Caspase-11-Gasdermin D-Mediated Pyroptosis Is Involved in the Pathogenesis of Atherosclerosis

Mengqing Jiang; Xuejing Sun; Suzhen Liu; Yan Tang; Yunming Shi; Yuanyuan Bai; Yujie Wang; Qiong Yang; Qize Yang; Weihong Jiang; Hong Yuan; Qixia Jiang; Jingjing Cai

doi:10.3389/fphar.2021.657486

Caspase-11-Gasdermin D-Mediated Pyroptosis Is Involved in the Pathogenesis of Atherosclerosis

Front Pharmacol. 2021 Apr 26:12:657486. doi: 10.3389/fphar.2021.657486. eCollection 2021.

Authors

Mengqing Jiang¹, Xuejing Sun¹, Suzhen Liu¹, Yan Tang¹, Yunming Shi¹, Yuanyuan Bai¹, Yujie Wang¹, Qiong Yang¹, Qize Yang², Weihong Jiang¹, Hong Yuan³, Qixia Jiang⁴, Jingjing Cai^{1

3}

Affiliations

¹ Department of Cardiology, The Third Xiangya Hospital, Central South University, Changsha, China.
² Suzhou Science and Technology Town Foreign Language School, Jiangsu, China.
³ The Center of Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha, China.
⁴ Department of Cardiology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Abstract

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.

Keywords: atherosclerosis; cardiovascular diseases; caspase-11; gasdermin D; immunity; inflammation; macrophage; pyroptosis.