ER stress activates the NLRP3 inflammasome via an UPR-independent pathway

Cell Death Dis. 2012 Jan 26;3(1):e261. doi: 10.1038/cddis.2011.132.


Uncontrolled endoplasmic reticulum (ER) stress responses are proposed to contribute to the pathology of chronic inflammatory diseases such as type 2 diabetes or atherosclerosis. However, the connection between ER stress and inflammation remains largely unexplored. Here, we show that ER stress causes activation of the NLRP3 inflammasome, with subsequent release of the pro-inflammatory cytokine interleukin-1β. This ER-triggered proinflammatory signal shares the same requirement for reactive oxygen species production and potassium efflux compared with other known NLRP3 inflammasome activators, but is independent of the classical unfolded protein response (UPR). We thus propose that the NLRP3 inflammasome senses and responds to ER stress downstream of a previously uncharacterized ER stress response signaling pathway distinct from the UPR, thus providing mechanistic insight to the link between ER stress and chronic inflammatory diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Differentiation / drug effects
  • Cell Line
  • Endoplasmic Reticulum Stress*
  • Gene Expression / drug effects
  • Humans
  • Inflammasomes / immunology
  • Inflammasomes / metabolism*
  • Inflammation / immunology
  • Inflammation / metabolism*
  • Interleukin-1beta / biosynthesis
  • Interleukin-1beta / immunology
  • Lentivirus
  • Mice
  • Mice, Knockout
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Potassium / metabolism
  • RNA, Small Interfering / genetics
  • Reactive Oxygen Species / metabolism
  • Signal Transduction / drug effects*
  • Tetradecanoylphorbol Acetate / pharmacology
  • Tunicamycin / pharmacology
  • Unfolded Protein Response


  • Carrier Proteins
  • Inflammasomes
  • Interleukin-1beta
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • RNA, Small Interfering
  • Reactive Oxygen Species
  • Tunicamycin
  • Tetradecanoylphorbol Acetate
  • Potassium