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1.
Curr Biol ; 30(14): R790-R795, 2020 07 20.
Article En | MEDLINE | ID: mdl-32693066

Scavenger receptors (SRs) are a large family of cell-surface receptors that are diverse in their structure and biological function and are divided into different classes. SRs can bind to a range of ligands and enhance the elimination of altered-self or non-self targets. The functional mechanisms that lead to their clearance of harmful substances involve phagocytosis, endocytosis, adhesion, and signaling.


Receptors, Scavenger/metabolism , Receptors, Scavenger/physiology , Alarmins , Animals , Autoimmune Diseases/etiology , Autoimmune Diseases/therapy , Endocytosis , Humans , Immunity, Innate , Inflammation , Ligands , Macrophages/metabolism , Molecular Targeted Therapy , Neurodegenerative Diseases/etiology , Pathogen-Associated Molecular Pattern Molecules , Phagocytosis , Receptors, Scavenger/chemistry , Receptors, Scavenger/classification , Signal Transduction , Toll-Like Receptors
2.
J Immunol ; 198(10): 3775-3789, 2017 05 15.
Article En | MEDLINE | ID: mdl-28483986

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.


Receptors, Scavenger/classification , Receptors, Scavenger/physiology , Animals , Endocytosis , Humans , Ligands , Mice , National Institute of Allergy and Infectious Diseases (U.S.)/standards , Phagocytosis , Receptors, Immunologic/physiology , Scavenger Receptors, Class A/physiology , Signal Transduction , Terminology as Topic , United States
3.
Cardiovasc Res ; 109(1): 24-33, 2016 Jan 01.
Article En | MEDLINE | ID: mdl-26472132

Scavenger receptors (SRs), which recognize modified low-density lipoprotein (LDL) by oxidation or acetylation, are a group of receptors on plasma membrane of macrophages and other cell types. These receptors by facilitating modified LDL uptake are a primary step in the intracellular accumulation of modified LDL and formation of fatty streak. Non-coding RNAs (ncRNAs) are a group of functional RNA nucleotides that are not translated into protein, and include microRNAs (miRs), snoRNAs, siRNAs, snRNAs, exRNAs, piRNAs, and the long ncRNAs (lncRNAs). Recently, ncRNAs have received much attention due to their effects in a variety of disease states such as atherosclerotic cardiovascular disease and cancers. A host of ncRNAs, such as miRs and lncRNAs, have been found to be involved in the regulation of SRs and the inflammatory cascade and subsequently atherosclerosis. Here, we review this important area to create interest in this growing field among researchers and clinicians alike.


Atherosclerosis/etiology , RNA, Untranslated/physiology , Receptors, Scavenger/physiology , Animals , Humans , Receptors, Scavenger/classification
4.
J Immunol ; 192(5): 1997-2006, 2014 Mar 01.
Article En | MEDLINE | ID: mdl-24563502

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 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 U.S. 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 non-self 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. The discussion and nomenclature recommendations described in this report only refer to mammalian scavenger receptors. The purpose of this article is to describe the proposed mammalian nomenclature and classification developed at the workshop and to solicit additional feedback from the broader research community.


Receptors, Scavenger/classification , Animals , Humans , Receptors, Scavenger/immunology , Terminology as Topic
5.
J Neuropathol Exp Neurol ; 72(2): 106-18, 2013 Feb.
Article En | MEDLINE | ID: mdl-23334594

Autoantibodies and complement opsonization have been implicated in the process of demyelination in the major human CNS demyelinating disease multiple sclerosis (MS), but scavenger receptors (SRs) may also play pathogenetic roles. We characterized SR mRNA and protein expression in postmortem brain tissue from 13 MS patients in relation to active demyelination. CD68, chemokine (C-X-C motif) ligand 16 (CXCL16), class A macrophage SR (SR-AI/II), LOX-1 (lectin-like oxidized low-density lipoprotein receptor 1), FcγRIII, and LRP-1 (low-density lipoprotein receptor-related protein 1) mRNA were upregulated in the rims of chronic active MS lesions. CD68 and CXCL16 mRNA were also upregulated around chronic active MS lesions. By immunohistochemistry, CD68, CXCL16, and SR-AI/II were expressed by foamy macrophages in the rim and by ramified microglia around chronic active MS lesions. CXCL16 and SR-AI/II were also expressed by astrocytes in MS lesions and by primary human microglia and astrocytes in vitro. These data suggest that SRs are involved in myelin uptake in MS, and that upregulation of CD68, CXCL16, and SR-AI/II is one of the initial events in microglia as they initiate myelin phagocytosis. As demyelination continues, additional upregulation of LOX-1, FcγRIII, and LRP-1 may facilitate this process.


Brain/metabolism , Demyelinating Diseases/pathology , Multiple Sclerosis/pathology , Receptors, Scavenger/metabolism , Up-Regulation , Adult , Aged , Antigens, CD/metabolism , Astrocytes/metabolism , Brain/pathology , Calcium-Binding Proteins , Chemokine CXCL16 , Chemokines, CXC/metabolism , DNA-Binding Proteins/metabolism , Demyelinating Diseases/etiology , Female , Glial Fibrillary Acidic Protein/metabolism , HLA-D Antigens/metabolism , Humans , Laser Capture Microdissection , Low Density Lipoprotein Receptor-Related Protein-1/metabolism , Male , Microfilament Proteins , Microglia/metabolism , Middle Aged , Multiple Sclerosis/complications , Myelin Proteolipid Protein/metabolism , RNA, Messenger/metabolism , Receptors, Scavenger/classification , Receptors, Scavenger/genetics , Scavenger Receptors, Class E/genetics , Scavenger Receptors, Class E/metabolism , Statistics as Topic
6.
J Immunol ; 181(6): 4043-51, 2008 Sep 15.
Article En | MEDLINE | ID: mdl-18768860

B lymphocytes can function independently as efficient APCs. However, our previous studies demonstrate that both dendritic cells and macrophages are necessary to propagate immune responses initiated by B cell APCs. This finding led us to identify a process in mice whereby Ag-specific B cells transfer Ag to other APCs. In this study, we report the ability and mechanism by which human B lymphocytes can transfer BCR-captured Ag to macrophages. The transfer of Ag involves direct contact between the two cells followed by the capture of B cell-derived membrane and/or intracellular components by the macrophage. These events are abrogated by blocking scavenger receptor A, a receptor involved in the exchange of membrane between APCs. Macrophages acquire greater amounts of Ag in the presence of specific B cells than in their absence. This mechanism allows B cells to amplify or edit the immune response to specific Ag by transferring BCR-captured Ag to other professional APCs, thereby increasing the frequency of its presentation. Ag transfer may perpetuate chronic autoimmune responses to specific self-proteins and help explain the efficacy of B cell-directed therapies in human disease.


Antigen Presentation/immunology , B-Lymphocyte Subsets/immunology , B-Lymphocyte Subsets/metabolism , Cell Communication/immunology , Macrophages/immunology , Macrophages/metabolism , Receptors, Scavenger/physiology , Antigen-Presenting Cells/immunology , Antigen-Presenting Cells/metabolism , Cell Line, Transformed , Cell Line, Tumor , Cell Membrane/immunology , Cell Membrane/metabolism , Coculture Techniques , Cytosol/immunology , Cytosol/metabolism , Humans , Protein Transport/immunology , Receptors, Scavenger/classification , Signal Transduction/immunology
7.
Methods ; 43(3): 207-17, 2007 Nov.
Article En | MEDLINE | ID: mdl-17920517

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.


Macrophages/physiology , Molecular Chaperones/physiology , Receptors, Scavenger/classification , Receptors, Scavenger/physiology , Scavenger Receptors, Class A/physiology , Animals , Humans , Ligands , Receptors, Scavenger/genetics , Scavenger Receptors, Class A/genetics
8.
J Exp Med ; 204(10): 2259-65, 2007 Oct 01.
Article En | MEDLINE | ID: mdl-17893199

Apoptotic cells are considered to be a major source for autoantigens in autoimmune diseases such as systemic lupus erythematosus (SLE). In agreement with this, defective clearance of apoptotic cells has been shown to increase disease susceptibility. Still, little is known about how apoptotic cell-derived self-antigens activate autoreactive B cells and where this takes place. In this study, we find that apoptotic cells are taken up by specific scavenger receptors expressed on macrophages in the splenic marginal zone and that mice deficient in these receptors have a lower threshold for autoantibody responses. Furthermore, antibodies against scavenger receptors are found before the onset of clinical symptoms in SLE-prone mice, and they are also found in diagnosed SLE patients. Our findings describe a novel mechanism where autoantibodies toward scavenger receptors can alter the response to apoptotic cells, affect tolerance, and thus promote disease progression. Because the autoantibodies can be detected before onset of disease in mice, they could have predictive value as early indicators of SLE.


Apoptosis/immunology , Autoantibodies/immunology , Immune Tolerance/immunology , Lupus Erythematosus, Systemic/diagnosis , Lupus Erythematosus, Systemic/immunology , Receptors, Scavenger/immunology , Adult , Animals , Autoantigens/immunology , Humans , Macrophages/immunology , Mice , Mice, Knockout , Receptors, Immunologic/deficiency , Receptors, Immunologic/genetics , Receptors, Immunologic/immunology , Receptors, Immunologic/metabolism , Receptors, Scavenger/classification , Receptors, Scavenger/deficiency , Receptors, Scavenger/genetics , Spleen/immunology
9.
J Biochem ; 139(5): 821-9, 2006 May.
Article En | MEDLINE | ID: mdl-16751589

Cellular interactions with advanced glycation end products (AGE)-modified proteins are known to induce several biological responses, not only endocytic uptake and degradation, but also the induction of cytokines and growth factors, combined responses that may be linked to the development of diabetic vascular complications. In this study we demonstrate that A549 cells, a human pulmonary epithelial cell line, possess a specific binding site for AGE-modified bovine serum albumin (AGE-BSA) (K(d) = 27.8 nM), and additionally for EN-RAGE (extracellular newly identified RAGE binding protein) (K(d) = 118 nM). Western blot and RT-PCR analysis showed that RAGE (receptor for AGE) is highly expressed on A549 cells, while the expression of other known AGE-receptors such as galectin-3 and SR-A (class A scavenger receptor), are below the level of detection. The binding of (125)I-AGE-BSA to these cells is inhibited by unlabeled AGE-BSA, but not by EN-RAGE. In contrast, the binding of (125)I-EN-RAGE is significantly inhibited by unlabeled EN-RAGE and soluble RAGE, but not by AGE-BSA. Our results indicate that A549 cells possess at least two binding sites, one specific for EN-RAGE and the other specific for AGE-BSA. The latter receptor on A549 cells is distinct from the scavenger receptor family and RAGE.


Epithelial Cells/metabolism , Glycation End Products, Advanced/metabolism , Receptors, Immunologic/classification , Animals , Cattle , Cells, Cultured , Glycation End Products, Advanced/pharmacokinetics , Humans , Lung/metabolism , Protein Binding , Receptor for Advanced Glycation End Products , Receptors, Immunologic/agonists , Receptors, Scavenger/agonists , Receptors, Scavenger/classification , Receptors, Scavenger/metabolism , Recombinant Proteins/metabolism , Serum Albumin, Bovine/metabolism , Serum Albumin, Bovine/pharmacokinetics , Signal Transduction , Substrate Specificity
10.
Curr Opin Lipidol ; 16(5): 525-35, 2005 Oct.
Article En | MEDLINE | ID: mdl-16148537

PURPOSE OF REVIEW: Scavenger receptors were originally defined by their ability to bind and internalize modified lipoproteins. Nowadays the family of scavenger receptors is composed of structurally different surface receptors which recognize a broad pattern of common ligands which include, besides modified lipoproteins, apoptotic cells and pathogens. This review focuses on the role of scavenger receptors in the development of atherosclerotic lesions. RECENT FINDINGS: Recent studies indicate that scavenger receptor A activity can be regulated by phosphorylation, glucosidases, 8-isoprostane, high glucose and nobiletin. Modulation of these regulatory components may beneficially influence scavenger receptor A's proatherogenic function. It appears that statins do lead to a reduction in CD36 transcription and could modulate in this way CD36-mediated atherosclerotic foam cell formation. Macrophage scavenger receptor BI appears to facilitate the development of small fatty streak lesions, whereas the formation of advanced atherosclerotic lesions is reduced, indicating a unique dual role for macrophage scavenger receptor BI in the pathogenesis of atherosclerosis. SUMMARY: It is proposed that the presence of scavenger receptors in macrophages is beneficial because they remove potential deleterious material from the arterial wall. Inadequate handling of the internalized material by the macrophages will lead to foam cell formation. If adequate levels of ATP-binding cassette transporters and accepting HDL are present, however, the macrophage is perfectly able to metabolize and secrete the internalized atherogenic substances whereby HDL facilitates further transport from the arterial wall to the liver, leading to release in bile.


Atherosclerosis/etiology , Atherosclerosis/metabolism , Receptors, Scavenger/physiology , Animals , Atherosclerosis/pathology , Atherosclerosis/prevention & control , Humans , Protein Isoforms/classification , Protein Isoforms/physiology , Receptors, Scavenger/classification
11.
Int J Immunopathol Pharmacol ; 18(3): 391-402, 2005.
Article En | MEDLINE | ID: mdl-16164823

Macrophage-targeted photodynamic therapy (PDT) may have applications in the selective killing of cells involved in atherosclerosis, inflammation and tumor. We have previously shown that a conjugate between the photosensitizer chlorin(e6) (ce6) and maleylated bovine serum albumin (BSA-mal) gives highly selective targeting to macrophages. In this report we examine the effect of macrophage activation and scavenger receptor class A (SRA) expression on this targeting in two murine macrophage tumor cell lines (RAW264.7 and P388D1) and a control murine mammary sarcoma cell line (EMT-6). Cells were pretreated with interferon gamma (IFNgamma) and/or lipopolysaccharide (LPS) followed byBSA-ce6-mal addition, and SRA expression, tumor necrosis factor alpha (TNFalpha) release, conjugate uptake and PDT killing were measured. Both macrophage cell lines expressed SRA and took up conjugate specifically in an SRA-dependent manner, but differences were observed in their response to activation. RAW264.7 expressed increasingly more SRA and took up increasingly more BSA-ce6-mal in response to IFNgamma, LPS, and IFNgamma+LPS, respectively. The PDT killing did not follow the same pattern as the uptake of the photosensitizer. The increase in uptake in the IFNgamma treated cells did not lead to an increase in PDT killing, while stimulation with LPS or IFNgamma + LPS resulted in a significant protection against PDT, despite a significant increase in photosensitizer uptake. P388D1 was responsive to neither IFNgamma, nor to LPS, or to IFNgamma +LPS with respect to SRA expression, conjugate uptake, and PDT killing. These data may have implications for the use of PDT to target physiologically undesirable macrophage subtypes implicated in disease, and on how manipulation of the activation status of the macrophage will influence the PDT effect.


Macrophage Activation/radiation effects , Macrophages/metabolism , Photochemotherapy , Receptors, Scavenger/metabolism , Animals , Cattle , Cell Line , Cell Line, Tumor , Interferon-gamma/pharmacology , Lipopolysaccharides/pharmacology , Macrophages/drug effects , Mice , Microscopy, Confocal , Photosensitizing Agents/metabolism , Receptors, Scavenger/classification , Serum Albumin, Bovine/administration & dosage , Serum Albumin, Bovine/chemistry , Serum Albumin, Bovine/metabolism , Serum Albumin, Bovine/pharmacokinetics , Tumor Necrosis Factor-alpha/metabolism
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