The LPS2 Mutation in TRIF is Atheroprotective in Hyperlipidemic LDL Receptor Knockout Mice

Signalling through myeloid differentiation primary response gene 88 (MyD88), an adaptor utilized by all Toll-like receptors (TLR) 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 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 weeks, 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 (Mϕ) in response to hyperlipidemia. Moreover, heart sinus valves from hyperlipidemic LDLr−/− TRIF Lps2 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 proatherogenic events.