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Published on: April 3, 2017
Macrophage-Derived GSDMD Plays an Essential Role in Atherosclerosis and Cross Talk Between Macrophages via the
Xiaoxi Fan1, Jibo Han2, Lingfeng Zhong1
1Department 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.).
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.
Insights
Gasdermin D (GSDMD) promotes atherosclerosis by triggering pyroptosis in macrophages, leading to plaque formation. Inhibiting GSDMD effectively reduces atherosclerotic lesions and offers a potential therapeutic target.
Area of Science:
- Cardiovascular Biology
- Immunology
- Cell Death Mechanisms
Background:
- Macrophages are key players in atherosclerotic plaque development.
- Macrophage death significantly influences atherosclerosis progression.
- Gasdermin D (GSDMD)-mediated pyroptosis is a programmed cell death pathway involving membrane pores and inflammatory factor release.
Purpose of the Study:
- To investigate the role of macrophage-derived GSDMD in atherosclerosis.
- To elucidate the molecular mechanisms by which GSDMD influences atherosclerotic plaque formation.
- To evaluate GSDMD as a potential therapeutic target for atherosclerosis.
Main Methods:
- Utilized ApoE mice models, bone marrow transplantation, and adeno-associated virus (AAV) delivery of shRNA targeting GSDMD (F4/80-shGSDMD).
- Employed single-cell RNA sequencing to analyze cellular changes and GSDMD localization in atherosclerotic aortas.
- Investigated mechanistic pathways including mitochondrial integrity and the STING-IRF3/NF-κB axis.
Main Results:
- GSDMD activation was observed in human and mouse atherosclerotic plaques, with GSDMD deficiency attenuating lesion area in ApoE mice.
- Single-cell RNA sequencing confirmed predominant GSDMD expression in atherosclerotic macrophages.
- Macrophage-derived GSDMD was linked to aortic pyroptosis and injury, involving mitochondrial perforation, DNA leakage, and activation of the STING-IRF3/NF-κB pathway.
- GSDMD inhibition using GI-Y1 significantly alleviated atherosclerosis progression.
Conclusions:
- Identified a novel mechanism of macrophage-derived GSDMD promoting atherosclerosis via pyroptosis.
- Demonstrated that GSDMD plays a critical role in the inflammatory processes driving atherosclerosis.
- Established GSDMD as a promising therapeutic target for managing atherosclerosis.
