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

Ming He, Hou-Hsien Chiang, Hanzhi Luo, Zhifang Zheng, Qi Qiao, Li Wang, Mingdian Tan, Rika Ohkubo, Wei-Chieh Mu, Shimin Zhao, Hao Wu, Danica Chen

Research output: Contribution to journalArticlepeer-review

266 Scopus citations

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.

Original languageEnglish
Pages (from-to)580-591.e5
Number of pages17
JournalCell Metabolism
Volume31
Issue number3
DOIs
StatePublished - Mar 3 2020
Externally publishedYes

Keywords

  • Acetylation
  • Aging/pathology
  • Amino Acid Sequence
  • Animals
  • Chronic Disease
  • Disease Models, Animal
  • Glucose/metabolism
  • Homeostasis
  • Inflammasomes/metabolism
  • Inflammation/pathology
  • Insulin Resistance
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Models, Biological
  • NLR Family, Pyrin Domain-Containing 3 Protein/chemistry
  • Overnutrition/pathology
  • Peptides/chemistry
  • Sirtuin 2/metabolism

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