Caspase-11 activates a canonical NLRP3 inflammasome by promoting K(+) efflux

Eur J Immunol. 2015 Oct;45(10):2927-36. doi: 10.1002/eji.201545772. Epub 2015 Aug 6.


Recognition of microbe-associated molecular patterns or endogenous danger signals by a subset of cytosolic PRRs results in the assembly of multiprotein signaling complexes, the so-called inflammasomes. Canonical inflammasomes are assembled by NOD-like receptor (NLR) or PYHIN family members and activate caspase-1, which promotes the induction of pyroptosis and the release of mature interleukin-1β/-18. Recently, a noncanonical inflammasome pathway was discovered that results in caspase-11 activation in response to bacterial lipopolysaccharide (LPS) in the cytosol. Interestingly, caspase-11 induces pyroptosis by itself, but requires NLRP3, the inflammasome adapter ASC, and caspase-1 to promote cytokine secretion. Here, we have studied the mechanism by which caspase-11 controls IL-1β secretion. Investigating NLRP3/ASC complex formation, we find that caspase-11 functions upstream of a canonical NLRP3 inflammasome. The activation of NLRP3 by caspase-11 during LPS transfection is a cell-intrinsic process and is independent of the release of danger signals. Furthermore, we show that active caspase-11 leads to a drop of intracellular potassium levels, which is necessary to activate NLRP3. Our study, therefore, sheds new light on the mechanism of noncanonical inflammasome signaling.

Keywords: Caspase-11; Inflammasome; Interleukin-1 beta (IL-1β); Lipopolysaccharide; NLRP3; Potassium efflux; Pyroptosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / immunology
  • CARD Signaling Adaptor Proteins
  • Carrier Proteins / genetics
  • Carrier Proteins / immunology*
  • Caspases / genetics
  • Caspases / immunology*
  • Caspases, Initiator
  • Enzyme Activation / drug effects
  • Enzyme Activation / genetics
  • Enzyme Activation / immunology
  • Inflammasomes / genetics
  • Inflammasomes / immunology*
  • Interleukin-1beta / genetics
  • Interleukin-1beta / immunology
  • Ion Transport / drug effects
  • Ion Transport / genetics
  • Ion Transport / immunology
  • Lipopolysaccharides / pharmacology
  • Mice
  • Mice, Knockout
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Potassium / immunology*


  • Apoptosis Regulatory Proteins
  • CARD Signaling Adaptor Proteins
  • Carrier Proteins
  • IL1B protein, mouse
  • Inflammasomes
  • Interleukin-1beta
  • Lipopolysaccharides
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • Pycard protein, mouse
  • Casp4 protein, mouse
  • Caspases
  • Caspases, Initiator
  • Potassium