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

Cell Metab. 2020 Mar 3;31(3):580-591.e5. doi: 10.1016/j.cmet.2020.01.009. Epub 2020 Feb 6.

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.

Keywords: NLRP3; SIRT1; SIRT2; SIRT3; SIRT4; SIRT5; SIRT6; SIRT7; caspase 1; inflammasome.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism*
  • Overnutrition / pathology
  • Peptides / chemistry
  • Sirtuin 2 / metabolism

Substances

  • Inflammasomes
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Peptides
  • Sirtuin 2
  • Glucose