刺
巨噬细胞
细胞生物学
线粒体
NF-κB
交叉展示
免疫学
内部收益率3
化学
生物
信号转导
先天免疫系统
免疫系统
物理
T细胞
体外
抗原呈递
生物化学
热力学
作者
Xiaoxi Fan,Jibo Han,Lingfeng Zhong,Wenyuan Zheng,Ruiyin Shao,Yucong Zhang,Si Shi,Shuang Lin,Zhouqing Huang,Weijian Huang,Xueli Cai,Bozhi Ye
标识
DOI:10.1161/atvbaha.123.320612
摘要
BACKGROUND: Macrophages play a crucial role in atherosclerotic plaque formation, and the death of macrophages is a vital factor in determining the fate of atherosclerosis. GSDMD (gasdermin D)-mediated pyroptosis is a programmed cell death, characterized by membrane pore formation and inflammatory factor release. METHODS: ApoE −/− and Gsdmd −/− ApoE −/− mice, bone marrow transplantation, and AAV (adeno-associated virus serotype 9)-F4/80-shGSDMD (shRNA-GSDMD) were used to examine the effect of macrophage-derived GSDMD on atherosclerosis. Single-cell RNA sequencing was used to investigate the changing profile of different cellular components and the cellular localization of GSDMD during atherosclerosis. RESULTS: First, we found that GSDMD is activated in human and mouse atherosclerotic plaques and Gsdmd −/− attenuates the atherosclerotic lesion area in high-fat diet–fed ApoE −/− mice. We performed single-cell RNA sequencing of ApoE −/− and Gsdmd −/− ApoE −/− mouse aortas and showed that GSDMD is principally expressed in atherosclerotic macrophages. Using bone marrow transplantation and AAV-F4/80-shGSDMD, we identified the potential role of macrophage-derived GSDMD in aortic pyroptosis and atherosclerotic injuries in vivo. Mechanistically, GSDMD contributes to mitochondrial perforation and mitochondrial DNA leakage and subsequently activates the STING (stimulator of interferon gene)-IRF3 (interferon regulatory factor 3)/NF-κB (nuclear factor kappa B) axis. Meanwhile, GSDMD regulates the STING pathway activation and macrophage migration via cytokine secretion. Inhibition of GSDMD with GSDMD-specific inhibitor GI-Y1 (GSDMD inhibitor Y1) can effectively alleviate the progression of atherosclerosis. CONCLUSIONS: Our study has provided a novel macrophage-derived GSDMD mechanism in the promotion of atherosclerosis and demonstrated that GSDMD can be a potential therapeutic target for atherosclerosis.
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