Deficient Chaperone-Mediated Autophagy Promotes Inflammation and Atherosclerosis. Issue 12 (3rd December 2021)

• Record Type: Journal Article
• Authors: Qiao, Lei; Ma, Jing; Zhang, Zihao; Sui, Wenhai; Zhai, Chungang; Xu, Dan; Wang, Zunzhe; Lu, Huixia; Zhang, Meng; Zhang, Cheng; Chen, Wenqiang; Zhang, Yun
• Is Part Of: Circulation research. Volume 129:Issue 12(2021)
• Publication Date: 2021-12-03
• Subjects: atherosclerosis -- chaperone-mediated autophagy -- inflammasome -- lysosomes -- macrophages; Cardiovascular system -- Periodicals; Blood -- Circulation -- Periodicals; Blood Circulation; Cardiovascular System; Vascular Diseases; Sang -- Circulation -- Périodiques; Appareil cardiovasculaire -- Périodiques; 612.1
• DOI: 10.1161/CIRCRESAHA.121.318908
• Languages: English
• ISSNs: 0009-7330

Abstract

Abstract : Rationale: The NLRP3 (NLR [NOD-like receptor] family, pyrin domain containing 3) inflammasome is an important driver of atherosclerosis. Our previous study shows that chaperone-mediated autophagy (CMA), 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 (lysosome-associated membrane protein type 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 (interleukin)-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. Abstract : Supplemental Digital Content is available in the text.