获取途径

作者

Lei Qiao, Jing Ma, Zihao Zhang, Wenhai Sui, Chungang Zhai, Dan Xu, Zunzhe Wang, Huixia Lu, Meng Zhang, Cheng Zhang, Wenqiang Chen, Yun Zhang

作者单位

Cardiovascular Disease Research Center of Shandong First Medical University, Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China (C.Z.). The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China (L.Q., J.M., Z.Z., W.S., C.Z., D.X., Z.W., H.L., M.Z., W.C., Y.Z.). Affiliations

刊名

Circulation research

年份

2021

卷号

Vol.129 No.12

页码

1141-1157

ISSN

1524-4571

关键词

atherosclerosis chaperone-mediated autophagy inflammasome lysosomes macrophages.

摘要

Rationale: The NLRP3 inflammasome is an important driver of atherosclerosis. Our previous study shows that chaperone-mediated autophagy , one of the main lysosomal degradative process, has a regulatory role in lipid metabolism of macrophages. However, whether the NLRP3 inflammasome is regulated by CMA, and the role of CMA in atherosclerosis remains unclear. Objective: To determine the role of CMA in the regulation of NLRP3 inflammasome and atherosclerosis. Methods and results: The expression of...更多

Rationale: The NLRP3 inflammasome is an important driver of atherosclerosis. Our previous study shows that chaperone-mediated autophagy , one of the main lysosomal degradative process, has a regulatory role in lipid metabolism of macrophages. However, whether the NLRP3 inflammasome is regulated by CMA, and the role of CMA in atherosclerosis remains unclear. Objective: To determine the role of CMA in the regulation of NLRP3 inflammasome and atherosclerosis. Methods and results: The expression of CMA marker, LAMP-2A , was first analyzed in ApoE -/- mouse aortas and human coronary atherosclerotic plaques, and a significant downregulation of LAMP-2A in advanced atherosclerosis in both mice and humans was observed. To selectively block CMA, we generated macrophage-specific conditional LAMP-2A knockout mouse strains in C57BL/6 mice and ApoE -/- mice. Deletion of macrophage LAMP-2A accelerated atherosclerotic lesion formation in the aortic root and the whole aorta in ApoE -/- mice. Mechanistically, LAMP-2A deficiency promoted NLRP3 inflammasome activation and subsequent release of mature IL -1β in macrophages and atherosclerotic plaques. Furthermore, gain-of-function studies verified that restoration of LAMP-2A levels in LAMP-2A-deficient macrophages greatly attenuated NLRP3 inflammasome activation. Importantly, we identified the NLRP3 protein as a CMA substrate and demonstrated that LAMP-2A deficiency did not affect the NLRP3 mRNA levels but hindered degradation of the NLRP3 protein through CMA pathway. Conclusions: CMA function becomes impaired during the progression of atherosclerosis, which increases NLRP3 inflammasome activation and secretion of IL-1β, promoting vascular inflammation and atherosclerosis progression. Our study unveils a new mechanism by which NLRP3 inflammasome is regulated in macrophages and atherosclerosis, thus providing a new insight into the role of autophagy-lysosomal pathway in atherosclerosis. Pharmacological activation of CMA may provide a novel therapeutic strategy for atherosclerosis and other NLRP3 inflammasome/IL-1β-driven diseases.收起

文献类型

期刊

浏览量

5