Deficient Chaperone-Mediated Autophagy Promotes Inflammation and Atherosclerosis

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.

Rutin Inhibits Ox-LDL-Mediated Macrophage Inflammation and Foam Cell Formation by Inducing Autophagy and Modulating PI3K/ATK Signaling

“…In previous studies, autophagy was shown to play a substantial role in the pathogenesis of atherosclerosis [13,14]. To that end, we investigated the possible association between rutin and autophagy-related proteins using western blot analysis and electron microscopy.…”

Autophagy, Pyroptosis, and Ferroptosis: New Regulatory Mechanisms for Atherosclerosis

“…The NLRP3 inflammasome can also be activated by oxidative or apoptosis-induced mtDNA, which is released during autophagy repression ( Sollberger et al, 2015 ). Impaired CMA has also been proven to increase NLRP3 inflammasome activation and secretion of IL-1β, promoting vascular inflammation and atherosclerosis ( Qiao et al, 2021 ). Therefore, autophagy can negatively regulate pyroptosis by restraining the activation of the inflammasome and caspase-1/GSDMD pathway ( Wang X. et al, 2020 ).…”

Chaperone-Mediated Autophagy in Pericytes: A Key Target for the Development of New Treatments against Glioblastoma Progression

“…TAMs seem to produce IL-17 to activate CMA and become tolerant to apoptosis-inducing treatments in cancer [ 81 ]. Hence, normal macrophages seem to need the inhibition of CMA activity to promote inflammatory responses through inflammasome activation ( Figure 3 A) [ 29 ].…”

“…CMA activity is highly regulated by cell context and thereby the stimuli that the cell receives, as these modulate the amount of functional LAMP-2A that is mobilized to the lysosomal membrane [ 21 , 22 ]. CMA is an essential quality control system for specific proteins, contributes to the supply of amino acids during long starvation periods, controls proteome remodeling in response to cell context [ 24 , 25 , 26 , 27 ], and, when dysregulated, affects cellular functions leading to diseases such as cancer [ 20 , 28 , 29 , 30 , 31 ].…”