BAX/BAK-Induced Apoptosis Results in Caspase-8-Dependent IL-1β Maturation in Macrophages

Chauhan, Dhruv; Bartok, Eva; Gaidt, Moritz M.; Bock, Florian; Herrmann, Jennifer; Seeger, Jens M.; Brož, Petr; Beckmann, Roland; Kashkar, Hamid; Tait, Stephen W.G.; Müller, Rolf; Hornung, Veit

doi:10.1016/j.celrep.2018.10.087

Cited by 79 publications

(73 citation statements)

References 66 publications

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“…IL‐1β release, however, was only partially decreased in pannexin‐1 −/− cells (Chen et al , ). They speculate that this is due to apoptosis‐driven caspase‐8‐mediated IL‐1β cleavage, which has also been reported by others (Chauhan et al , ; Vince et al , ). It should be noted, however, that all studies detected rather low levels of released IL‐1β suggesting either inefficient transcription/translation or maturation of pro‐IL‐1β.…”

Section: Mechanisms Of Cell Death: the Connections Between Caspases Asupporting

confidence: 71%

Chopping GSDMD : caspase‐8 has joined the team of pyroptosis‐mediating caspases

2019

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Inflammatory and apoptotic caspases mediate two distinct forms of cell death: pyroptosis and apoptosis, respectively. Three independent studies have now demonstrated that the “apoptotic” caspase‐8 can cleave gasdermin D (GSDMD) leading to pyroptosis‐like cell death and IL‐1β release in murine macrophages (Orning et al, 2018; Sarhan et al, 2018; Chen et al, 2019). Orning et al and Chen/Demarco et al also show that the NLRP3 inflammasome is activated downstream of active caspase‐8, but they attribute this inflammasome activation to different pore‐forming proteins, GSDMD and pannexin‐1, respectively (Orning et al, 2018; Chen et al, 2019).

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Section: Mechanisms Of Cell Death: the Connections Between Caspases Asupporting

confidence: 71%

Chopping GSDMD : caspase‐8 has joined the team of pyroptosis‐mediating caspases

2019

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“…Caspase‐1 processing was remarkably reduced in LPS‐primed and LPS‐unprimed Panx1 −/− BMDMs compared to WT cells (Figs G and EV4D). Given that caspase‐1 and caspase‐8 both promote pro‐IL‐1β cleavage during apoptosis (Chauhan et al , ; Vince et al , ), Panx1 deficiency only partially reduced IL‐1β secretion into the cell culture supernatant compared to WT cells (Fig H).…”

Section: Resultsmentioning

confidence: 86%

“…While these observations suggest that apoptosis is indeed immunologically silent during homeostasis, emerging evidence from us and others indicates that exposure of innate immune cells such as macrophages and neutrophils to various therapeutics designed for cancer chemotherapy or inflammatory disorders such as SMAC mimetics, TAK1 inhibitor and BH3 mimetics promotes inflammation by driving caspase‐8 or caspase‐9‐dependent inflammatory cell death and NLRP3 inflammasome activation (Vince et al , , ; Lawlor et al , ; Wicki et al , ; Chauhan et al , ; Chen et al , ; Malireddi et al , ). However, the mechanism by which caspase‐8 or caspase‐9 triggers cell lysis and NLRP3 activation is still undefined.…”

Section: Introductionmentioning

confidence: 99%

Extrinsic and intrinsic apoptosis activate pannexin‐1 to drive NLRP 3 inflammasome assembly

et al. 2019

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Pyroptosis is a form of lytic inflammatory cell death driven by inflammatory caspase-1, caspase-4, caspase-5 and caspase-11. These caspases cleave and activate the pore-forming protein gasdermin D (GSDMD) to induce membrane damage. By contrast, apoptosis is driven by apoptotic caspase-8 or caspase-9 and has traditionally been classified as an immunologically silent form of cell death. Emerging evidence suggests that therapeutics designed for cancer chemotherapy or inflammatory disorders such as SMAC mimetics, TAK1 inhibitors and BH3 mimetics promote caspase-8 or caspase-9-dependent inflammatory cell death and NLRP3 inflammasome activation. However, the mechanism by which caspase-8 or caspase-9 triggers cell lysis and NLRP3 activation is still undefined. Here, we demonstrate that during extrinsic apoptosis, caspase-1 and caspase-8 cleave GSDMD to promote lytic cell death. By engineering a novel Gsdmd D88A knock-in mouse, we further demonstrate that this proinflammatory function of caspase-8 is counteracted by caspase-3-dependent cleavage and inactivation of GSDMD at aspartate 88, and is essential to suppress GSDMD-dependent cell lysis during caspase-8-dependent apoptosis. Lastly, we provide evidence that channel-forming glycoprotein pannexin-1, but not GSDMD or GSDME promotes NLRP3 inflammasome activation during caspase-8 or caspase-9-dependent apoptosis.

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“…B; Fig. # 11,). BAX/BAK activation, upon chemical/genetic BCL‐XL and MCL‐1 loss, or treatment with myxobacteria‐derived cyclic peptides, vioprolides (targets BCL‐2 and MCL‐1), was shown to cause IAP degradation to promote caspase‐8‐mediated activation of IL‐1β .…”

Section: Modes Of Nlrp3 Inflammasome Activationmentioning

confidence: 99%

Stressing out the mitochondria: Mechanistic insights into NLRP3 inflammasome activation

Yabal

Calleja

Simpson

et al. 2018

Journal of Leukocyte Biology

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Inflammasomes are multimeric protein complexes that induce the cleavage and release of bioactive IL-1 and cause a lytic form of cell death, termed pyroptosis. Due to its diverse triggers, ranging from infectious pathogens and host danger molecules to environmental irritants, the NOD-like receptor protein 3 (NLRP3) inflammasome remains the most widely studied inflammasome to date. Despite intense scrutiny, a universal mechanism for its activation remains elusive, although, recent research has focused on mitochondrial dysfunction or potassium (K + ) efflux as key events. In this review, we give a general overview of NLRP3 inflammasome activation and explore the recently emerging noncanonical and alternative pathways to NLRP3 activation. We highlight the role of the NLRP3 inflammasome in the pathogenesis of metabolic disease that is associated with mitochondrial and oxidative stress. Finally, we interrogate the mechanisms proposed to trigger NLRP3 inflammasome assembly and activation. A greater understanding of how NLRP3 inflammasome activation is triggered may reveal new therapeutic targets for the treatment of inflammatory disease. K E Y W O R D Scaspases, inflammasome, metabolism, mitochondria, reactive oxygen species Abbreviations: AIM2, absent in Melanoma; AMPK, AMP-activated protein kinase; APAF-1, apoptosis protease activating factor-1; ASC, apoptosis-associated speck-like protein containing a caspase recruitment domain; BMDCs, bone marrow dendritic

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BAX/BAK-Induced Apoptosis Results in Caspase-8-Dependent IL-1β Maturation in Macrophages

Abstract: Highlights d Mitochondrial apoptosis is not a silent cell death pathway d BAX/BAK-induced MOMP results in IL-1b maturation and lytic cell death d MOMP initiates intrinsic apoptosis and IAP depletion d This IAP depletion results in ripoptosome-caspase-8dependent IL-1b maturation

Cited by 79 publications

References 66 publications

Chopping GSDMD : caspase‐8 has joined the team of pyroptosis‐mediating caspases

Chopping GSDMD : caspase‐8 has joined the team of pyroptosis‐mediating caspases

Extrinsic and intrinsic apoptosis activate pannexin‐1 to drive NLRP 3 inflammasome assembly

Stressing out the mitochondria: Mechanistic insights into NLRP3 inflammasome activation

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