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An Acetylation Switch of the NLRP3 Inflammasome Regulates Aging-Associated Chronic Inflammation and Insulin Resistance.

ABSTRACT: It is well documented that the rate of aging can be slowed, but it remains unclear to which extent aging-associated conditions can be reversed. How the interface of immunity and metabolism impinges upon the diabetes pandemic is largely unknown. Here, we show that NLRP3, a pattern recognition receptor, is modified by acetylation in macrophages and is deacetylated by SIRT2, an NAD⁺-dependent deacetylase and a metabolic sensor. We have developed a cell-based system that models aging-associated inflammation, a defined co-culture system that simulates the effects of inflammatory milieu on insulin resistance in metabolic tissues during aging, and aging mouse models; and demonstrate that SIRT2 and NLRP3 deacetylation prevent, and can be targeted to reverse, aging-associated inflammation and insulin resistance. These results establish the dysregulation of the acetylation switch of the NLRP3 inflammasome as an origin of aging-associated chronic inflammation and highlight the reversibility of aging-associated chronic inflammation and insulin resistance.

SUBMITTER: He M

PROVIDER: S-EPMC7104778 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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An Acetylation Switch of the NLRP3 Inflammasome Regulates Aging-Associated Chronic Inflammation and Insulin Resistance.

He Ming M Chiang Hou-Hsien HH Luo Hanzhi H Zheng Zhifang Z Qiao Qi Q Wang Li L Tan Mingdian M Ohkubo Rika R Mu Wei-Chieh WC Zhao Shimin S Wu Hao H Chen Danica D

Cell metabolism 20200206 3

It is well documented that the rate of aging can be slowed, but it remains unclear to which extent aging-associated conditions can be reversed. How the interface of immunity and metabolism impinges upon the diabetes pandemic is largely unknown. Here, we show that NLRP3, a pattern recognition receptor, is modified by acetylation in macrophages and is deacetylated by SIRT2, an NAD<sup>+</sup>-dependent deacetylase and a metabolic sensor. We have developed a cell-based system that models aging-asso ...[more]

PMID: 32032542

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Project description:BackgroundInsulin resistance is one of the most common and important pathological features of type 2 diabetes (T2D). Recently, insulin resistance is increasingly considered to be associated with systemic chronic inflammation. Elevated levels of tumor necrosis factor (TNF)-? and interleukin (IL)-1? in blood are predictive indicators of the development of T2D. Mesenchymal stem cell (MSC)-based therapies have been proven to have potential immunomodulation and anti-inflammatory properties through their paracrine effects; however, the mechanism for the anti-inflammatory effect of MSCs in enhancing insulin sensitivity is still uncertain.MethodsIn the present experiment, we used HepG2 cells, a human hepatoma cell line, and a MSC-HepG2 transwell culturing system to investigate the anti-inflammatory mechanism of human umbilical cord-derived MSCs (UC-MSCs) under palmitic acid (PA) and lipopolysaccharide (LPS)-induced insulin resistance in vitro. Insulin resistance was confirmed by glycogen assay kit and glucose assay kit. Inflammatory factor release was detected by ELISA, gene expression was tested by quantitative real-time PCR, and insulin signaling activation was determined by western blotting analysis. The changes of inflammatory factors and insulin signaling protein were also tested in T2D rats injected with UC-MSCs.ResultsTreating HepG2 cells with PA-LPS caused NLRP3 inflammation activation, including overexpression of NLRP3 and caspase-1, and overproduction of IL-1? and IL-18 as well as TNF-? from HepG2 cells. The elevated levels of these inflammatory cytokines impaired insulin receptor action and thereby prevented downstream signaling pathways, exacerbating insulin resistance in HepG2 cells. Importantly, UC-MSCs cocultured with HepG2 could effectively alleviate PA and LPS-induced insulin resistance by blocking the NLRP3 inflammasome activation and inflammatory agents. Furthermore, knockdown of NLRP3 or IL-1? partially improved PA and LPS-induced insulin signaling impairments in the presence of UC-MSCs. Similarly, UC-MSC infusion significantly ameliorated hyperglycemia in T2D rats and decreased inflammatory activity, which resulted in improved insulin sensitivity in insulin target tissues.ConclusionsOur results indicated that UC-MSCs could attenuate insulin resistance and this regulation was correlated with their anti-inflammatory activity. Thus, MSCs might become a novel therapeutic strategy for insulin resistance and T2D in the near future.

Dataset Information

An Acetylation Switch of the NLRP3 Inflammasome Regulates Aging-Associated Chronic Inflammation and Insulin Resistance.

Publications

An Acetylation Switch of the NLRP3 Inflammasome Regulates Aging-Associated Chronic Inflammation and Insulin Resistance.

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