Oxysterol Restraint of Cholesterol Synthesis Prevents AIM2 Inflammasome Activation

Cell. 2017 Nov 16;171(5):1057-1071.e11. doi: 10.1016/j.cell.2017.09.029. Epub 2017 Oct 12.


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.

Keywords: 25-hydroxycholesterol; AIM2; Ch25h; IL-1β; SREBP; cholesterol; inflammasome; macrophage; mitochondria; oxysterol.

MeSH terms

  • Animals
  • Cholesterol / biosynthesis
  • Cholesterol / metabolism*
  • DNA, Mitochondrial / metabolism
  • DNA-Binding Proteins / metabolism
  • Humans
  • Hydroxycholesterols / metabolism
  • Inflammasomes / immunology
  • Inflammasomes / metabolism*
  • Inflammation / immunology
  • Inflammation / pathology
  • Interleukin-1beta / immunology
  • Interleukin-1beta / metabolism
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Listeria monocytogenes / physiology
  • Listeriosis / immunology
  • Macrophages / cytology
  • Macrophages / immunology
  • Macrophages / metabolism*
  • Membrane Proteins / metabolism
  • Mice
  • Mitochondria / metabolism
  • Oxysterols / metabolism


  • AIM2 protein, human
  • DNA, Mitochondrial
  • DNA-Binding Proteins
  • Hydroxycholesterols
  • Inflammasomes
  • Interleukin-1beta
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Oxysterols
  • SREBP cleavage-activating protein
  • 25-hydroxycholesterol
  • Cholesterol