A Two-Cell Model for IL-1β Release Mediated by Death-Receptor Signaling

Cell Rep. 2020 Apr 7;31(1):107466. doi: 10.1016/j.celrep.2020.03.030.


Interleukin-1β (IL-1β) is a key orchestrator of anti-microbial immunity whose secretion is typically dependent on activation of inflammasomes. However, many pathogens have evolved strategies to evade inflammasome activation. Here we describe an alternative, two-cell model for IL-1β release where invariant natural killer T (iNKT) cells use the death receptor pathway to instruct antigen-presenting cells to secrete IL-1β. Following cognate interactions with TLR-primed bone marrow-derived dendritic cells (BMDCs), iNKT cells rapidly translocate intracellular Fas ligand to the surface to engage Fas on BMDCs. Fas ligation activates a caspase-8-dependent signaling cascade in BMDCs that drives IL-1β release largely independent of inflammasomes. The apoptotic program initiated by Fas ligation rapidly transitions into a pyroptosis-like form of cell death mediated by gasdermin D. Together, our findings support a two-cell model for IL-1β secretion that may supersede inflammasome activation when cytosolic triggers fail.

Keywords: Fas; Fas ligand; NKT cell; apoptosis; caspase; cell death; gasdermin; inflammasome; interleukin-1; pyroptosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Caspase 1 / metabolism
  • Caspase 8 / metabolism
  • Dendritic Cells / metabolism
  • Female
  • Humans
  • Inflammasomes / metabolism
  • Interleukin-1beta / metabolism*
  • Interleukin-1beta / physiology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
  • Natural Killer T-Cells / metabolism*
  • Pyroptosis
  • Receptors, Death Domain / metabolism*
  • Signal Transduction


  • IL1B protein, human
  • Inflammasomes
  • Interleukin-1beta
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Receptors, Death Domain
  • CASP8 protein, human
  • Caspase 8
  • Caspase 1