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 TRIFLps2 lack-of-function mutation was atheroprotective in hyperlipidemic low density lipoprotein (LDL) receptor knockout (LDLr−/−) mice. LDLr−/− mice were crossed with either TRIFLps2 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 TRIFLps2 were significantly protected from atherosclerosis. TRIFLps2 led to a reduction in cytokines secreted from peritoneal macrophages (Mϕ) in response to hyperlipidemia. Moreover, heart sinus valves from hyperlipidemic LDLr−/− TRIFLps2 mice had significantly fewer lesional Mϕ. 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.