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CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer
Open accessAbstract
In atherosclerosis and Alzheimer's disease, deposition of the altered self components oxidized low-density lipoprotein (LDL) and amyloid-beta triggers a protracted sterile inflammatory response. Although chronic stimulation of the innate immune system is believed to underlie the pathology of these diseases, the molecular mechanisms of activation remain unclear. Here we show that oxidized LDL and amyloid-beta trigger inflammatory signaling through a heterodimer of Toll-like receptors 4 and 6. Assembly of this newly identified heterodimer is regulated by signals from the scavenger receptor CD36, a common receptor for these disparate ligands. Our results identify CD36-TLR4-TLR6 activation as a common molecular mechanism by which atherogenic lipids and amyloid-beta stimulate sterile inflammation and suggest a new model of TLR heterodimerization triggered by coreceptor signaling events.
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“The binding of Aβ to CD36 (cell surface microglial co-receptor) promotes the TLR4 and/or TLR6 phosphorylation and activation, resulting in the production of inflammatory cytokines and chemokines (Stewart et al., 2010).”
From The role of microglia in retinal neurodegeneration: Alzheimer’s disease, parkinson, and glaucoma. (2017) · cites this paper as Stewart et al., 2010
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“Stewart and colleagues demonstrated that Aβ-mediated release of proinflammatory factors and neurotoxicity partially involved signaling through the CD36/ TLR4/TRL6 complex (108).”
From Microglia in Alzheimer's disease (2017) · cites this paper as [108]
In the citing paper
“CD36 mediates heterodimer formation of TLR4 and TLR6 (REF. 104), and this co-receptor complex upregulates the production of chemokines and cytokines such as pro-IL-1β through the activation of NF-κb.”
From Sterile inflammation: sensing and reacting to damage (2010) · cites this paper as [105]
In the citing paper
“The Soluble Aβ oligomers and Aβ fibrils can react to various receptors expressed by microglia, including CD14, CD36, CD47, α6β1 integrin, class A scavenger receptor, receptor for advanced glycosylation end products (RAGE) and TLRs (Stewart et al., 2010).”
From The role of microglia in retinal neurodegeneration: Alzheimer’s disease, parkinson, and glaucoma. (2017) · cites this paper as Stewart et al., 2010
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Metadata
- Authors
- Stewart, C. R., Stuart, L. M., Wilkinson, K., van Gils, J. M., Deng, J., Halle, A., Rayner, K. J., Boyer, L., Zhong, R., Frazier, W. A., Lacy-Hulbert, A., Khoury, J. E., Golenbock, D. T., & Moore, K. J.
- Affiliations
- Harvard University (US)
- University of Massachusetts Chan Medical School (US)
- Washington University in St. Louis (US)
- Corresponding author
- Moore, Kathryn J
- ORCID
- Venue
- Nature Immunology
- Published
- 2009-12-27
- Volume
- 11
- Issue
- 2
- Pages
- 155-161
- ISSN
- 1529-2908 (ISSN-L)
- 1529-2916
- PMC
- PMC2809046
- OpenAlex
- W2045772297
- Cited by
- 1,513
- References
- 42
- Citations by year
- 2026: 53 · 2025: 69 · 2024: 107 · 2023: 74 · 2022: 108 · 2021: 96 · 2020: 102 · 2019: 97 · 2018: 99 · 2017: 94 · 2016: 98 · 2015: 108 · 2014: 81 · 2013: 92 · 2012: 104
- FWCI
- 33.44
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Immunology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- The Journal of the American Medical Association (JAMA) Network (American Medical Association) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Leiden Repository (Leiden University) (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Funders
- Wellcome Trust (068089)
- National Institute on Aging (R01AG20255, R01AG020255, R01AG032349)
- National Institute of Allergy and Infectious Diseases (R01AI079198)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK043351)
- National Institute of Neurological Disorders and Stroke (R01NS059005)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Keywords
- CD36, TLR4, TLR6, sterile inflammation, oxidized LDL, amyloid-beta, atherosclerosis, Alzheimer's disease, innate immune activation
- MeSH terms
- Animals, Cell Line, Humans, Inflammation, Lipoproteins, LDL, Mice, Inbred C57BL, Blotting, Western, Signal Transduction, Gene Expression, Amyloid beta-Peptides, Microglia, Mice, Knockout, Chemokines, CD36 Antigens, Reverse Transcriptase Polymerase Chain Reaction, Immunoprecipitation, Atherosclerosis, Toll-Like Receptor 4, Toll-Like Receptor 6, Mice
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