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The macrophage scavenger receptor type A is expressed by activated macrophages and protects the host against lethal endotoxic shock.

Haworth R, Platt N, Keshav S, Hughes D, Darley E, Suzuki H, Kurihara Y, Kodama T, Gordon S - J. Exp. Med. (1997)

Bottom Line: We show that activated Mphi express SR-A and that this molecule is functional in assays of adhesion and endocytic uptake.Thus SR-A, expressed by activated Mphi, plays a protective role in host defense by scavenging LPS as well as by reducing the release by activated Mphi of proinflammatory cytokines.Modulation of SR-A may provide a novel therapeutic approach to control endotoxic shock.

View Article: PubMed Central - PubMed

Affiliation: Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, United Kingdom.

ABSTRACT
During gram-negative bacterial infections, lipopolysaccharide (LPS) stimulates primed macrophages (Mphi) to release inflammatory mediators such as tumor necrosis factor (TNF)-alpha, which can cause hypotension, organ failure, and often death. Several different receptors on Mphi have been shown to bind LPS, including the type A scavenger receptor (SR-A). This receptor is able to bind a broad range of polyanionic ligands such as modified lipoproteins and lipoteichoic acid of gram-positive bacteria, which suggests that SR-A plays a role in host defense. In this study, we used mice lacking the SR-A (SRKO) to investigate the role of SR-A in acquired immunity using a viable bacillus Calmette Guérin (BCG) infection model. We show that activated Mphi express SR-A and that this molecule is functional in assays of adhesion and endocytic uptake. After BCG infection, SRKO mice are able to recruit Mphi to sites of granuloma formation where they become activated and restrict BCG replication. However, infected mice lacking the SR-A are more susceptible to endotoxic shock and produce more TNF-alpha and interleukin-6 in response to LPS. In addition, we show that an antibody which blocks TNF-alpha activity reduces LPS-induced mortality in these mice. Thus SR-A, expressed by activated Mphi, plays a protective role in host defense by scavenging LPS as well as by reducing the release by activated Mphi of proinflammatory cytokines. Modulation of SR-A may provide a novel therapeutic approach to control endotoxic shock.

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Role of SR-A in a model of endotoxic shock. SRKO and  129 mice were injected intraperitoneally with 107 CFU of BCG. At days  12–14 of infection, the mice were injected with various doses of LPS  (μg). The mice were observed for 5 d and mortality was noted. The percentage of survival for each dose point represents the mean mortality of a  group of at least five mice. The dose of LPS producing 50% mortality  (LD50; ng/ml) of the 129 mice is: 34.1 ± 6.6 (standard error), which is  significantly different from the SRKO LD50: 4.7 ± 1.5; P <0.0001.
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Figure 4: Role of SR-A in a model of endotoxic shock. SRKO and 129 mice were injected intraperitoneally with 107 CFU of BCG. At days 12–14 of infection, the mice were injected with various doses of LPS (μg). The mice were observed for 5 d and mortality was noted. The percentage of survival for each dose point represents the mean mortality of a group of at least five mice. The dose of LPS producing 50% mortality (LD50; ng/ml) of the 129 mice is: 34.1 ± 6.6 (standard error), which is significantly different from the SRKO LD50: 4.7 ± 1.5; P <0.0001.

Mentions: Wild-type and SRKO mice were infected with BCG, resulting in the production of numerous Mφ-rich granulomas in parenchymatous organs. Groups of BCG-infected mice were challenged with a range of LPS doses by intraperitoneal injection at days 12–14 of infection. The significant discovery was that the SRKO mice showed approximately sevenfold higher morbidity and mortality than wild-type mice (Fig. 4). In preliminary studies, similar results were obtained when an inactivated preparation of C. parvum was used to prime the mice before LPS challenge (e.g., LPS dose 10 μg: mortality of 129, 0%; of SRKO, 75%; n = 4). In addition, increased susceptibility to LPS challenge of the SRKO mice can be demonstrated even in uninfected mice which have received no stimulus for IFN-γ priming of Mφ, although doses of LPS required are two orders of magnitude higher (e.g., LPS dose 500 μg: mortality of 129, 0%; of SRKO, 66%; n = 3).


The macrophage scavenger receptor type A is expressed by activated macrophages and protects the host against lethal endotoxic shock.

Haworth R, Platt N, Keshav S, Hughes D, Darley E, Suzuki H, Kurihara Y, Kodama T, Gordon S - J. Exp. Med. (1997)

Role of SR-A in a model of endotoxic shock. SRKO and  129 mice were injected intraperitoneally with 107 CFU of BCG. At days  12–14 of infection, the mice were injected with various doses of LPS  (μg). The mice were observed for 5 d and mortality was noted. The percentage of survival for each dose point represents the mean mortality of a  group of at least five mice. The dose of LPS producing 50% mortality  (LD50; ng/ml) of the 129 mice is: 34.1 ± 6.6 (standard error), which is  significantly different from the SRKO LD50: 4.7 ± 1.5; P <0.0001.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2199123&req=5

Figure 4: Role of SR-A in a model of endotoxic shock. SRKO and 129 mice were injected intraperitoneally with 107 CFU of BCG. At days 12–14 of infection, the mice were injected with various doses of LPS (μg). The mice were observed for 5 d and mortality was noted. The percentage of survival for each dose point represents the mean mortality of a group of at least five mice. The dose of LPS producing 50% mortality (LD50; ng/ml) of the 129 mice is: 34.1 ± 6.6 (standard error), which is significantly different from the SRKO LD50: 4.7 ± 1.5; P <0.0001.
Mentions: Wild-type and SRKO mice were infected with BCG, resulting in the production of numerous Mφ-rich granulomas in parenchymatous organs. Groups of BCG-infected mice were challenged with a range of LPS doses by intraperitoneal injection at days 12–14 of infection. The significant discovery was that the SRKO mice showed approximately sevenfold higher morbidity and mortality than wild-type mice (Fig. 4). In preliminary studies, similar results were obtained when an inactivated preparation of C. parvum was used to prime the mice before LPS challenge (e.g., LPS dose 10 μg: mortality of 129, 0%; of SRKO, 75%; n = 4). In addition, increased susceptibility to LPS challenge of the SRKO mice can be demonstrated even in uninfected mice which have received no stimulus for IFN-γ priming of Mφ, although doses of LPS required are two orders of magnitude higher (e.g., LPS dose 500 μg: mortality of 129, 0%; of SRKO, 66%; n = 3).

Bottom Line: We show that activated Mphi express SR-A and that this molecule is functional in assays of adhesion and endocytic uptake.Thus SR-A, expressed by activated Mphi, plays a protective role in host defense by scavenging LPS as well as by reducing the release by activated Mphi of proinflammatory cytokines.Modulation of SR-A may provide a novel therapeutic approach to control endotoxic shock.

View Article: PubMed Central - PubMed

Affiliation: Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, United Kingdom.

ABSTRACT
During gram-negative bacterial infections, lipopolysaccharide (LPS) stimulates primed macrophages (Mphi) to release inflammatory mediators such as tumor necrosis factor (TNF)-alpha, which can cause hypotension, organ failure, and often death. Several different receptors on Mphi have been shown to bind LPS, including the type A scavenger receptor (SR-A). This receptor is able to bind a broad range of polyanionic ligands such as modified lipoproteins and lipoteichoic acid of gram-positive bacteria, which suggests that SR-A plays a role in host defense. In this study, we used mice lacking the SR-A (SRKO) to investigate the role of SR-A in acquired immunity using a viable bacillus Calmette Guérin (BCG) infection model. We show that activated Mphi express SR-A and that this molecule is functional in assays of adhesion and endocytic uptake. After BCG infection, SRKO mice are able to recruit Mphi to sites of granuloma formation where they become activated and restrict BCG replication. However, infected mice lacking the SR-A are more susceptible to endotoxic shock and produce more TNF-alpha and interleukin-6 in response to LPS. In addition, we show that an antibody which blocks TNF-alpha activity reduces LPS-induced mortality in these mice. Thus SR-A, expressed by activated Mphi, plays a protective role in host defense by scavenging LPS as well as by reducing the release by activated Mphi of proinflammatory cytokines. Modulation of SR-A may provide a novel therapeutic approach to control endotoxic shock.

Show MeSH
Related in: MedlinePlus