MLKL and FADD Are Critical for Suppressing Progressive Lymphoproliferative Disease and Activating the NLRP3 Inflammasome

Cell Rep. 2016 Sep 20;16(12):3247-3259. doi: 10.1016/j.celrep.2016.06.103. Epub 2016 Aug 4.


MLKL, a key component downstream of RIPK3, is suggested to be a terminal executor of necroptosis. Genetic studies have revealed that Ripk3 ablation rescues embryonic lethality in Fadd- or Caspase-8-deficient mice. Given that RIPK3 has also been implicated in non-necroptotic pathways including apoptosis and inflammatory signaling, it remains unclear whether the lethality in Fadd(-/-) mice is indeed caused by necropotosis. Here, we show that genetic deletion of Mlkl rescues the developmental defect in Fadd-deficient mice and that Fadd(-/-)Mlkl(-/-) mice are viable and fertile. Mlkl(-/-)Fadd(-/-) mice display significantly accelerated lymphoproliferative disease characterized by lymphadenopathy and splenomegaly when compared to Ripk3(-/-)Fadd(-/-) mice. Mlkl(-/-)Fadd(-/-) bone-marrow-derived macrophages and dendritic cells have impaired NLRP3 inflammasome activation associated with defects in ASC speck formation and NF-κB-dependent NLRP3 transcription. Our findings reveal that MLKL and FADD play critical roles in preventing lymphoproliferative disease and activating the NLRP3 inflammasome.

MeSH terms

  • Animals
  • Fas-Associated Death Domain Protein / genetics
  • Fas-Associated Death Domain Protein / immunology*
  • Inflammasomes / immunology*
  • Lymphoproliferative Disorders / genetics*
  • Lymphoproliferative Disorders / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NLR Family, Pyrin Domain-Containing 3 Protein / immunology*
  • Protein Kinases / genetics
  • Protein Kinases / immunology*


  • Fadd protein, mouse
  • Fas-Associated Death Domain Protein
  • Inflammasomes
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • MLKL protein, mouse
  • Protein Kinases