Abstract
Inflammation, especially involving the NLRP3 inflammasome, is critical to atherosclerotic plaque formation. Enhanced autophagy can inhibit the development of atherosclerosis, and recent studies have revealed that NLRP3 inflammasome can be degraded by autophagy in atherosclerosis. In the present study, we established a foam-cell model to investigate the impact of oxidized low density lipoproteins (ox-LDLs) on autophagy and the inflammasome in atherosclerosis-related inflammation. We observed that ox-LDLs activated NLRP3 inflammasomes in macrophages and restricted autophagy in a time-and dose-dependent manner. We further observed through immunoprecipitation and siRNA knockdown that autophagic degradation of the NLRP3 inflammasome is dependent on K63 polyubiquitation of its NLRP3 subunit and subsequent binding by the adaptor protein p62. Our findings uncover a mechanism by which autophagy inhibits inflammation in atherosclerosis and the role of K63 in that process.
Highlights
Ischemic stroke is a debilitating and potentially lethal disease, and the leading cause of death in modern society
nucleotide-binding domain and leucine-rich repeatprotein-3 (NLRP3), a caspase recruitment domain (ASC), pro-caspase-1, pro-IL-1β, and activated caspase-1 (p20) in cell lysates was measured by western blot, while the expression of IL-1β in the supernatants was determined by Enzyme-linked immunosorbent assay (ELISA)
Www.aging-us.com www.aging-us.com regulation of NLRP3 inflammasomes is mediated by the autophagy adaptor protein p62 and that this process was achieved through the recognition of p62 to the K63 ubiquitin chains on the NLRP3 protein
Summary
Ischemic stroke is a debilitating and potentially lethal disease, and the leading cause of death in modern society. The main pathogenesis of ischemic stroke is considered to be atherosclerosis [1], a proven chronic inflammatory disease [2]. Exploring the inflammatory mechanism of atherosclerosis and manipulating the function of NLRP3 inflammasomes have emerged as new approaches to understanding and treating the disease. The NLRP3 inflammasome consists of three units: a sensor, nucleotide-binding domain and leucine-rich repeatprotein-3 (NLRP3); an adaptor, apoptosisassociated speck-like protein containing a caspase recruitment domain (ASC); and an effector, protease caspase-1 [9]. When ligands bind to the leucine-rich repeat domain of NLRP3, NLRP3, ASC, and pro-caspase oligomerize to form inflammasomes and convert dormant pro-caspase-1 into active capase-1. This, in turn, processes pro-IL-1β into mature IL-1β [10, 11]
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