CLICs-dependent chloride efflux is an essential and proximal upstream event for NLRP3 inflammasome activation

Nat Commun. 2017 Aug 4;8(1):202. doi: 10.1038/s41467-017-00227-x.


The NLRP3 inflammasome can sense different pathogens or danger signals, and has been reported to be involved in the development of many human diseases. Potassium efflux and mitochondrial damage are both reported to mediate NLRP3 inflammasome activation, but the underlying, orchestrating signaling events are still unclear. Here we show that chloride intracellular channels (CLIC) act downstream of the potassium efflux-mitochondrial reactive oxygen species (ROS) axis to promote NLRP3 inflammasome activation. NLRP3 agonists induce potassium efflux, which causes mitochondrial damage and ROS production. Mitochondrial ROS then induces the translocation of CLICs to the plasma membrane for the induction of chloride efflux to promote NEK7-NLRP3 interaction, inflammasome assembly, caspase-1 activation, and IL-1β secretion. Thus, our results identify CLICs-dependent chloride efflux as an essential and proximal upstream event for NLRP3 activation.The NLRP3 inflammasome is key to the regulation of innate immunity against pathogens or stress, but the underlying signaling regulation is still unclear. Here the authors show that chloride intracellular channels (CLIC) interface between mitochondria stress and inflammasome activation to modulate inflammatory responses.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cells, Cultured
  • Chloride Channels / genetics
  • Chloride Channels / metabolism*
  • Chlorides / metabolism*
  • Humans
  • Immunoblotting
  • Inflammasomes / genetics
  • Inflammasomes / metabolism*
  • Ion Transport
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria / metabolism
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism
  • NLR Family, Pyrin Domain-Containing 3 Protein / genetics
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism*
  • Potassium / metabolism
  • Protein Binding
  • RNA Interference
  • Reactive Oxygen Species / metabolism


  • CLIC protein, mouse
  • CLIC5 protein, mouse
  • Chloride Channels
  • Chlorides
  • Clic1 protein, mouse
  • Inflammasomes
  • Mitochondrial Proteins
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • Reactive Oxygen Species
  • Potassium