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.).
Cardiovascular Disease Research Center of Shandong First Medical University, Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China (C.Z.).
Circ Res. 2021 Dec 3;129(12):1141-1157. doi: 10.1161/CIRCRESAHA.121.318908. Epub 2021 Oct 27.
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.
背景：NLRP3（NLR [NOD 样受体] 家族，包含 pyrin 域 3）炎性小体是动脉粥样硬化的重要驱动因素。我们之前的研究表明，伴侣介导的自噬（CMA）是主要的溶酶体降解途径之一，它在巨噬细胞的脂质代谢中具有调节作用。然而，NLRP3 炎性小体是否受 CMA 调节以及 CMA 在动脉粥样硬化中的作用尚不清楚。 目的：确定 CMA 在 NLRP3 炎性小体调节和动脉粥样硬化中的作用。 方法和结果：首先分析了 ApoE 小鼠主动脉和人冠状动脉粥样硬化斑块中 CMA 标志物 LAMP-2A（溶酶体相关膜蛋白 2A）的表达，发现 LAMP-2A 在小鼠和人类的晚期动脉粥样硬化中均显著下调。为了选择性阻断 CMA，我们在 C57BL/6 小鼠和 ApoE 小鼠中生成了巨噬细胞特异性条件性 LAMP-2A 敲除鼠株。巨噬细胞 LAMP-2A 缺失加速了 ApoE 小鼠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 缺失促进了巨噬细胞和粥样斑块中 NLRP3 炎性小体的激活及其随后成熟的白细胞介素-1β（IL-1β）的释放。此外，功能获得研究证实，在 LAMP-2A 缺陷型巨噬细胞中恢复 LAMP-2A 水平可极大地减弱 NLRP3 炎性小体的激活。重要的是，我们鉴定出 NLRP3 蛋白是 CMA 的底物，并表明 LAMP-2A 缺失不影响 NLRP3 mRNA 水平，但通过 CMA 途径阻碍 NLRP3 蛋白的降解。 结论：在动脉粥样硬化的进展过程中，CMA 功能受损，这增加了 NLRP3 炎性小体的激活和白细胞介素-1β（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 NLRP3 炎性小体在巨噬细胞和动脉粥样硬化中受调节的新机制，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认识。CMA 的药理学激活可能为动脉粥样硬化和其他 NLRP3 炎性小体/IL-1β 驱动的疾病提供新的治疗策略。
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