Oral Presentation Lorne Infection and Immunity 2018

Mitochondrial apoptotic effectors BAX/BAK activate caspase-3 and -7 to trigger NLRP3 inflammasome and caspase-8 driven IL-1β activation in innate immune cells (#21)

James E Vince 1 2 , Dominic De Nardo 1 2 , Wenqing Gao 3 , Angelina J Vince 1 , Cathrine Hall 1 , Kate McArthur 1 2 4 , Swarna Lekha Vijayaraj 1 2 , Lisa M Lindqvist 1 2 , Mark A Rizzacasa 5 , John Silke 1 2 , Seth L Masters 1 2 , Guillaume Lessene 1 2 , David CS Huang 1 2 , Daniel H Gray 1 2 , Benjamin T Kile 4 , Feng Shao 3 , Kate E Lawlor 1 2 6 7
  1. The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
  2. Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia
  3. National Institute of Biological Sciences, Beijing, China
  4. Department of Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia
  5. School of Chemistry, The Bio21 Institute, The University of Melbourne, Melbourne, VIC, Australia
  6. Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC, Australia
  7. Department of Molecular and Translational Science, Monash University, Clayton, VIC, Australia

Apoptotic cell death is classically regarded as immunologically silent. However, recent genetic evidence acquired from the study of innate immune cells has shown that death receptor apoptotic signaling, initiated by TNF Receptor 1 (TNFR1), Fas or Toll-like Receptor (TLR) ligation, can induce potent inflammatory cytokine responses1. In fact, deficiency or mutations in negative regulators of TNFR1 and TLR signaling can cause hyperinflammatory disease in humans and mice1,2. In most of these cases, TLR- or TNFR1-induced caspase-8 activity drives activation of IL-1β and the NLRP3 inflammasome3,4. Here we now show that, in macrophages, activation of intrinsic apoptotic effectors, BAX and BAK, 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 activation and caspase-1-dependent IL-1β maturation that is dependent on potassium efflux. Remarkably, the apoptotic executioner caspases, caspase-3 and -7, acted upstream of both caspase-8 and NLRP3-induced activation of IL-1β.  Conversely, the recently identified pyroptotic cell death effectors for caspase-1 and caspase-3, gasdermin D and gasdermin E, respectively, were not essential for BAX/BAK-induced release of IL-1β. These findings genetically demonstrate that the intrinsic apoptosis pathway can activate a potent pro-inflammatory signal, and provide a potential explanation as to why IL-1β activation is often associated with cellular stress, such as during chemotherapy.

  1. Feltham R, Vince JE, Lawlor KE. (2017) Caspase-8: Not so silently deadly. Clinical and Translational Immunology 6:e124
  2. Lawlor K.E et al. (2017) XIAP Loss Triggers RIPK3- and Caspase-8-Driven IL-1beta Activation and Cell Death as a Consequence of TLR-MyD88-Induced cIAP1-TRAF2 Degradation. Cell Reports 20, 668-682.
  3. Lawlor KE et al. (2015). RIPK3 promotes cell death and NLRP3 inflammasome activation in the absence of MLKL. Nat Commun 6, 6282.
  4. Vince JE et al. (2012). Inhibitor of apoptosis proteins limit RIP3 kinase-dependent interleukin-1 activation. Immunity 36, 215-227.