The Role of the NLRP3 Inflammasome and Programmed Cell Death in Acute Liver Injury

Yu, Cui; Chen, Peng; Miao, Longyu; Di, Guohu

doi:10.3390/ijms24043067

Cited by 25 publications

(15 citation statements)

References 188 publications

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“…Studies have shown that the aberrant activation of the nod-like receptor protein 3 (NLRP3) in ammasome plays an important role in LPS D-GALN induced ALF and that the activation of the NLRP3 in ammasome causes various types of programmed cell death (PCD), and the most typical cell death form is pyroptosis. [20] In ammation is a key feature of LPS D-GALN induced acute liver injury. This occurs due to the release of DAMPs such as mitochondrial DNA, high mobility group box 1 (HMGB1), and nuclear fragments following lytic cell death.…”

Section: Discussionmentioning

confidence: 99%

Identification and validation of genes involved in pyroptosis of LPS and D-GALN induced acute liver injury

Zuo

2024

Preprint

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Pyroptosis plays an important role in the development of acute liver failure (ALF). In this study, we aimed to identify and validate important pyroptosis-related genes in ALF by bioinformatics analysis. The pyroptosis-related genes involved in the differential expression of ALF were identified using the gene expression comprehensive database (GEO) and the mRNA expression profile dataset GSE217659 provided by R software. The Gene Ontology (GO) enrichment analysis and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed for the differentially expressed related genes.Further screened the module genes by WGCNA and identified four genes (Gzmb, Mefv, Gbp 2 and Casp 4), which could be used as potential diagnostic biomarkers for ALF. Subsequently, the hub gene was modeled using nomogram to assess whether the model was good.

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Section: Discussionmentioning

confidence: 99%

Identification and validation of genes involved in pyroptosis of LPS and D-GALN induced acute liver injury

Zuo

2024

Preprint

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“…assembly of a protein complex (including nlrP3 oligomers and aSc) responsible for binding and cleaving caspase-1, which in turn generates the cleaved gasdermin d (GSdMd) n-terminal fragment (GSdMd-n) and forms pores in the cell membrane to induce pyroptosis, as well as releasing proinflammatory cytokines IL-1β and IL-18 (12)(13)(14). Numerous studies have reported that nlrP3 activates pyroptosis in various liver diseases (15)(16)(17)(18). However, the role of NLRP3 during APAP overdose has not been elucidated.…”

Section: Nlrp3 Deficiency Protects Against Acetaminophen-induced Live...mentioning

confidence: 99%

NLRP3 deficiency protects against acetaminophen‑induced liver injury by inhibiting hepatocyte pyroptosis

Yuan,

Chen,

Luan

et al. 2024

Mol Med Rep

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Acetaminophen (APAP) overdose is the primary cause of drug-induced acute liver failure in numerous Western countries. NLR family pyrin domain containing 3 (NLRP3) inflammasome activation serves a pivotal role in the pathogenesis of various forms of acute liver injury. However, the cellular source for NLRP3 induction and its involvement during APAP-induced hepatotoxicity have not been thoroughly investigated. In the present study, hematoxylin and eosin staining was performed to assess histopathological changes of liver tissue. Immunohistochemistry staining(NLRP3, Caspase-1, IL-1β, GSDMD and Caspase-3), western blotting (NLRP3, Caspase-1, IL-1β, GSDMD and Caspase-3) and RT-qPCR (NLRP3, Caspase-1 and IL-1β) were performed to assess the expression of NLRP3/GSDMD signaling pathway. TUNEL staining was performed to assess apoptosis of liver tissue. The serum expression levels of inflammatory factors (IL-6, IL-18, IL-1β and TNF-α) were assessed using ELISA and inflammation of liver tissue was assessed using immunohistochemistry (Ly6G and CD68) and RT-qPCR (TNF-α, Il-6, Mcp-1, Cxcl-1, Cxcl-2). A Cell Counting Kit-8 was performed to assess cell viability and apoptosis. Protein and gene expression were analyzed by western blotting (PCNA, CCND1) and RT-qPCR ( CyclinA2, CyclinD1 and CyclinE1). Through investigation of an APAP-induced acute liver injury model (AILI), the present study demonstrated that APAP overdose induced activation of NLRP3 and cleavage of gasdermin D (GSDMD) in hepatocytes, both in vivo and in vitro . Additionally, mice with hepatocyte-specific knockout of Nlrp3 exhibited reduced liver injury and lower mortality following APAP intervention, accompanied by decreased infiltration of inflammatory cells and attenuated inflammatory response. Furthermore, pharmacological blockade of NLRP3/GSDMD signaling using MCC950 or disulfiram significantly ameliorated liver injury and reduced hepatocyte death. Notably, hepatocyte Nlrp3 deficiency promoted liver recovery by enhancing hepatocyte proliferation. Collectively, the present study demonstrated that inhibition of the NLRP3 inflammasome protects against APAP-induced acute liver injury by reducing hepatocyte pyroptosis and suggests that targeting NLRP3 may hold therapeutic potential for treating AILI.

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“…Cold IRI is associated with sinusoidal endothelial cells (SECs) damage[ 11 ]. Although the initial cells are different, they do share common subsequent reactions: activation of cell death programs such as apoptosis, necrosis, pyroptosis, and autophagy, thus contributing to the development of inflammation[ 1 , 16 - 18 ].…”

Section: Hiri and The Underlying Mechanismsmentioning

confidence: 99%

Non-coding RNAs: The potential biomarker or therapeutic target in hepatic ischemia-reperfusion injury

Shao,

Wang,

Xiao

et al. 2023

World J Gastroenterol

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Delayed passage of meconium or constipation during the perinatal period is traditionally regarded as a signal to initiate further work up to evaluate for serious diagnoses such as Hirschsprung’s disease (HD), meconium ileus due to Cystic Fibrosis, etc. The diagnosis of HD particularly warrants invasive testing to confirm the diagnosis, such as anorectal manometry or rectal suction biopsy. What if there was another etiology of perinatal constipation, that is far lesser known? Cow’s milk protein allergy (CMPA) is often diagnosed in infants within the first few weeks of life, however, there are studies that show that the CMPA allergen can be passed from mother to an infant in-utero, therefore allowing symptoms to show as early as day one of life. The presentation is more atypical, with perinatal constipation rather than with bloody stools, diarrhea, and vomiting. The diagnosis and management would be avoidance of cow's milk protein within the diet, with results and symptom improvement in patients immediately. Therefore, we discuss whether an alternative pathway to address perinatal constipation should be further discussed and implemented to potentially avoid invasive techniques in patients. This entails first ruling out CMPA with safe, noninvasive techniques with diet modification, and if unsuccessful, then moving forward with further diagnostic modalities.

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The Role of the NLRP3 Inflammasome and Programmed Cell Death in Acute Liver Injury

Cited by 25 publications

References 188 publications

Identification and validation of genes involved in pyroptosis of LPS and D-GALN induced acute liver injury

Identification and validation of genes involved in pyroptosis of LPS and D-GALN induced acute liver injury

NLRP3 deficiency protects against acetaminophen‑induced liver injury by inhibiting hepatocyte pyroptosis

Non-coding RNAs: The potential biomarker or therapeutic target in hepatic ischemia-reperfusion injury

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