NLRP3 inflammasome activation results in hepatocyte pyroptosis, liver inflammation and fibrosis

By A. Wree, A. Eguchi, Matthew D. McGeough, C. Peña, Casey D. Johnson, Ali Canbay, Hal M. Hoffman, Ariel E. Feldstein. Hepatology, 2014

844 citations recorded by the source corpus.

Inflammasome activation plays a central role in the development of drug‐induced and obesity‐associated liver disease. However, the sources and mechanisms of inflammasome‐mediated liver damage remain poorly understood. Our aim was to investigate the effect of NLRP3 inflammasome activation on the liver using novel mouse models. We generated global and myeloid cell‐specific conditional mutant Nlrp3 knock‐in mice expressing the D301N Nlrp3 mutation (ortholog of D303N in human NLRP3), resulting in a hyperactive NLRP3. To study the presence and significance of NLRP3‐initiated pyroptotic cell death, we separated hepatocytes from nonparenchymal cells and developed a novel flow‐cytometry–based (fluorescence‐activated cell sorting; FACS) strategy to detect and quantify pyroptosis in vivo based on detection of active caspase 1 (Casp1)‐ and propidium iodide (PI)‐positive cells. Liver inflammation was quantified histologically by FACS and gene expression analysis. Liver fibrosis was assessed by Sirius Red staining and quantitative polymerase chain reaction for markers of hepatic stellate cell (HSC) activation. NLRP3 activation resulted in shortened survival, poor growth, and severe liver inflammation; characterized by neutrophilic infiltration and HSC activation with collagen deposition in the liver. These changes were partially attenuated by treatment with anakinra, an interleukin‐1 receptor antagonist. Notably, hepatocytes from global Nlrp3‐mutant mice showed marked hepatocyte pyroptotic cell death, with more than a 5‐fold increase in active Casp1/PI double‐positive cells. Myeloid cell‐restricted mutant NLRP3 activation resulted in a less‐severe liver phenotype in the absence of detectable pyroptotic hepatocyte cell death. Conclusions: Our data demonstrate that global and, to a lesser extent, myeloid‐specific NLRP3 inflammasome activation results in severe liver inflammation and fibrosis while identifying hepatocyte pyroptotic cell death as a novel mechanism of NLRP3‐mediated liver damage. (Hepatology 2014;59:898–910)

Subfields: Hepatology, Molecular Biology, Pharmacology

View Paper: https://www.semanticscholar.org/paper/9f8754003adf76d4d47e535772634da0301b15af

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Citations in the corpus

Hepatic Inflammation and Fibrosis: Functional Links and Key Pathways (2015, background): “Knock-in mice, with constitutive activation of NODlike receptor family pyrin domain containing 3 (NLRP3) and hyperproduction of IL-1b, develop spontaneous liver injury and fibrosis.(55) TNF-a is another highly proinflammatory cytokine.”
Role of pyroptosis in inflammation and cancer (2022, background): “Anakinra, an antagonist of the IL-1 receptor, significantly decreases TNF-α, proIL-1β, and pro-caspase-1 to suppress pyroptosis, which alleviates severe liver inflammation in mutant NLRP3 knockout mice [253].”
Liver Fibrosis: Mechanistic Concepts and Therapeutic Perspectives (2020, background): “Finally, it was shown that activation of NLRP3 in hepatocytes results in pyroptosis, a form of programmed cell death involving caspase 1, liver inflammation, and fibrosis [167].”
NLRP3 inflammasome blockade reduces liver inflammation and fibrosis in experimental NASH in mice (2017, methodology): “We determined hepatic expression of specific mRNAs by reverse-transcriptase quantitative PCR (RT-qPCR), following extraction of total RNA from liver tissue [19,20].”
Sepsis: current dogma and new perspectives. (2014, background): “Inflammasomes also mediate pyroptosis, a form of programmed cell death that scatters additional cell components and contents into the extracellular space (Wree et al., 2014).”