Human Monocytes Engage an Alternative Inflammasome Pathway

Immunity. 2016 Apr 19;44(4):833-46. doi: 10.1016/j.immuni.2016.01.012. Epub 2016 Mar 29.


Interleukin-1β (IL-1β) is a cytokine whose bioactivity is controlled by activation of the inflammasome. However, in response to lipopolysaccharide, human monocytes secrete IL-1β independently of classical inflammasome stimuli. Here, we report that this constituted a species-specific response that is not observed in the murine system. Indeed, in human monocytes, lipopolysaccharide triggered an "alternative inflammasome" that relied on NLRP3-ASC-caspase-1 signaling, yet was devoid of any classical inflammasome characteristics including pyroptosome formation, pyroptosis induction, and K(+) efflux dependency. Genetic dissection of the underlying signaling pathway in a monocyte transdifferentiation system revealed that alternative inflammasome activation was propagated by TLR4-TRIF-RIPK1-FADD-CASP8 signaling upstream of NLRP3. Importantly, involvement of this signaling cascade was limited to alternative inflammasome activation and did not extend to classical NLRP3 activation. Because alternative inflammasome activation embraces both sensitivity and promiscuity of TLR4, we propose a pivotal role for this signaling cascade in TLR4-driven, IL-1β-mediated immune responses and immunopathology in humans.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carrier Proteins / immunology*
  • Caspase 1 / immunology
  • Cell Line
  • Cell Transdifferentiation / immunology
  • Humans
  • Inflammasomes / immunology*
  • Interleukin-1beta / immunology*
  • Interleukin-1beta / metabolism
  • Lipopolysaccharides
  • Mice
  • Monocytes / immunology*
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Potassium / metabolism
  • Potassium Channels / immunology
  • Pyroptosis / immunology
  • Signal Transduction / immunology
  • Toll-Like Receptor 4 / immunology*


  • Carrier Proteins
  • IL1B protein, human
  • Inflammasomes
  • Interleukin-1beta
  • Lipopolysaccharides
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLRP3 protein, human
  • Potassium Channels
  • TLR4 protein, human
  • Toll-Like Receptor 4
  • Caspase 1
  • Potassium