Journal Article

Lack of Toll-Like Receptor 4 or Myeloid Differentiation Factor 88 Reduces Atherosclerosis and Alters Plaque Phenotype in Mice Deficient in Apolipoprotein E

Zhang, Wenxuan, Wong, Michelle H., Shah, Prediman K., Yano, Juliana, Doherty, Terence M., Ignarro, Louis J., Michelsen, Kathrin S., Akira, Shizuo, Rajavashisth, Tripathi B., Arditi, Moshe

2004

Overview

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 proinflamatory 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.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: Adaptor Proteins, Signal Transducing / Animals / Antigens, Differentiation - genetics / Antigens, Differentiation - immunology / Aorta / Aorta - cytology / Aorta - pathology / Apolipoproteins E - genetics / Apolipoproteins E - metabolism / Arteriosclerosis - genetics / Arteriosclerosis - immunology / Arteriosclerosis - pathology / Atherosclerosis / Biological Sciences / Cells, Cultured / Chemokine CCL2 - metabolism / Cyclooxygenase 2 / Cytokines / Endothelial Cells - cytology / Endothelial Cells - metabolism / Female / Humans / Immune system / Immunity, Innate - physiology / Immunology / Interleukin-12 - blood / Isoenzymes - metabolism / Lesions / Leukocytes / Lipid Metabolism / Lipids / Lipids - chemistry / Macrophages / Macrophages - metabolism / Male / Membrane Glycoproteins - genetics / Membrane Glycoproteins - immunology / Membrane Proteins / Mice / Mice, Inbred C57BL / Mice, Knockout / Molecules / Myeloid Differentiation Factor 88 / Phenotype / Prostaglandin-Endoperoxide Synthases - metabolism / Receptors / Receptors, Cell Surface - genetics / Receptors, Cell Surface - immunology / Receptors, Immunologic - genetics / Receptors, Immunologic - immunology / Rodents / Signal Transduction - physiology / Sinus of Valsalva / Toll-Like Receptor 4 / Toll-Like Receptors