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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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Immunohistochemistry of BCG granulomata in  SRKO and wild-type (129)  mice. Livers were collected from  SRKO and wild-type (129) mice  at day 25 of BCG infection and  frozen in OCT embedding medium. Sections of liver were cut  and immunostained with a range  of primary antibodies. a, c, e, and  g: control sections. b, d, f, and h:  SRKO sections. (a and b) F4/80;  resident macrophages (Kupffer  cells) and newly recruited activated macrophages forming  granulomata are stained. (c and d)  FA11; macrosialin is found in all  macrophages and here shows  the similar morphology of granulomas in wild-type and SRKO  mice. (e and f) TIB 120; both  129 and SRKO Kupffer cells and  granuloma macrophages express  high levels of MHC class II. (g  and h) 2F8, which recognizes the  type I and II SR-A. (g) Shows  that SR-A is expressed on Kupffer  cells, freshly recruited macrophages, and the hepatic endothelium, whereas h shows the absence  of SR-A in the SRKO sections.  Original magnification: ×500.
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Figure 3: Immunohistochemistry of BCG granulomata in SRKO and wild-type (129) mice. Livers were collected from SRKO and wild-type (129) mice at day 25 of BCG infection and frozen in OCT embedding medium. Sections of liver were cut and immunostained with a range of primary antibodies. a, c, e, and g: control sections. b, d, f, and h: SRKO sections. (a and b) F4/80; resident macrophages (Kupffer cells) and newly recruited activated macrophages forming granulomata are stained. (c and d) FA11; macrosialin is found in all macrophages and here shows the similar morphology of granulomas in wild-type and SRKO mice. (e and f) TIB 120; both 129 and SRKO Kupffer cells and granuloma macrophages express high levels of MHC class II. (g and h) 2F8, which recognizes the type I and II SR-A. (g) Shows that SR-A is expressed on Kupffer cells, freshly recruited macrophages, and the hepatic endothelium, whereas h shows the absence of SR-A in the SRKO sections. Original magnification: ×500.

Mentions: To investigate whether SR-A is involved in the adhesion and recruitment of Mφ to sites of infection in vivo, wild-type and SRKO mice were injected intraperitoneally with BCG. In this model of cellular immunity, Mφ are recruited to sites of infection (granulomata) and undergo the process of activation mediated by IFN-γ. Using immunohistochemistry of the liver, we discovered that SR-A is expressed not only on resident Kupffer cells and endothelium but also on activated Mφ in granulomata of wild-type mice (Fig. 3). In addition, staining with F4/80 and FA11 established that, despite lacking SR-A, Mφ are efficiently recruited to sites of infection in vivo (Fig. 3, b and d). These Mφ fail to stain with 2F8 since they lack SR-A, but become activated and upregulate MHC class II (Fig. 3, f and h). Examination of BCG CFU for up to 2 wk of infection in liver, spleen, and lung showed that SRKO mice were able to limit mycobacterial replication (e.g., liver BCG CFU at day 8 of infection: wild-type, 6.20 ± 1.23 × 107; SRKO, 6.26 ± 3.19 × 107).


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)

Immunohistochemistry of BCG granulomata in  SRKO and wild-type (129)  mice. Livers were collected from  SRKO and wild-type (129) mice  at day 25 of BCG infection and  frozen in OCT embedding medium. Sections of liver were cut  and immunostained with a range  of primary antibodies. a, c, e, and  g: control sections. b, d, f, and h:  SRKO sections. (a and b) F4/80;  resident macrophages (Kupffer  cells) and newly recruited activated macrophages forming  granulomata are stained. (c and d)  FA11; macrosialin is found in all  macrophages and here shows  the similar morphology of granulomas in wild-type and SRKO  mice. (e and f) TIB 120; both  129 and SRKO Kupffer cells and  granuloma macrophages express  high levels of MHC class II. (g  and h) 2F8, which recognizes the  type I and II SR-A. (g) Shows  that SR-A is expressed on Kupffer  cells, freshly recruited macrophages, and the hepatic endothelium, whereas h shows the absence  of SR-A in the SRKO sections.  Original magnification: ×500.
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Figure 3: Immunohistochemistry of BCG granulomata in SRKO and wild-type (129) mice. Livers were collected from SRKO and wild-type (129) mice at day 25 of BCG infection and frozen in OCT embedding medium. Sections of liver were cut and immunostained with a range of primary antibodies. a, c, e, and g: control sections. b, d, f, and h: SRKO sections. (a and b) F4/80; resident macrophages (Kupffer cells) and newly recruited activated macrophages forming granulomata are stained. (c and d) FA11; macrosialin is found in all macrophages and here shows the similar morphology of granulomas in wild-type and SRKO mice. (e and f) TIB 120; both 129 and SRKO Kupffer cells and granuloma macrophages express high levels of MHC class II. (g and h) 2F8, which recognizes the type I and II SR-A. (g) Shows that SR-A is expressed on Kupffer cells, freshly recruited macrophages, and the hepatic endothelium, whereas h shows the absence of SR-A in the SRKO sections. Original magnification: ×500.
Mentions: To investigate whether SR-A is involved in the adhesion and recruitment of Mφ to sites of infection in vivo, wild-type and SRKO mice were injected intraperitoneally with BCG. In this model of cellular immunity, Mφ are recruited to sites of infection (granulomata) and undergo the process of activation mediated by IFN-γ. Using immunohistochemistry of the liver, we discovered that SR-A is expressed not only on resident Kupffer cells and endothelium but also on activated Mφ in granulomata of wild-type mice (Fig. 3). In addition, staining with F4/80 and FA11 established that, despite lacking SR-A, Mφ are efficiently recruited to sites of infection in vivo (Fig. 3, b and d). These Mφ fail to stain with 2F8 since they lack SR-A, but become activated and upregulate MHC class II (Fig. 3, f and h). Examination of BCG CFU for up to 2 wk of infection in liver, spleen, and lung showed that SRKO mice were able to limit mycobacterial replication (e.g., liver BCG CFU at day 8 of infection: wild-type, 6.20 ± 1.23 × 107; SRKO, 6.26 ± 3.19 × 107).

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