An Acetylation Switch of the NLRP3 Inflammasome Regulates Aging-Associated Chronic Inflammation and Insulin Resistance
An Acetylation Switch of the NLRP3 Inflammasome Regulates Aging-Associated Chronic Inflammation and Insulin Resistance
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DOI：
10.1016/j.cmet.2020.01.009
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发表时间：
2020-03-03
期刊：
影响因子：
29
通讯作者：
Chen, Danica
中科院分区：
文献类型：
--
作者：
He, Ming;Chiang, Hou-Hsien;Chen, Danica
有充分的证据表明，衰老的速度可以减缓，但目前仍不清楚与衰老相关的疾病可以逆转到何种程度。免疫和代谢的界面如何影响糖尿病流行在很大程度上是未知的。在这里，我们表明，NLRP 3，一种模式识别受体，在巨噬细胞中被乙酰化修饰，并被SIRT 2，一种NAD（+）依赖性脱乙酰酶和代谢传感器脱乙酰化。我们已经开发了一种基于细胞的系统，该系统模拟了衰老相关的炎症，一种确定的共培养系统，该系统模拟了炎症环境对衰老期间代谢组织中胰岛素抵抗的影响，以及衰老小鼠模型;并证明SIRT 2和NLRP 3脱乙酰化预防并可靶向逆转衰老相关的炎症和胰岛素抵抗。这些结果确立了NLRP 3炎性体的乙酰化开关的失调作为衰老相关慢性炎症的起源，并突出了衰老相关慢性炎症和胰岛素抵抗的可逆性。
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.