UCP2-induced fatty acid synthase promotes NLRP3 inflammasome activation during sepsis. Academic Article uri icon

Overview

MeSH

  • Animals
  • Caspase 1
  • Down-Regulation
  • Enzyme Induction
  • Humans
  • Interleukin-18
  • Interleukin-1beta
  • Lipids
  • Mice
  • Mice, Knockout
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Uncoupling Protein 2

MeSH Major

  • Carrier Proteins
  • Fatty Acid Synthase, Type I
  • Inflammasomes
  • Ion Channels
  • Macrophages
  • Mitochondrial Proteins
  • Sepsis

abstract

  • Cellular lipid metabolism has been linked to immune responses; however, the precise mechanisms by which de novo fatty acid synthesis can regulate inflammatory responses remain unclear. The NLRP3 inflammasome serves as a platform for caspase-1-dependent maturation and secretion of proinflammatory cytokines. Here, we demonstrated that the mitochondrial uncoupling protein-2 (UCP2) regulates NLRP3-mediated caspase-1 activation through the stimulation of lipid synthesis in macrophages. UCP2-deficient mice displayed improved survival in a mouse model of polymicrobial sepsis. Moreover, UCP2 expression was increased in human sepsis. Consistently, UCP2-deficient mice displayed impaired lipid synthesis and decreased production of IL-1β and IL-18 in response to LPS challenge. In macrophages, UCP2 deficiency suppressed NLRP3-mediated caspase-1 activation and NLRP3 expression associated with inhibition of lipid synthesis. In UCP2-deficient macrophages, inhibition of lipid synthesis resulted from the downregulation of fatty acid synthase (FASN), a key regulator of fatty acid synthesis. FASN inhibition by shRNA and treatment with the chemical inhibitors C75 and cerulenin suppressed NLRP3-mediated caspase-1 activation and inhibited NLRP3 and pro-IL-1β gene expression in macrophages. In conclusion, our results suggest that UCP2 regulates the NLRP3 inflammasome by inducing the lipid synthesis pathway in macrophages. These results identify UCP2 as a potential therapeutic target in inflammatory diseases such as sepsis.

publication date

  • February 2015

has subject area

  • Animals
  • Carrier Proteins
  • Caspase 1
  • Down-Regulation
  • Enzyme Induction
  • Fatty Acid Synthase, Type I
  • Humans
  • Inflammasomes
  • Interleukin-18
  • Interleukin-1beta
  • Ion Channels
  • Lipids
  • Macrophages
  • Mice
  • Mice, Knockout
  • Mitochondrial Proteins
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Sepsis
  • Uncoupling Protein 2

Research

keywords

  • Journal Article

Identity

Language

  • eng

PubMed Central ID

  • PMC4319445

Digital Object Identifier (DOI)

  • 10.1172/JCI78253

PubMed ID

  • 25574840

Additional Document Info

start page

  • 665

end page

  • 680

volume

  • 125

number

  • 2