Dataset Information

K63 ubiquitin chains target NLRP3 inflammasome for autophagic degradation in ox-LDL-stimulated THP-1 macrophages.

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.

SUBMITTER: Zhou Z

PROVIDER: S-EPMC7053591 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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K63 ubiquitin chains target NLRP3 inflammasome for autophagic degradation in ox-LDL-stimulated THP-1 macrophages.

Zhou Zhenfeng Z Zhu Xiaoyan X Yin Ruihua R Liu Tianwei T Yang Shaonan S Zhou Lingyan L Pan Xudong X Ma Aijun A

Aging 20200129 2

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 ...[more]

PMID: 32003754

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Project description:Inflammasome, activated by pathogen-derived and host-derived danger signals, constitutes a multimolecular signaling complex that serves as a platform for caspase-1 (CASP1) activation and interleukin-1beta (IL1B) maturation. The activation of NLRP3 inflammasome requires two-step signals. The first “priming” signal (Signal 1) enhances gene expression of inflammasome components. The second “activation” signal (Signal 2) promotes the assembly of inflammasome components. Deregulated activation of NLRP3 inflammasome contributes to the pathological processes of Alzheimer’s disease (AD) and multiple sclerosis (MS). However, at present, the precise mechanism regulating NLRP3 inflammasome activation and deactivation remains largely unknown. By genome-wide gene expression profiling, we studied the molecular network of NLRP3 inflammasome activation-responsive genes in a human monocyte cell line THP-1 sequentially given two-step signals. We identified the set of 83 NLRP3 inflammasome activation-responsive genes. Among them, we found the NR4A nuclear receptor family NR4A1, NR4A2, and NR4A3, the EGR family EGR1, EGR2, and EGR3, the IkappaB family NFKBIZ, NFKBID, and NFKBIA as a key group of the genes that possibly constitute a negative feedback loop for shutting down inflammation following NLRP3 inflammasome activation. By molecular network analysis, we identified a complex network of NLRP3 inflammasome activation-responsive genes involved in cellular development and death, and immune and inflammatory responses, where transcription factors AP-1, NR4A, and EGR serve as a hub. Thus, NLRP3 inflammasome activation-responsive genes constitute the molecular network composed of a set of negative feedback regulators for prompt resolution of inflammation. To load the Signal 1 (S1), THP-1 cells were incubated for 3 hours in the culture medium with or without inclusion of 0.2 microgram/ml lipopolysaccharide (LPS). To load the Signal 2 (S2), they were incubated further for 2 hours in the culture medium with inclusion of 10 microM nigericin sodium salt dissolved in ethanol or the equal v/v% concentration of ethanol (vehicle), followed by processing for microarray analysis on Human Gene 1.0 ST Array (Affymetrix).

Dataset Information

K63 ubiquitin chains target NLRP3 inflammasome for autophagic degradation in ox-LDL-stimulated THP-1 macrophages.

Publications

K63 ubiquitin chains target NLRP3 inflammasome for autophagic degradation in ox-LDL-stimulated THP-1 macrophages.

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