Mitochondrial apoptosis is dispensable for NLRP3 activation but non-apoptotic caspase-8 is required for inflammasome priming — ASN Events

Mitochondrial apoptosis is dispensable for NLRP3 activation but non-apoptotic caspase-8 is required for inflammasome priming (#301)

Ramanjaneyulu Allam , Kate Lawlor 1 2 , Chi Wang Yu 3 , Donia M Moujalled 1 2 , Rowena S Lewis 1 2 , Francine Ke 1 2 , Alison Mildenhall 1 2 , Kylie D Mason 1 2 , Lorraine A O’Reilly 1 2 , Michael J White 1 2 , Andreas Strasser 1 2 , David L Vaux 1 2 , John Silke 1 2 , Warren Alexander 1 2 , Benjamin T Kile 1 2 , James E Vince 1 2
  1. Walter and Eliza Hall Institute, Parkville, VIC, Australia
  2. Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia
  3. Department of Biochemistry, University of Lausanne, Epalinges, Switzerland

The NOD-like receptor protein 3 (NLRP3) inflammasome senses a variety of pathogen, host and environmental molecular patterns to mediate caspase-1 activation, thereby promoting caspase-1 processing and secretion of the pro-inflammatory cytokines IL-1b and IL-18. The current paradigm states that mitochondrial damage is a critical determinant of NLRP3 inflammasome activation. Here, we genetically assess whether mitochondrial signalling represents a unified mechanism to explain how NLRP3 is activated by divergent stimuli. Neither co-deletion of the essential executioners of mitochondrial apoptosis BAK and BAX, nor removal of the mitochondrial permeability transition pore component cyclophilin D, nor loss of the mitophagy regulator Parkin, nor deficiency in MAVS affects NLRP3 inflammasome function. In contrast, caspase-8, a caspase essential for death-receptor-mediated apoptosis, is required for efficient Toll-like-receptor-induced inflammasome priming and cytokine production. Collectively, these results demonstrate that mitochondrial apoptosis is not required for NLRP3 activation, and highlight an important non-apoptotic role for caspase-8 in regulating inflammasome activation and pro-inflammatory cytokine levels.