Back to Search
Start Over
Macrophage-Derived GSDMD Plays an Essential Role in Atherosclerosis and Cross Talk Between Macrophages via the Mitochondria-STING-IRF3/NF-κB Axis.
- Source :
-
Arteriosclerosis, thrombosis, and vascular biology [Arterioscler Thromb Vasc Biol] 2024 Jun; Vol. 44 (6), pp. 1365-1378. Date of Electronic Publication: 2024 May 02. - Publication Year :
- 2024
-
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.<br />Methods: ApoE <superscript>-/-</superscript> and Gsdmd <superscript>-/-</superscript> ApoE <superscript>-/-</superscript> 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.<br />Results: First, we found that GSDMD is activated in human and mouse atherosclerotic plaques and Gsdmd <superscript>-/-</superscript> attenuates the atherosclerotic lesion area in high-fat diet-fed ApoE <superscript>-/-</superscript> mice. We performed single-cell RNA sequencing of ApoE <superscript>-/-</superscript> and Gsdmd <superscript>-/-</superscript> ApoE <superscript>-/-</superscript> 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.<br />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.<br />Competing Interests: Disclosures None.
- Subjects :
- Animals
Mice
Humans
Male
Mice, Knockout, ApoE
Plaque, Atherosclerotic
Aortic Diseases pathology
Aortic Diseases metabolism
Aortic Diseases genetics
Aortic Diseases prevention & control
Gasdermins
Atherosclerosis metabolism
Atherosclerosis pathology
Atherosclerosis genetics
Macrophages metabolism
Membrane Proteins metabolism
Membrane Proteins genetics
Phosphate-Binding Proteins metabolism
Phosphate-Binding Proteins genetics
Interferon Regulatory Factor-3 metabolism
Interferon Regulatory Factor-3 genetics
NF-kappa B metabolism
Mitochondria metabolism
Mitochondria pathology
Signal Transduction
Intracellular Signaling Peptides and Proteins metabolism
Intracellular Signaling Peptides and Proteins genetics
Disease Models, Animal
Mice, Inbred C57BL
Pyroptosis
Subjects
Details
- Language :
- English
- ISSN :
- 1524-4636
- Volume :
- 44
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Arteriosclerosis, thrombosis, and vascular biology
- Publication Type :
- Academic Journal
- Accession number :
- 38695170
- Full Text :
- https://doi.org/10.1161/ATVBAHA.123.320612