Endoplasmic Reticulum Stress Activates the Inflammasome via NLRP3- and Caspase-2-Driven Mitochondrial Damage

Immunity. 2015 Sep 15;43(3):451-62. doi: 10.1016/j.immuni.2015.08.008. Epub 2015 Sep 1.

Abstract

Endoplasmic reticulum (ER) stress is observed in many human diseases, often associated with inflammation. ER stress can trigger inflammation through nucleotide-binding domain and leucine-rich repeat containing (NLRP3) inflammasome, which might stimulate inflammasome formation by association with damaged mitochondria. How ER stress triggers mitochondrial dysfunction and inflammasome activation is ill defined. Here we have used an infection model to show that the IRE1α ER stress sensor regulates regulated mitochondrial dysfunction through an NLRP3-mediated feed-forward loop, independently of ASC. IRE1α activation increased mitochondrial reactive oxygen species, promoting NLRP3 association with mitochondria. NLRP3 was required for ER stress-induced cleavage of caspase-2 and the pro-apoptotic factor, Bid, leading to subsequent release of mitochondrial contents. Caspase-2 and Bid were necessary for activation of the canonical inflammasome by infection-associated or general ER stress. These data identify an NLRP3-caspase-2-dependent mechanism that relays ER stress to the mitochondria to promote inflammation, integrating cellular stress and innate immunity.

Publication types

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

MeSH terms

  • Animals
  • BH3 Interacting Domain Death Agonist Protein / genetics
  • BH3 Interacting Domain Death Agonist Protein / immunology
  • BH3 Interacting Domain Death Agonist Protein / metabolism
  • Blotting, Western
  • Brucella abortus / immunology
  • Brucella abortus / physiology
  • Carrier Proteins / genetics
  • Carrier Proteins / immunology*
  • Carrier Proteins / metabolism
  • Caspase 2 / genetics
  • Caspase 2 / immunology*
  • Caspase 2 / metabolism
  • Cells, Cultured
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / immunology
  • DNA-Binding Proteins / metabolism
  • Endoplasmic Reticulum Stress / genetics
  • Endoplasmic Reticulum Stress / immunology*
  • Endoribonucleases / immunology
  • Endoribonucleases / metabolism
  • HEK293 Cells
  • Host-Pathogen Interactions / immunology
  • Humans
  • Inflammasomes / immunology*
  • Inflammasomes / metabolism
  • Interleukin-1beta / immunology
  • Interleukin-1beta / metabolism
  • Macrophages / immunology
  • Macrophages / metabolism
  • Macrophages / microbiology
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria / genetics
  • Mitochondria / immunology*
  • Mitochondria / metabolism
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Protein-Serine-Threonine Kinases / immunology
  • Protein-Serine-Threonine Kinases / metabolism
  • RNA Interference / immunology
  • Reactive Oxygen Species / immunology
  • Reactive Oxygen Species / metabolism
  • Regulatory Factor X Transcription Factors
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transcription Factors / genetics
  • Transcription Factors / immunology
  • Transcription Factors / metabolism

Substances

  • BH3 Interacting Domain Death Agonist Protein
  • Carrier Proteins
  • DNA-Binding Proteins
  • Inflammasomes
  • Interleukin-1beta
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • Reactive Oxygen Species
  • Regulatory Factor X Transcription Factors
  • TXNIP protein, human
  • Transcription Factors
  • Ern1 protein, mouse
  • Protein-Serine-Threonine Kinases
  • Endoribonucleases
  • Caspase 2