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Clinica Chimica Acta; International... Sep 2013Atherosclerosis is a chronic disease characterized by the deposition of excessive cholesterol in the arterial intima. Macrophage foam cells play a critical role in the... (Review)
Review
Atherosclerosis is a chronic disease characterized by the deposition of excessive cholesterol in the arterial intima. Macrophage foam cells play a critical role in the occurrence and development of atherosclerosis. The generation of these cells is associated with imbalance of cholesterol influx, esterification and efflux. CD36 and scavenger receptor class A (SR-A) are mainly responsible for uptake of lipoprotein-derived cholesterol by macrophages. Acyl coenzyme A:cholesterol acyltransferase-1 (ACAT1) and neutral cholesteryl ester hydrolase (nCEH) regulate cholesterol esterification. ATP-binding cassette transporters A1(ABCA1), ABCG1 and scavenger receptor BI (SR-BI) play crucial roles in macrophage cholesterol export. When inflow and esterification of cholesterol increase and/or its outflow decrease, the macrophages are ultimately transformed into lipid-laden foam cells, the prototypical cells in the atherosclerotic plaque. The aim of this review is to describe what is known about the mechanisms of cholesterol uptake, esterification and release in macrophages. An increased understanding of the process of macrophage foam cell formation will help to develop novel therapeutic interventions for atherosclerosis.
Topics: ATP Binding Cassette Transporter 1; ATP Binding Cassette Transporter, Subfamily G, Member 1; ATP-Binding Cassette Transporters; Acetyl-CoA C-Acetyltransferase; Atherosclerosis; Biological Transport; CD36 Antigens; Carboxylic Ester Hydrolases; Cholesterol; Foam Cells; Gene Expression Regulation; Humans; Lipoproteins, LDL; Scavenger Receptors, Class A; Scavenger Receptors, Class B; Signal Transduction; Sterol Esterase
PubMed: 23782937
DOI: 10.1016/j.cca.2013.06.006 -
Cardiovascular Research Jun 2020The founding member of the lipoprotein receptor family, low-density lipoprotein receptor (LDLR) plays a major role in the atherogenesis through the receptor-mediated... (Review)
Review
The founding member of the lipoprotein receptor family, low-density lipoprotein receptor (LDLR) plays a major role in the atherogenesis through the receptor-mediated endocytosis of LDL particles and regulation of cholesterol homeostasis. Since the discovery of the LDLR, many other structurally and functionally related receptors have been identified, which include low-density lipoprotein receptor-related protein (LRP)1, LRP5, LRP6, very low-density lipoprotein receptor, and apolipoprotein E receptor 2. The scavenger receptor family members, on the other hand, constitute a family of pattern recognition proteins that are structurally diverse and recognize a wide array of ligands, including oxidized LDL. Among these are cluster of differentiation 36, scavenger receptor class B type I and lectin-like oxidized low-density lipoprotein receptor-1. In addition to the initially assigned role as a mediator of the uptake of macromolecules into the cell, a large number of studies in cultured cells and in in vivo animal models have revealed that these lipoprotein receptors participate in signal transduction to modulate cellular functions. This review highlights the signalling pathways by which these receptors influence the process of atherosclerosis development, focusing on their roles in the vascular cells, such as macrophages, endothelial cells, smooth muscle cells, and platelets. Human genetics of the receptors is also discussed to further provide the relevance to cardiovascular disease risks in humans. Further knowledge of the vascular biology of the lipoprotein receptors and their ligands will potentially enhance our ability to harness the mechanism to develop novel prophylactic and therapeutic strategies against cardiovascular diseases.
Topics: Animals; Arteries; Atherosclerosis; Humans; Plaque, Atherosclerotic; Receptors, LDL; Receptors, Scavenger; Signal Transduction
PubMed: 31834409
DOI: 10.1093/cvr/cvz338 -
Frontiers in Immunology 2022Macrophage scavenger receptor 1 (MSR1), also named CD204, holds key inflammatory roles in multiple pathophysiologic processes. Present primarily on the surface of... (Review)
Review
Macrophage scavenger receptor 1 (MSR1), also named CD204, holds key inflammatory roles in multiple pathophysiologic processes. Present primarily on the surface of various types of macrophage, this receptor variably affects processes such as atherosclerosis, innate and adaptive immunity, lung and liver disease, and more recently, cancer. As highlighted throughout this review, the role of MSR1 is often dichotomous, being either host protective or detrimental to the pathogenesis of disease. We will discuss the role of MSR1 in health and disease with a focus on the molecular mechanisms influencing expression, how altered expression affects disease process and macrophage function, the limited cell signalling pathways discovered thus far, the emerging role of MSR1 in tumour associated macrophages as well as the therapeutic potential of targeting MSR1.
Topics: Humans; Scavenger Receptors, Class A; Macrophages; Lung; Signal Transduction; Neoplasms
PubMed: 36325338
DOI: 10.3389/fimmu.2022.1012002 -
Nature Communications Oct 2022Liver metastasis is highly aggressive and treatment-refractory, partly due to macrophage-mediated immune suppression. Understanding the mechanisms leading to functional...
Liver metastasis is highly aggressive and treatment-refractory, partly due to macrophage-mediated immune suppression. Understanding the mechanisms leading to functional reprogramming of macrophages in the tumor microenvironment (TME) will benefit cancer immunotherapy. Herein, we find that the scavenger receptor CD36 is upregulated in metastasis-associated macrophages (MAMs) and deletion of CD36 in MAMs attenuates liver metastasis in mice. MAMs contain more lipid droplets and have the unique capability in engulfing tumor cell-derived long-chain fatty acids, which are carried by extracellular vesicles. The lipid-enriched vesicles are preferentially partitioned into macrophages via CD36, that fuel macrophages and trigger their tumor-promoting activities. In patients with liver metastases, high expression of CD36 correlates with protumoral M2-type MAMs infiltration, creating a highly immunosuppressive TME. Collectively, our findings uncover a mechanism by which tumor cells metabolically interact with macrophages in TME, and suggest a therapeutic potential of targeting CD36 as immunotherapy for liver metastasis.
Topics: Animals; CD36 Antigens; Fatty Acids; Liver Neoplasms; Macrophages; Mice; Receptors, Scavenger; Tumor Microenvironment
PubMed: 36184646
DOI: 10.1038/s41467-022-33349-y -
Current Atherosclerosis Reports May 2022As both a cholesterol acceptor and carrier in the reverse cholesterol transport (RCT) pathway, high-density lipoprotein (HDL) is putatively atheroprotective. However,... (Review)
Review
PURPOSE OF REVIEW
As both a cholesterol acceptor and carrier in the reverse cholesterol transport (RCT) pathway, high-density lipoprotein (HDL) is putatively atheroprotective. However, current pharmacological therapies to increase plasma HDL cholesterol (HDL-c) concentration have paradoxically failed to prevent or reduce atherosclerosis and cardiovascular disease (CVD). Given that free cholesterol (FC) transfer between surfaces of lipoproteins and cells is reversible, excess plasma FC can be transferred to the cells of peripheral tissue sites resulting in atherosclerosis. Here, we summarize potential mechanisms contributing to this paradox and highlight the role of excess free cholesterol (FC) bioavailability in atherosclerosis vs. atheroprotection.
RECENT FINDINGS
Recent findings have established a complex relationship between HDL-c concentration and atherosclerosis. Systemic scavenger receptor class B type 1 (SR-B1) knock out (KO) mice exhibit with increased diet-induced atherosclerosis despite having an elevated plasma HDL-c concentration compared to wild type (WT) mice. The greater bioavailability of HDL-FC in SR-B1 vs. WT mice is associated with a higher FC content in multiple cell types and tissue sites. These results suggest that dysfunctional HDL with high FC bioavailability is atheroprone despite high HDL-c concentration. Past oversimplification of HDL-c involvement in cholesterol transport has led to the failures in HDL targeted therapy. Evidence suggests that FC-mediated functionality of HDL is of higher importance than its quantity; as a result, deciphering the regulatory mechanisms by which HDL-FC bioavailability can induce atherosclerosis can have far-reaching clinical implications.
Topics: Animals; Atherosclerosis; Cholesterol; Cholesterol, HDL; Humans; Lipoproteins, HDL; Mice; Mice, Knockout; Scavenger Receptors, Class B
PubMed: 35332444
DOI: 10.1007/s11883-022-01011-z -
Cells Dec 2022Cluster of differentiation 36 (CD36) belongs to the B2 receptors of the scavenger receptor class B family, which is comprised of single-chain secondary transmembrane... (Review)
Review
Cluster of differentiation 36 (CD36) belongs to the B2 receptors of the scavenger receptor class B family, which is comprised of single-chain secondary transmembrane glycoproteins. It is present in a variety of cell types, including monocytes, macrophages, microvascular endothelial cells, adipocytes, hepatocytes, platelets, skeletal muscle cells, kidney cells, cardiomyocytes, taste bud cells, and a variety of other cell types. CD36 can be localized on the cell surface, mitochondria, endoplasmic reticulum, and endosomes, playing a role in lipid accumulation, oxidative stress injury, apoptosis, and inflammatory signaling. Recent studies have found that CD36 is expressed in a variety of ocular cells, including retinal pigment epithelium (RPE), retinal microvascular endothelial cells, retinal ganglion cells (RGC), Müller cells, and photoreceptor cells, playing an important role in eye diseases, such as age-related macular degeneration (AMD), diabetic retinopathy (DR), and glaucoma. Therefore, a comprehensive understanding of CD36 function and downstream signaling pathways is of great significance for the prevention and treatment of eye diseases. This article reviews the molecular characteristics, distribution, and function of scavenger receptor CD36 and its role in ophthalmology in order to deepen the understanding of CD36 in eye diseases and provide new ideas for treatment strategies.
Topics: Endothelial Cells; CD36 Antigens; Membrane Proteins; Retinal Pigment Epithelium; Receptors, Scavenger
PubMed: 36611964
DOI: 10.3390/cells12010171 -
Journal of Immunology (Baltimore, Md. :... Mar 2014Scavenger receptors constitute a large family of proteins that are structurally diverse and participate in a wide range of biological functions. These receptors are... (Review)
Review
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.
Topics: Animals; Humans; Receptors, Scavenger; Terminology as Topic
PubMed: 24563502
DOI: 10.4049/jimmunol.1490003 -
Biomolecules Jul 2019The Stabilin receptors are a two-member family in the type H class of scavenger receptors. These dynamic receptors bind and internalize multiple ligands from the cell... (Review)
Review
The Stabilin receptors are a two-member family in the type H class of scavenger receptors. These dynamic receptors bind and internalize multiple ligands from the cell surface for the purpose of clearing extracellular material including some synthetic drugs and for sensing the external environment of the cell. Stabilin-1 was the first receptor to be cloned, though the biological activity of Hyaluronic Acid Receptor for Endocytosis (HARE)/Stabilin-2 was observed about 10 years prior to the cloning of Stabilin-1. Stabilin-1 has a more diverse expression profile among the tissues than HARE/Stabilin-2. This review will focus on HARE/Stabilin-2 and its interactions with hyaluronan, heparin, and phosphorothioate antisense oligonucleotides and what is known about how this receptor participates in signaling upon ligand binding.
Topics: Animals; Cell Adhesion Molecules, Neuronal; Endocytosis; Humans; Hyaluronic Acid; Receptors, Scavenger; Signal Transduction
PubMed: 31336723
DOI: 10.3390/biom9070273 -
Methods in Molecular Biology (Clifton,... 2018Extracellular heat shock proteins (HSP) play important roles in cell signaling and immunity. Many of these effects are mediated by surface receptors expressed on a wide...
Extracellular heat shock proteins (HSP) play important roles in cell signaling and immunity. Many of these effects are mediated by surface receptors expressed on a wide range of cell types. We have investigated the nature of such proteins by cloning candidate receptors into cells (CHO-K1) with the rare property of being null for HSP binding. Using this approach we have discovered that Hsp70 binds avidly to at least two classes of receptors including: (1) c-type lectin receptors (CLR) and (2) scavenger receptors (SR). However, the structural nature of the receptor-ligand interactions is not clear at this time. Hsp70 can bind to LOX-1 (a member of both the CLR and SR), with the c-type lectin binding domain (CTLD) as well as the SR family members SREC-I and FEEL-1/CLEVER-1/STABILIN-1, which by contrast have arrays of EGF-like repeats in their extracellular domains. In this chapter we will discuss: (1) methods for discovery of HSP receptors, (2) approaches to the study of individual receptors in cells that contain multiple such receptors, and (3) methods for investigating HSP receptor function in vivo.
Topics: Animals; CHO Cells; Cell Line, Tumor; Chromatography, Ion Exchange; Cloning, Molecular; Cricetulus; HSP70 Heat-Shock Proteins; HSP90 Heat-Shock Proteins; Humans; Lectins, C-Type; Mice; Mice, Inbred C57BL; Mice, Knockout; Receptors, Scavenger; Sf9 Cells; Spodoptera
PubMed: 29177670
DOI: 10.1007/978-1-4939-7477-1_24 -
Critical Reviews in Immunology 2014Scavenger receptor A (SR-A), also known as the macrophage scavenger receptor and cluster of differentiation 204 (CD204), plays roles in lipid metabolism, atherogenesis,... (Review)
Review
Scavenger receptor A (SR-A), also known as the macrophage scavenger receptor and cluster of differentiation 204 (CD204), plays roles in lipid metabolism, atherogenesis, and a number of metabolic processes. However, recent evidence points to important roles for SR-A in inflammation, innate immunity, host defense, sepsis, and ischemic injury. Herein, we review the role of SR-A in inflammation, innate immunity, host defense, sepsis, cardiac and cerebral ischemic injury, Alzheimer's disease, virus recognition and uptake, bone metabolism, and pulmonary injury. Interestingly, SR-A is reported to be host protective in some disease states, but there is also compelling evidence that SR-A plays a role in the pathophysiology of other diseases. These observations of both harmful and beneficial effects of SR-A are discussed here in the framework of inflammation, innate immunity, and endoplasmic reticulum stress.
Topics: Animals; Atherosclerosis; Humans; Immunity, Innate; Inflammation; Intracellular Space; Organ Specificity; Scavenger Receptors, Class A; Sepsis; Signal Transduction; Virus Diseases
PubMed: 24941076
DOI: 10.1615/critrevimmunol.2014010267