The LPS2 mutation in TRIF is atheroprotective in hyperlipidemic low density lipoprotein receptor knockout mice.
Signaling through MyD88, an adaptor utilized by all TLRs except TLR3, is pro-atherogenic; however, it is unknown whether signaling through TIR-domain-containing adaptor-inducing interferon-β (TRIF), an adaptor used only by TLRs 3 and 4, is relevant to atherosclerosis. We determined that the TRIF(Lps2) lack-of-function mutation was atheroprotective in hyperlipidemic low density lipoprotein (LDL) receptor knockout (LDLr(-/-)) mice. LDLr(-/-) mice were crossed with either TRIF(Lps2) or TLR3 knockout mice. After feeding an atherogenic diet for 10-15 wks, atherosclerotic lesions in the heart sinus and aorta were quantitated. LDLr(-/-) mice with TRIF(Lps2) were significantly protected from atherosclerosis. TRIF(Lps2) led to a reduction in cytokines secreted from peritoneal macrophages (M) in response to hyperlipidemia. Moreover, heart sinus valves from hyperlipidemic LDLr(-/-) TRIF(Lps2) mice had significantly fewer lesional M. However, LDLr(-/-) mice deficient in TLR3 showed some enhancement of disease. Collectively, these data suggest that hyperlipidemia resulting in endogenous activation of the TRIF signaling pathway from TLR4 leads to pro-atherogenic events.
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA.
M Rachel
MR
Richards
Audrey S
AS
Black
David J
DJ
Bonnet
Grant D
GD
Barish
Connie W
CW
Woo
Ira
I
Tabas
Linda K
LK
Curtiss
Peter S
PS
Tobias
D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001011:Aorta / Q000473:pathology; D050197:Atherosclerosis / Q000209:etiology / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control; D003331:Coronary Vessels / Q000473:pathology; D016207:Cytokines / Q000276:immunology; D004036:Diet, Atherogenic; D006949:Hyperlipidemias / Q000150:complications / Q000235:genetics* / Q000473:pathology; D008077:Lipoproteins, LDL / Q000235:genetics / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009154:Mutation / Q000235:genetics; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D051196:Toll-Like Receptor 3 / Q000235:genetics / Q000378:metabolism*
D033942:Adaptor Proteins, Vesicular Transport; D016207:Cytokines; D008077:Lipoproteins, LDL; D053594:Myeloid Differentiation Factor 88; D051196:Toll-Like Receptor 3; C476286:Ticam1 protein, mouse; C495344:TLR3 protein, human