The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1997/11/1431/ $5.00
The Journal of Experimental Medicine, Volume 186, Number 9, November 3, 1997 1431-1439

Article

The Macrophage Scavenger Receptor Type A Is Expressed by Activated Macrophages and Protects the Host Against Lethal Endotoxic Shock

Richard Haworth*, Nick Platt*, Satish Keshav*, Derralynn Hughes*, Elisabeth Darley*, Hiroshi Suzuki{ddagger}, Yukiko Kurihara{ddagger}, Tatsuhiko Kodama{ddagger}, and Siamon Gordon*

From the * Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, United Kingdom; and {ddagger} The Third Department of Internal Medicine, University of Tokyo and Tokyo University Hospital, Tokyo 113, Japan

During gram-negative bacterial infections, lipopolysaccharide (LPS) stimulates primed macrophages (M{varphi}) to release inflammatory mediators such as tumor necrosis factor (TNF)-{alpha}, which can cause hypotension, organ failure, and often death. Several different receptors on M{varphi} 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 M{varphi} 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 M{varphi} 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 M{varphi}, plays a protective role in host defense by scavenging LPS as well as by reducing the release by activated M{varphi} of proinflammatory cytokines. Modulation of SR-A may provide a novel therapeutic approach to control endotoxic shock.

Address correspondence to Professor Siamon Gordon, Sir William Dunn School of Pathology, University of Oxford, South Parks Rd., Oxford OX1 3RE, UK. Phone: 01-865-275534; FAX: 01-865-275501.

1 Abbreviations used in this paper: Ac, acetylated; BCG, bacillus Calmette-Guérin; CP, CAMPATH; DiI, 1,1-dioctadecyl-1,3,3,3',3'-tetramethylindocarbocyanineperchlorate; LDL, low density lipoproteins; M{varphi}, macrophages; SR, scavenger receptor; SRKO, SR-A–deficient; TCP, tissue culture plastic.


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