STING, a cytosolic DNA sensor, plays a critical role in atherogenesis: a link between innate immunity and chronic inflammation caused by lifestyle-related diseases.

Abstract

AIMS:

Lifestyle-related diseases promote atherosclerosis, a chronic inflammatory disease; however, the molecular mechanism remains largely unknown. Endogenous DNA fragments released under over-nutrient condition provoke sterile inflammation through the recognition by DNA sensors. Here, we investigated the role of stimulator of interferon genes (STING), a cytosolic DNA sensor, in atherogenesis.

METHODS AND RESULTS:

Apolipoprotein E-deficient (Apoe-/-) mice fed a western-type diet (WTD), a hypercholesterolaemic mouse model, showed higher STING expression and markers for DNA damage such as γH2AX, p53, and single-stranded DNA (ssDNA) accumulation in macrophages in the aorta compared with wild-type (WT) mice. The level of cGAMP, a STING agonist, in the aorta was higher in Apoe-/- mice. Genetic deletion of Sting in Apoe-/- mice reduced atherosclerotic lesions in the aortic arch, lipid, and macrophage accumulation in plaques, and inflammatory molecule expression in the aorta compared with the control. Pharmacological blockade of STING using a specific inhibitor, C-176, ameliorated atherogenesis in Apoe-/- mice. In contrast, bone marrow-specific STING expression in Apoe-/- mice stimulated atherogenesis. Expression or deletion of STING did not affect metabolic parameters and blood pressure. In vitro studies revealed that STING activation by cGAMP or mitochondrial DNA accelerated inflammatory molecule expression (e.g. TNF-α or IFN-β) in mouse and human macrophages. Activation of nuclear factor-κB and TANK binding kinase 1 was involved in STING-associated vascular inflammation and macrophage activation. Furthermore, human atherosclerotic lesions in the carotid arteries expressed STING and cGAMP.

CONCLUSION:

Stimulator of interferon genes stimulates pro-inflammatory activation of macrophages, leading to the development of atherosclerosis. Stimulator of interferon genes signalling may serve as a potential therapeutic target for atherosclerosis.

• Authors: Phuong Tran Pham, Daiju Fukuda, Sachiko Nishimoto, Joo-Ri Kim-Kaneyama, Xiao-Feng Lei, Yutaka Takahashi, Tomohito Sato, Kimie Tanaka, Kumiko Suto, Yutaka Kawabata, Koji Yamaguchi, Shusuke Yagi, Kenya Kusunose, Hirotsugu Yamada, Takeshi Soeki, Tetsuzo Wakatsuki, Kenji Shimada, Yasuhisa Kanematsu, Yasushi Takagi, Michio Shimabukuro, Mitsutoshi Setou, Glen N Barber, Masataka Sata
• Journal: European heart journal (Eur Heart J) Vol. 42 Issue 42 Pg. 4336-4348 (11 07 2021) ISSN: 1522-9645 [Electronic] England
• PMID: 34226923 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: [email protected].

Chemical References

• DNA

Topics

• Animals
• Atherosclerosis (genetics)
• DNA
• Disease Models, Animal
• Immunity, Innate
• Inflammation
• Life Style
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Plaque, Atherosclerotic