Details

Autor(en) / Beteiligte

• Vince, James E.
• De Nardo, Dominic
• Gao, Wenqing
• Vince, Angelina J.
• Hall, Cathrine
• McArthur, Kate
• Simpson, Daniel
• Vijayaraj, Swarna
• Lindqvist, Lisa M.
• Bouillet, Philippe
• Rizzacasa, Mark A.
• Man, Si Ming
• Silke, John
• Masters, Seth L.
• Lessene, Guillaume
• Huang, David C.S.
• Gray, Daniel H.D.
• Kile, Benjamin T.
• Shao, Feng
• Lawlor, Kate E.

Titel

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

Ist Teil von

• Cell reports (Cambridge), 2018-11, Vol.25 (9), p.2339-2353.e4

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2018

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. [Display omitted] •MCL-1 and BCL-XL prevent BAX/BAK-induced IL-1β activation and death in macrophages•BAX/BAK-induced IL-1β requires the downstream effector caspases, caspase-3 and -7•Caspase-3/-7 cause potassium efflux to activate the NLRP3 inflammasome and IL-1β•BAX/BAK-induced caspase-3/-7 and IAP loss also trigger caspase-8 to cleave IL-1β BAX/BAK-mediated apoptosis is considered immunologically silent. Vince et al. show that in macrophages, MCL-1 and BCL-XL restrain BAX/BAK-induced pro-inflammatory IL-1β activation. IAP degradation and activation of caspase-3 and -7 downstream of BAX/BAK triggers caspase-8-mediated cleavage and activation of IL-1β and cause potassium ion efflux to trigger NLRP3 inflammasome formation.