NLRC4 inflammasome–dependent cell death occurs by a complementary series of three death pathways and determines lethality in mice

Zhang, Peipei; Liu, Yifei; Hu, Lichen; Huang, Kai; Hong, Mao; Wang, Yuze; Fan, Xinrui; Ulevitch, Richard J.; Han, Jiahuai

doi:10.1126/sciadv.abi9471

Cited by 25 publications

(39 citation statements)

References 55 publications

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“…Double knockout of Gsdmd and Asc cannot block cell death, which is contributed by the third/intrinsic apoptosis pathway mediated by caspase-1 (Figure 1(b), blue background). The caspase-1-induced intrinsic apoptosis pathway involves the Bid-Apaf-1-caspase-9-caspase-3 axis [18,27], which is also confirmed by using Gsdmd -/-Casp8 -/-, Gsdmd -/-Casp8 -/-Casp1 -/-, Gsdmd -/-Casp8 -/-Apaf1 -/-, and Gsdmd -/-Casp8 -/-Casp9 -/cells in our recent study [9]. Moreover, the caspase-1 recruited by NLRP1b-ASC complex can also induce the occurrence of pyroptosis via cleaving GSDMD [26].…”

Section: Resultssupporting

confidence: 78%

“…GSDMD or caspase-1 deletion switches NLRP3 inflammasomemediated pyroptosis to apoptosis was previously reported in both RAW-asc cells and BMDM [3]. Besides, our recent study observed the same effect of GSDMD or caspase-1 deletion on cell death induced by AIM2 inflammasome in J774A.1 cells [9]. Caspase-1 deletion in NLRP3 or AIM2 inflammasomes was confirmed that triggers the ASC-caspase-8-dependent apoptosis in BMDM [54,55], while GSDMD deletion in these inflammasomes induces caspase-1-dependent apoptosis [18].…”

Section: Discussionsupporting

confidence: 81%

“…C1_ASC keeps at a high level, but C1_GD and C3_C1 remain inactive. C8_ASC (caspase-8 binding to ASC) is slightly formed with extremely low level of GSDMD, which is supported by our previous result that ASC oligomerization is somewhat enhanced in Gsdmd -/-RAW-asc cells [9]. Moreover, six transducers, cleaved caspase-1/8/9/3, C8_C1 (caspase-8 binding to caspase-1), and C9_C1 (caspase-9 binding to caspase-1), are synchronously increased with GSDMD decrease.…”

Section: Impairment Of Caspase-1 and Gsdmd Severally Switchessupporting

confidence: 87%

“…The release of LDH (Figures 3(c) and 3(e)) and the massively occurrence of apoptosis (Figures 4(c) and 4(d)) in Gsdmd -/or Casp1 -/cells suggest that only a small amount of cells possibly undergo secondary necrosis/pyroptosis. Besides, our previous study indicates that no difference was observed of the LDH release or cell death between Gsdmd -/and Gsdmd -/-Gsdme -/macrophages, confirming that the LDH release and cell death in Gsdmd -/or Casp1 -/cells are not attributed to the GSDME-induced secondary pyroptosis [9]. Actually, a relatively high expression of GSDME is required for overriding apoptotic appearance in caspase-3activated cells [31], while little GSDME is expressed in RAW 264.7 cells [30].…”

Section: Discussionsupporting

confidence: 60%

“…In the case of NLRC4 and murine NLRP1b, they can recruit ASC directly through their CARD and subsequently activate caspase-1. Besides, NLRC4 and NLRP1b can also directly interact with caspase-1 via their CARD to mediate pyroptosis in an ASC-independent manner [ 2 , 9 ].…”

Section: Introductionmentioning

confidence: 99%

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Caspase-1 and Gasdermin D Afford the Optimal Targets with Distinct Switching Strategies in NLRP1b Inflammasome-Induced Cell Death

Zhang

Yin

et al. 2022

Research

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Inflammasomes are essential complexes of innate immune system, which form the first line of host defense against pathogens. Mounting evidence accumulates that inflammasome signaling is highly correlated with coronavirus disease 2019 (COVID-19). However, there remains a significant gap in our understanding of the regulatory mechanism of inflammasome signaling. Combining mathematical modeling with experimental analysis of NLRP1b inflammasome signaling, we found that only the expression levels of caspase-1 and GSDMD have the potential to individually switch cell death modes. Reduction of caspase-1 or GSDMD switches cell death from pyroptosis to apoptosis. Caspase-1 and GSDMD present different thresholds and exert distinct pathway choices in switching death modes. Pyroptosis switches to apoptosis with an extremely low threshold level of caspase-1, but with a high threshold of GSDMD. Caspase-1-impaired cells employ ASC-caspase-8-dependent pathway for apoptosis, while GSDMD-impaired cells primarily utilize caspase-1-dependent pathway. Additionally, caspase-1 and GSDMD can severally ignite the cooccurrence of pyroptosis and apoptosis. Landscape topography unravels that the cooccurrence is dramatically different in caspase-1- and GSDMD-impaired cells. Besides pyroptosis state and apoptosis state, a potential new “coexisting” state in single cells is proposed when GSDMD acts as the driving force of the landscape. The “seesaw model” is therefore proposed, which can well describe the death states that are controlled by caspase-1 or GSDMD in single cells. Our study sheds new light on NLRP1b inflammasome signaling and uncovers the switching mechanisms among various death modes, providing potential clues to guide the development of more rational control strategies for diseases.

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Section: Resultssupporting

confidence: 78%

Section: Discussionsupporting

confidence: 81%

Section: Impairment Of Caspase-1 and Gsdmd Severally Switchessupporting

confidence: 87%

Section: Discussionsupporting

confidence: 60%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Caspase-1 and Gasdermin D Afford the Optimal Targets with Distinct Switching Strategies in NLRP1b Inflammasome-Induced Cell Death

Zhang

Yin

et al. 2022

Research

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NLRC4‐mediated pyroptosis was involved in coagulation disorders of acute pancreatitis

Hu,

Lin,

Chen

et al. 2024

The Journal of Gene Medicine

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BackgroundAcute pancreatitis (AP) is a potentially lethal acute disease highly involved in coagulation disorders. Pyroptosis has been reported to exacerbate coagulation disorders, yet this implication has not been illustrated completely in AP.MethodsRNA sequencing data of peripheral blood of AP patients were downloaded from the Gene Expression Omnibus database. Gene set variation analysis and single sample gene set enrichment analysis were used to calculate the enrichment score of coagulation‐related signatures and pyroptosis. Spearman and Pearson correlation analysis was used for correlation analysis. Peripheral blood samples and related clinical parameters were collected from patients with AP and healthy individuals. A severe AP (SAP) model of mice was established using caerulein and lipopolysaccharide. Enzyme‐linked immunosorbent assay, chemiluminescence immunoassay and immunohistochemical analysis were employed to detect the level of coagulation indicators and pyroptosis markers in serum and pancreas tissues. Additionally, we evaluated the effect of pyroptosis inhibition and NLRC4 silence on the function of human umbilical vein endothelial cells (HUVECs).ResultsCoagulation disorders were significantly positively correlated to the severity of AP, and they could be a predictor for AP severity. Further analyses indicated that six genes—DOCK9, GATA3, FCER1G, NLRC4, C1QB and C1QC—may be involved in coagulation disorders of AP. Among them, NLRC4 was positively related to pyroptosis that had a positive association with most coagulation‐related signatures. Data from patients showed that NLRC4 and other pyroptosis markers, including IL‐1β, IL‐18, caspase1 and GSDMD, were significant correlation to AP severity. In addition, NLRC4 was positively associated with coagulation indicators in AP patients. Data from mice showed that NLRC4 was increased in the pancreas tissues of SAP mice. Treatment with a pyroptosis inhibitor effectively alleviated SAP and coagulation disorders in mice. Finally, inhibiting pyroptosis or silencing NLRC4 could relieve endothelial dysfunction in HUVECs.ConclusionsNLRC4‐mediated pyroptosis damages the function of endothelial cells and thereby exacerbates coagulation disorders of AP. Inhibiting pyroptosis could improve coagulation function and alleviate AP.

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Inflammasome: structure, biological functions, and therapeutic targets

Dai,

Zhou,

Shi

2023

MedComm

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Inflammasomes are a group of protein complex located in cytoplasm and assemble in response to a wide variety of pathogen‐associated molecule patterns, damage‐associated molecule patterns, and cellular stress. Generally, the activation of inflammasomes will lead to maturation of proinflammatory cytokines and pyroptotic cell death, both associated with inflammatory cascade amplification. A sensor protein, an adaptor, and a procaspase protein interact through their functional domains and compose one subunit of inflammasome complex. Under physiological conditions, inflammasome functions against pathogen infection and endogenous dangers including mtROS, mtDNA, and so on, while dysregulation of its activation can lead to unwanted results. In recent years, advances have been made to clarify the mechanisms of inflammasome activation, the structural details of them and their functions (negative/positive) in multiple disease models in both animal models and human. The wide range of the stimuli makes the function of inflammasome diverse and complex. Here, we review the structure, biological functions, and therapeutic targets of inflammasomes, while highlight NLRP3, NLRC4, and AIM2 inflammasomes, which are the most well studied. In conclusion, this review focuses on the activation process, biological functions, and structure of the most well‐studied inflammasomes, summarizing and predicting approaches for disease treatment and prevention with inflammasome as a target. We aim to provide fresh insight into new solutions to the challenges in this field.

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NLRC4 inflammasome–dependent cell death occurs by a complementary series of three death pathways and determines lethality in mice

Abstract: The death of cells elicited by NLRC4 inflammasome overactivation plays a decisive role in lethal outcome of the mice.

Cited by 25 publications

References 55 publications

Caspase-1 and Gasdermin D Afford the Optimal Targets with Distinct Switching Strategies in NLRP1b Inflammasome-Induced Cell Death

Caspase-1 and Gasdermin D Afford the Optimal Targets with Distinct Switching Strategies in NLRP1b Inflammasome-Induced Cell Death

NLRC4‐mediated pyroptosis was involved in coagulation disorders of acute pancreatitis

Inflammasome: structure, biological functions, and therapeutic targets

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