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Cardiovascular Research Jan 2022CD36, also known as the scavenger receptor B2, is a multifunctional receptor widely expressed in various organs. CD36 plays a crucial role in the uptake of long-chain... (Review)
Review
CD36, also known as the scavenger receptor B2, is a multifunctional receptor widely expressed in various organs. CD36 plays a crucial role in the uptake of long-chain fatty acids, the main metabolic substrate in myocardial tissue. The maturation and transportation of CD36 is regulated by post-translational modifications, including phosphorylation, ubiquitination, glycosylation, and palmitoylation. CD36 is decreased in pathological cardiac hypertrophy caused by ischaemia-reperfusion and pressure overload, and increased in diabetic cardiomyopathy and atherosclerosis. Deficiency of CD36 alleviates diabetic cardiomyopathy and atherosclerosis, while overexpression of CD36 eliminates ischaemia-reperfusion damage, together suggesting that CD36 is closely associated with the progression of cardiovascular diseases and may be a new therapeutic target. This review summarizes the regulation and post-translational modifications of CD36 and evaluates its role in cardiovascular diseases and its potential as a therapeutic target.
Topics: Animals; CD36 Antigens; Cardiovascular Diseases; Genetic Predisposition to Disease; Humans; Myocytes, Cardiac; Polymorphism, Genetic; Protein Processing, Post-Translational; Signal Transduction
PubMed: 33210138
DOI: 10.1093/cvr/cvaa319 -
The Journal of Experimental Medicine Jun 2022CD36 is a type 2 cell surface scavenger receptor widely expressed in many immune and non-immune cells. It functions as both a signaling receptor responding to DAMPs and... (Review)
Review
CD36 is a type 2 cell surface scavenger receptor widely expressed in many immune and non-immune cells. It functions as both a signaling receptor responding to DAMPs and PAMPs, as well as a long chain free fatty acid transporter. Recent studies have indicated that CD36 can integrate cell signaling and metabolic pathways through its dual functions and thereby influence immune cell differentiation and activation, and ultimately help determine cell fate. Its expression along with its dual functions in both innate and adaptive immune cells contribute to pathogenesis of common diseases, including atherosclerosis and tumor progression, which makes CD36 and its downstream effectors potential therapeutic targets. This review comprehensively examines the dual functions of CD36 in a variety of immune cells, especially macrophages and T cells. We also briefly discuss CD36 function in non-immune cells, such as adipocytes and platelets, which impact the immune system via intercellular communication. Finally, outstanding questions in this field are provided for potential directions of future studies.
Topics: Atherosclerosis; CD36 Antigens; Fatty Acids; Humans; Macrophages; Membrane Transport Proteins; Signal Transduction
PubMed: 35438721
DOI: 10.1084/jem.20211314 -
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 -
Theranostics 2019CD36, a scavenger receptor expressed in multiple cell types, mediates lipid uptake, immunological recognition, inflammation, molecular adhesion, and apoptosis. CD36 is a... (Review)
Review
CD36, a scavenger receptor expressed in multiple cell types, mediates lipid uptake, immunological recognition, inflammation, molecular adhesion, and apoptosis. CD36 is a transmembrane glycoprotein that contains several posttranslational modification sites and binds to diverse ligands, including apoptotic cells, thrombospondin-1 (TSP-1), and fatty acids (FAs). Beyond fueling tumor metastasis and therapy resistance by enhancing lipid uptake and FA oxidation, CD36 attenuates angiogenesis by binding to TSP-1 and thereby inducing apoptosis or blocking the vascular endothelial growth factor receptor 2 pathway in tumor microvascular endothelial cells. Moreover, CD36-driven lipid metabolic reprogramming and functions in tumor-associated immune cells lead to tumor immune tolerance and cancer development. Notable advances have been made in demonstrating the regulatory networks that govern distinct physiological properties of CD36, and this has identified targeting CD36 as a potential strategy for cancer treatment. Here, we provide an overview on the structure, regulation, ligands, functions, and clinical trials of CD36 in cancer.
Topics: Animals; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; CD36 Antigens; Humans; Lipid Metabolism; Neoplasms; Oligopeptides; Signal Transduction
PubMed: 31410189
DOI: 10.7150/thno.36037 -
Theranostics 2020Approximately 10% of bone fractures do not heal satisfactorily, leading to significant clinical and socioeconomic implications. Recently, the role of macrophages in...
Approximately 10% of bone fractures do not heal satisfactorily, leading to significant clinical and socioeconomic implications. Recently, the role of macrophages in regulating bone marrow stem cell (BMSC) differentiation through the osteogenic pathway during fracture healing has attracted much attention. : The tibial monocortical defect model was employed to determine the critical role of macrophage scavenger receptor 1 (MSR1) during intramembranous ossification (IO) . The potential functions and mechanisms of MSR1 were explored in a co-culture system of bone marrow-derived macrophages (BMDMs), RAW264.7 cells, and BMSCs using qPCR, Western blotting, immunofluorescence, and RNA sequencing. : In this study, using the tibial monocortical defect model, we observed delayed IO in MSR1 knockout (KO) mice compared to MSR1 wild-type (WT) mice. Furthermore, macrophage MSR1 mediated PI3K/AKT/GSK3β/β-catenin signaling increased ability to promote osteogenic differentiation of BMSCs in the co-culture system. We also identified proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) as the target gene for macrophage MSR1-activated PI3K/AKT/GSK3β/β-catenin pathway in the co-culture system that facilitated M2-like polarization by enhancing mitochondrial oxidative phosphorylation. : Our findings revealed a previously unrecognized function of MSR1 in macrophages during fracture repair. Targeting MSR1 might, therefore, be a new therapeutic strategy for fracture repair.
Topics: Animals; Cell Differentiation; Macrophages; Mesenchymal Stem Cells; Mice; Mice, Inbred C57BL; Mice, Knockout; Osteogenesis; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; RAW 264.7 Cells; Scavenger Receptors, Class A; Signal Transduction; beta Catenin
PubMed: 31903103
DOI: 10.7150/thno.36930 -
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 -
Immunity Jul 2021A common metabolic alteration in the tumor microenvironment (TME) is lipid accumulation, a feature associated with immune dysfunction. Here, we examined how CD8 tumor...
A common metabolic alteration in the tumor microenvironment (TME) is lipid accumulation, a feature associated with immune dysfunction. Here, we examined how CD8 tumor infiltrating lymphocytes (TILs) respond to lipids within the TME. We found elevated concentrations of several classes of lipids in the TME and accumulation of these in CD8 TILs. Lipid accumulation was associated with increased expression of CD36, a scavenger receptor for oxidized lipids, on CD8 TILs, which also correlated with progressive T cell dysfunction. Cd36 T cells retained effector functions in the TME, as compared to WT counterparts. Mechanistically, CD36 promoted uptake of oxidized low-density lipoproteins (OxLDL) into T cells, and this induced lipid peroxidation and downstream activation of p38 kinase. Inhibition of p38 restored effector T cell functions in vitro, and resolution of lipid peroxidation by overexpression of glutathione peroxidase 4 restored functionalities in CD8 TILs in vivo. Thus, an oxidized lipid-CD36 axis promotes intratumoral CD8 T cell dysfunction and serves as a therapeutic avenue for immunotherapies.
Topics: Animals; Biological Transport; CD36 Antigens; CD8-Positive T-Lymphocytes; Cell Line, Tumor; HEK293 Cells; Humans; Leukocytes, Mononuclear; Lipid Peroxidation; Lipoproteins, LDL; Lymphocytes, Tumor-Infiltrating; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neoplasms; Receptors, Scavenger; Tumor Microenvironment
PubMed: 34102100
DOI: 10.1016/j.immuni.2021.05.003 -
Cells Dec 2019Autophagy is a conserved bulk degradation and recycling process that plays important roles in multiple biological functions, including inflammatory responses. As an... (Review)
Review
Autophagy is a conserved bulk degradation and recycling process that plays important roles in multiple biological functions, including inflammatory responses. As an important component of the innate immune system, macrophages are involved in defending cells from invading pathogens, clearing cellular debris, and regulating inflammatory responses. During the past two decades, accumulated evidence has revealed the intrinsic connection between autophagy and macrophage function. This review focuses on the role of autophagy, both as nonselective and selective forms, in the regulation of the inflammatory and phagocytotic functions of macrophages. Specifically, the roles of autophagy in pattern recognition, cytokine release, inflammasome activation, macrophage polarization, LC3-associated phagocytosis, and xenophagy are comprehensively reviewed. The roles of autophagy receptors in the macrophage function regulation are also summarized. Finally, the obstacles and remaining questions regarding the molecular regulation mechanisms, disease association, and therapeutic applications are discussed.
Topics: Animals; Autophagy; Biomarkers; Disease Susceptibility; Energy Metabolism; Humans; Inflammation; Lectins, C-Type; Macrophages; Phagocytosis; Receptors, Pattern Recognition; Receptors, Scavenger; Signal Transduction
PubMed: 31892110
DOI: 10.3390/cells9010070 -
Cells Jun 2023Cluster of differentiation 36 (CD36) is a cell surface scavenger receptor that plays critical roles in many different types of cancer, notably breast, brain, and ovarian... (Review)
Review
Cluster of differentiation 36 (CD36) is a cell surface scavenger receptor that plays critical roles in many different types of cancer, notably breast, brain, and ovarian cancers. While it is arguably most well-known for its fatty acid uptake functions, it is also involved in regulating cellular adhesion, immune response, and apoptosis depending on the cellular and environmental contexts. Here, we discuss the multifaceted role of CD36 in cancer biology, such as its role in mediating metastasis, drug resistance, and immune evasion to showcase its potential as a therapeutic target. We will also review existing approaches to targeting CD36 in pre-clinical studies, as well as discuss the only CD36-targeting drug to advance to late-stage clinical trials, VT1021. Given the roles of CD36 in the etiology of metabolic disorders, such as atherosclerosis, diabetes, and non-alcoholic fatty liver disease, the clinical implications of CD36-targeted therapy are wide-reaching, even beyond cancer.
Topics: Female; Humans; Non-alcoholic Fatty Liver Disease; Ovarian Neoplasms; Fatty Acids; CD36 Antigens
PubMed: 37371076
DOI: 10.3390/cells12121605