Protective role for toll-like receptor-9 in the development of atherosclerosis in apolipoprotein e-deficient mice

Koulis, Christine, Chen, Yung-Chih, Hausding, Christian, Ahrens, Ingo, Kyaw, Tin Soe, Tay, Christopher, Allen, Terri, Jandeleit-Dahm, Karin, Sweet, Matthew J., Akira, Shizuo, Bobik, Alexander, Peter, Karlheinz and Agrotis, Alex (2014) Protective role for toll-like receptor-9 in the development of atherosclerosis in apolipoprotein e-deficient mice. Arteriosclerosis, Thrombosis, and Vascular Biology, 34 3: 516-525. doi:10.1161/ATVBAHA.113.302407

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Author Koulis, Christine
Chen, Yung-Chih
Hausding, Christian
Ahrens, Ingo
Kyaw, Tin Soe
Tay, Christopher
Allen, Terri
Jandeleit-Dahm, Karin
Sweet, Matthew J.
Akira, Shizuo
Bobik, Alexander
Peter, Karlheinz
Agrotis, Alex
Title Protective role for toll-like receptor-9 in the development of atherosclerosis in apolipoprotein e-deficient mice
Journal name Arteriosclerosis, Thrombosis, and Vascular Biology   Check publisher's open access policy
ISSN 1079-5642
1524-4636
Publication date 2014-01-16
Sub-type Article (original research)
DOI 10.1161/ATVBAHA.113.302407
Open Access Status
Volume 34
Issue 3
Start page 516
End page 525
Total pages 10
Place of publication Philadelphia, PA, United States
Publisher Lippincott Williams & Wilkins
Collection year 2015
Language eng
Formatted abstract
Objective: Atherosclerosis is driven by inflammatory reactions that are shared with the innate immune system. Toll-like receptor-9 (TLR9) is an intracellular pattern recognition receptor of the innate immune system that is currently under clinical investigation as a therapeutic target in inflammatory diseases. Here, we investigated whether TLR9-/- has a role in the development of atherosclerosis in apolipoprotein E-deficient (ApoE -/-) mice.

Approach and Results: Newly generated double-knockout ApoE-/-:TLR9-/- mice and control ApoE-/- mice were fed a high-fat diet from 8 weeks and effects on lesion size, cellular composition, inflammatory status, and plasma lipids were assessed after 8, 12, 15, and 20 weeks. All 4 time points demonstrated exacerbated atherosclerotic lesion severity in ApoE-/-:TLR9-/- mice, with a corresponding increase in lipid deposition and accumulation of macrophages, dendritic cells, and CD4 T cells. Although ApoE-/-:TLR9-/- mice exhibited an increase in plasma very low-density lipoprotein/low-density- lipoprotein cholesterol, the very low-density lipoprotein/low-density lipoprotein:high-density lipoprotein ratio was unaltered because of a parallel increase in plasma high-density lipoprotein cholesterol. As a potential mechanism accounting for plaque progression in ApoE-/-:TLR9 -/- mice, CD4 T-cell accumulation was further investigated and depletion of these cells in ApoE-/-:TLR9-/- mice significantly reduced lesion severity. As a final translational approach, administration of a TLR9-/- agonist (type B CpG oligodeoxynucleotide 1668) to ApoE-/- mice resulted in a reduction of lesion severity.

Conclusions: Genetic deletion of the innate immune receptor TLR9 -/- exacerbated atherosclerosis in ApoE-/- mice fed a high-fat diet. CD4 T cells were identified as potential mediators of this effect. A type B CpG oligodeoxynucleotide TLR9-/- agonist reduced lesion severity, thus identifying a novel therapeutic approach in atherosclerosis.  
Keyword Atherosclerosis
CpG ODN
Inflammation
Toll-like receptor-9
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2015 Collection
Institute for Molecular Bioscience - Publications
 
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Created: Wed, 05 Mar 2014, 10:56:38 EST by Susan Allen on behalf of Institute for Molecular Bioscience