Abstract
Toll-like receptors (TLRs) and the downstream adaptor molecule myeloid differentiation factor 88 (MyD88) play an essential role in the innate immune responses. Here, we demonstrate that genetic deficiency of TLR4 or MyD88 is associated with a significant reduction of aortic plaque areas in atherosclerosis-prone apolipoprotein E-deficient mice, despite persistent hypercholesterolemia, implying an important role for the innate immune system in atherogenesis. Apolipoprotein E-deficient mice that also lacked TLR4 or MyD88 demonstrated reduced aortic atherosclerosis that was associated with reductions in circulating levels of proinflammatory cytokines IL-12 or monocyte chemoattractant protein 1, plaque lipid content, numbers of macrophage, and cyclooxygenase 2 immunoreactivity in their plaques. Endothelial-leukocyte adhesion in response to minimally modified low-density lipoprotein was reduced in aortic endothelial cells derived from MyD88-deficient mice. Taken together, our results suggest an important role for TLR4 and MyD88 signaling in atherosclerosis in a hypercholesterolemic mouse model, providing a pathophysiologic link between innate immunity, inflammation, and atherogenesis.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adaptor Proteins, Signal Transducing
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Animals
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Antigens, Differentiation / genetics
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Antigens, Differentiation / immunology*
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Aorta / cytology
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Aorta / pathology
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Apolipoproteins E / genetics
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Apolipoproteins E / metabolism*
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Arteriosclerosis / genetics
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Arteriosclerosis / immunology*
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Arteriosclerosis / pathology*
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Cells, Cultured
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Chemokine CCL2 / metabolism
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Cyclooxygenase 2
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Endothelial Cells / cytology
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Endothelial Cells / metabolism
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Female
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Humans
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Immunity, Innate / physiology
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Interleukin-12 / blood
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Isoenzymes / metabolism
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Lipid Metabolism
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Lipids / chemistry
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Macrophages / metabolism
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Male
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / immunology*
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Membrane Proteins
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Myeloid Differentiation Factor 88
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Phenotype
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Prostaglandin-Endoperoxide Synthases / metabolism
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Receptors, Cell Surface / genetics
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Receptors, Cell Surface / immunology*
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Receptors, Immunologic / genetics
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Receptors, Immunologic / immunology*
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Signal Transduction / physiology
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Toll-Like Receptor 4
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Toll-Like Receptors
Substances
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Adaptor Proteins, Signal Transducing
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Antigens, Differentiation
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Apolipoproteins E
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CCL2 protein, human
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Ccl2 protein, mouse
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Chemokine CCL2
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Isoenzymes
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Lipids
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MYD88 protein, human
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Membrane Glycoproteins
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Membrane Proteins
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Myd88 protein, mouse
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Myeloid Differentiation Factor 88
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Receptors, Cell Surface
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Receptors, Immunologic
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TLR4 protein, human
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Toll-Like Receptor 4
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Toll-Like Receptors
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Interleukin-12
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Cyclooxygenase 2
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PTGS2 protein, human
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Prostaglandin-Endoperoxide Synthases