期刊
INNATE IMMUNITY
卷 19, 期 1, 页码 20-29出版社
SAGE PUBLICATIONS LTD
DOI: 10.1177/1753425912447130
关键词
TRIF; MyD88; TLR3; murine models; inflammation; atherosclerosis
资金
- Fellowship AHA [0825013F]
- NIH [HL088093, HL087123, HL075662]
- CIHR
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-beta (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 (Mf) in response to hyperlipidemia. Moreover, heart sinus valves from hyperlipidemic LDLr-/- TRIFLps2 mice had significantly fewer lesional Mf. 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.
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