Proteomics reveals distinct mechanisms regulating the release of cytokines and alarmins during pyroptosis

Phulphagar, Kshiti; Kühn, Lars I.; Ebner, Stefan; Frauenstein, Annika; Swietlik, Jonathan J.; Rieckmann, Jan C.; Meissner, Felix

doi:10.1016/j.celrep.2021.108826

Cited by 46 publications

(37 citation statements)

References 69 publications

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“…Comparative analysis of supernatants detected approximatively 450 proteins that were mostly enriched extracellularly (more than two fold) upon NETosis, including Histones core components (Histone H3) or Histoneassociated proteins (Histone H1) (Figure 5D, Table S1). To the contrary, both pyroptotic and NETotic neutrophils released the necrotic markers Ldh or the alarmins IL36γ, HMGB1 and HMGB2 (Henry et al, 2016;Phulphagar et al, 2021) to a similar extend, suggesting that pyroptosis of neutrophils might interfere with the release of specific DAMPs (Figure 5D). These features were then further validated by immunoblotting and ELISA against HMGB1 or Histones release upon both NETosis and pyroptosis induction (Figures 5E, S5C, D).…”

Section: Histones Upon Caspase-1-induced Pyroptosismentioning

confidence: 97%

Caspase-1-driven neutrophil pyroptosis promotes an incomplete NETosis upon Pseudomonas aeruginosa infection

Santoni

Péricat

Pinilla

et al. 2021

Preprint

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Neutrophils mediate essential immune and microbicidal processes. Consequently, to counteract neutrophil attack, pathogens have developed various virulence strategies. Here, we showed that Pseudomonas aeruginosa (P. aeruginosa) phospholipase ExoU drives pathological NETosis in neutrophils. Surprisingly, inhibition of ExoU activity uncovered a fully functional Caspase-1-driven pyroptosis pathway in neutrophils. Mechanistically, activated NLRC4 inflammasome promoted Caspase-1-dependent Gasdermin-D activation, IL-1β cytokine release and neutrophil pyroptosis. Whereas both pyroptotic and netotic neutrophils released alarmins, only NETosis liberated the destructive DAMPs Histones, which exacerbated Pseudomonas-induced mouse lethality. To the contrary, subcortical actin allowed pyroptotic neutrophils to physically limit poisonous inflammation by keeping Histones intracellularly. Finally, mouse models of infection highlighted that both NETosis and neutrophil Caspase-1 contributed to P. aeruginosa spreading. Overall, we established the host deleterious consequences of Pseudomonas-induced-NETosis but also uncovered an unsuspected ability of neutrophils to undergo Caspase-1-dependent pyroptosis, a process where neutrophils exhibit a self-regulatory function that limit Histone release.

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Section: Histones Upon Caspase-1-induced Pyroptosismentioning

confidence: 97%

Caspase-1-driven neutrophil pyroptosis promotes an incomplete NETosis upon Pseudomonas aeruginosa infection

Santoni

Péricat

Pinilla

et al. 2021

Preprint

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“…Pyroptosis is a lytic programmed cell death (PCD) that involves cell swelling and the rupturing of the plasma membrane, and it remains a major pathway for the release of proinflammatory proteins in macrophages [207], dendritic cells and partially in neutrophils [208,209]. This cell death was first observed by Friedlander et al in 1986 in primary mouse macrophages with anthrax lethal toxin (LT) treatment leading to the rapid release of cell contents [210] and later established in Shigella flexneri-infected macrophages by Zychlinsky and his co-workers in 1922 [211].…”

Section: Nod-like Receptors In the Regulation Of Pyroptosis Cell Deathmentioning

confidence: 99%

“…Until 2015, when gasdermin D was discovered as a substrate target of caspase 1/4/5/11, the pyroptosis effector molecule was unknown [ 218 , 219 ]. The oligomerization of the cleaved active form of gasdermin protein (N-terminal of GSDMD) [ 217 , 218 ] results in the lysis of cells and facilitates the release of proinflammatory cytokines (such as IL-1β, IL-18 and TNF) and alarmins, such as high mobility group box 1 (HMGB1) [ 207 , 208 ]. It is noteworthy to mention that the first report of the gasdermin gene (now GSDMA) in the gastrointestinal tract (tightly restricted to the esophagus and stomach) and skin of a mouse was 2000 [ 220 ], and since then, many members of the gasdermin family have been reported; GSDMB, GSDMC, GSDMD, GSDME (also known as DFNA5) and PJVK (also known as DFNB59), with different activating enzymes both in human and mouse [ 221 , 222 , 223 ].…”

Section: Nod-like Receptors In the Regulation Of Pyroptosis Cell Deathmentioning

confidence: 99%

Nod-like Receptors: Critical Intracellular Sensors for Host Protection and Cell Death in Microbial and Parasitic Infections

Babamale

Chen

2021

IJMS

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Cell death is an essential immunological apparatus of host defense, but dysregulation of mutually inclusive cell deaths poses severe threats during microbial and parasitic infections leading to deleterious consequences in the pathological progression of infectious diseases. Nucleotide-binding oligomerization domain (NOD)-Leucine-rich repeats (LRR)-containing receptors (NLRs), also called nucleotide-binding oligomerization (NOD)-like receptors (NLRs), are major cytosolic pattern recognition receptors (PRRs), their involvement in the orchestration of innate immunity and host defense against bacteria, viruses, fungi and parasites, often results in the cleavage of gasdermin and the release of IL-1β and IL-18, should be tightly regulated. NLRs are functionally diverse and tissue-specific PRRs expressed by both immune and non-immune cells. Beyond the inflammasome activation, NLRs are also involved in NF-κB and MAPK activation signaling, the regulation of type I IFN (IFN-I) production and the inflammatory cell death during microbial infections. Recent advancements of NLRs biology revealed its possible interplay with pyroptotic cell death and inflammatory mediators, such as caspase 1, caspase 11, IFN-I and GSDMD. This review provides the most updated information that caspase 8 skews the NLRP3 inflammasome activation in PANoptosis during pathogen infection. We also update multidimensional roles of NLRP12 in regulating innate immunity in a content-dependent manner: novel interference of NLRP12 on TLRs and NOD derived-signaling cascade, and the recently unveiled regulatory property of NLRP12 in production of type I IFN. Future prospects of exploring NLRs in controlling cell death during parasitic and microbial infection were highlighted.

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“…GSDMD pores allow secretion of pro-inflammatory cytokines (IL-1β, IL-18) and the release of a myriad of DAMPS (e.g. ATP, Galectin-1) [ 100 , 101 ]. Additionally, GSDMD pores generate potassium efflux to allow caspase-1 activation through the NLRP3 inflammasome, downstream of the non-canonical inflammasome [ 102 , 103 ].…”

Section: Inflammatory Caspases Substrates and Signallingmentioning

confidence: 99%

Great balls of fire: activation and signalling of inflammatory caspases

Bateman

Hill

Knight

et al. 2021

Biochemical Society Transactions

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Innate immune responses are tightly regulated by various pathways to control infections and maintain homeostasis. One of these pathways, the inflammasome pathway, activates a family of cysteine proteases called inflammatory caspases. They orchestrate an immune response by cleaving specific cellular substrates. Canonical inflammasomes activate caspase-1, whereas non-canonical inflammasomes activate caspase-4 and -5 in humans and caspase-11 in mice. Caspases are highly specific enzymes that select their substrates through diverse mechanisms. During inflammation, caspase activity is responsible for the secretion of inflammatory cytokines and the execution of a form of lytic and inflammatory cell death called pyroptosis. This review aims to bring together our current knowledge of the biochemical processes behind inflammatory caspase activation, substrate specificity, and substrate signalling.

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Proteomics reveals distinct mechanisms regulating the release of cytokines and alarmins during pyroptosis

Cited by 46 publications

References 69 publications

Caspase-1-driven neutrophil pyroptosis promotes an incomplete NETosis upon Pseudomonas aeruginosa infection

Caspase-1-driven neutrophil pyroptosis promotes an incomplete NETosis upon Pseudomonas aeruginosa infection

Nod-like Receptors: Critical Intracellular Sensors for Host Protection and Cell Death in Microbial and Parasitic Infections

Great balls of fire: activation and signalling of inflammatory caspases

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