Cited by 1,019Atherosclerosis and Cardiovascular DiseasesCholesterol and Lipid MetabolismImmune Response and Inflammation

Lack of Toll-like receptor 4 or myeloid differentiation factor 88 reduces atherosclerosis and alters plaque phenotype in mice deficient in apolipoprotein E

Open access
Michelsen, Kathrin S., Wong, Michelle H., Shah, Prediman K., Zhang, Wenxuan, Yano, Juliana, Doherty, Terence M., Akira, Shizuo, Rajavashisth, Tripathi B. +1 more·2004·Proceedings of the National Academy of Sciences

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.

Integrity signals

Registry

Crossref · 10.1073/pnas.0403249101

Cites

58 of 58 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

We couldn’t retrieve this paper’s full text, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Deficiency in either TLR2 or TLR4 signalling reduced atherosclerotic disease in mouse models.

    “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]

  • TLR signalling is implicated in the pathogenesis of atherosclerotic disease.

    “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]

Cites

Flagged first, then by citations

Cited by

Sorted by citations

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
Venue
Proceedings of the National Academy of Sciences
Published
2004-07-12
Volume
101
Issue
29
Pages
10679-10684
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
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
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
  • Health Sciences › Medicine › Surgery › 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

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review