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

M. Rachel Richards, Audrey S. Black, David J. Bonnet, Grant D. Barish, Connie W. Woo, Ira Tabas, Linda K. Curtiss, Peter S. Tobias*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

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 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.

Original languageEnglish (US)
Pages (from-to)20-29
Number of pages10
JournalInnate Immunity
Volume19
Issue number1
DOIs
StatePublished - Feb 2013

Keywords

  • MyD88
  • TLR3
  • TRIF
  • atherosclerosis
  • inflammation
  • murine models

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Molecular Biology
  • Cell Biology
  • Infectious Diseases

Fingerprint Dive into the research topics of 'The LPS2 mutation in TRIF is atheroprotective in hyperlipidemic low density lipoprotein receptor knockout mice'. Together they form a unique fingerprint.

Cite this