CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer.
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.
Stewart
Cameron R
CR
Lipid Metabolism Unit, Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
Stuart
Lynda M
LM
Wilkinson
Kim
K
van Gils
Janine M
JM
Deng
Jiusheng
J
Halle
Annett
A
Rayner
Katey J
KJ
Boyer
Laurent
L
Zhong
Ruiqin
R
Frazier
William A
WA
Lacy-Hulbert
Adam
A
El Khoury
Joseph
J
Golenbock
Douglas T
DT
Moore
Kathryn J
KJ
D016229:Amyloid beta-Peptides / Q000276:immunology; D000818:Animals; D050197:Atherosclerosis / Q000276:immunology / Q000378:metabolism; D015153:Blotting, Western; D018955:CD36 Antigens / Q000276:immunology* / Q000378:metabolism; D002460:Cell Line; D018925:Chemokines / Q000096:biosynthesis / Q000276:immunology; D015870:Gene Expression; D006801:Humans; D047468:Immunoprecipitation; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000276:immunology* / Q000378:metabolism; D051216:Toll-Like Receptor 6 / Q000276:immunology* / Q000378:metabolism
D016229:Amyloid beta-Peptides; D018955:CD36 Antigens; D018925:Chemokines; D008077:Lipoproteins, LDL; C493487:Tlr4 protein, mouse; C495369:Tlr6 protein, mouse; D051197:Toll-Like Receptor 4; D051216:Toll-Like Receptor 6; C099252:oxidized low density lipoprotein