title: The intersection of cell death and inflammasome activation.
abstract: Inflammasomes sense cellular danger to activate the cysteine-aspartic protease caspase-1, which processes precursor interleukin-1β (IL-1β) and IL-18 into their mature bioactive fragments. In addition, activated caspase-1 or the related inflammatory caspase, caspase-11, can cleave gasdermin D to induce a lytic cell death, termed pyroptosis. The intertwining of IL-1β activation and cell death is further highlighted by research showing that the extrinsic apoptotic caspase, caspase-8, may, like caspase-1, directly process IL-1β, activate the NLRP3 inflammasome itself, or bind to inflammasome complexes to induce apoptotic cell death. Similarly, RIPK3- and MLKL-dependent necroptotic signaling can activate the NLRP3 inflammasome to drive IL-1β inflammatory responses in vivo. Here, we review the mechanisms by which cell death signaling activates inflammasomes to initiate IL-1β-driven inflammation, and highlight the clinical relevance of these findings to heritable autoinflammatory diseases. We also discuss whether the act of cell death can be separated from IL-1β secretion and evaluate studies suggesting that several cell death regulatory proteins can directly interact with, and modulate the function of, inflammasome and IL-1β containing protein complexes.
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia. vince@wehi.edu.au.|Department of Medical Biology, The University of Melbourne, Parkville, VIC, 3050, Australia. vince@wehi.edu.au.
authors.forename: James E
authors.initials: JE
authors.lastname: Vince
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.|Department of Medical Biology, The University of Melbourne, Parkville, VIC, 3050, Australia.
authors.forename: John
authors.initials: J
authors.lastname: Silke
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D020170:Caspase 1 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D007249:Inflammation / Q000473:pathology; D020382:Interleukin-18 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D051379:Mice; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism; D000069292:Pyroptosis / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D058847:Inflammasomes; D020382:Interleukin-18; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D017382:Reactive Oxygen Species; C570693:MLKL protein, human; D011494:Protein Kinases; C119705:RIPK3 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D053181:Caspase 8; D020170:Caspase 1
keywords: Apoptosis; Caspase-1; Caspase-8; Inflammasome; MLKL; Necroptosis; Pyroptosis; RIPK3