Reduced atherosclerosis in MyD88-null mice links elevated serum cholesterol levels to activation of innate immunity signaling pathways
Abstract
Atherosclerosis, the leading cause of death in developed countries, has been linked to hypercholesterolemia for decades. More recently, atherosclerotic lesion progression has been shown to depend on persistent, chronic inflammation in the artery wall. Although several studies have implicated infectious agents in this process, the role of infection in atherosclerosis remains controversial. Because the involvement of monocytes and macrophages in the pathogenesis of atherosclerosis is well established, we investigated the possibility that macrophage innate immunity signaling pathways normally activated by pathogens might also be activated in response to hyperlipidemia. We examined atherosclerotic lesion development in uninfected, hyperlipidemic mice lacking expression of either lipopolysaccharide (LPS) receptor CD14 or myeloid differentiation protein-88 (MyD88), which transduces cell signaling events downstream of the Toll-like receptors (TLRs), as well as receptors for interleukin-1 (IL-1) and IL-18. Whereas the MyD88-deficient mice evinced a marked reduction in early atherosclerosis, mice deficient in CD14 had no decrease in early lesion development. Inactivation of the MyD88 pathway led to a reduction in atherosclerosis through a decrease in macrophage recruitment to the artery wall that was associated with reduced chemokine levels. These findings link elevated serum lipid levels to a proinflammatory signaling cascade that is also engaged by microbial pathogens.
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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 [37]
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 [37]
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- Authors
- Björkbacka, H., Kunjathoor, V. V., Moore, K. J., Koehn, S., Ordija, C. M., Lee, M. A., Means, T., Halmen, K., Luster, A. D., Golenbock, D. T., & Freeman, M. W.
- Affiliations
- Harvard University (US)
- University of Massachusetts Chan Medical School (US)
- Corresponding author
- Freeman, Mason W
- ORCID
- Venue
- Nature Medicine
- Published
- 2004-03-14
- Volume
- 10
- Issue
- 4
- Pages
- 416-421
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W2083709056
- Cited by
- 634
- References
- 36
- Citations by year
- 2026: 2 · 2025: 12 · 2024: 7 · 2023: 7 · 2022: 12 · 2021: 12 · 2020: 21 · 2019: 22 · 2018: 22 · 2017: 21 · 2016: 19 · 2015: 40 · 2014: 20 · 2013: 45 · 2012: 45
- FWCI
- 18.36
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (HL 66678, U01HL066678, HL45098, R01HL045098)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-50305, P01DK050305)
- National Center for Research Resources (RR-14466, R24RR014466)
- 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
- atherosclerosis, MyD88, CD14, hypercholesterolemia, innate immunity, macrophage recruitment, macrophages, chemokines, Toll-like receptors, lipopolysaccharide, interleukin-1, IL-18, chronic inflammation, hyperlipidemia, atherosclerotic plaque
- MeSH terms
- Animals, Arteriosclerosis, Cholesterol, Immunity, Innate, Mice, Inbred C57BL, Signal Transduction, Mice, Knockout, Mice
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