Oxysterol Restraint of Cholesterol Synthesis Prevents AIM2 Inflammasome Activation

Eric V. Dang, Jeffrey G. McDonald, David W. Russell, Jason G. Cyster

Research output: Contribution to journalArticle

43 Citations (Scopus)

Abstract

Type I interferon restrains interleukin-1β (IL-1β)-driven inflammation in macrophages by upregulating cholesterol-25-hydroxylase (Ch25h) and repressing SREBP transcription factors. However, the molecular links between lipid metabolism and IL-1β production remain obscure. Here, we demonstrate that production of 25-hydroxycholesterol (25-HC) by macrophages is required to prevent inflammasome activation by the DNA sensor protein absent in melanoma 2 (AIM2). We find that in response to bacterial infection or lipopolysaccharide (LPS) stimulation, macrophages upregulate Ch25h to maintain repression of SREBP2 activation and cholesterol synthesis. Increasing macrophage cholesterol content is sufficient to trigger IL-1β release in a crystal-independent but AIM2-dependent manner. Ch25h deficiency results in cholesterol-dependent reduced mitochondrial respiratory capacity and release of mitochondrial DNA into the cytosol. AIM2 deficiency rescues the increased inflammasome activity observed in Ch25h -/-. Therefore, activated macrophages utilize 25-HC in an anti-inflammatory circuit that maintains mitochondrial integrity and prevents spurious AIM2 inflammasome activation. Cholesterol overload directly triggers mitochondrial DNA release and activation of the AIM2 inflammasome in activated macrophages.

Original languageEnglish (US)
JournalCell
DOIs
StateAccepted/In press - 2017

Fingerprint

Inflammasomes
Macrophages
Melanoma
Chemical activation
Cholesterol
Interleukin-1
Mitochondrial DNA
Interferon Type I
Lipid Metabolism
Bacterial Infections
Cytosol
Lipopolysaccharides
Oxysterols
Anti-Inflammatory Agents
Transcription Factors
Up-Regulation
Inflammation
Crystals
cholesterol 25-hydroxylase
Networks (circuits)

Keywords

  • 25-hydroxycholesterol
  • AIM2
  • Ch25h
  • Cholesterol
  • IL-1β
  • Inflammasome
  • Macrophage
  • Mitochondria
  • Oxysterol
  • SREBP

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Oxysterol Restraint of Cholesterol Synthesis Prevents AIM2 Inflammasome Activation. / Dang, Eric V.; McDonald, Jeffrey G.; Russell, David W.; Cyster, Jason G.

In: Cell, 2017.

Research output: Contribution to journalArticle

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AU - Cyster, Jason G.

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