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PMID: 20037584 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer.

Nature immunology ·Vol. 11 ·No. 2 ·2010-02-00 ·Pages 155-61

Stewart CR, Stuart LM, Wilkinson K, van Gils JM, Deng J, Halle A, Rayner KJ, Boyer L, Zhong R, Frazier WA, Lacy-Hulbert A, El Khoury J, Golenbock DT, Moore KJ

Abstract

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.

MeSH Terms
Amyloid beta-Peptides/immunology Animals Atherosclerosis/immunology,metabolism Blotting, Western CD36 Antigens/immunology,metabolism Cell Line Chemokines/biosynthesis,immunology Gene Expression Humans Immunoprecipitation Inflammation/immunology,metabolism Lipoproteins, LDL/immunology Mice Mice, Inbred C57BL Mice, Knockout Microglia/immunology,metabolism Reverse Transcriptase Polymerase Chain Reaction Signal Transduction/immunology Toll-Like Receptor 4/immunology,metabolism Toll-Like Receptor 6/immunology,metabolism
Chemicals
Amyloid beta-Peptides CD36 Antigens Chemokines Lipoproteins, LDL Tlr4 protein, mouse Tlr6 protein, mouse Toll-Like Receptor 4 Toll-Like Receptor 6 oxidized low density lipoprotein
Authors & Affiliations
14 authors, click to expand affiliations / ORCID
Stewart Cameron R
Lipid Metabolism Unit, Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
Stuart Lynda M
Wilkinson Kim
van Gils Janine M
Deng Jiusheng
Halle Annett
Rayner Katey J
Boyer Laurent
Zhong Ruiqin
Frazier William A
Lacy-Hulbert Adam
El Khoury Joseph
Golenbock Douglas T
Moore Kathryn J
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Article Info
Journal
Nature immunology
Abbr.
Nat Immunol
ISSN
1529-2916
DOI
10.1038/ni.1836
Published
2010-02-00
Epub
2009-00-27
Pages
155-61
Language
English
Region
United States
NLM ID
100941354
PMCID
PMC2809046
Subset
IM
Grants
NINDS NIH HHS · R01 NS059005 · United States
NIDDK NIH HHS · P30 DK043351 · United States
Wellcome Trust · 068089 · United Kingdom
NIA NIH HHS · R01 AG032349 · United States
NIA NIH HHS · R01 AG020255 · United States
NIAID NIH HHS · R01 AI079198 · United States
NIA NIH HHS · R01AG20255 · United States
NINDS NIH HHS · R01NS059005 · United States
Wellcome Trust · 068089/Z/02/Z · United Kingdom
External Links
PubMed source DOI: 10.1038/ni.1836 PMC Full Text View journal details
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