Potassium efflux fires the canon: Potassium efflux as a common trigger for canonical and noncanonical NLRP3 pathways

Eur J Immunol. 2015 Oct;45(10):2758-61. doi: 10.1002/eji.201545958. Epub 2015 Sep 21.


Murine caspase-11 and its human orthologues, caspase-4 and caspase-5, activate an inflammatory response following cytoplasmic recognition of cell wall constituents from Gram-negative bacteria, such as LPS. This inflammatory response involves pyroptotic cell death and the concomitant release of IL-1α, as well as the production of IL-1β and IL-18 through the noncanonical NLR family, pyrin domain containing 3 (NLRP3) pathway. This commentary discusses three papers in this issue of the European Journal of Immunology that advance our understanding of the roles of caspase-11, -4, and -5 in the noncanonical pathway. By utilizing the new gene editing technique, clustered regularly interspaced short palindromic repeats (CRISPR), as well as sensitive cell imaging techniques, these papers establish that cytoplasmic LPS-dependent IL-1β production requires the NLRP3 inflammasome and that its activation is dependent on K(+) efflux, whereas IL-1α release and pyroptotic cell death pathways are NLRP3-independent. These findings expand on previous research implicating K(+) efflux as the principal trigger for NLRP3 activation and suggest that canonical and noncanonical NLRP3 pathways are not as dissimilar as first thought.

Keywords: Caspase-11; Caspase-4; Caspase-5; LPS; NLRP3 inflammasome; Noncanonical; Pyroptosis.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Carrier Proteins / immunology*
  • Caspases / immunology
  • Caspases, Initiator
  • Humans
  • Inflammasomes / immunology*
  • Interleukin-18 / immunology
  • Interleukin-1beta / immunology
  • Ion Transport / immunology
  • Mice
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Potassium / metabolism*
  • Signal Transduction / immunology*


  • Carrier Proteins
  • IL1B protein, mouse
  • Inflammasomes
  • Interleukin-18
  • Interleukin-1beta
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • Casp4 protein, mouse
  • Caspases
  • Caspases, Initiator
  • Potassium