Caspase-4 mediates non-canonical activation of the NLRP3 inflammasome in human myeloid cells

Eur J Immunol. 2015 Oct;45(10):2911-7. doi: 10.1002/eji.201545523. Epub 2015 Aug 6.


Inflammasome activation culminates in activation of caspase-1, which leads to the maturation and subsequent release of cytokines of the interleukin 1 (IL-1) family and results in a particular form of cell death known as pyroptosis. In addition, in the murine system, a so-called non-canonical inflammasome involving caspase-11 has been described that directly responds to cytosolic LPS. Here, we show that the human monocytic cell line THP1 activates the inflammasome in response to cytosolic LPS in a TLR4-independent fashion. This response is mediated by caspase-4 and accompanied by caspase-1 activation, pyroptosis, and IL-1β maturation. In addition to caspase-4, efficient IL-1β conversion upon intracellular LPS delivery relies on potassium efflux, NLRP3, ASC, and caspase-1, indicating that although caspase-4 activation alone is sufficient to induce pyroptosis, this process depends on the NLRP3 inflammasome activation to drive IL-1β maturation. Altogether, this study provides evidence for the presence of a non-canonical inflammasome in humans and its dependence on caspase-4.

Keywords: Caspase-4; Myeloid cells; NLRP3; Non-canonical inflammasome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carrier Proteins / genetics
  • Carrier Proteins / immunology*
  • Caspase 1 / genetics
  • Caspase 1 / immunology
  • Caspases, Initiator / genetics
  • Caspases, Initiator / immunology*
  • Cell Line, Tumor
  • Enzyme Activation / drug effects
  • Humans
  • Inflammasomes / genetics
  • Inflammasomes / immunology*
  • Interleukin-1beta / genetics
  • Interleukin-1beta / immunology
  • Lipopolysaccharides / pharmacology
  • Myeloid Cells / cytology
  • Myeloid Cells / immunology*
  • NLR Family, Pyrin Domain-Containing 3 Protein


  • Carrier Proteins
  • IL1B protein, human
  • Inflammasomes
  • Interleukin-1beta
  • Lipopolysaccharides
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLRP3 protein, human
  • CASP4 protein, human
  • Caspases, Initiator
  • Caspase 1