ID 113231
Title Alternative
Role of Toll-Like Receptor 9 in Atherogenesis
Author
Nishimoto, Sachiko Tokushima University
Aini, Kunduziayi Tokushima University
Tanaka, Atsushi Wakayama Medical University
Nishiguchi, Tsuyoshi Wakayama Medical University
Kim-Kaneyama, Joo-ri Showa University
Lei, Xiao-Feng Showa University
Tanaka, Kimie The University of Tokyo
Higashikuni, Yasutomi The University of Tokyo
Hirata, Yoichiro The University of Tokyo
Akasaka, Takashi Wakayama Medical University
Shimabukuro, Michio Tokushima University|Fukushima Medical University KAKEN Search Researchers
Keywords
atherosclerosis
inflammation
macrophage
Toll-like receptor 9
vascular inflammation
Content Type
Journal Article
Description
Background
Toll-like receptor (TLR) 9 recognizes bacterial DNA, activating innate immunity, whereas it also provokes inflammation in response to fragmented DNA released from mammalian cells. We investigated whether TLR9 contributes to the development of vascular inflammation and atherogenesis using apolipoprotein E–deficient (Apoe-/-) mice.
Methods and Results
Tlr9-deficient Apoe-/- (Tlr9-/-Apoe-/-) mice and Apoe-/- mice on a Western-type diet received subcutaneous angiotensin II infusion (1000 ng/kg per minute) for 28 days. Angiotensin II increased the plasma level of double-stranded DNA, an endogenous ligand of TLR9, in these mice. Genetic deletion or pharmacologic blockade of TLR9 in angiotensin II–infused Apoe-/- mice attenuated atherogenesis in the aortic arch (P<0.05), reduced the accumulation of lipid and macrophages in atherosclerotic plaques, and decreased RNA expression of inflammatory molecules in the aorta with no alteration of metabolic parameters. On the other hand, restoration of TLR9 in bone marrow in Tlr9-/-Apoe-/- mice promoted atherogenesis in the aortic arch (P<0.05). A TLR9 agonist markedly promoted proinflammatory activation of Apoe-/- macrophages, partially through p38 mitogen-activated protein kinase signaling. In addition, genomic DNA extracted from macrophages promoted inflammatory molecule expression more effectively in Apoe-/- macrophages than in Tlr9-/-Apoe-/- macrophages. Furthermore, in humans, circulating double-stranded DNA in the coronary artery positively correlated with inflammatory features of coronary plaques determined by optical coherence tomography in patients with acute myocardial infarction (P<0.05).
Conclusions
TLR9 plays a pivotal role in the development of vascular inflammation and atherogenesis through proinflammatory activation of macrophages. TLR9 may serve as a potential therapeutic target for atherosclerosis.
Journal Title
Journal of the American Heart Association
ISSN
20479980
Publisher
The American Heart Association|Wiley
Volume
8
Issue
7
Start Page
e010860
Published Date
2019-03-23
Rights
©2019 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License(https://creativecommons.org/licenses/by-nc/4.0/), which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
EDB ID
DOI (Published Version)
URL ( Publisher's Version )
FullText File
language
eng
TextVersion
Publisher
departments
Medical Sciences
University Hospital