Cutting Edge: Blockade of Inhibitor of Apoptosis Proteins Sensitizes Neutrophils to TNF- but Not Lipopolysaccharide-Mediated Cell Death and IL-1β Secretion

Kaiwen W Chen, Kate E Lawlor, Jessica B von Pein, Dave Boucher, Motti Gerlic, Ben A Croker, Jelena S Bezbradica, James E Vince, Kate Schroder

Research output: Contribution to journalArticlepeer-review


The mammalian inhibitor of apoptosis proteins (IAPs) are key regulators of cell death and inflammation. A major function of IAPs is to block the formation of a cell death-inducing complex, termed the ripoptosome, which can trigger caspase-8-dependent apoptosis or caspase-independent necroptosis. Recent studies report that upon TLR4 or TNF receptor 1 (TNFR1) signaling in macrophages, the ripoptosome can also induce NLRP3 inflammasome formation and IL-1β maturation. Whether neutrophils have the capacity to assemble a ripoptosome to induce cell death and inflammasome activation during TLR4 and TNFR1 signaling is unclear. In this study, we demonstrate that murine neutrophils can signal via TNFR1-driven ripoptosome assembly to induce both cell death and IL-1β maturation. However, unlike macrophages, neutrophils suppress TLR4-dependent cell death and NLRP3 inflammasome activation during IAP inhibition via deficiencies in the CD14/TRIF arm of TLR4 signaling.

Original languageEnglish
Pages (from-to)3341-3346
Number of pages6
JournalJournal of Immunology
Issue number10
Early online date15 May 2018
Publication statusPublished - 15 May 2018

Bibliographical note

Copyright © 2018 by The American Association of Immunologists, Inc.


  • Animals
  • Apoptosis/drug effects
  • Caspases/metabolism
  • Cell Death/drug effects
  • Inflammasomes/metabolism
  • Inflammation/metabolism
  • Inhibitor of Apoptosis Proteins/metabolism
  • Interleukin-1beta/metabolism
  • Lipopolysaccharides/pharmacology
  • Macrophages/drug effects
  • Mice
  • Mice, Inbred C57BL
  • NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
  • Necrosis/metabolism
  • Neutrophils/drug effects
  • Receptors, Tumor Necrosis Factor, Type I/metabolism
  • Signal Transduction/physiology
  • Toll-Like Receptor 4/metabolism
  • Tumor Necrosis Factors/metabolism

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