TUDCA alleviates atherosclerosis by inhibiting AIM2 inflammasome and enhancing cholesterol efflux capacity in macrophage

Xuyang Wang; Yuesheng Zhang; Luping Du; Zhengchen Jiang; Yan Guo; Kai Wang; Yijiang Zhou; Xiang Yin; Xiaogang Guo

doi:10.1016/j.isci.2024.109849

TUDCA alleviates atherosclerosis by inhibiting AIM2 inflammasome and enhancing cholesterol efflux capacity in macrophage

iScience. 2024 Apr 27;27(6):109849. doi: 10.1016/j.isci.2024.109849. eCollection 2024 Jun 21.

Authors

Xuyang Wang¹, Yuesheng Zhang¹, Luping Du¹, Zhengchen Jiang², Yan Guo¹, Kai Wang¹, Yijiang Zhou¹, Xiang Yin¹, Xiaogang Guo¹

Affiliations

¹ Department of Cardiology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
² Department of Gastric Surgery, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institutes of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou 310022, China.

Abstract

Cholesterol efflux capacity (CEC) dysfunction in macrophages is important in atherosclerosis. However, the mechanism underlying CEC dysfunction remains unclear. We described the characteristics of ATF4 and inflammasome activation in macrophages during atherosclerosis through scRNA sequencing analysis. Then model of hyperlipemia was established in ApoE^-/- mice; some were treated with tauroursodeoxycholic acid (TUDCA). TUDCA decreased the ATF4, Hspa, and inflammasome activation, reduced plaque area of the artery, and promoted CEC in macrophages. Furthermore, TUDCA abolished oxLDL-induced foam cell formation by inhibiting activation of the PERK/eIF2α/ATF4 and AIM2 inflammasome in macrophages. Further assays revealed ATF4 binding to AIM2 promoter, promoting its transcriptional activity significantly. Then we discovered that ATF4 affected AIM2-mediated foam cell formation by targeting ABCA1, which could be blocked by TUDCA. Our study demonstrated that TUDCA alleviates atherosclerosis by inhibiting AIM2 inflammasome and enhancing CEC of macrophage, which provided possibilities for the development of therapies.

Keywords: Components of the immune system; Immunology; Molecular biology; Transcriptomics.