Scavenger receptor-A mediates gp96/GRP94 and calreticulin internalization by antigen-presenting cells

Berwin, Brent; Hart, Justin P.; Rice, Stuart A.; Gass, Cecilia; Pizzo, Salvatore V.; Post, Steven R.; Nicchitta, Christopher V.

doi:10.1093/emboj/cdg572

Cited by 226 publications

(199 citation statements)

References 121 publications

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“…Quantification of Cytokine Generation in LPS-stimulated Macrophages-Bone marrow-derived macrophages were cultured as described previously (30). Briefly, bone marrow cells were cultured in a 6-well plate at 2 ϫ 10 6 cells/well in RPMI 1640 medium containing 20% fetal bovine serum and 25 ng/ml of mouse macrophage colony stimulate factor for 6 days.…”

Section: Sr-bi-null Mice-sr-bimentioning

confidence: 99%

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

Guo

Song

et al. 2009

Journal of Biological Chemistry

126

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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...

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Section: Sr-bi-null Mice-sr-bimentioning

confidence: 99%

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

Guo

Song

et al. 2009

Journal of Biological Chemistry

126

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“…Indeed, a complex of CD91 and CRT serves as a collectin receptor on the surface of macrophages and can mediate the phagocytosis of apoptotic cells opsonized with C1q, MBL, SP-A or SP-D [8,11]. Furthermore, scavenger receptor-A has now been reported as a second receptor involved in binding and internalization of CRT and gp96 [46]. Scavenger receptor-A is prominently expressed not only on macrophages but also on DC and therefore might also be involved in the uptake of apoptotic material opsonized with C1q and collectins.…”

Section: Introductionmentioning

confidence: 99%

Mini‐review: A pivotal role for innate immunity in the clearance of apoptotic cells

et al. 2004

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Apoptotic cells can be recognized and taken up by both macrophages and dendritic cells. Phagocytosis of apoptotic cells generally leads to active suppression of cytokine production by professional phagocytes. This is different from the response towards cells that die by necrosis, which induce a pro-inflammatory cytokine profile. Uptake of apoptotic cells involves a large number of receptors and opsonins, which bind to cellular ligands exposed during the various stages of apoptotic cell death. Among the opsonins of apoptotic cells, complement factors, including C1q, and complement-activating members of the pentraxin family play an important role. This is indicated by in vitro phagocytosis studies and supported by the susceptibility to systemic autoimmunity of carriers of genetic deficiencies for early complement proteins. The present review summarizes the role of molecules of innate immunity in the handling of apoptotic cells by macrophages and dendritic cells. It is proposed that C1q and other opsonins prevent autoimmunity and maintain self-tolerance by supporting the efficient clearance of apoptotic material, as well as by actively modulating phagocyte function.

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“…cell meditated immunity [62]. They also stimulate innate immunity and activate dendritic cells and natural killer cells by binding with CD40, TLR-2, TLR-4, CD14 and, scavenging receptor-A [63][64][65][66]. These immune effector functions mediated by the heat shock proteins and modulation of chaperone activities have been exploited heat shock proteins as therapeutic agents as wall as therapeutic targets in several infectious diseases, cancers and neurodegenerative disorders.…”

Section: Therapeutic Potential Of Heat Shock Proteinsmentioning

confidence: 99%

Role of Heat Shock Proteins in Diseases and Their Therapeutic Potential

Kaul

Thippeswamy

2011

Indian J Microbiol

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Heat shock proteins are ubiquitously expressed intracellular proteins and act as molecular chaperones in processes like protein folding and protein trafficking between different intracellular compartments. They are induced during stress conditions like oxidative stress, nutritional deficiencies and radiation. They are released into extracellular compartment during necrosis. However, recent research findings highlights that, they are not solely present in cytoplasm, but also released into extracellular compartment during normal conditions and even in the absence of necrosis. When present in extracellular compartment, they have been shown to perform various functions like antigen presentation, intercellular signaling and induction of pro-inflammatory cytokines. Heat shock proteins represents as dominant microbial antigens during infection. The phylogenetic similarity between prokaryotic and eukaryotic heat shock proteins has led to proposition that, microbial heat shock proteins can induce self reactivity to host heat shock proteins and result in autoimmune diseases. The self-reactivity of heat shock proteins protects host against disease by controlling induction and release of pro-inflammatory cytokines. However, antibodies to self heat shock proteins haven been implicated in pathogenesis of autoimmune diseases like arthritis and atherosclerosis. Some heat shock proteins are potent inducers of innate and adaptive immunity. They activate dendritic cells and natural killer cells through toll-like receptors, CD14 and CD91. They play an important role in MHC-antigen processing and presentation. These immune effector functions of heat shock proteins are being exploited them as therapeutic agents as well as therapeutic targets for various infectious diseases and cancers.

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Scavenger receptor-A mediates gp96/GRP94 and calreticulin internalization by antigen-presenting cells

Cited by 226 publications

References 121 publications

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

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

Mini‐review: A pivotal role for innate immunity in the clearance of apoptotic cells

Role of Heat Shock Proteins in Diseases and Their Therapeutic Potential

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