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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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Production of TNF-α after LPS challenge of SRKO and wild-type (129) mice. (A and B). SRKO and 129 mice were injected intraperitoneally with 107 CFU of BCG, or (C) inactivated C. parvum. At 14 d after infection, mice were injected with 10 μg of LPS intraperitoneally. The concentration of (A and C) TNF-α or (B) IL-6 in the serum was determined using capture ELISAs as described in Materials and Methods. Results at each time  point represent the mean concentration ± SD of a group of five mice. *P <0.05 compared to SRKO serum cytokine levels.
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Figure 5: Production of TNF-α after LPS challenge of SRKO and wild-type (129) mice. (A and B). SRKO and 129 mice were injected intraperitoneally with 107 CFU of BCG, or (C) inactivated C. parvum. At 14 d after infection, mice were injected with 10 μg of LPS intraperitoneally. The concentration of (A and C) TNF-α or (B) IL-6 in the serum was determined using capture ELISAs as described in Materials and Methods. Results at each time point represent the mean concentration ± SD of a group of five mice. *P <0.05 compared to SRKO serum cytokine levels.

Mentions: During the course of serious gram-negative bacterial infections, LPS induces stimulation of macrophages, which results in the release of inflammatory mediators (32). The activity of these mediators, which include prostaglandins and cytokines (e.g., TNF-α, IL-6, and IL-1β) is, in turn, responsible for hypotension, organ failure, and often death. TNF-α is produced in large amounts by activated Mφ in response to LPS (33). We reasoned that this molecule was a candidate mediator of the difference in mortality observed between wild-type and SRKO mice. Therefore, we assayed plasma cytokine levels in BCG infected mice after LPS challenge. Significantly higher levels of TNF-α were present in the plasma of SRKO mice relative to wild-type mice (Fig. 5 A). To confirm that the measured differences in this cytokine were not confounded by differences in response to viable microorganisms, mice were injected with inactivated C. parvum and subsequently challenged with LPS. When serum was assayed 3 h after LPS challenge, levels of TNF-α were also higher in those samples from mice deficient in SR-A (Fig. 5 B). In addition, levels of serum IL-6 were assayed at the same time points and similar differences between the wild-type and SRKO were observed (Fig. 5 C). In contrast, serum levels of IL-10 showed no significant difference at these time points (results not shown).


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)

Production of TNF-α after LPS challenge of SRKO and wild-type (129) mice. (A and B). SRKO and 129 mice were injected intraperitoneally with 107 CFU of BCG, or (C) inactivated C. parvum. At 14 d after infection, mice were injected with 10 μg of LPS intraperitoneally. The concentration of (A and C) TNF-α or (B) IL-6 in the serum was determined using capture ELISAs as described in Materials and Methods. Results at each time  point represent the mean concentration ± SD of a group of five mice. *P <0.05 compared to SRKO serum cytokine levels.
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Related In: Results  -  Collection

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Figure 5: Production of TNF-α after LPS challenge of SRKO and wild-type (129) mice. (A and B). SRKO and 129 mice were injected intraperitoneally with 107 CFU of BCG, or (C) inactivated C. parvum. At 14 d after infection, mice were injected with 10 μg of LPS intraperitoneally. The concentration of (A and C) TNF-α or (B) IL-6 in the serum was determined using capture ELISAs as described in Materials and Methods. Results at each time point represent the mean concentration ± SD of a group of five mice. *P <0.05 compared to SRKO serum cytokine levels.
Mentions: During the course of serious gram-negative bacterial infections, LPS induces stimulation of macrophages, which results in the release of inflammatory mediators (32). The activity of these mediators, which include prostaglandins and cytokines (e.g., TNF-α, IL-6, and IL-1β) is, in turn, responsible for hypotension, organ failure, and often death. TNF-α is produced in large amounts by activated Mφ in response to LPS (33). We reasoned that this molecule was a candidate mediator of the difference in mortality observed between wild-type and SRKO mice. Therefore, we assayed plasma cytokine levels in BCG infected mice after LPS challenge. Significantly higher levels of TNF-α were present in the plasma of SRKO mice relative to wild-type mice (Fig. 5 A). To confirm that the measured differences in this cytokine were not confounded by differences in response to viable microorganisms, mice were injected with inactivated C. parvum and subsequently challenged with LPS. When serum was assayed 3 h after LPS challenge, levels of TNF-α were also higher in those samples from mice deficient in SR-A (Fig. 5 B). In addition, levels of serum IL-6 were assayed at the same time points and similar differences between the wild-type and SRKO were observed (Fig. 5 C). In contrast, serum levels of IL-10 showed no significant difference at these time points (results not shown).

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