+ Site Statistics
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

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



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



Hepatology



Inflammasome activation has been recently recognized to play 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 constitutively activated NLRP3. To study the presence and significance of NLRP3 initiated pyroptotic cell death, we separated hepatocytes from non-parenchymal cells and developed a novel flow cytometry-based (FACS)strategy to detect and quantify pyroptosis in vivo based on detection of active caspase1 and propidium iodide (PI) positive cells. Liver inflammation was quantified histologically, by FACS and via gene expression analysis. Liver fibrosis was assessed by Sirius-Red-staining and qPCR 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 fivefold increase in active caspase1-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. Our data demonstrates 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.

Please choose payment method:






(PDF emailed within 0-6 h: $19.90)

Accession: 036955458

Download citation: RISBibTeXText

DOI: 10.1002/hep.26592


Related references

NLRP3 inflammasome activation results in hepatocyte pyroptosis, liver inflammation, and fibrosis in mice. Hepatology 59(3): 898-910, 2014

CdSe/ZnS quantum dots induce hepatocyte pyroptosis and liver inflammation via NLRP3 inflammasome activation. Biomaterials 90: 27-39, 2016

Nlrp3 inflammasome activation in hepatocytes results in pyroptotic cell death, release of Nlrp3 particles and liver fibrosis. Journal of Hepatology 68: S31-S32, 2018

Nlrp3 Inflammasome Activation Leading to Il-1 Il-17 Dependent Lung Inflammation and Fibrosis. Current Respiratory Medicine Reviews 10(1): 64-70, 2014

IL-36 Signaling Facilitates Activation of the NLRP3 Inflammasome and IL-23/IL-17 Axis in Renal Inflammation and Fibrosis. Journal of the American Society of Nephrology 28(7): 2022-2037, 2017

The mechanisms of NLRP3 inflammasome/pyroptosis activation and their role in Parkinson's disease. International Immunopharmacology 67: 458-464, 2019

Pirfenidone ameliorates lipopolysaccharide-induced pulmonary inflammation and fibrosis by blocking NLRP3 inflammasome activation. Molecular Immunology 99: 134-144, 2018

NLRP3 inflammasome blockade reduces liver inflammation and fibrosis in experimental NASH in mice. Journal of Hepatology 66(5): 1037-1046, 2017

E2-Induced Activation of the NLRP3 Inflammasome Triggers Pyroptosis and Inhibits Autophagy in HCC Cells. Oncology Research 27(7): 827-834, 2019

Nlrp3 inflammasome activation and Gasdermin D-driven pyroptosis are immunopathogenic upon gastrointestinal norovirus infection. Plos Pathogens 15(4): E1007709, 2019

The SGK1 inhibitor EMD638683, prevents Angiotensin II-induced cardiac inflammation and fibrosis by blocking NLRP3 inflammasome activation. Biochimica et Biophysica Acta. Molecular Basis of Disease 1864(1): 1-10, 2018

Mesoporous silica nanoparticles induced hepatotoxicity via NLRP3 inflammasome activation and caspase-1-dependent pyroptosis. Nanoscale 10(19): 9141-9152, 2018

NLR Family Pyrin Domain-Containing 3 Inflammasome Activation in Hepatic Stellate Cells Induces Liver Fibrosis in Mice. Hepatology 69(2): 845-859, 2019

Comparative effects of schisandrin A, B, and C on Propionibacterium acnes-induced, NLRP3 inflammasome activation-mediated IL-1β secretion and pyroptosis. Biomedicine and PharmacoTherapy 96: 129-136, 2017

UFL1 modulates NLRP3 inflammasome activation and protects against pyroptosis in LPS-stimulated bovine mammary epithelial cells. Molecular Immunology 112: 1-9, 2019