FADD and Caspase-8 Mediate Priming and Activation of the Canonical and Noncanonical Nlrp3 Inflammasomes

The Nlrp3 inflammasome is critical for host immunity, but the mechanisms controlling its activation are enigmatic. In this study, we show that loss of FADD or caspase-8 in a RIP3-deficient background, but not RIP3 deficiency alone, hampered transcriptional priming and posttranslational activation of the canonical and noncanonical Nlrp3 inflammasome. Deletion of caspase-8 in the presence or absence of RIP3 inhibited caspase-1 and caspase-11 activation by Nlrp3 stimuli but not the Nlrc4 inflammasome. In addition, FADD deletion prevented caspase-8 maturation, positioning FADD upstream of caspase-8. Consequently, FADD- and caspase-8-deficient mice had impaired IL-1β production when challenged with LPS or infected…

• YU
  Yale University
• SJ
  St. Jude Children's Research Hospital
• AL
  American Lebanese Syrian Associated Charities

  Awards: CA163507, AR056296, AI101935
• VR
  Vlaamse regering
• NI
  National Institutes of Health

  Awards: AR056296, CA163507, AI101935
• G
  Genentech
• UO
  University of California, San Diego
• TO
  Takeda Oncology