799 (2005). n

81

83 Dreux M, Dao Thi VL, Fresquet J et al.:

Receptor complementation and mutagenesis reveal SR-BI as an essential HCV entry factor and functionally imply its intra- and extra-cellular domains. PLoS Pathogens 5(2), E1000310 (2009).

73 Cocquerel L, Voisset C, Dubuisson J:

Hepatitis C virus entry: potential receptors and their biological functions. J. Gen. Virol. 87(Pt 5), 1075–1084 (2006). 74

Pileri P, Uematsu Y, Campagnoli S et al.: Binding of hepatitis C virus to CD81. Science (NY) 282(5390), 938–941 (1998).

75 Hemler ME: Targeting of tetraspanin

proteins – potential benefits and strategies. Nat. Rev. Drug Discov. 7(9), 747–758 (2008). 76 Ploss A, Evans MJ, Gaysinskaya VA et al.:

Human occludin is a hepatitis C virus entry factor required for infection of mouse cells. Nature 457(7231), 882–886 (2009). 77 Liu S, Yang W, Shen L, Turner JR,

Coyne CB, Wang T: Tight junction proteins claudin-1 and occludin control hepatitis C Immunotherapy (2011) 3(3)

Von Hahn T, Lindenbach BD, Boullier A et al.: Oxidized low-density lipoprotein inhibits hepatitis C virus cell entry in human hepatoma cells. Hepatology 43(5), 932–942 (2006). High-avidity monoclonal antibodies against the human scavenger class B type I receptor efficiently block hepatitis C virus infection in the presence of high-density lipoprotein. J. Virol. 81(15), 8063–8071 (2007).

human scavenger receptor class B type I is a novel candidate receptor for the hepatitis C virus. EMBO J. 21(19), 5017–5025 (2002). Identifies a novel Toll-like receptor 9-independent mechanism of CpG-induced signaling and immune function that is mediated by SR-BI.

References [79] and [80] show how SR-BImediated viral infection depends on its lipid exchange activity.

82 Catanese MT, Graziani R, Von Hahn T et al.:

72 Scarselli E, Ansuini H, Cerino R et al.: The

n

References [79] and [80] show how SR-BImediated viral infection depends on its lipid exchange activity.

80 Voisset C, Callens N, Blanchard E,

71 Zhong J, Gastaminza P, Cheng G et al.:

62 Zhu X, Lee JY, Timmins JM et al.: Increased

cellular free cholesterol in macrophagespecific ABCA1 knock-out mice enhances pro-inflammatory response of macrophages. J. Biol. Chem. 283(34), 22930–22941 (2008).

An interplay between hypervariable region 1 of the hepatitis C virus E2 glycoprotein, the scavenger receptor BI, and high-density lipoprotein promotes both enhancement of infection and protection against neutralizing antibodies. J. Virol. 79(13), 8217–8229 (2005).

68 Hsu M, Zhang J, Flint M et al.: Hepatitis C

receptor BI protects against septic death through its role in modulating inflammatory response. J. Biol. Chem. 284(30), 19826–19834 (2009).

60 Zhu P, Liu X, Treml LS, Cancro MP,

79 Bartosch B, Verney G, Dreux M et al.:

67 Bartosch B, Dubuisson J, Cosset FL:

59 Guo L, Song Z, Li M et al.: Scavenger

n

Kang CY: Hepatitis C virus E2 links soluble human CD81 and SR-B1 protein. Virus Res. 121(1), 58–64 (2006).

initiation of HCV RNA replication in cell culture. Science (NY) 290(5498), 1972–1974 (2000).

58 Triantafilou M, Gamper FG, Haston RM

et al.: Membrane sorting of Toll-like receptor (TLR)-2/6 and TLR2/1 heterodimers at the cell surface determines heterotypic associations with CD36 and intracellular targeting. J. Biol. Chem. 281(41), 31002–31011 (2006).

78 Heo TH, Lee SM, Bartosch B, Cosset FL,

66 Blight KJ, Kolykhalov AA, Rice CM: Efficient

57 Stewart CR, Stuart LM, Wilkinson K et al.:

CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer. Nat. Immunol. 11(2), 155–161 (2010).

Lohmann V, Korner F, Koch J, Herian U, Theilmann L, Bartenschlager R: Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line. Science (NY) 285(5424), 110–113 (1999).

virus entry and are downregulated during infection to prevent superinfection. J. Virol. 83(4), 2011–2014 (2009).

n

First paper describing SR-BI as essential in hepatitis C virus infection.

84 Brimacombe CL, Grove J, Meredith LW

et al.: Neutralizing antibody resistant hepatitis C virus cell-to-cell transmission. J. Virol. 85(1), 596–605 (2010). 85 Casares S, Brumeanu TD, Richie TL: The

RTS, S malaria vaccine. Vaccine 28(31), 4880–4894 (2010). 86 Silvie O, Rubinstein E, Franetich Jf et al.:

Hepatocyte CD81 is required for Plasmodium falciparum and Plasmodium yoelii sporozoite infectivity. Nat. Med. 9(1), 93–96 (2003). 87 Silvie O, Charrin S, Billard M et al.:

Cholesterol contributes to the organization of tetraspanin-enriched microdomains and to



CD81-dependent infection by malaria sporozoites. J. Cell Sci. 119(Pt 10), 1992–2002 (2006). 88 Yalaoui S, Zougbede S, Charrin S et al.:

Hepatocyte permissiveness to Plasmodium infection is conveyed by a short and structurally conserved region of the CD81 large extracellular domain. PLoS Pathogens 4(2), E1000010 (2008). 89 Rodrigues CD, Hannus M, Prudencio M

et al.: Host scavenger receptor SR-BI plays a dual role in the establishment of malaria parasite liver infection. Cell Host Microbe 4(3), 271–282 (2008). n

Describes the role of SR-BI in both Plasmodium sporozoite invasion and intracellular parasite development.

90 Yalaoui S, Huby T, Franetich JF et al.:

Scavenger receptor BI boosts hepatocyte permissiveness to Plasmodium infection. Cell Host Microbe 4(3), 283–292 (2008). 91

Bowen DG, Walker CM: Adaptive immune responses in acute and chronic hepatitis C virus infection. Nature 436(7053), 946–952 (2005).

92 Thimme R, Oldach D, Chang KM,

Steiger C, Ray SC, Chisari FV: Determinants of viral clearance and persistence during acute hepatitis C virus infection. J. Exp. Med. 194(10), 1395–1406 (2001). 93 Villadangos JA, Heath WR, Carbone FR:

Outside looking in: the inner workings of the cross-presentation pathway within dendritic cells. Trends Immunol. 28(2), 45–47 (2007). 94 Goutagny N, Fatmi A, De Ledinghen V

et al.: Evidence of viral replication in circulating dendritic cells during hepatitis C virus infection. J. Infect. Dis. 187(12), 1951–1958 (2003). 95 Laporte J, Bain C, Maurel P, Inchauspe G,

Agut H, Cahour A: Differential distribution and internal translation efficiency of hepatitis C virus quasispecies present in dendritic and liver cells. Blood 101(1), 52–57 (2003). 96 Pachiadakis I, Pollara G, Chain BM,

Naoumov NV: Is hepatitis C virus infection of dendritic cells a mechanism facilitating viral persistence? Lancet Infect. Dis. 5(5), 296–304 (2005). 97 Marukian S, Jones CT, Andrus L et al.: Cell

culture-produced hepatitis C virus does not infect peripheral blood mononuclear cells. Hepatology 48(6), 1843–1850 (2008). 98 Barth H, Schnober EK, Neumann-

Haefelin C et al.: Scavenger receptor class B is required for hepatitis C virus uptake and cross-presentation by human dendritic cells. J. Virol. 82(7), 3466–3479 (2008).


99 Lambotin M, Baumert TF, Barth H:

Distinct intracellular trafficking of hepatitis C virus in myeloid and plasmacytoid dendritic cells. J. Virol. 84(17), 8964–8969 (2010). 100 Dreux M, Pietschmann T, Granier C et al.:

High density lipoprotein inhibits hepatitis C virus-neutralizing antibodies by stimulating cell entry via activation of the scavenger receptor BI. J. Biol. Chem. 281(27), 18285–18295 (2006). 101 Gordon T, Castelli WP, Hjortland MC,

Kannel WB, Dawber TR: High density lipoprotein as a protective factor against coronary heart disease. The Framingham study. Am. J. Med. 62(5), 707–714 (1977). 102 Nissen SE, Tsunoda T, Tuzcu EM et al.:

Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial. JAMA 290(17), 2292–2300 (2003). 103 Parolini C, Marchesi M, Lorenzon P et al.:

Dose-related effects of repeated ETC-216 (recombinant apolipoprotein A-I Milano/1palmitoyl-2-oleoyl phosphatidylcholine complexes) administrations on rabbit lipid-rich soft plaques: in vivo assessment by intravascular ultrasound and magnetic resonance imaging. J. Am. Coll. Cardiol. 51(11), 1098–1103 (2008). 104 Cockerill GW, Rye KA, Gamble JR,

Vadas MA, Barter PJ: High-density lipoproteins inhibit cytokine-induced expression of endothelial cell adhesion molecules. Arterioscler. Thromb. Vasc. Biol. 15(11), 1987–1994 (1995). 105 Calabresi L, Franceschini G, Sirtori CR

et al.: Inhibition of VCAM-1 expression in endothelial cells by reconstituted high density lipoproteins. Biochem. Biophys. Res. Commun. 238(1), 61–65 (1997). 106 Park SH, Park JH, Kang JS, Kang YH:

Involvement of transcription factors in plasma HDL protection against TNF-ainduced vascular cell adhesion molecule-1 expression. Int. J. Biochem. Cell Biol. 35(2), 168–182 (2003). 107 Kimura T, Tomura H, Mogi C et al.: Role of

scavenger receptor class B type I and sphingosine 1-phosphate receptors in high density lipoprotein-induced inhibition of adhesion molecule expression in endothelial cells. J. Biol. Chem. 281(49), 37457–37467 (2006). 108 Kimura T, Tomura H, Sato K et al.:

Mechanism and role of high density lipoprotein-induced activation of AMPactivated protein kinase in endothelial cells. J. Biol. Chem. 285(7), 4387–4397 (2010).

www.futuremedicine.com

Review

109 Hoang A, Murphy Aj, Coughlan Mt et al.:

Advanced glycation of apolipoprotein A-I impairs its anti-atherogenic properties. Diabetologia 50(8), 1770–1779 (2007). 110 Nobecourt E, Davies MJ, Brown BE et al.:

The impact of glycation on apolipoprotein A-I structure and its ability to activate lecithin:cholesterol acyltransferase. Diabetologia 50(3), 643–653 (2007). 111 Shao B, Bergt C, Fu X et al.: Tyrosine 192 in

apolipoprotein A-I is the major site of nitration and chlorination by myeloperoxidase, but only chlorination markedly impairs ABCA1-dependent cholesterol transport. J. Biol. Chem. 280(7), 5983–5993 (2005). 112 Shao B, Oda MN, Bergt C et al.:

Myeloperoxidase impairs ABCA1dependent cholesterol efflux through methionine oxidation and site-specific tyrosine chlorination of apolipoprotein A-I. J. Biol. Chem. 281(14), 9001–9004 (2006). 113 Shao B, Pennathur S, Pagani I et al.:

Modifying apolipoprotein A-I by malondialdehyde, but not by an array of other reactive carbonyls, blocks cholesterol efflux by the ABCA1 pathway. J. Biol. Chem. 285(24), 18473–18484 (2010). 114 Shao B, Cavigiolio G, Brot N, Oda MN,

Heinecke JW: Methionine oxidation impairs reverse cholesterol transport by apolipoprotein A-I. Proc. Natl Acad. Sci. USA 105(34), 12224–12229 (2008). 115 Uhlar CM, Burgess CJ, Sharp PM,

Whitehead AS: Evolution of the serum amyloid A (SAA) protein superfamily. Genomics 19(2), 228–235 (1994). 116 Coetzee GA, Strachan AF,

van der Westhuyzen DR, Hoppe HC, Jeenah MS, De Beer FC: Serum amyloid A-containing human high density lipoprotein 3. Density, size, and apolipoprotein composition. J. Biol. Chem. 261(21), 9644–9651 (1986). 117 Malle E, De Beer FC: Human serum

amyloid A (SAA) protein: a prominent acute-phase reactant for clinical practice. Eur. J. Clin. Invest. 26(6), 427–435 (1996). 118 Cabana VG, Feng N, Reardon CA et al.:

Influence of ApoA-I and ApoE on the formation of serum amyloid A-containing lipoproteins in vivo and in vitro. J. Lipid Res. 45(2), 317–325 (2004). 119 Kushner I: The phenomenon of the acute

phase response. Ann. NY Acad. Sci. 389, 39–48 (1982). 120 Van Lenten BJ, Hama SY, De Beer FC et al.:

Anti-inflammatory HDL becomes pro-inflammatory during the acute phase

405

Review


response. Loss of protective effect of HDL against LDL oxidation in aortic wall cell cocultures. J. Clin. Invest. 96(6), 2758–2767 (1995). n

Describing the switch from antiinflammatory high density lipoproteins to proinflammatory HDLs in acute‑phase response.

121 He R, Sang H, Ye RD: Serum amyloid A

induces IL-8 secretion through a G proteincoupled receptor, FPRL1/LXA4R. Blood 101(4), 1572–1581 (2003). 122 Mullan RH, Bresnihan B, Golden-Mason L

et al.: Acute-phase serum amyloid A stimulation of angiogenesis, leukocyte recruitment, and matrix degradation in rheumatoid arthritis through an NF-kBdependent signal transduction pathway. Arthritis Rheum. 54(1), 105–114 (2006). 123 Cai L, De Beer MC, De Beer FC, Van Der

Westhuyzen DR: Serum amyloid A is a ligand for scavenger receptor class B type I and inhibits high density lipoprotein binding and selective lipid uptake. J. Biol. Chem. 280(4), 2954–2961 (2005). 124 Baranova IN, Vishnyakova TG,

Bocharov AV et al.: Serum amyloid A binding to CLA-1 (CD36 and LIMPII analogous-1) mediates serum amyloid A protein-induced activation of ERK1/2 and p38 mitogen-activated protein kinases. J. Biol. Chem. 280(9), 8031–8040 (2005). 125 Schonfeld G, Pfleger B, Roy R: Structure of

human high density lipoprotein reassembled in vitro. Radioimmunoassay studies. J. Biol. Chem. 250(19), 7934–7950 (1975). 126 Eriksson M, Carlson LA, Miettinen TA,

Angelin B: Stimulation of fecal steroid excretion after infusion of recombinant proapolipoprotein A-I. Potential reverse cholesterol transport in humans. Circulation 100(6), 594–598 (1999). 127 Nicholls SJ, Tuzcu EM, Sipahi I et al.:

Relationship between atheroma regression and change in lumen size after infusion of apolipoprotein A-I Milano. J. Am. Coll. Cardiol. 47(5), 992–997 (2006). 128 Spieker Le, Sudano I, Hurlimann D et al.:

High-density lipoprotein restores endothelial function in hypercholesterolemic men. Circulation 105(12), 1399–1402 (2002).

406

129 Tardif JC, Gregoire J, L’allier Pl et al.:

Effects of reconstituted high-density lipoprotein infusions on coronary atherosclerosis: a randomized controlled trial. JAMA 297(15), 1675–1682 (2007). 130 Nanjee MN, Cooke CJ, Garvin R et al.:

Intravenous apoA-I/lecithin discs increase pre-b-HDL concentration in tissue fluid and stimulate reverse cholesterol transport in humans. J. Lipid Res. 42(10), 1586–1593 (2001). 131 Bisoendial RJ, Hovingh GK, Levels JH et al.:

Restoration of endothelial function by increasing high-density lipoprotein in subjects with isolated low high-density lipoprotein. Circulation 107(23), 2944–2948 (2003). 132 Patel S, Drew BG, Nakhla S et al.:

Reconstituted high-density lipoprotein increases plasma high-density lipoprotein anti-inflammatory properties and cholesterol efflux capacity in patients with Type 2 diabetes. J. Am. Coll. Cardiol. 53(11), 962–971 (2009). 133 Shaw JA, Bobik A, Murphy A et al.: Infusion

of reconstituted high-density lipoprotein leads to acute changes in human atherosclerotic plaque. Circ. Res. 103(10), 1084–1091 (2008). 134 Segrest JP, Jones MK, De Loof H,

Brouillette CG, Venkatachalapathi YV, Anantharamaiah GM: The amphipathic helix in the exchangeable apolipoproteins: a review of secondary structure and function. J. Lipid Res. 33(2), 141–166 (1992). 135 Datta G, Chaddha M, Hama S et al.: Effects

of increasing hydrophobicity on the physical-chemical and biological properties of a class A amphipathic helical peptide. J. Lipid Res. 42(7), 1096–1104 (2001). 136 Navab M, Anantharamaiah GM, Hama S

et al.: Oral administration of an Apo A-I mimetic Peptide synthesized from d-amino acids dramatically reduces atherosclerosis in mice independent of plasma cholesterol. Circulation 105(3), 290–292 (2002). 137 Garber DW, Datta G, Chaddha M et al.:

A new synthetic class A amphipathic peptide analogue protects mice from diet-induced atherosclerosis. J. Lipid Res. 42(4), 545–552 (2001).


138 D’souza W, Stonik JA, Murphy A et al.:

Structure/function relationships of Apolipoprotein A-I mimetic peptides. Implications for antiatherogenic activities of high-density lipoprotein. Circ. Res. 107(2), 217–227 (2010). 139 Bloedon LT, Dunbar R, Duffy D et al.:

Safety, pharmacokinetics, and pharmacodynamics of oral ApoA-I mimetic peptide D-4F in high-risk cardiovascular patients. J. Lipid Res. 49(6), 1344–1352 (2008). 140 Nieland TJ, Penman M, Dori L, Krieger M,

Kirchhausen T: Discovery of chemical inhibitors of the selective transfer of lipids mediated by the HDL receptor SR-BI. Proc. Natl Acad. Sci. USA 99(24), 15422–15427 (2002). 141 Nieland TJ, Chroni A, Fitzgerald ML et al.:

Cross-inhibition of SR-BI- and ABCA1mediated cholesterol transport by the small molecules BLT-4 and glyburide. J. Lipid Res. 45(7), 1256–1265 (2004). 142 Masson D, Koseki M, Ishibashi M et al.:

Increased HDL cholesterol and apoA-I in humans and mice treated with a novel SR-BI inhibitor. Arterioscler. Thromb. Vasc. Biol. 29(12), 2054–2060 (2009). 143 Syder AJ, Lee H, Zeisel MB et al.: Small

molecule scavenger receptor BI antagonists are potent HCV entry inhibitors. J. Hepatol. 54(1), 48–55 (2010). 144 Assanasen C, Mineo C, Seetharam D et al.:

Cholesterol binding, efflux, and a PDZinteracting domain of scavenger receptor-BI mediate HDL-initiated signaling. J. Clin. Invest. 115(4), 969–977 (2005). 145 Yuhanna IS, Zhu Y, Cox BE et al.:

High-density lipoprotein binding to scavenger receptor-BI activates endothelial nitric oxide synthase. Nat. Med. 7(7), 853–857 (2001). 146 Bulat N, Waeber G, Widmann C: LDLs

stimulate p38 MAPKs and wound healing through SR-BI independently of Ras and PI3 kinase. J. Lipid Res. 50(1), 81–89 (2009). 147 Dole VS, Matuskova J, Vasile E et al.:

Thrombocytopenia and platelet abnormalities in high-density lipoprotein receptor-deficient mice. Arterioscler. Thromb. Vasc. Biol. 28(6), 1111–1116 (2008).
