The Mitochondrial Apoptotic Effectors BAX/BAK Activate Caspase-3 and -7 to Trigger NLRP3 Inflammasome and Caspase-8 Driven IL-1β Activation Academic Article uri icon

abstract

  • Intrinsic apoptosis resulting from BAX/BAK-mediated mitochondrial membrane damage is regarded as immunologically silent. We show here that in macrophages, BAX/BAK activation results in inhibitor of apoptosis (IAP) protein degradation to promote caspase-8-mediated activation of IL-1β. Furthermore, BAX/BAK signaling induces a parallel pathway to NLRP3 inflammasome-mediated caspase-1-dependent IL-1β maturation that requires potassium efflux. Remarkably, following BAX/BAK activation, the apoptotic executioner caspases, caspase-3 and -7, act upstream of both caspase-8 and NLRP3-induced IL-1β maturation and secretion. Conversely, the pyroptotic cell death effectors gasdermin D and gasdermin E are not essential for BAX/BAK-induced IL-1β release. These findings highlight that innate immune cells undergoing BAX/BAK-mediated apoptosis have the capacity to generate pro-inflammatory signals and provide an explanation as to why IL-1β activation is often associated with cellular stress, such as during chemotherapy.

authors

  • Vince, James E
  • De Nardo, D
  • Gao, W
  • Vince, AJ
  • Hall, C
  • McArthur, K
  • Simpson, D
  • Vijayaraj, S
  • Lindqvist, LM
  • Bouillet, P
  • Rizzacasa, MA
  • Man, SM
  • Silke, John H
  • Masters, SL
  • Lessene, G
  • Huang, DCS
  • Gray, DHD
  • Kile, BT
  • Shao, F
  • Lawlor, KE

publication date

  • 2018