Soluble CD36 ectodomain binds negatively charged diacylglycerol ligands and acts as a co-receptor for TLR2

Cluster of differentiation 36 (CD36) is a transmembrane glycoprotein involved in many biological processes, such as platelet biology, angiogenesis and in the aetiopathology of atherosclerosis and cardiovascular diseases. Toll-like receptors (TLRs) are one of the most important receptors of the innat...

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Bibliographic Details
Published in:PloS one 2009-10, Vol.4 (10), p.e7411-e7411
Main Authors: Jimenez-Dalmaroni, Maximiliano J, Xiao, Nengming, Corper, Adam L, Verdino, Petra, Ainge, Gary D, Larsen, Dave S, Painter, Gavin F, Rudd, Pauline M, Dwek, Raymond A, Hoebe, Kasper, Beutler, Bruce, Wilson, Ian A
Format: Article
Language:English
Subjects:
Activation
Allergies
Alzheimer's disease
Alzheimers disease
Angiogenesis
Animals
Arteriosclerosis
Atherosclerosis
B cells
Bacteria
Biochemistry
Biological activity
Carbohydrates
Cardiovascular diseases
CD14 antigen
CD36 antigen
CD36 Antigens - biosynthesis
Chemistry
Chromatography
Chronic diseases
Cloning
Clusters
Cytokines
Development and progression
Diabetes mellitus
Diabetics
Diacylglycerol
Differentiation
Diglycerides
Diglycerides - chemistry
Diglycerides - metabolism
Glycoproteins
Glycoproteins - metabolism
Heart diseases
Immune response
Immune System
Immunology
Immunology/Immune Response
Immunology/Innate Immunity
Inflammation
Inflammatory response
Innate immunity
Ligands
Lipopolysaccharide Receptors - biosynthesis
Lipoproteins
Lipoteichoic acid
Macrophages
Mice
Mice, Inbred C57BL
Mice, Transgenic
Microorganisms
Molecular biology
Molecular weight
Mortality
Polysaccharides - chemistry
Protein Structure, Secondary
Protein Structure, Tertiary
Proteins
Receptor mechanisms
Receptors
Recognition
Selectivity
Signal Transduction
Signaling
T cell receptors
TLR2 protein
Toll-Like Receptor 2 - chemistry
Toll-like receptors
Transcription
Tumor necrosis factor-TNF
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Summary:Cluster of differentiation 36 (CD36) is a transmembrane glycoprotein involved in many biological processes, such as platelet biology, angiogenesis and in the aetiopathology of atherosclerosis and cardiovascular diseases. Toll-like receptors (TLRs) are one of the most important receptors of the innate immune system. Their main function is the recognition of conserved structure of microorganisms. This recognition triggers signaling pathways that activate transcription of cytokines and co-stimulatory molecules which participate in the generation of an immune response against microbes. In particular, TLR2 has been shown to recognize a broad range of ligands. Recently, we showed that CD36 serves as a co-receptor for TLR2 and enhances recognition of specific diacylglycerides derived from bacteria. Here, we investigate the mechanism by which CD36 contributes to ligand recognition and activation of TLR2 signaling pathway. We show that the ectodomain of murine CD36 (mCD36ED) directly interacts with negatively charged diacylglycerol ligands, which explains the specificity and selectivity of CD36 as a TLR2 co-receptor. We also show that mCD36ED amplifies the pro-inflammatory response to lipoteichoic acid in macrophages of wild-type mice and restores the pro-inflammatory response of macrophages from mice deficient in CD36 (oblivious), but not from mice deficient in cluster of differentiation 14 (CD14) (heedless). CONCLUSION/ SIGNIFICANCE: These data indicate that the CD36 ectodomain is the only relevant domain for activation of TLR2 signaling pathway and that CD36 and CD14 have a non-redundant role for loading ligands onto TLR2 in the plasma-membrane. The pro-inflammatory role of soluble CD36 can be relevant in the activation of the immune response against pathogens, as well as in the progression of chronic diseases. Therefore, an increased level of soluble forms of CD36, which has been reported to be increased in type II diabetic patients, could accelerate atherosclerosis by increasing the pro-inflammatory response to diacylglycerol ligands.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0007411