Scavenger Receptor BI Protects against Septic Death through Its Role in Modulating Inflammatory Response

Abstract

Sepsis is a leading cause of death that is characterized by uncontrolled inflammatory response. In this study, we report that scavenger receptor BI (SR-BI), a high density lipoprotein receptor, is a critical survival factor of sepsis. We induced sepsis using an established septic animal model, cecal ligation and puncture (CLP). CLP induced 100% fatality in SR-BI-null mice but only 21% fatality in wild type littermates. SR-BI-null mice exhibited aberrant inflammatory responses with delayed inflammatory cytokine generation at the early stage of sepsis and highly elevated inflammatory cytokine production 20 h after CLP treatment. To understand the mechanisms underlying SR-BI protection, we elucidated the effect of macrophage SR-BI on inflammatory cytokine generation. Macrophages from SR-BI-null mice produced significantly higher levels of inflammatory cytokines than those of wild type controls in response to LPS. Importantly, transgenic mice overexpressing SR-BI were more resistant to CLP-induced septic death. Using an HEKBlue TM cell system, we demonstrated that expression of SR-BI suppressed TLR4-mediated NF-B activation. To understand why SR-BI-null mice had a delayed inflammatory response, we elucidated the effect of SR-BI on LPS clearance during sepsis. Compared with wild type controls, SR-BI-null mice had lower plasma LPS levels in the early stage of sepsis and elevated plasma LPS levels 20 h following CLP treatment. In conclusion, our findings demonstrate that SR-BI is a critical protective modulator of sepsis in mice. SR-BI exerts its protective function through its role in modulating inflammatory response in macrophages and facilitating LPS recruitment and clearance.Sepsis is one of the major causes of death that claims over 215,000 lives and costs $16.7 billion per year in America alone (1-4). The death rate from sepsis is high, exceeding 50%, due to poor understanding of the disease (5). Identifying molecules involved in sepsis, especially endogenous protective modulators, is of great importance not only in understanding the mechanisms but also in providing new insights for efficient therapies.Scavenger receptor BI (SR-BI 2 or Scarb1) is a 75-kDa membrane protein expressed in the liver, endothelial cells, macrophages, and steroidogenic tissues (6, 7). It is a well established high density lipoprotein (HDL) receptor. It mediates intracellular uptake of cholesterol ester from HDL, which plays a key role in regulating plasma cholesterol levels and steroidogenesis (8 -11). Mice deficient in SR-BI have a 2-fold increase in plasma cholesterol levels and develop cardiovascular diseases (10,(12)(13)(14)(15)(16). Recent studies reveal that SR-BI is a multifunctional protein. It activates endothelial nitric-oxide synthase in endothelial cells in the presence of HDL (17-20), induces apoptosis in the absence of HDL/endothelial nitric-oxide synthase (21), and protects against nitric oxide (NO)-induced oxidative damage (22). Emerging evidence indicates that specific expression of SR-BI in macrophages provides protecti...

Cholesteryl Ester Transfer Protein Expression Partially Attenuates the Adverse Effects of SR-BI Receptor Deficiency on Cholesterol Metabolism and Atherosclerosis

“…Thus, using different atherogenic diets (1.25% cholesterol-enriched diets containing cholate (4) or not (this study)) and in different contexts of cholesterol transport (presence or absence of CETP), we clearly demonstrated the peripheral atheroprotective role mediated by SR-BI. Whether such a protective role relies on the multiligands receptor nature of SR-BI, its function in steroidogenic tissues for cholesterol supply, its activities in promoting endothelial repair (40), in facilitating endothelial nitric oxide (NO) production (41), or inversely in protecting against NO cytotoxicity (42), or as a modulator of the inflammatory response in macrophages (43) remains to be established. Cross-breeding of the hypomSR-BI mouse model with cell-specific CRE transgenic lines should provide valuable mouse models to investigate these possibilities.…”

Hepatic Scavenger Receptor BI Protects Against Polymicrobial-induced Sepsis through Promoting LPS Clearance in Mice

“…CLP Septic Animal Model-CLP was performed on 10 -12-week-old Scarb1 I179N and C57BL/6J mice as described previously (50 Biochemical Assays-10 -12-week-old mice were euthanized by CO 2 inhalation 6 and 20 h following CLP. The blood was obtained by cardiac puncture and stored at Ϫ80°C.…”

“…Quantification of Cytokine Generation in LPS-stimulated Macrophages-Bone marrow-derived macrophages were cultured as described previously (50). Briefly, bone marrow cells were cultured in a 12-well plate at 1.5 ϫ 10 6 cells/well in RPMI1640 medium containing 20% FBS and 15% supernatant of L929 cell culture for 5 days.…”

“…Assay for Bacterial Load-Bacterial load in liver and spleen was analyzed as previously described (50).…”

“…Available evidence suggests that SR-BI may exert its protection via multiple mechanisms. Macrophage SR-BI suppresses inflammatory response by modulating LPS-TLR4 signaling in macrophages, which contributes to protection against septic animal death (50, 52); Adrenal SR-BI is a key determinant of inducible glucocorticoid (GC) generation in response to stress (49,50,53), and SR-BI null mice are completely deficient in inducible GC generation in CLP-induced sepsis (50); A number of studies suggest that SR-BI may provide protection against sepsis through detoxifying LPS. SR-BI binds to LPS and mediates the uptake of LPS in vitro (54), and SR-BI-null mice display impaired LPS clearance in circulation in LPS-induced endotoxemia or CLP-induced sepsis (49,50).…”