The LPS2 mutation in TRIF is atheroprotective in hyperlipidemic low density lipoprotein receptor knockout mice.

Abstract

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.

DOI: 10.1177/1753425912447130

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@article{Richards2013TheLM, title={The LPS2 mutation in TRIF is atheroprotective in hyperlipidemic low density lipoprotein receptor knockout mice.}, author={Meredith Richards and Audrey S Black and David J Bonnet and Grant D. Barish and Connie W Woo and Ira A. Tabas and Linda K. Curtiss and Peter S. Tobias}, journal={Innate immunity}, year={2013}, volume={19 1}, pages={20-9} }