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Siamon Gordon - One of the best experts on this subject based on the ideXlab platform.
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Role of macrophage Scavenger Receptors in atherosclerosis.
Immunobiology, 2012Co-Authors: Julia Kzhyshkowska, Claudine Neyen, Siamon GordonAbstract:Accumulating evidence indicates that atherosclerosis is a chronic inflammatory disease. The key innate immune cells that are involved in the pathogenesis of atherosclerosis are circulating monocytes and plaque macrophages. Complex interplay between immune and metabolic processes results in pathological activity of these cells. The best understood pathological process mediated by macrophages is their inability to process modified lipoproteins properly resulting in the formation of foamy cells, which are a dangerous component of atherosclerotic plaques. Key molecules involved in the recognition and processing of modified lipoproteins are Scavenger Receptors (SR). This is a large family of surface expressed structurally heterogeneous Receptors with a broad spectrum of endogenous and exogenous ligands. The common functional feature of SR is internalisation of extracellular components and targeting them for lysosomal degradation. However, these relatively simple functions can have complex consequences, since they are linked to diverse specific signalling pathways and to other membrane transport pathways. Moreover, Scavenger Receptors can co-operate with other types of Receptors increasing the variability of the macrophage response to multiple extracellular ligands. At least some SRs respond to modified lipoproteins by amplification of inflammation and accumulation of macrophages in the plaque, while some SRs may support tolerogenic reactions. Outcome of different SR activities will be the decision of monocytes and macrophage to guard homeostatic balance, support atherosclerosis progression and plaque instability by inflammatory reactions, or support rapid fibrotic processes in the plaque that stabilise it. Despite the accumulating knowledge about the molecular mechanisms of Scavenger receptor action, their role in the progression of atherosclerosis remains controversial. The activities of Scavenger Receptors that can contribute to each of these processes are a subject of current review.
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Scavenger Receptors role in innate immunity and microbial pathogenesis
Cellular Microbiology, 2009Co-Authors: Thomas Areschoug, Siamon GordonAbstract:Summary Accumulating evidence shows that many Scavenger Receptors (SR), including SR-A, MARCO and CD36, represent an important part of the innate immune defence by acting as pattern-recognition Receptors (PRR), in particular against bacterial pathogens. Several SR are expressed on macrophages and dendritic cells, where they act as phagocytic Receptors mediating non-opsonic phagocytosis of pathogenic microbes. Another important function of some SR is to act as co-Receptors to TLRs, modulating the inflammatory response to TLR agonists. On bacteria, the SR ligands have commonly been reported to be LPS and LTA, but recent advances in the field indicate that bacterial surface proteins play a more important role as target molecules for SR than previously thought. Interestingly, recent data show that major pathogens, including Streptococcus pyogenes and the group B streptococcus (GBS), have evolved mechanisms to evade SR-mediated recognition. Moreover, intracellular pathogens, such as hepatitis C virus (HCV) and Plasmodium falciparum, utilize the SR to gain entry into host cells, focusing interest on the importance of SR also in the molecular pathogenesis of infectious diseases. This review highlights the complex interactions between SR and pathogenic microbes, and discusses the role of these interactions in host defence and microbial pathogenesis. (Less)
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Scavenger Receptors: role in innate immunity and microbial pathogenesis.
Cellular microbiology, 2009Co-Authors: Thomas Areschoug, Siamon GordonAbstract:Accumulating evidence shows that many Scavenger Receptors (SR), including SR-A, MARCO and CD36, represent an important part of the innate immune defence by acting as pattern-recognition Receptors, in particular against bacterial pathogens. Several SR are expressed on macrophages and dendritic cells, where they act as phagocytic Receptors mediating non-opsonic phagocytosis of pathogenic microbes. Another important function of some SR is to act as co-Receptors to Toll-like Receptors (TLR), modulating the inflammatory response to TLR agonists. On bacteria, the SR ligands have commonly been reported to be lipopolysaccharide and lipoteichoic acid, but recent advances in the field indicate that bacterial surface proteins play a more important role as target molecules for SR than previously thought. Interestingly, recent data show that major pathogens, including Streptococcus pyogenes and the group B streptococcus, have evolved mechanisms to evade SR-mediated recognition. Moreover, intracellular pathogens, such as hepatitis C virus and Plasmodium falciparum, utilize the SR to gain entry into host cells, focusing interest on the importance of SR also in the molecular pathogenesis of infectious diseases. This review highlights the complex interactions between SR and pathogenic microbes, and discusses the role of these interactions in host defence and microbial pathogenesis.
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Conserved domains of the class A Scavenger Receptors: evolution and function
Immunological reviews, 2009Co-Authors: Dawn M. E. Bowdish, Siamon GordonAbstract:Summary: The class A Scavenger Receptors are phagocytic pattern recognition Receptors that are well represented in vertebrate genomes. The high level of conservation among vertebrates implies that this is an evolutionarily conserved family of Receptors and indicates the presence of a common ancestral gene. The identity of this ancestral gene is not clear, as it appears that many of the domains of the Scavenger Receptors (e.g. collagenous, Scavenger receptor cysteine rich) originated early in evolutionary history and are found in many combinations, often in genes of unknown function. These early Receptors may function in cell–cell recognition, aggregation, or lipid recognition, and their involvement in pattern recognition, phagocytosis, and homeostasis may have been adaptations of such conserved patterns. Herein, we reclassify the class A Scavenger Receptors based on recent discoveries of new members of this family, describe the evolution of the various domains of the class A Scavenger Receptors, and discuss the appearance and function of these domains through evolutionary history.
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Macrophage Scavenger Receptors and host-derived ligands.
Methods (San Diego Calif.), 2007Co-Authors: Annette Plüddemann, Claudine Neyen, Siamon GordonAbstract:The Scavenger Receptors are a large family of molecules that are structurally diverse and have been implicated in a range of functions. They are expressed by myeloid cells, selected endothelial cells and some epithelial cells and recognise many different ligands, including microbial pathogens as well as endogenous and modified host-derived molecules. This review will focus on the eight classes of Scavenger Receptors (class A-H) in terms of their structure, expression and recognition of host-derived ligands. Scavenger Receptors have been implicated in a range of physiological and pathological processes, such as atherosclerosis and Alzheimer's disease, and function in adhesion and tissue maintenance. More recently, some of the Scavenger Receptors have been shown to mediate binding and endocytosis of chaperone proteins, such as the heat shock proteins, thereby playing an important role in antigen cross-presentation.
Monty Krieger - One of the best experts on this subject based on the ideXlab platform.
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a consensus definitive classification of Scavenger Receptors and their roles in health and disease
Journal of Immunology, 2017Co-Authors: Mercy Prabhudas, Lester Kobzik, Dawn M. E. Bowdish, Cynthia L Baldwin, Paul L Bollyky, Kurt Drickamer, Maria Febbraio, Joachim Herz, Monty KriegerAbstract:Scavenger Receptors constitute a large family of proteins that are structurally diverse and participate in a wide range of biological functions. These Receptors are expressed predominantly by myeloid cells and recognize a diverse variety of ligands including endogenous and modified host-derived molecules and microbial pathogens. There are currently eight classes of Scavenger Receptors, many of which have multiple names, leading to inconsistencies and confusion in the literature. To address this problem, a workshop was organized by the United States National Institute of Allergy and Infectious Diseases, National Institutes of Health, to help develop a clear definition of Scavenger Receptors and a standardized nomenclature based on that definition. Fifteen experts in the Scavenger receptor field attended the workshop and, after extensive discussion, reached a consensus regarding the definition of Scavenger Receptors and a proposed Scavenger receptor nomenclature. Scavenger Receptors were defined as cell surface Receptors that typically bind multiple ligands and promote the removal of nonself or altered-self targets. They often function by mechanisms that include endocytosis, phagocytosis, adhesion, and signaling that ultimately lead to the elimination of degraded or harmful substances. Based on this definition, nomenclature and classification of these Receptors into 10 classes were proposed. This classification was discussed at three national meetings and input from participants at these meetings was requested. The following manuscript is a consensus statement that combines the recommendations of the initial workshop and incorporates the input received from the participants at the three national meetings.
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The other side of Scavenger Receptors: pattern recognition for host defense
Current opinion in lipidology, 1997Co-Authors: Monty KriegerAbstract:Scavenger Receptors bind modified lipoproteins and may play an important role both in normal and in pathological lipid metabolism. A number of different classes of Scavenger Receptors have been identified and several of these are multiligand Receptors. Studies, both in vitro and in vivo, have indicated that at least some of these Scavenger Receptors may serve as pattern recognition Receptors because they are able to bind a wide variety of pathogens. As a consequence, they may play key roles in innate immunity and host defense.
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the class b Scavenger Receptors sr bi and cd36 are Receptors for anionic phospholipids
Journal of Biological Chemistry, 1995Co-Authors: Attilio Rigotti, Susan L Acton, Monty KriegerAbstract:The specific recognition of anionic phospholipids in the outer leaflets of cell membranes and lipoproteins by cell surface Receptors may play an important role in a variety of physiologic and pathophysiologic processes (e.g. recognition of damaged or senescent cells by the reticuloendothelial system or lipoprotein homeostasis). Several investigators have described anionic phospholipid binding to cells, and phosphatidylserine (PS) binding to a partially purified approximately 95-kDa membrane protein has recently been reported (Sambrano, G.R., and Steinberg, D. (1995) Proc. Natl. Acad. Sci. U.S.A. 92, 1396-1400). Using both direct binding and ligand competition assays in transfected cells, we have found that two class B Scavenger Receptors, SR-BI and CD36, can tightly bind PS and phosphatidylinositol (PI)-containing liposomes (Kd for PS liposome binding to SR-BI is approximately 15 micrograms phospholipid/ml or 0.18 nM (mol PS liposomes/l), but not phosphatidylcholine, phosphatidylethanolamine, or sphingomyelin liposomes. PS and PI liposomes, but not the others, could effectively compete with PS liposomes and modified or native lipoproteins for binding to these Receptors. Phosphatidic acid, another anionic phospholipid, could also compete, but was not as effective as PS or PI. Class B Scavenger Receptors are the first molecularly well-defined, specific cell surface Receptors for anionic phospholipids to be described.
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structures and high and low affinity ligand binding properties of murine type i and type ii macrophage Scavenger Receptors
Journal of Lipid Research, 1993Co-Authors: John Ashkenas, Susan L Acton, Mason W. Freeman, Marsha Penman, Eliza Vasile, Monty KriegerAbstract:Macrophage Scavenger Receptors have been implicated in various macrophage-associated processes, including atherosclerosis and clearance of bacterial endotoxin. They bind to a wide variety of polyanionic ligands and display complex binding characteristics. cDNAs from the murine macrophage-like cell line P388D1 encoding the full-length type I and type II murine Scavenger Receptors were cloned, sequenced, and expressed in Chinese hamster ovary cells. A fragment of the corresponding murine genomic DNA was also cloned, partially sequenced, and the positions of the cloned intron/exon boundaries were determined. Comparisons of the murine Scavenger Receptors' sequences with the bovine, rabbit, and human sequences were used to refine a multidomain model of these trimeric, fibrous, membrane Receptors. Metabolic labeling/immunoprecipitation experiments showed that most of the macrophage Scavenger receptor protein expressed by P388D1 cells was the N-glycosylated type II receptor; only small amounts of type I receptor were detected. Analysis of the binding properties of the Receptors provided evidence that such differential expression of the type I and type II forms may have functional significance. There were substantial receptor-type (I vs. II), as well as receptor-species (bovine vs. murine), differences in the inhibition of 125I-labeled AcLDL (acetylated low density lipoprotein) binding by ReLPS, a form of bacterial endotoxin. These differences arose, in part, because these Receptors exhibited both high (Kd1(4 degrees C) = 0.05-0.2 micrograms protein/ml) and low (Kd2(4 degrees C) = 2.5-12.8 micrograms protein/ml) affinity binding of 125I-labeled AcLDL. The ability of ReLPS (1 mg/ml) to inhibit either or both of these two classes of binding interactions varied depending on the species and type of receptor.
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the collagenous domains of macrophage Scavenger Receptors and complement component c1q mediate their similar but not identical binding specificities for polyanionic ligands
Journal of Biological Chemistry, 1993Co-Authors: Susan L Acton, D Resnick, Matthew Freeman, Y Ekkel, John Ashkenas, Monty KriegerAbstract:Macrophage Scavenger Receptors have been implicated in the development of atherosclerosis and other macrophage-associated functions, including host defense. The mechanism by which these Receptors bind a wide array of polyanions, such as acetylated low density lipoprotein (Ac-LDL), with high affinity has not yet been elucidated; however, it has been proposed that the positively charged extracellular collagenous domain of Scavenger Receptors plays a key role in ligand binding. To test this proposal, we generated truncation mutants of the bovine and murine Scavenger Receptors and studied their expression in transiently transfected COS cells. These mutants contain only 8 (bovine) or 5 (murine) of the 24 Gly-X-Y tripeptide repeats found in the collagenous domains of the full-length Receptors. Immunochemical analyses established that the truncation of the bovine Scavenger receptor did not interfere significantly with its synthesis, trimerization, post-translational processing, intracellular transport, surface expression, or stability. However, unlike their full-length counterparts, the truncated bovine and murine Receptors were unable to bind Ac-LDL. Thus, the collagenous domain was necessary for normal ligand binding. In addition, cotransfection of the expression vector for the truncated bovine Scavenger receptor with that for the full-length receptor resulted in dramatically reduced activity of the full-length construct (dominant negative effect). A ligand bead-binding assay was used to show that the isolated collagenous domain from a different protein, complement component C1q, could bind a wide variety of polyanions with a specificity which was similar, but not identical, to that of Scavenger Receptors. These results suggest that the collagenous domain of the Scavenger receptor is both necessary and sufficient to determine the broad binding specificity that characterizes this unusual receptor. Scavenger Receptors and C1q, along with the mannose-binding protein, conglutinin, and lung surfactant apoprotein A, help define a set of proteins which all contain short collagenous domains and which all appear to participate in host defense. Their short collagenous domains may contribute significantly to their host-defense functions.
David L Williams - One of the best experts on this subject based on the ideXlab platform.
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human monocyte Scavenger Receptors are pattern recognition Receptors for 1 3 β d glucans
Journal of Leukocyte Biology, 2002Co-Authors: Peter J Rice, John Kalbfleisch, David L Williams, Harry E Ensley, Grigorij Kogan, Jim Kelley, William I BrowderAbstract:Glucans are cell wall constituents of fungi and bacteria that bind to pattern recognition Receptors and modulate innate immunity, in part, by macrophage activation. We used surface plas- mon resonance to examine the binding of glucans, differing in fine structure and charge density, to Scavenger Receptors on membranes isolated from human monocyte U937 cells. Experiments were performed at 25°C using a biosensor surface with immobilized acetylated low density lipoprotein (AcLDL). Inhibition of the binding by polyinosinic acid, but not polycytidylic acid, confirmed the in- teraction of Scavenger Receptors. Competition studies showed that there are at least two AcLDL binding sites on human U937 cells. Glucan phos- phate interacts with all sites, and the CM-glucans and laminarin interact with a subset of sites. Poly- mer charge has a dramatic effect on the affinity of glucans with macrophage Scavenger Receptors. However, it is also clear that human monocyte Scavenger Receptors recognize the basic glucan structure independent of charge. J. Leukoc. Biol. 72: 140-146; 2002.
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human monocyte Scavenger Receptors are pattern recognition Receptors for 1 3 β d glucans
Journal of Leukocyte Biology, 2002Co-Authors: Peter J Rice, John Kalbfleisch, David L Williams, Harry E Ensley, Grigorij Kogan, Jim Kelley, William I BrowderAbstract:Glucans are cell wall constituents of fungi and bacteria that bind to pattern recognition Receptors and modulate innate immunity, in part, by macrophage activation. We used surface plasmon resonance to examine the binding of glucans, differing in fine structure and charge density, to Scavenger Receptors on membranes isolated from human monocyte U937 cells. Experiments were performed at 25 degrees C using a biosensor surface with immobilized acetylated low density lipoprotein (AcLDL). Inhibition of the binding by polyinosinic acid, but not polycytidylic acid, confirmed the interaction of Scavenger Receptors. Competition studies showed that there are at least two AcLDL binding sites on human U937 cells. Glucan phosphate interacts with all sites, and the CM-glucans and laminarin interact with a subset of sites. Polymer charge has a dramatic effect on the affinity of glucans with macrophage Scavenger Receptors. However, it is also clear that human monocyte Scavenger Receptors recognize the basic glucan structure independent of charge.
Lester Kobzik - One of the best experts on this subject based on the ideXlab platform.
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a consensus definitive classification of Scavenger Receptors and their roles in health and disease
Journal of Immunology, 2017Co-Authors: Mercy Prabhudas, Lester Kobzik, Dawn M. E. Bowdish, Cynthia L Baldwin, Paul L Bollyky, Kurt Drickamer, Maria Febbraio, Joachim Herz, Monty KriegerAbstract:Scavenger Receptors constitute a large family of proteins that are structurally diverse and participate in a wide range of biological functions. These Receptors are expressed predominantly by myeloid cells and recognize a diverse variety of ligands including endogenous and modified host-derived molecules and microbial pathogens. There are currently eight classes of Scavenger Receptors, many of which have multiple names, leading to inconsistencies and confusion in the literature. To address this problem, a workshop was organized by the United States National Institute of Allergy and Infectious Diseases, National Institutes of Health, to help develop a clear definition of Scavenger Receptors and a standardized nomenclature based on that definition. Fifteen experts in the Scavenger receptor field attended the workshop and, after extensive discussion, reached a consensus regarding the definition of Scavenger Receptors and a proposed Scavenger receptor nomenclature. Scavenger Receptors were defined as cell surface Receptors that typically bind multiple ligands and promote the removal of nonself or altered-self targets. They often function by mechanisms that include endocytosis, phagocytosis, adhesion, and signaling that ultimately lead to the elimination of degraded or harmful substances. Based on this definition, nomenclature and classification of these Receptors into 10 classes were proposed. This classification was discussed at three national meetings and input from participants at these meetings was requested. The following manuscript is a consensus statement that combines the recommendations of the initial workshop and incorporates the input received from the participants at the three national meetings.
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Scavenger Receptors and β-glucan Receptors participate in the recognition of yeasts by murine macrophages
Inflammation Research, 2012Co-Authors: Szczepan Jozefowski, Zhiping Yang, Janusz Marcinkiewicz, Lester KobzikAbstract:Objectives Numerous Receptors have been implicated in recognition of pathogenic fungi by macrophages, including the β-glucan receptor dectin-1. The role of Scavenger Receptors (SRs) in anti-fungal immunity is not well characterized. Methods We studied uptake of unopsonized Saccharomycetes cerevisiae (zymosan) and live Candida albicans yeasts as well as zymosan-stimulated H_2O_2 production in J774 macrophage-like cells and peritoneal exudate macrophages (PEMs). The role of different Receptors was assessed with the use of competitive ligands, transfected cells and receptor-deficient macrophages. Results The uptake of zymosan by untreated J774 cells was mediated approximately half by SRs and half by a β-glucan receptor which was distinct from dectin-1 and not linked to stimulation of H_2O_2 production. Ligands of β-glucan Receptors and of SRs also inhibited uptake of C. albicans by macrophages (J774 cells and PEMs). In macrophages pretreated with a CpG motif-containing oligodeoxynucleotide (CpG-ODN) the relative contribution of SRs to yeast uptake increased and that of β-glucan Receptors decreased. Whereas the class A SR MARCO participated in the uptake of both zymosan and C. albicans by CpG-ODN-pretreated, but not untreated macrophages, the related receptor SR-A/CD204 was involved in the uptake of zymosan, but not of C. albicans . The reduction of zymosan-stimulated H_2O_2 production observed in DS-pretreated J774 cells and in class A SRs-deficient PEMs suggest that class A SRs mediate part of this process. Conclusions Our results revealed that SRs belong to a redundant system of Receptors for yeasts. Binding of yeasts to different Receptors in resting versus CpG-ODN-pre-exposed macrophages may differentially affect polarization of adaptive immune responses.
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Scavenger Receptors SR-AI/II and MARCO Limit Pulmonary Dendritic Cell Migration and Allergic Airway Inflammation
Journal of Immunology, 2007Co-Authors: Mohamed S. Arredouani, Francesca Franco, Steven D Shapiro, Amy Imrich, Alexey V. Fedulov, David L. Perkins, Raija Soininen, Karl Tryggvason, Xin Lu, Lester KobzikAbstract:The class A Scavenger Receptors (SR-A) MARCO and SR-AI/II are expressed on lung macrophages (MΦs) and dendritic cells (DCs) and function in innate defenses against inhaled pathogens and particles. Increased expression of SR-As in the lungs of mice in an OVA-asthma model suggested an additional role in modulating responses to an inhaled allergen. After OVA sensitization and aerosol challenge, SR-AI/II and MARCO-deficient mice exhibited greater eosinophilic airway inflammation and airway hyperresponsiveness compared with wild-type mice. A role for simple SR-A-mediated Ag clearance (“scavenging”) by lung MΦs was excluded by the observation of a comparable uptake of fluorescent OVA by wild-type and SR-A-deficient lung MΦs and DCs. In contrast, airway instillation of fluorescent Ag revealed a significantly higher traffic of labeled DCs to thoracic lymph nodes in SR-A-deficient mice than in controls. The increased migration of SR-A-deficient DCs was accompanied by the enhanced proliferation in thoracic lymph nodes of adoptively transferred OVA-specific T cells after airway OVA challenge. The data identify a novel role for SR-As expressed on lung DCs in the down-regulation of specific immune responses to aeroallergens by the reduction of DC migration from the site of Ag uptake to the draining lymph nodes.
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disparate regulation and function of the class a Scavenger Receptors sr ai ii and marco
Journal of Immunology, 2005Co-Authors: Szczepan Jozefowski, Mohamed S. Arredouani, Timothy H Sulahian, Lester KobzikAbstract:The macrophage class A Scavenger Receptors, macrophage receptor with a collagenous structure (MARCO) and type I/II class A Scavenger receptor (SR-AI/II), share structural features and roles in host defense, but little is known about their regulation and signaling properties. Ligation of MARCO on mouse thioglycollate-elicited peritoneal macrophages (PEMs) with immobilized mAb costimulated IL-12 production, in contrast to previously reported inhibition by SR-AI/II. PEMs from MARCO-deficient mice exhibited 2.7 times lower IL-12 production in responses to stimulation with LPS and IFN-gamma and lack of significant IL-12 production on stimulation with LPS alone. Conversely, SR-AI/II-deficient PEMs produced 2.4 and 1.8 times more IL-12 than wild-type PEMs in response to LPS or LPS and IFN-gamma, respectively. Corresponding differences in regulation of SR-A and MARCO expression were also observed. Th1 adjuvants (LPS, a CpG motif-containing oligodeoxynucleotide (CpG-ODN), IL-12, and GM-CSF) increased, whereas Th2-polarizing factors (IL-4, M-CSF, and non-CpG ODN) decreased expression of MARCO on J774 macrophage-like cells. Expression of SR-A was regulated in the opposite manner to MARCO or not affected. Whereas MARCO was involved in opsonin-independent phagocytosis in CpG-ODN-pretreated but not in IL-4-pretreated J774 cells, anti-SR-A Abs inhibited particle uptake in untreated and IL-4-pretreated but not in CpG-ODN-pretreated cells. SR-A and MARCO are regulated differently and mediate distinct negative and positive effects on IL-12 production in macrophages. These differences may contribute to sustained Th1 or Th2 polarization of ongoing immune responses.
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Receptors for unopsonized particles: the role of alveolar macrophage Scavenger Receptors.
Current molecular medicine, 2001Co-Authors: Aiyappa Palecanda, Lester KobzikAbstract:The lung is constantly exposed to potentially pathogenic particles and microorganisms. Alveolar macrophage (AM) binding of inhaled environmental particles is a critical first step in phagocytosis and clearance, and must be accomplished without the benefit of opsonization by specific antibodies. Opsonin-independent phagocytosis is initiated by direct recognition of phagocytic target. The identities of Receptors on AMs that mediate unopsonized particle binding were, until recently, not known. Using flow cytometry, monoclonal antibody and expression cloning techniques we have found a major role for the Scavenger receptor, MARCO in AM binding of particles and bacteria. In this review we will discuss the role of Scavenger Receptors in AM binding of unopsonized particles and the use of flow cytomety in analyzing AM-particle interaction. We will also discuss other non-Scavenger Receptors involved in opsonin-independent phagocytosis.
Mason W. Freeman - One of the best experts on this subject based on the ideXlab platform.
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Scavenger Receptors in Atherosclerosis: Beyond Lipid Uptake
Arteriosclerosis thrombosis and vascular biology, 2006Co-Authors: Kathryn J. Moore, Mason W. FreemanAbstract:Atherosclerotic vascular disease arises as a consequence of the deposition and retention of serum lipoproteins in the artery wall. Macrophages in lesions have been shown to express ≥6 structurally different Scavenger Receptors for uptake of modified forms of low-density lipoproteins (LDLs) that promote the cellular accumulation of cholesterol. Because cholesterol-laden macrophage foam cells are the primary component of the fatty streak, the earliest atherosclerotic lesion, lipid uptake by these pathways has long been considered a requisite and initiating event in the pathogenesis of atherosclerosis. Although the removal of proinflammatory modified LDLs from the artery wall via Scavenger Receptors would seem beneficial, the pathways distal to Scavenger receptor uptake that metabolize the modified lipoproteins appear to become overwhelmed, leading to the accumulation of cholesterol-laden macrophages and establishment of a chronic inflammatory setting. These observations have led to the current dogma concerning Scavenger Receptors, which is that they are proatherogenic molecules. However, recent studies suggest that the effects of Scavenger Receptors on atherogenesis may be more complex. In addition to modified lipoprotein uptake, these proteins are now known to regulate apoptotic cell clearance, initiate signal transduction, and serve as pattern recognition Receptors for pathogens, activities that may contribute both to proinflammatory and anti-inflammatory forces regulating atherogenesis. In this review, we focus on recent advances in our knowledge of Scavenger receptor regulation and signal transduction, their roles in sterile inflammation and infection, and the potential impact of these pathways in regulating the balance of lipid accumulation and inflammation in the artery wall.
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Scavenger Receptors class a i ii and cd36 are the principal Receptors responsible for the uptake of modified low density lipoprotein leading to lipid loading in macrophages
Journal of Biological Chemistry, 2002Co-Authors: Vidya V Kunjathoor, Kathryn J. Moore, Eugene A. Podrez, Maria Febbraio, Lorna P Andersson, Stephanie L Koehn, Jeongmi S Rhee, Roy L Silverstein, Henry F Hoff, Mason W. FreemanAbstract:Modification of low density lipoprotein (LDL) can result in the avid uptake of these lipoproteins via a family of macrophage transmembrane proteins referred to as Scavenger Receptors (SRs). The genetic inactivation of either of two SR family members, SR-A or CD36, has been shown previously to reduce oxidized LDL uptake in vitro and atherosclerotic lesions in mice. Several other SRs are reported to bind modified LDL, but their contribution to macrophage lipid accumulation is uncertain. We generated mice lacking both SR-A and CD36 to determine their combined impact on macrophage lipid uptake and to assess the contribution of other SRs to this process. We show that SR-A and CD36 account for 75-90% of degradation of LDL modified by acetylation or oxidation. Cholesteryl ester derived from modified lipoproteins fails to accumulate in macrophages taken from the double null mice, as assessed by histochemistry and gas chromatography-mass spectrometry. These results demonstrate that SR-A and CD36 are responsible for the preponderance of modified LDL uptake in macrophages and that other Scavenger Receptors do not compensate for their absence.
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structures and high and low affinity ligand binding properties of murine type i and type ii macrophage Scavenger Receptors
Journal of Lipid Research, 1993Co-Authors: John Ashkenas, Susan L Acton, Mason W. Freeman, Marsha Penman, Eliza Vasile, Monty KriegerAbstract:Macrophage Scavenger Receptors have been implicated in various macrophage-associated processes, including atherosclerosis and clearance of bacterial endotoxin. They bind to a wide variety of polyanionic ligands and display complex binding characteristics. cDNAs from the murine macrophage-like cell line P388D1 encoding the full-length type I and type II murine Scavenger Receptors were cloned, sequenced, and expressed in Chinese hamster ovary cells. A fragment of the corresponding murine genomic DNA was also cloned, partially sequenced, and the positions of the cloned intron/exon boundaries were determined. Comparisons of the murine Scavenger Receptors' sequences with the bovine, rabbit, and human sequences were used to refine a multidomain model of these trimeric, fibrous, membrane Receptors. Metabolic labeling/immunoprecipitation experiments showed that most of the macrophage Scavenger receptor protein expressed by P388D1 cells was the N-glycosylated type II receptor; only small amounts of type I receptor were detected. Analysis of the binding properties of the Receptors provided evidence that such differential expression of the type I and type II forms may have functional significance. There were substantial receptor-type (I vs. II), as well as receptor-species (bovine vs. murine), differences in the inhibition of 125I-labeled AcLDL (acetylated low density lipoprotein) binding by ReLPS, a form of bacterial endotoxin. These differences arose, in part, because these Receptors exhibited both high (Kd1(4 degrees C) = 0.05-0.2 micrograms protein/ml) and low (Kd2(4 degrees C) = 2.5-12.8 micrograms protein/ml) affinity binding of 125I-labeled AcLDL. The ability of ReLPS (1 mg/ml) to inhibit either or both of these two classes of binding interactions varied depending on the species and type of receptor.
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expression of type i and type ii bovine Scavenger Receptors in chinese hamster ovary cells lipid droplet accumulation and nonreciprocal cross competition by acetylated and oxidized low density lipoprotein
Proceedings of the National Academy of Sciences of the United States of America, 1991Co-Authors: Mason W. Freeman, Marsha Penman, Neil J Freedman, Yelena Ekkel, Lucia Rohrer, Guy M Chisolm, Monty KriegerAbstract:Abstract Type I and type II Scavenger Receptors, which have been implicated in the development of atherosclerosis and other macrophage-associated functions, differ only by the presence in the type I receptor of an extracellular cysteine-rich C-terminal domain. Stable Chinese hamster ovary (CHO) cell transfectants expressing high levels of either the type I or type II bovine Scavenger Receptors have been generated. Type I and type II Receptors in these cells mediated high-affinity saturable endocytosis of both 125I-labeled acetylated low density lipoprotein (LDL) and 125I-labeled oxidized LDL with the distinctive broad ligand specificity characteristic of Scavenger Receptors. After incubation for 2 days with acetylated LDL, the transfected cells accumulated oil red O-staining lipid droplets reminiscent of those in macrophage foam cells, whereas untransfected CHO cells did not. Thus, macrophage-specific gene products other than the Scavenger receptor are not required for modified-LDL-induced intracellular lipid accumulation. In transfected cells, acetylated LDL efficiently competed for both its own endocytosis and that of oxidized LDL. In contrast, oxidized LDL competed effectively for its own endocytosis but only poorly for that of acetylated LDL. This nonreciprocal cross competition suggests that these ligands may bind to nonidentical but interacting sites on a single receptor. Results were similar for transfectants expressing either type I or type II Scavenger Receptors. Therefore, the nonreciprocal cross competition previously reported for cultured peritoneal macrophages may not be the result of differences between the type I and type II Receptors. The nonreciprocal cross competition seen in the transfected CHO cells differs from that previously observed with cultured macrophages.
