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. Author manuscript; available in PMC: 2024 Mar 19.
Published in final edited form as: Curr Opin Endocrinol Diabetes Obes. 2014 Apr;21(2):121–128. doi: 10.1097/MED.0000000000000046

Scavenger receptor class B type I and immune dysfunctions

Zhong Zheng a,b, Junting Ai a,b, Xiang-An Li a,b,c
PMCID: PMC10949371  NIHMSID: NIHMS1971097  PMID: 24569553

Abstract

Purpose of review

To summarize the recent findings about the roles of scavenger receptor class B type I (SR-BI) in immunity and discuss the underlying mechanisms by which SR-BI prevents immune dysfunctions.

Recent findings

SR-BI is well known as a high-density lipoprotein (HDL) receptor playing key roles in HDL metabolism and in protection against atherosclerosis. Recent studies have indicated that SR-BI is also an essential modulator in immunity. SR-BI deficiency in mice causes immune dysfunctions, including increased atherosclerosis, elevated susceptibility to sepsis, impaired lymphocyte homeostasis, and autoimmune disorders. SR-BI exerts its protective roles through a variety of HDL-dependent and HDL-independent mechanisms. SR-BI is also involved in hepatitis C virus cell entry. A deficiency of SR-BI in humanized mice has been shown to decrease hepatitis C virus infectivity.

Summary

SR-BI regulates immunity via multiple mechanisms and its deficiency causes numerous diseases. A comprehensive understanding of the roles of SR-BI in protection against immune dysfunctions may provide a therapeutic target for intervention against its associated diseases.

Keywords: atherosclerosis, dysfunctions, HDL, immunity, inflammation, sepsis, SR-BI

INTRODUCTION

Scavenger receptor class B type I (SR-BI or Scarb1) is a transmembrane protein most abundantly expressed in liver and steroidogenic tissues. SR-BI has a horse-shoe-like structure with two short cytoplasmic domains, two transmembrane domains, and a large extracellular loop [1]. Initially found able to bind ligands including modified low-density lipoprotein (LDL), naïve LDL, and anionic phospholipids [2,3], SR-BI was identified as a physiological high-density lipoprotein (HDL) receptor [4-6]. It modulates the selective uptake of cholesteryl ester from HDL, which plays a key role in HDL metabolism and reverse cholesterol transportation (RCT) [4,7-10,11■]. SR-BI also facilitates free cholesterol efflux from peripheral cells to HDL [12-15]. Furthermore, SR-BI participates in the HDL transport between blood and interstitial fluid. For instance, SR-BI is involved in the transcytosis of lipid-poor HDL across aortic endothelial cells to the periphery [16]. Likewise, in the process of HDL returning from the periphery to the blood via lymph [17■■,18■■], SR-BI plays a key role in mediating the transcytosis of HDL to enter lymphatic vessels [17■■]. Given the critical roles of SR-BI in regulating HDL metabolism, it is not surprising that SR-BI plays a protective role in atherosclerosis [19,20■■] (Fig. 1). Mutations in human SR-BI cause elevated plasma HDL concentration and are associated with female infertility and changes in cholesterol metabolism in macrophages and platelets, indicating a role of SR-BI in human diseases [21-24].

FIGURE 1.

FIGURE 1.

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Major immune phenotypes of SR-BI-deficient mice. SR-BI deficiency leads to immune dysfunctions, including increased atherosclerosis, elevated susceptibility to septic death, and impaired lymphocyte homeostasis. However, absence of SR-BI suppresses HCV infection. HCV, hepatitis C virus; SR-BI, scavenger receptor BI.

A body of evidence indicates that SR-BI is a multifunctional protein. In addition to mediating intracellular cholesterol uptake from HDL, SR-BI has been shown to activate endothelial nitric oxide synthase (eNOS) in endothelial cells [25-28], induce apoptosis [29,30], modulate erythrocyte development [31,32] and platelet function [33-36], protect against lipopolysaccharide (LPS)-induced endotoxemia and polymicrobial bacteria-induced sepsis [37-39], and regulate lymphocyte homeostasis and autoimmunity [40]. Moreover, SR-BI is involved in pathogenesis of hepatitis C virus (HCV) infection [41,42]. This review will focus on the types of SR-BI deficiency-induced immune dysfunctions and their underlying mechanisms (Fig. 1).

ROLE OF SCAVENGER RECEPTOR CLASS B TYPE I IN ATHEROSCLEROSIS

Atherosclerotic lesions represent a chronic inflammatory response against multiple risk agents such as cholesterol and oxidized LDL (oxLDL) [43-45]. Thus, atherosclerosis can be considered a disease of altered immunity. The protective role of SR-BI in atherosclerosis has been convincingly demonstrated, as shown by the findings that attenuation or ablation of SR-BI expression increases atherosclerosis in different atherosclerotic mouse models [46-49]; and SR-BI overexpression decreases the development of diet-induced fatty streak lesions [50]. The atheroprotective effects of SR-BI are largely attributed to the ability of hepatic SR-BI to mediate RCT. Hepatic overexpression of SR-BI accelerates RCT and reduces atherosclerosis in cholesterol-fed LDL receptor-knockout mice [51,52]. Liver-specific deficiency or knockdown of SR-BI blocks RCT and accelerates atherosclerosis [53,54■,55]. Paradoxically, extremely high levels of overexpressed SR-BI in liver are also proatherogenic in mice; however, the underlying mechanisms remain to be clarified [50].

Numerous studies have shown that lacking SR-BI expression in hematopoietic cells contributes to elevated atherosclerosis, although this does not alter circulating cholesterol concentrations in mice [14,47,56,57■,58]. It is believed that the atheroprotective effects of hematopoietic SR-BI are primarily provided by macrophage SR-BI, as evidenced by impaired cholesterol homeostasis [59] and exaggerated cytokine secretion in SR-BI-deficient macrophages [38,39,57■]. Meanwhile, SR-BI-facilitated bidirectional cholesterol efflux influences foam cell formation. Though hematopoietic SR-BI deficiency does not cause foam cell accumulation alone, it exaggerates foam cell accumulation when hematopoietic adenosine triphosphate-binding cassette transporter A1 is absent, suggesting that SR-BI may perform a compensatory route of cholesterol efflux to decrease foam cell formation [58,60].

In addition, SR-BI may be involved in HDL-mediated atheroprotective pathways. HDL can protect against atherosclerosis through its anti-oxidation properties, which are mainly attributed to two HDL-bound antioxidative enzymes, paraoxonase 1 (PON1) and platelet-activating factor acetylhydrolase (PAF-AH) [61-63]. SR-BI deficiency decreases PON1 and PAF-AH activity, causing an increased oxidative stress in mice [64]. SR-BI is also involved in the pathway in which PON1 directly dampens macrophage inflammatory responses [65■]. These data suggest that SR-BI deficiency may increase atherosclerosis by impairing anti-oxidation properties of HDL. Furthermore, SR-BI expression in endothelial cells may contribute to protection against atherosclerosis. Endothelial SR-BI mediates HDL-induced endothelial cell migration and repair [66], and activates eNOS to induce anti-atherogenic nitric oxide production in the presence of HDL [25-28].

ROLE OF SCAVENGER RECEPTOR CLASS B TYPE I IN SEPSIS

Sepsis is an exacerbated systemic inflammatory response induced by infections [67■]. It is a major health issue, claiming over 215 000 lives in the USA annually with a death rate exceeding 30% [68-70]. Our group first reported a protective role of SR-BI in sepsis [37,39]. LPS was shown to induce 90% fatality in SR-BI-deficient mice, whereas all wildtype littermates survived [37]; similarly, cecal ligation and puncture (CLP) induces 100% fatality in SR-BI-deficient mice, compared with only 21% fatality in wildtype littermates [39]. Associated with the increased septic death, SR-BI-deficient mice display uncontrolled inflammatory cytokine production, delayed LPS clearance, and augmented tissue damage [38,39]. These findings establish SR-BI as a critical protective molecule in sepsis. Findings from our laboratory and others further demonstrate that SR-BI exerts its protective functions through multiple mechanisms which are discussed below.

Scavenger receptor class B type I protects against nitric-oxide-induced cytotoxicity

In response to infections, the expression of inducible nitric oxide synthase is markedly upregulated to generate high levels of nitric oxide, which are required for fighting against pathogens. However, excess nitric oxide is highly cytotoxic, causing cell damage and tissue injury [71]. Our earlier study demonstrated that SR-BI protects against nitric oxide-induced cytotoxicity: in cell lines, expression of SR-BI protects against sodium nitroprusside-induced cell death [37]; and in mice, absence of SR-BI leads to increased tyrosine nitrated proteins, representing more nitric oxide-induced damage [37]. The lack of SR-BI-mediated protection against nitric oxide-induced cytotoxicity is likely partly responsible for the increased tissue damage during sepsis in SR-BI-deficient mice (Fig. 2).

FIGURE 2.

FIGURE 2.

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Multiple protective roles of SR-BI in sepsis. SR-BI-deficient mice show elevated susceptibility to septic death associated with uncontrolled inflammatory response, delayed LPS clearance, and increased tissue injury. A number of possible mechanisms may contribute to the protective effects of SR-BI in sepsis. First, SR-BI protects against NO-induced cytotoxicity (up left), which prevents tissue damage. Second, adrenal SR-BI mediates the uptake of cholesterol ester from HDL to provide cholesterol for inducible steroid synthesis (up right), which keeps inflammatory responses under control. Third, macrophage SR-BI inhibits LPS-induced inflammatory signaling involving TLR4, JNK, p38, and NF-κB pathways (bottom right), which controls inflammatory cytokine production. Finally, hepatic SR-BI mediates LPS uptake and facilitates LPS clearance (bottom left), which alleviates inflammatory response. HDL, high-density lipoprotein; HCV, hepatitis C virus; LPS, lipopolysaccharide; NO, nitric oxide; SR-BI, scavenger receptor BI.

Scavenger receptor class B type I mediates inducible glucocorticoid production

Glucocorticoids are markedly induced in response to septic stress and serve as potent inflammatory modulators during sepsis [72]. An earlier study demonstrated that SR-BI-mediated selective uptake of cholesterol from HDL is an essential pathway for adrenal glands to acquire cholesterol for glucocorticoid synthesis [73]. Notably, this pathway is critical for inducible glucocorticoid production: SR-BI-deficient mice exhibit normal physiological glucocorticoid concentrations but fail to produce inducible glucocorticoids in response to LPS [38], CLP [39], or prolonged fasting [74,75■■]. Given the potent effect of glucocorticoids in suppressing inflammatory response, it is plausible that the lack of inducible glucocorticoid production in SR-BI-deficient mice is responsible for the exaggerated inflammation and elevated septic death. Using an LPS endotoxic model, Cai et al. [38] showed that supplementation of corticosterone in drinking water 8h prior to LPS treatment suppresses LPS-induced cytokine production and protects against LPS-induced endotoxic animal death in SR-BI-deficient mice. Unexpectedly, supplementation of corticosterone following the same regimen fails to rescue SR-BI-deficient mice from CLP-induced septic death [39]. Corticosterone supplementation may have failed because glucocorticoids are a heterogeneous group of molecules with varied potency, half-life, and function [76,77], which work together to produce complementary effects. Simply supplementing one type of glucocorticoids may not effectively provide protection in sepsis. To test this speculation, we generated adrenal-specific SR-BI-null mice by adrenal transplantation. We found that the adrenal SR-BI wildtype mice are significantly more resistant to CLP-induced septic death than adrenal SR-BI-null mice (unpublished observation). Thus, SR-BI-mediated inducible glucocorticoid production plays a critical protective role in sepsis (Fig. 2).

Scavenger receptor class B type I modulates inflammatory response in macrophages

Macrophages are a major cell type responsible for cytokine production. SR-BI appears to play a role in modulating inflammatory signaling in macrophages (Fig. 2). Using bone marrow-derived macrophages and a HEK-Blue cell system, it has been shown that the expression of SR-BI suppresses inflammatory cytokine production in LPS-stimulated macrophages by modulating the TLR4–NF-κB pathway [39]. Further study demonstrated that the regulation of SR-BI involves JNK and P38 signaling pathways [78■]. Using a bone marrow transplantation mouse model, it was reported that hematopoietic SR-BI deficiency causes higher cytokine production in response to LPS, suggesting that macrophage SR-BI helps to control inflammatory response in vivo [78■]. The inhibitory effects of SR-BI on the macrophage inflammatory response may contribute to protection against septic death – for instance, overexpression of SR-BIC323G (a mutant SR-BI lacking activity for glucocorticoid generation but capable of suppressing TLR4–NF-κB signaling) in SR-BI-deficient mice significantly improves their survival under CLP challenge [39].

Scavenger receptor class B type I mediates lipopolysaccharide clearance

Like other scavenger receptors, SR-BI not only scavenges unwanted self-molecules, but also recognizes and mediates the removal of nonself molecules [79-82]. LPS is one of the nonself ligands of SR-BI [83]. More than recognizing LPS, SR-BI is able to mediate the uptake of LPS [83]. SR-BI-deficient hepatocytes display decreased ability to uptake LPS in vitro, and SR-BI-deficient mice have decreased hepatic LPS uptake and increased plasma LPS retention after LPS injection [38]. The delayed LPS clearance is also observed in the CLP model in SR-BI-deficient mice [39] (Fig. 2). Interestingly, during the early stage of sepsis, SR-BI-deficient mice display lower plasma LPS concentrations than wildtype mice, suggesting that SR-BI-mediated LPS uptake may be essential for transporting the LPS from the inflammation site to circulation [39]. In addition to LPS, SR-BI can also mediate the uptake of Gram-negative bacteria, Gram-positive bacteria, and lipoteichoic acid, the key component of Gram-positive cell walls [84]. In one report, it was claimed that when glucocorticoids and mineralcorticoids are supplemented in the presence of antibiotics, SR-BI-deficient mice show reduced bacterial load associated with an increase in survival upon CLP [85]. However, this study seems to be problematic because of its inappropriate experimental approaches [86]. For example, C57BL/6N mice, which are much more susceptible to CLP-induced septic death than mice in mixed background, were used as controls of SR-BI-deficient mice in C57BL/6J/129 mixed background [86]. In addition, dexamethasone was administered 24h prior to CLP, which completely abolishes adrenal SR-BI expression in wildtype controls [87]. This study essentially compared two groups of mice that are different in background, but both lack adrenal SR-BI expression when challenged with CLP. Nevertheless, further investigation is required to determine the contribution of SR-BI-mediated uptake of bacteria in sepsis.

ROLE OF SCAVENGER RECEPTOR CLASS B TYPE I IN LYMPHOCYTE HOMEOSTASIS AND AUTOIMMUNITY

In the recent years, several players in RCT have been identified as modulators in adaptive immunity [62,88-92]. The roles of SR-BI in adaptive immunity were also revealed using SR-BI-deficient mice [40]. SR-BI-deficient mice display splenomegaly and significant splenic lymphocyte expansions. Interestingly, the lymphocyte expansions are imbalanced, as shown by a 30% decrease in T/B cell ratio. SR-BI deficiency also causes lymphocyte hyperactivation and hyperproliferation. As a consequence of impaired lymphocyte homeostasis, the aged SR-BI-deficient mice exhibit profound autoimmune disorders [40]. These findings demonstrate that SR-BI is essential in maintaining lymphocyte homeostasis and preventing autoimmune disorders.

The adaptive immune defects in SR-BI-deficient mice are at least partly attributed to their abnormal HDL particles, which are larger in size and characterized by the accumulation of free cholesterol [6]. Functionally, SR-BI-deficient HDL shows reduced ability to mediate selective cholesterol uptake [93], as well as decreased antioxidative enzyme activity [64], and it is responsible for female infertility [94,95]. This dysfunctional HDL partly loses its ability to inhibit anti-CD3-stimulated T-cell proliferation and LPS-induced B-cell proliferation, suggesting that SR-BI can modulate lymphocyte function by regulating HDL properties [40]. Intriguingly, we recently found that HDL promotes glucocorticoid-induced thymocyte apoptosis, but HDL from SR-BI-deficient mice completely loses this regulatory activity, providing another piece of evidence that SR-BI modulates adaptive immunity through regulating HDL functions (unpublished observation).

ROLE OF SCAVENGER RECEPTOR CLASS B TYPE I IN HEPATITIS C VIRUS INFECTION

Recent studies revealed that SR-BI mediates HCV entry [41], which questions whether SR-BI is always a beneficial molecule. The involvement of SR-BI in HCV entry was demonstrated by that down-regulating or blocking human SR-BI decreases HCV infectivity in cell lines [96-100]. In vivo, SR-BI was confirmed as an HCV entry factor: in mice genetically humanized for HCV infection, SR-BI deficiency reduces HCV infection [101]; and in mice with humanized livers, antibodies against SR-BI inhibit HCV infection [102■,103■]. Therefore, SR-BI is regarded as a potential target to treat HCV infection [104].

Initially, it was thought that SR-BI mediates HCV entry by binding HCV. However, later research indicated that binding of SR-BI to HCV may not be necessary for HCV entry (although human SR-BI is able to bind soluble E2 glycoprotein from HCV [105], it fails to recognize natural serum-derived HCV [106]; and mouse SR-BI, which is able to mediate HCV entry [101], cannot bind HCV [107]). Instead, the lipid transfer function of SR-BI seems to be essential in this process [41]. On one hand, HDL can enhance HCV cell entry, which is suppressed by blocking SR-BI-mediated lipid transfer [108,109]. On the other hand, very low-density lipoprotein and oxLDL, the other two ligands of SR-BI, inhibit HCV cell entry in an SR-BI-dependent manner [106,110]. Notably, SR-BI may also be important in initiating the host defense against HCV, as dendritic cells also depend on SR-BI to uptake HCV [111]. The detailed roles of SR-BI in HCV infection warrant further investigation.

CONCLUSION

SR-BI acts as a critical modulator of both innate and adaptive immunity, and its deficiency alters its immune response in a variety of diseases, including atherosclerosis, sepsis, and autoimmune disorders. It is worth noting that, in addition to directly modulating immunity, SR-BI may participate indirectly in modulating immunity through its role in regulating HDL metabolism, and a lack of SR-BI-mediated HDL metabolism may render HDL dysfunctional. Given the diversity of cell types that express SR-BI and the multiple ligands recognized by SR-BI that are yet uninvestigated, our understanding of the functions of SR-BI is just emerging. Further efforts are warranted to better understand the roles of SR-BI in regulating immunity and preventing immune dysfunction.

KEY POINTS.

  • SR-BI is well known as a HDL receptor playing key roles in HDL metabolism and in protection against atherosclerosis.

  • SR-BI is an essential immune modulator and its deficiency causes immune dysfunctions, including elevated susceptibility to sepsis, impaired lymphocyte homeostasis, and autoimmune disorders.

  • SR-BI is required for HCV infectivity.

Acknowledgements

Funding sources: This publication was made possible by the grant numbers R01GM085231, R01GM085231-2S1, and R01GM085231-5S1 from NIGMS or NIH. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIGMS or NIH. This work was also supported by a grant from the Children’s Miracle Network.

Footnotes

Conflicts of interest

There are no conflicts of interest.

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