Deficient Chaperone-Mediated Autophagy Promotes Inflammation and Atherosclerosis.
Deficient Chaperone-Mediated Autophagy Promotes Inflammation and Atherosclerosis.
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伴侣介导的自噬缺陷促进炎症和动脉粥样硬化
DOI：
10.1161/circresaha.121.318908
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发表时间：
2021-12-03
影响因子：
20.1
通讯作者：
Zhang Y
中科院分区：
文献类型：
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作者：
Qiao L;Ma J;Zhang Z;Sui W;Zhai C;Xu D;Wang Z;Lu H;Zhang M;Zhang C;Chen W;Zhang Y
补充数字内容可在文本中找到。基本原理：NLRP 3（NLR [NOD样受体]家族，含pyrin结构域3）炎性小体是动脉粥样硬化的重要驱动因素。我们前期的研究表明，分子伴侣介导的自噬（CMA）是巨噬细胞主要的溶酶体降解过程之一，对巨噬细胞的脂质代谢具有调节作用。然而，NLRP 3炎性小体是否受CMA的调节，以及CMA在动脉粥样硬化中的作用仍不清楚。目的：探讨CMA对NLRP 3炎性小体和动脉粥样硬化的调节作用。方法和结果：CMA标志物LAMP-2A（溶酶体相关膜蛋白2A型）的表达首先在ApoE−/−小鼠动脉粥样硬化和人类冠状动脉粥样硬化斑块中进行了分析，并观察到小鼠和人类晚期动脉粥样硬化中LAMP-2A的显著下调。为了选择性阻断CMA，我们在C57 BL/6小鼠和ApoE−/−小鼠中产生了巨噬细胞特异性条件性LAMP-2A敲除小鼠品系。在ApoE−/−小鼠中，巨噬细胞LAMP-2A的缺失加速了主动脉根部和整个主动脉的动脉粥样硬化病变形成。在机制上，LAMP-2A缺陷促进了NLRP 3炎性小体活化，并随后在巨噬细胞和动脉粥样硬化斑块中释放成熟IL（白细胞介素）-1β。此外，功能获得性研究证实，LAMP-2A缺陷型巨噬细胞中LAMP-2A水平的恢复极大地减弱了NLRP 3炎性小体活化。重要的是，我们鉴定了NLRP 3蛋白作为CMA底物，并证明LAMP-2A缺陷不影响NLRP 3 mRNA水平，但阻碍了NLRP 3蛋白通过CMA途径的降解。结论：在动脉粥样硬化的进展过程中，CMA功能受损，这增加了NLRP 3炎性体的激活和IL-1β的分泌，促进了血管炎症和动脉粥样硬化的进展。我们的研究揭示了NLRP 3炎性体在巨噬细胞和动脉粥样硬化中的调节机制，从而为自噬-溶酶体途径在动脉粥样硬化中的作用提供了新的见解。CMA的药理学激活可能为动脉粥样硬化和其他NLRP 3炎性小体/IL-1β驱动的疾病提供新的治疗策略。
Supplemental Digital Content is available in the text. 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.