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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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FACS® staining of isolated BCG-activated peritoneal cells.  Peritoneal cells were recruited after intraperitoneal inoculation of 107  CFU of BCG. Cells were harvested and stained with a range of primary  antibodies. a, c, e: wild-type (129) cells. b, d, f : SRKO cells. (a and b) 2F8,  which recognizes the type I and II SR-A; (c and d) FA11, recognizes macrosialin, a macrophage specific marker; (e and f) TIB 120, recognizes  MHC class II antigen. Filled histograms show the indicated surface markers, and unfilled histograms represent isotype-matched control antibodies.  The results shown are representative of three independent experiments.
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Figure 1: FACS® staining of isolated BCG-activated peritoneal cells. Peritoneal cells were recruited after intraperitoneal inoculation of 107 CFU of BCG. Cells were harvested and stained with a range of primary antibodies. a, c, e: wild-type (129) cells. b, d, f : SRKO cells. (a and b) 2F8, which recognizes the type I and II SR-A; (c and d) FA11, recognizes macrosialin, a macrophage specific marker; (e and f) TIB 120, recognizes MHC class II antigen. Filled histograms show the indicated surface markers, and unfilled histograms represent isotype-matched control antibodies. The results shown are representative of three independent experiments.

Mentions: 4–6 d after intraperitoneal injection of BCG, a mixed leukocyte population which is rich in Mφ can be harvested (28). These Mφ have undergone a process of activation mediated by IFN-γ, resulting in changes in both secreted products and cell surface receptor expression. Using immunostaining with FA11, a pan-Mφ marker which recognizes the intracellular protein macrosialin, the Mφ in the peritoneal population were identified (Fig. 1, c and d; reference 22).


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)

FACS® staining of isolated BCG-activated peritoneal cells.  Peritoneal cells were recruited after intraperitoneal inoculation of 107  CFU of BCG. Cells were harvested and stained with a range of primary  antibodies. a, c, e: wild-type (129) cells. b, d, f : SRKO cells. (a and b) 2F8,  which recognizes the type I and II SR-A; (c and d) FA11, recognizes macrosialin, a macrophage specific marker; (e and f) TIB 120, recognizes  MHC class II antigen. Filled histograms show the indicated surface markers, and unfilled histograms represent isotype-matched control antibodies.  The results shown are representative of three independent experiments.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 1: FACS® staining of isolated BCG-activated peritoneal cells. Peritoneal cells were recruited after intraperitoneal inoculation of 107 CFU of BCG. Cells were harvested and stained with a range of primary antibodies. a, c, e: wild-type (129) cells. b, d, f : SRKO cells. (a and b) 2F8, which recognizes the type I and II SR-A; (c and d) FA11, recognizes macrosialin, a macrophage specific marker; (e and f) TIB 120, recognizes MHC class II antigen. Filled histograms show the indicated surface markers, and unfilled histograms represent isotype-matched control antibodies. The results shown are representative of three independent experiments.
Mentions: 4–6 d after intraperitoneal injection of BCG, a mixed leukocyte population which is rich in Mφ can be harvested (28). These Mφ have undergone a process of activation mediated by IFN-γ, resulting in changes in both secreted products and cell surface receptor expression. Using immunostaining with FA11, a pan-Mφ marker which recognizes the intracellular protein macrosialin, the Mφ in the peritoneal population were identified (Fig. 1, c and d; reference 22).

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