The relevance of pyroptosis in the pathogenesis of liver diseases

Guo, Huiting; Xie, Mingjie; Zhou, Cheng; Zheng, Min

doi:10.1016/j.lfs.2019.02.060

Cited by 50 publications

(41 citation statements)

References 44 publications

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“…Similarly, IL-1R signaling has been shown to be critical for the progression of steatohepatitis and hepatic fibrosis in hypercholesterolemic mice (50). The role of Gasdermin-D and pyroptosis has also been described in chronic liver diseases (51,52). During human NAFLD/NASH, GSDMD and its N-terminal peptide (GSDMD-N) are upregulated, besides MCD-fed Gsdmd −/− mice showed decreased severity of steatosis and inflammation comparing to WT (52).…”

Section: Discussionmentioning

confidence: 98%

NLRP6 Plays an Important Role in Early Hepatic Immunopathology Caused by Schistosoma mansoni Infection

et al. 2020

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Schistosomiasis is a debilitating parasitic disease that affects more than 200 million people worldwide and causes approximately 280,000 deaths per year. Inside the definitive host, eggs released by Schistosoma mansoni lodge in the intestine and especially in the liver where they induce a granulomatous inflammatory process, which can lead to fibrosis. The molecular mechanisms initiating or promoting hepatic granuloma formation remain poorly understood. Inflammasome activation has been described as an important pathway to induce pathology mediated by NLRP3 receptor. Recently, other components of the inflammasome pathway, such as NLRP6, have been related to liver diseases and fibrotic processes. Nevertheless, the contribution of these components in schistosomiasis-associated pathology is still unknown. In the present study, using dendritic cells, we demonstrated that NLRP6 sensor is important for IL-1β production and caspase-1 activation in response to soluble egg antigens (SEA). Furthermore, the lack of NLRP6 has been shown to significantly reduce periovular inflammation, collagen deposition in hepatic granulomas and mRNA levels of α-SMA and IL-13. Livers of Nlrp6 −/− mice showed reduced levels of CXCL1/KC, CCL2, CCL3, IL-5, and IL-10 as well as Myeloperoxidase (MPO) and Eosinophilic Peroxidase (EPO) enzymatic activity. Consistently, the frequency of macrophage and neutrophil populations were lower in the liver of NLRP6 knockout mice, after 6 weeks of infection. Finally, it was further demonstrated that the onset of hepatic granuloma and collagen deposition were also compromised in Caspase-1 −/− , IL-1R −/− and Gsdmd −/− mice. Our findings suggest that the NLRP6 inflammasome is an important component for schistosomiasis-associated pathology.

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Section: Discussionmentioning

confidence: 98%

NLRP6 Plays an Important Role in Early Hepatic Immunopathology Caused by Schistosoma mansoni Infection

et al. 2020

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“…In this study, we showed that lnc-Lfar1 silencing alleviated liver injury-induced upregulation of LY6C, IL-1β, IL-6, TNF-α, MCP-1, CCL5 and CXCL10 in vivo and in vitro, suggesting that lnc-Lfar1 knockdown might be beneficial for preventing liver fibrosis by targeting these chemokines. On the other hand, pyroptosis is a novel programmed and proinflammatory cell death, which is initiated by inflammasomes and executed by GSDMD, and plays a vital role in liver inflammation and fibrosis 2,7,8,11 . Therefore, inhibition of NLRP3 inflammasome and GSDMD could be a potential therapeutic approach for the prevention and therapy of liver inflammation and fibrosis through regulating pyroptosis.…”

Section: Discussionmentioning

confidence: 99%

“…Pyroptosis is a novel programmed and proinflammatory cell death, which is initiated by inflammasomes and executed by Gasdermin D (GSDMD), leading to pore formation in the plasma membrane, fluid influx, cell swelling, rapid plasma membrane rupture and massive release of lactate dehydrogenase (LDH) and the proinflammatory cytokines such as IL-1β and IL-18 7,8 . Inflammasomes are a group of multimeric protein complexes usually composed of the activated NOD-like receptor (NLR), the adapter apoptosis-associated speck-like protein containing CARD (ASC) and the effector pro-caspase 1.…”

Section: Introductionmentioning

confidence: 99%

“…Upon activation, the N-terminal pyrin segment (PYD) of NLRP3 serves as a scaffold to induce the oligomerization of ASC and recruits pro-caspase-1. Then, the oligomerization of pro-caspase1 proteins facilitates its auto-processing into active caspase1 or cleaved caspase1, which cleaves pro-IL-1β and pro-IL-18 into biologically active cytokines IL-1β and IL-18, respectively 2,7,8 . In addition to processing proinflammatory cytokines, active caspase-1 also cleaves the Gasdermin-D into a 22-kDa C-terminal fragment and a 31-kDa N-terminal fragment (GSDMD-N), which forms the membrane pores to induce mature IL-1β and IL-18 release 8 .…”

Section: Introductionmentioning

confidence: 99%

“…In addition to processing proinflammatory cytokines, active caspase-1 also cleaves the Gasdermin-D into a 22-kDa C-terminal fragment and a 31-kDa N-terminal fragment (GSDMD-N), which forms the membrane pores to induce mature IL-1β and IL-18 release 8 . Growing evidences suggest that NLRP3 inflammasome and pyroptosis play an important role in liver inflammation and fibrosis 7,[9][10][11] . It has been reported that NLRP3 hyperactivation-initiated pyroptosis resulted in more severe liver inflammation and fibrosis, while NLRP3 deficiency alleviates carbon tetrachloride (CCl 4 )-induced liver fibrosis 10 .…”

Section: Introductionmentioning

confidence: 99%

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Silencing lncRNA Lfar1 alleviates the classical activation and pyoptosis of macrophage in hepatic fibrosis

et al. 2020

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Hepatic fibrosis is a common pathological consequence of a sustained wound healing response to continuous liver injury, characterized by increased production and accumulation of extracellular matrix. If unresolved, the fibrotic process results in organ failure, and eventually death after the development of cirrhosis. It has been suggested that macrophages play central role in the progression of hepatic fibrosis, which is related to inflammation and pyroptosis, a novel programmed and proinflammatory cell death. However, it remains far less clear if, or how, lncRNAs regulates the activation and pyroptosis of macrophage in hepatic fibrosis. In the present study, we demonstrated that the liverenriched lncRNA Lfar1, which has been reported to promote hepatic fibrosis through inducing hepatic stellate cells activation and hepatocytes apoptosis, was dysregulated during proinflammatory M1 activation and pyroptosis of macrophage. Our study revealed that silencing lnc-Lfar1 by a lentivirus-shRNA alleviated CCl 4 -and BDL-induced proinflammatory M1 macrophage activation and NLRP3 inflammasome-mediated pyroptosis. Furthermore, the in vitro experiments demonstrated that lnc-Lfar1 knockdown significantly suppressed LPS-and IFN-γ-induced proinflammatory activation of macrophages, and inhibited LPS/ATP-and LPS/Nigericin-induced NLRP3 inflammasome-mediated pyroptosis. Mechanistically, lnc-Lfar1 regulated LPS-and IFN-γ-induced proinflammatory activation of macrophages through the NF-ĸB pathway. All these data supported our conclusion that lnc-Lfar1 plays a vital role in controlling the activation and pyroptosis of macrophage, thus providing a possible therapeutic target against inflammation-related disorders including hepatic fibrosis.

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The dynamics of cell death patterns and regeneration during acute liver injury in mice

Shao

et al. 2022

FEBS Open Bio

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Acute liver injury is a serious clinical syndrome with multiple causes and unclear pathological process. Here, CCl4‐ and D‐galactosamine/lipopolysaccharide (D‐gal/LPS)‐induced acute liver injury was established to explore the cell death patterns and determine whether or not liver regeneration occurred. In CCl4‐induced hepatic injury, three phases, including the early, progressive, and recovery phase, were considered based on alterations of serum transaminases and liver morphology. Moreover, in this model, cytokines exhibited double‐peak fluctuations; apoptosis and pyroptosis persisted throughout all phases; autophagy occurred in the early and the progressive phases; and sufficient and timely hepatocyte regeneration was observed only during the recovery phase. All of these phenomena contribute to mild liver injury and subsequent regeneration. Strikingly, only the early and progressive phases were observed in the D‐gal/LPS model. Slight pyroptosis occurred in the early phase but diminished in the progressive phase, while apoptosis, reduced autophagy, and slight but subsequently diminished regeneration occurred only during the progressive phase, accompanied by a strong cytokine storm, resulting in severe liver injury with high mortality. Taken together, our work reveals variable modes and dynamics of cell death and regeneration, which lead to different consequences for mild and severe acute liver injury, providing a helpful reference for clinical therapy and prognosis.

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The relevance of pyroptosis in the pathogenesis of liver diseases

Cited by 50 publications

References 44 publications

NLRP6 Plays an Important Role in Early Hepatic Immunopathology Caused by Schistosoma mansoni Infection

NLRP6 Plays an Important Role in Early Hepatic Immunopathology Caused by Schistosoma mansoni Infection

Silencing lncRNA Lfar1 alleviates the classical activation and pyoptosis of macrophage in hepatic fibrosis

The dynamics of cell death patterns and regeneration during acute liver injury in mice

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