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

Haworth, Richard; Platt, Nick; Keshav, Satish; Hughes, Derralynn; Darley, Elisabeth; Suzuki, Hiroshi; Kurihara, Yukiko; Kodama, Tatsuhiko; Gordon, Siamon

doi:10.1084/jem.186.9.1431

Cited by 254 publications

(230 citation statements)

References 42 publications

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“…SR-A in LPS responses have yielded different outcomes, probably due to different challenging protocols [36,37]. The SR-A À/À mice were not included in our study, but the phenotypes were always more severe in the DKO mice than in those lacking MARCO only, indicating a functional role for both receptors.…”

Section: Discussionmentioning

confidence: 99%

A regulatory role for macrophage class A scavenger receptors in TLR4‐mediated LPS responses

et al. 2010

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Recognition of microbial components by TLR, key sensors of infection, leads to induction of inflammatory responses. We found that, in vivo, TLR4 engagement by LPS induces upregulation of the class A scavenger receptors (SR) macrophage receptor with a collagenous structure (MARCO) and SR-A, which occurs, at least in the case of MARCO, via both MyD88-dependent and -independent pathways. When challenging mice with a low dose of LPS followed by a high dose, class A SR-deficient mice showed a higher survival rate than WT mice. This was paired with increased production of IL-10 and anti-LPS Ab, as well as increased activation status of marginal zone B cells. However, the receptors were not crucial for survival when challenging mice i.p. with Neisseria meningitidis or Listeria monocytogenes, but they were found to contribute to microbial capture and clearance. This indicates physiological significance for the up-regulation of class A SR during early stages of bacterial infection. Thus, we believe that we have revealed a mechanism where SR regulate the activation status of the immune system and are involved in balancing a proper immune response to infection. This regulation could also be important in maintaining tolerance since these receptors have been shown to be involved in regulation of self-reactivity.Key words: Class A scavenger receptors . KO mice . LPS response . Spleen marginal zone B cells IntroductionLPS is a cell wall component of gram-negative bacteria, recognized, amongst others, by the TLR4/MD2 signalling receptor complex. Animals that have mutations in MD2 or TLR4 are susceptible to gram-negative bacterial infection due to the failure to sense LPS [1,2]. However, when animals sense LPS and respond too vigorously, they may be the victims of their own inflammatory overreaction. Therefore, the outcome of bacterial infection is determined not only by the ability to sense endotoxin, but also by mechanisms limiting the inflammatory response. Accordingly, mammals are equipped with many LPS detoxification mechanisms preventing vigorous inflammation [3]. For example, soluble proteins, such as natural Ab-binding LPS, prevent it from engaging the TLR4/MD2-complex and protect animals from endotoxin challenge [4,5]. Further, LPS can be Ã These authors contributed equally to this work. Class A SR MARCO (macrophage receptor with a collagenous structure) and SR-A (scavenger receptor A) have a potential for this type of regulation, since their ligand repertoire includes LPS and they are expressed by macrophages that respond quickly to infection. MARCO has a restricted expression pattern being expressed on specific macrophage subsets in spleen marginal zone (MZ), lymph nodes and peritoneum, whereas SR-A is more widely expressed. In vitro studies have shown that the expression of both receptors can be up-regulated in a TLR-dependent manner, suggesting that they might play a regulatory role in TLRmediated innate immune response [7,8].Being expressed primarily on MZ macrophages in the naïve spleen, MARCO and SR-A are in clos...

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Section: Discussionmentioning

confidence: 99%

A regulatory role for macrophage class A scavenger receptors in TLR4‐mediated LPS responses

et al. 2010

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“…The absence of SR-A may delay intracellular destruction of the particle, and hence, prolong persistence of the inflammatory stimulus. It may be that lack of the receptor reduces uptake significantly so that extracellular levels of the inflammatory stimulus remain high, but this was not the case for LPS clearance in SR-A Ϫ/Ϫ mice (22). Secretion of anti-inflammatory mediators may be reduced in the absence of the receptor.…”

Section: Discussionmentioning

confidence: 99%

The Class A Macrophage Scavenger Receptor Attenuates CXC Chemokine Production and the Early Infiltration of Neutrophils in Sterile Peritonitis

Cotena

Gordon

Platt

2004

The Journal of Immunology

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The macrophage scavenger receptor (SR-A) is a multifunctional receptor that is associated with several important pathological conditions, including atherosclerosis. In this study, we show, using a sterile peritonitis model, that it can regulate the inflammatory response. SR-A null mice display an increased initial granulocytic infiltration because of overproduction of the CXC chemokines, MIP-2 and keratinocyte-derived cytokine. This differential response is dependent upon particle internalization and can be mimicked by advanced glycation end product-BSA-conjugated latex beads. Thus SR-A is a nonactivating receptor, which is the first example of a pattern recognition receptor that serves to counter the activities of proinflammatory receptors and attenuates the production of specific chemokines to ensure an inflammatory response of the appropriate magnitude.

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“…CD204 ligands such as fucoidan are known to induce TNF-␣ and IL-1␤ production in macrophage cell lines (11,24). Furthermore, following endotoxin exposure, CD204Ϫ/Ϫ mice exhibited significantly higher plasma levels of IL-6 and TNF-␣, whereas IL-10 showed no change relative to wild-type mice at 14 days (22). Therefore, interaction of silica with CD204 on AM may promote Th1/Th2 orientation of immune responses by altering cytokine production.…”

Section: Discussionmentioning

confidence: 99%

Scavenger receptor class A type I/II (CD204) null mice fail to develop fibrosis following silica exposure

Beamer¹,

Holian²

2005

American Journal of Physiology-Lung Cellular and Molecular Phys

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Alveolar macrophages express the class A scavenger receptor (CD204) (Babaev VR, Gleaves LA, Carter KJ, Suzuki H, Kodama T, Fazio S, and Linton MF. Arterioscler Thromb Vasc Biol 20: 2593–2599, 2000); yet its role in vivo in lung defense against environmental particles has not been clearly defined. In the current study, CD204 null mice (129Sv background) were used to investigate the link between CD204 and downstream events of inflammation and fibrosis following silica exposure in vivo. CD204−/− macrophages were shown to recognize and uptake silica in vitro, although this response was attenuated compared with 129Sv wild-type mice. The production of tumor necrosis factor-α in lavage fluid was significantly enhanced in CD204 null mice compared with wild-type mice following silica exposure. Moreover, after exposure to environmental particles, CD204−/− macrophages exhibited improved cell viability in a dose-dependent manner compared with wild-type macrophages. Finally, histopathology from a murine model of chronic silicosis in 129Sv wild-type mice displayed typical focal lesions, interstitial thickening with increased connective tissue matrix, and cellular infiltrate into air space. In contrast, CD204−/− mice exhibited little to no deposition of collagen, yet they demonstrated enhanced accumulation of inflammatory cells largely composed of neutrophils. Our findings point to an important role of CD204 in mounting an efficient and appropriately regulated immune response against inhaled particles. Furthermore, these results indicate that the functions of CD204 are critical to the development of fibrosis and the resolution of inflammation.

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

Cited by 254 publications

References 42 publications

A regulatory role for macrophage class A scavenger receptors in TLR4‐mediated LPS responses

A regulatory role for macrophage class A scavenger receptors in TLR4‐mediated LPS responses

The Class A Macrophage Scavenger Receptor Attenuates CXC Chemokine Production and the Early Infiltration of Neutrophils in Sterile Peritonitis

Scavenger receptor class A type I/II (CD204) null mice fail to develop fibrosis following silica exposure

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