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Lack of Toll-like receptor 4 or myeloid differentiation factor 88 reduces atherosclerosis and alters plaque phenotype in mice deficient in apolipoprotein E
Open accessAbstract
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.
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“Deficiency in either TLR2 or TLR4 signalling also reduced atherosclerotic disease in mouse models35–37, and TLR4, specifically, has been shown to mediate inflammatory responses to free fatty acids,”
From Sterile inflammation: sensing and reacting to damage (2010) · cites this paper as [36]
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“TLR signalling is also implicated in the pathogenesis of atherosclerotic disease35–37.”
From Sterile inflammation: sensing and reacting to damage (2010) · cites this paper as [36]
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Metadata
- Authors
- Michelsen, K. S., Wong, M. H., Shah, P. K., Zhang, W., Yano, J., Doherty, T. M., Akira, S., Rajavashisth, T. B., & Arditi, M.
- Affiliations
- Cedars-Sinai Medical Center (US)
- Corresponding author
- Arditi, Moshe
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2004-07-12
- Volume
- 101
- Issue
- 29
- Pages
- 10679-10684
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC489994
- OpenAlex
- W2018788678
- Cited by
- 1,019
- References
- 57
- Citations by year
- 2026: 20 · 2025: 17 · 2024: 25 · 2023: 25 · 2022: 35 · 2021: 21 · 2020: 36 · 2019: 52 · 2018: 36 · 2017: 37 · 2016: 43 · 2015: 64 · 2014: 53 · 2013: 68 · 2012: 68
- FWCI
- 18.10
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01hl058555-04)
- National Heart, Lung, and Blood Institute (HL66436, HL 58555, R01HL066436, R29HL051980, HL 51980, R01HL051980)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- TLR4, MyD88, atherosclerosis, apolipoprotein E deficiency, innate immunity, atherogenesis, aortic plaque, hypercholesterolemia, inflammatory cytokines, IL-12, MCP-1, macrophages, cyclooxygenase-2, plaque inflammation
- MeSH terms
- Animals, Antigens, Differentiation, Aorta, Apolipoproteins E, Arteriosclerosis, Cells, Cultured, Female, Humans, Immunity, Innate, Isoenzymes, Lipids, Macrophages, Male, Membrane Glycoproteins, Membrane Proteins, Mice, Inbred C57BL, Phenotype, Prostaglandin-Endoperoxide Synthases, Receptors, Cell Surface, Receptors, Immunologic, Signal Transduction, Mice, Knockout, Interleukin-12, Chemokine CCL2, Endothelial Cells, Adaptor Proteins, Signal Transducing, Lipid Metabolism, Toll-Like Receptors, Toll-Like Receptor 4, Mice, Cyclooxygenase 2, Myeloid Differentiation Factor 88
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