Mitochondrial cardiolipin is required for Nlrp3 inflammasome activation

Immunity. 2013 Aug 22;39(2):311-323. doi: 10.1016/j.immuni.2013.08.001. Epub 2013 Aug 15.

Abstract

Nlrp3 inflammasome activation occurs in response to numerous agonists but the specific mechanism by which this takes place remains unclear. All previously evaluated activators of the Nlrp3 inflammasome induce the generation of mitochondrial reactive oxygen species (ROS), suggesting a model in which ROS is a required upstream mediator of Nlrp3 inflammasome activation. Here we have identified the oxazolidinone antibiotic linezolid as a Nlrp3 agonist that activates the Nlrp3 inflammasome independently of ROS. The pathways for ROS-dependent and ROS-independent Nlrp3 activation converged upon mitochondrial dysfunction and specifically the mitochondrial lipid cardiolipin. Cardiolipin bound to Nlrp3 directly and interference with cardiolipin synthesis specifically inhibited Nlrp3 inflammasome activation. Together these data suggest that mitochondria play a critical role in the activation of the Nlrp3 inflammasome through the direct binding of Nlrp3 to cardiolipin.

Publication types

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

MeSH terms

  • Acetamides / metabolism
  • Acetamides / pharmacology
  • Animals
  • Cardiolipins / immunology
  • Cardiolipins / metabolism*
  • Carrier Proteins / metabolism*
  • Cell Line
  • Cyclosporine / metabolism
  • Enzyme Activation
  • Humans
  • Inflammasomes / metabolism*
  • Inflammation / chemically induced
  • Interleukin-1beta / metabolism
  • Interleukin-6 / metabolism
  • Linezolid
  • Macrophages / immunology
  • Macrophages / metabolism
  • Mice
  • Mitochondria / immunology
  • Mitochondria / metabolism*
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Oxazolidinones / metabolism
  • Oxazolidinones / pharmacology
  • Potassium / metabolism
  • Reactive Oxygen Species / metabolism
  • Signal Transduction / immunology
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Acetamides
  • Cardiolipins
  • Carrier Proteins
  • Inflammasomes
  • Interleukin-1beta
  • Interleukin-6
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLRP3 protein, human
  • Oxazolidinones
  • Reactive Oxygen Species
  • Tumor Necrosis Factor-alpha
  • Cyclosporine
  • Linezolid
  • Potassium