Journal
FRONTIERS IN PHARMACOLOGY
Volume 12, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fphar.2021.657486
Keywords
atherosclerosis; inflammation; pyroptosis; macrophage; caspase-11; gasdermin D; cardiovascular diseases; immunity
Categories
Funding
- National Natural Science Foundation of China [81870171, 81770403, 81974054]
- National Key Research and Development Projects [2019YFF0216305, 2016YFC0900802, 2018YFC1311300]
- Hunan Distinguished Young Scholars [2018JJ1048]
- Hunan Young Scholars [2018JJ3805]
- Independent Exploration and Innovation Project for Graduate Students of Central South University [1053320184264]
- Scientific research project of health and Health Committee of Changning District [20194Y003]
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The study shows that oxidized phospholipids can induce pyroptosis via noncanonical inflammasome activation, promoting the development of atherosclerosis. Further experiments demonstrate that inflammatory signaling mediated by caspase-11 and gasdermin D is significantly activated in peripheral blood mononuclear cells from patients with coronary heart disease.
Background: Pyroptosis is a form of cell death triggered by proinflammatory signals. Recent studies have reported that oxidized phospholipids function as caspase-11 agonists to induce noncanonical inflammasome activation in immune cells. As the levels of oxidized phospholipids derived from ox-LDL are largely elevated in atherosclerotic lesions, this study sought to determine whether oxidized lipids trigger pyroptosis and subsequent inflammation in the pathogenesis of atherosclerosis. Methods and Results: In our current study, after integrating transcriptomic data available from the Gene Expression Omnibus with data from hyperlipidemic mice and ox-LDL-treated peritoneal macrophages, we discovered that caspase-4/11-gasdermin D-associated inflammatory signaling was significantly activated. Consistently, the mRNA expression of caspase-4 and gasdermin D was upregulated in peripheral blood mononuclear cells from patients with coronary heart disease. In particular, the expression of caspase-4 was closely associated with the severity of lesions in the coronary arteries. An in vivo study showed that caspase-11-gasdermin D activation occurred in response to a high-fat/high-cholesterol (HFHC) diet in ApoE(-/-) mice, while caspase-11 deletion largely attenuated the volume and macrophage infiltration of atherosclerotic lesions. An in vitro mechanistic study showed that caspase-11-mediated inflammation occurred partly via gasdermin D-mediated pyroptosis in macrophages. Suppressing gasdermin D in HFHC-fed ApoE(-/-) mice via delivery of an adeno-associated virus markedly decreased lesion volume and infiltrating macrophage numbers. Conclusion: Caspase-11-gasdermin D-mediated pyroptosis and the subsequent proinflammatory response in macrophages are involved in the pathogenesis of atherosclerosis. Therefore, targeting the caspase 11-gasdermin D may serve as an alternative strategy for the treatment of atherosclerosis.
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