title: Lack of Toll-like receptor 4 or myeloid differentiation factor 88 reduces atherosclerosis and alters plaque phenotype in mice deficient in apolipoprotein E.
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.
authors.affiliation: Division of Pediatric Infectious Diseases, Atherosclerosis Research Center, Burns and Allen Research Institute, Cedars-Sinai Medical Center and David Geffen School of Medicine, University of California, Los Angeles, CA 90048, USA.
authors.forename: Kathrin S
authors.initials: KS
authors.lastname: Michelsen
authors.forename: Michelle H
authors.initials: MH
authors.lastname: Wong
authors.forename: Prediman K
authors.initials: PK
authors.lastname: Shah
authors.forename: Wenxuan
authors.initials: W
authors.lastname: Zhang
authors.forename: Juliana
authors.initials: J
authors.lastname: Yano
authors.forename: Terence M
authors.initials: TM
authors.lastname: Doherty
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Tripathi B
authors.initials: TB
authors.lastname: Rajavashisth
authors.forename: Moshe
authors.initials: M
authors.lastname: Arditi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics / Q000276:immunology*; D001011:Aorta / Q000166:cytology / Q000473:pathology; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism*; D001161:Arteriosclerosis / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D051546:Cyclooxygenase 2; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D005260:Female; D006801:Humans; D007113:Immunity, Innate / Q000502:physiology; D018664:Interleukin-12 / Q000097:blood; D007527:Isoenzymes / Q000378:metabolism; D050356:Lipid Metabolism; D008055:Lipids / Q000737:chemistry; D008264:Macrophages / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology*; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88; D010641:Phenotype; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000276:immunology*; D011971:Receptors, Immunologic / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000502:physiology; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D001057:Apolipoproteins E; C111835:CCL2 protein, human; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D007527:Isoenzymes; D008055:Lipids; C507779:MYD88 protein, human; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D018664:Interleukin-12; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases