Macrophage-Derived GSDMD Plays an Essential Role in Atherosclerosis and Cross Talk Between Macrophages via the Mitochondria-STING-IRF3/NF-κB Axis

Xiaoxi Fan; Jibo Han; Lingfeng Zhong; Wenyuan Zheng; Ruiyin Shao; Yucong Zhang; Si Shi; Shuang Lin; Zhouqing Huang; Weijian Huang; Xueli Cai; Bozhi Ye

doi:10.1161/ATVBAHA.123.320612

Macrophage-Derived GSDMD Plays an Essential Role in Atherosclerosis and Cross Talk Between Macrophages via the Mitochondria-STING-IRF3/NF-κB Axis

Arterioscler Thromb Vasc Biol. 2024 May 2. doi: 10.1161/ATVBAHA.123.320612. Online ahead of print.

Authors

Xiaoxi Fan^#¹, Jibo Han^#², Lingfeng Zhong¹, Wenyuan Zheng³, Ruiyin Shao¹, Yucong Zhang¹, Si Shi⁴, Shuang Lin⁵, Zhouqing Huang¹, Weijian Huang¹, Xueli Cai¹, Bozhi Ye¹

Affiliations

¹ Department of Cardiology and The Key Laboratory of Cardiovascular Disease of Wenzhou, The First Affiliated Hospital, Wenzhou Medical University, Zhejiang, China (X.F., L.Z., R.S., Y.Z., Z.H., W.H., X.C., B.Y.).
² Department of Cardiology, The Second Affiliated Hospital of Jiaxing University, Zhejiang, China (J.H.).
³ Department of Cardiology, The First Affiliated Hospital of Ningbo University, Zhejiang, China (W.Z.).
⁴ First School of Medicine, Wenzhou Medical University, Zhejiang, China (S.S.).
⁵ Department of Cardiology, Ningbo Medical Center Li Huili Hospital, Zhejiang, China (S.L.).

^# Contributed equally.

PMID: 38695170
DOI: 10.1161/ATVBAHA.123.320612

Abstract

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-F4/80-shGSDMD 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 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.

Keywords: aorta; atherosclerosis; cytokines; macrophages; mitochondria.