Different bile acids display distinct ability to trigger Nlrp3 inflammasome activation in a cell-dependent manner contributing to cholestatic liver injury and fibrosis

2018 ◽  
Vol 68 ◽  
pp. S451
Author(s):  
M. Inzaugarat ◽  
T.M. Holtmann ◽  
M. Frissen ◽  
L.J. Geisler ◽  
J. Reissing ◽  
...  
Keyword(s):  
Liver Injury ◽  
Bile Acids ◽  
Nlrp3 Inflammasome ◽  
Inflammasome Activation ◽  
Dependent Manner ◽  
Nlrp3 Inflammasome Activation ◽  
A Cell ◽  
Cholestatic Liver Injury

scholarly journals Hydrogen Sulfide Protects against Paraquat-Induced Acute Liver Injury in Rats by Regulating Oxidative Stress, Mitochondrial Function, and Inflammation

2020 ◽  
Vol 2020 ◽  
pp. 1-16 ◽  
Author(s):  
Zhenning Liu ◽  
Xiaofeng Wang ◽  
Lei Li ◽  
Guigui Wei ◽  
Min Zhao
Keyword(s):  
Oxidative Stress ◽  
Antioxidant Enzymes ◽  
Hydrogen Sulfide ◽  
Liver Injury ◽  
Mitochondrial Function ◽  
Nlrp3 Inflammasome ◽  
Acute Liver Injury ◽  
Inflammasome Activation ◽  
Dependent Manner ◽  
Nlrp3 Inflammasome Activation

In addition to the lung, the liver is considered another major target for paraquat (PQ) poisoning. Hydrogen sulfide (H2S) has been demonstrated to be effective in the inhibition of oxidative stress and inflammation. The aim of this study was to investigate the protective effect of exogenous H2S against PQ-induced acute liver injury. The acute liver injury model was established by a single intraperitoneal injection of PQ, evidenced by histological alteration and elevated serum aminotransferase levels. Different doses of NaHS were administered intraperitoneally one hour before exposure to PQ. Analysis of the data shows that exogenous H2S attenuated the PQ-induced liver injury and oxidative stress in a dose-dependent manner. H2S significantly suppressed reactive oxygen species (ROS) generation and the elevation of malondialdehyde content while it increased the ratio of GSH/GSSG and levels of antioxidant enzymes including SOD, GSH-Px, HO-1, and NQO-1. When hepatocytes were subjected to PQ-induced oxidative stress, H2S markedly enhanced nuclear translocation of Nrf2 via S-sulfhydration of Keap1 and resulted in the increase in IDH2 activity by regulating S-sulfhydration of SIRT3. In addition, H2S significantly suppressed NLRP3 inflammasome activation and subsequent IL-1β excretion in PQ-induced acute liver injury. Moreover, H2S cannot reverse the decrease in SIRT3 and activation of the NLRP3 inflammasome caused by PQ in Nrf2-knockdown hepatocytes. In summary, H2S attenuated the PQ-induced acute liver injury by enhancing antioxidative capability, regulating mitochondrial function, and suppressing ROS-induced NLRP3 inflammasome activation. The antioxidative effect of H2S in PQ-induced liver injury can at least partly be attributed to the promotion of Nrf2-driven antioxidant enzymes via Keap1 S-sulfhydration and regulation of SIRT3/IDH2 signaling via Nrf2-dependent SIRT3 gene transcription as well as SIRT3 S-sulfhydration. Thus, H2S supplementation can form the basis for a promising novel therapeutic strategy for PQ-induced acute liver injury.

scholarly journals Epimedin B Through Enhancing NLRP3 Inflammasome Activation To Induces Idiosyncratic Hepatotoxicity

2021 ◽  
Author(s):  
Yuan Gao ◽  
Wei Shi ◽  
Can Tu ◽  
Guanyu Zhao ◽  
Guang Xu ◽  
...  
Keyword(s):  
Liver Injury ◽  
Nlrp3 Inflammasome ◽  
Bone Fractures ◽  
Inflammasome Activation ◽  
Promoting Effect ◽  
Drug Induced ◽  
Drug Induced Liver Injury ◽  
Nlrp3 Inflammasome Activation ◽  
Synergistic Induction ◽  
Induce Liver Injury

Abstract Background: The NLRP3 inflammasome plays a crucial role in the pathogenesis of various human diseases, also idiosyncratic drug-induced liver injury (IDILI). Epimedii Folium (EF) is commonly used for treating bone fractures, joint diseases and some chronic illness, but the EF also could induce IDILI. Several studies have confirmed that EF may induce liver injury by upregulating the activity of the NLRP3 inflammasome. However, the major active constituents of EF have not been well-studied. Results: In the present study, we showed that epimedin B, a major active ingredient of EF, induced the development of IDILI by promoting the activation of the NLRP3 inflammasome. Synergistic induction of mitochondrial reactive oxygen species was a crucial contributor to the promoting effect of epimedin B observed on nigericin- or ATP-induced NLRP3 inflammasome activation. Importantly, epimedin B induced liver injury in the LPS-mediated susceptibility mouse model of IDILI，while specifical NLRP3 inhibitor MCC950 pretreatment completely abrogated the Caspase-1 activation and IL-1β secretion then couldn't induce liver injury. Conclusions: Epimedin B specifically facilitated nigericin- or ATP-induced NLRP3 inflammasome activation and the development of IDILI, which is responsible for EF-induced liver injury. These findings suggest that epimedin B is one of the key constituents of liver injury caused by EF，the content of epimedin B in EF may be a risk factor for IDILI, especially in patients with diseases related to nigericin- or ATP-induced NLRP3 inflammasome activation.

scholarly journals Bile Acids Activate NLRP3 Inflammasome, Promoting Murine Liver Inflammation or Fibrosis in a Cell Type-Specific Manner

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2618
Author(s):  
Theresa Maria Holtmann ◽  
Maria Eugenia Inzaugarat ◽  
Jana Knorr ◽  
Lukas Geisler ◽  
Marten Schulz ◽  
...  
Keyword(s):  
Bile Acids ◽  
Liver Damage ◽  
Nlrp3 Inflammasome ◽  
Lithocholic Acid ◽  
Ex Vivo ◽  
Cell Types ◽  
Inflammasome Activation ◽  
Inflammatory Phenotype ◽  
Murine Liver ◽  
A Cell

Bile acids (BA) as important signaling molecules are considered crucial in development of cholestatic liver injury, but there is limited understanding on the involved cell types and signaling pathways. The aim of this study was to evaluate the inflammatory and fibrotic potential of key BA and the role of distinct liver cell subsets focusing on the NLRP3 inflammasome. C57BL/6 wild-type (WT) and Nlrp3−/− mice were fed with a diet supplemented with cholic (CA), deoxycholic (DCA) or lithocholic acid (LCA) for 7 days. Additionally, primary hepatocytes, Kupffer cells (KC) and hepatic stellate cells (HSC) from WT and Nlrp3−/− mice were stimulated with aforementioned BA ex vivo. LCA feeding led to strong liver damage and activation of NLRP3 inflammasome. Ex vivo KC were the most affected cells by LCA, resulting in a pro-inflammatory phenotype. Liver damage and primary KC activation was both ameliorated in Nlrp3-deficient mice or cells. DCA feeding induced fibrotic alterations. Primary HSC upregulated the NLRP3 inflammasome and early fibrotic markers when stimulated with DCA, but not LCA. Pro-fibrogenic signals in liver and primary HSC were attenuated in Nlrp3−/− mice or cells. The data shows that distinct BA induce NLRP3 inflammasome activation in HSC or KC, promoting fibrosis or inflammation.

scholarly journals A Synthetic Small Molecule F240B Decreases NLRP3 Inflammasome Activation by Autophagy Induction

2020 ◽  
Vol 11 ◽  
Author(s):  
Chun-Hsien Wu ◽  
Chin Heng Gan ◽  
Lan-Hui Li ◽  
Jen-Che Chang ◽  
Shin-Tai Chen ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Membrane Integrity ◽  
Mechanistic Study ◽  
Autophagic Flux ◽  
Inflammasome Activation ◽  
Dependent Manner ◽  
Inflammatory Agent ◽  
Nlrp3 Inflammasome Activation ◽  
Autophagy Induction ◽  
Anti Inflammatory

Conjugated polyenes are a class of widely occurring natural products with various biological functions. We previously identified 4-hydroxy auxarconjugatin B (4-HAB) as anti‐inflammatory agent with an IC50 of ~20 µM. In this study, we synthesized a new anti‐inflammatory 4-HAB analogue, F240B, which has an IC50 of less than 1 µM. F240B dose-dependently induced autophagy by increasing autophagic flux, LC3 speck formation and acidic vesicular organelle formation. F240B inhibited NACHT, LRR and PYD domain-containing protein 3 (NLRP3) inflammasome activation through autophagy induction. In a mechanistic study, F240B inhibited interleukin (IL)-1β (IL-1β) precursor expression, promoted degradation of NLRP3 and IL-1β, and reduced mitochondrial membrane integrity loss in an autophagy-dependent manner. Additionally, F240B inhibited apoptosis-associated speck-like protein containing a CARD (ASC) oligomerization and speck formation without affecting the interaction between NLRP3 and ASC or NIMA-related kinase 7 (NEK7) and double-stranded RNA-dependent kinase (PKR). Furthermore, F240B exerted in vivo anti-inflammatory activity by reducing the intraperitoneal influx of neutrophils and the levels of IL-1β, active caspase-1, IL-6 and monocyte chemoattractant protein-1 (MCP-1) in lavage fluids in a mouse model of uric acid crystal-induced peritonitis. In conclusion, F240B attenuated the NLRP3 inflammasome through autophagy induction and can be developed as an anti-inflammatory agent in the future.

scholarly journals DDX3X Links NLRP11 to the Regulation of Type I Interferon Responses and NLRP3 Inflammasome Activation

2021 ◽  
Vol 12 ◽  
Author(s):  
Ioannis Kienes ◽  
Sarah Bauer ◽  
Clarissa Gottschild ◽  
Nora Mirza ◽  
Jens Pfannstiel ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Nlrp3 Inflammasome ◽  
Inflammatory Cytokine ◽  
Inflammasome Activation ◽  
Type I ◽  
Dependent Manner ◽  
Type I Ifn ◽  
Central Target ◽  
Nlrp3 Inflammasome Activation ◽  
Lrr Domain

Tight regulation of inflammatory cytokine and interferon (IFN) production in innate immunity is pivotal for optimal control of pathogens and avoidance of immunopathology. The human Nod-like receptor (NLR) NLRP11 has been shown to regulate type I IFN and pro-inflammatory cytokine responses. Here, we identified the ATP-dependent RNA helicase DDX3X as a novel binding partner of NLRP11, using co-immunoprecipitation and LC-MS/MS. DDX3X is known to enhance type I IFN responses and NLRP3 inflammasome activation. We demonstrate that NLRP11 can abolish IKKϵ-mediated phosphorylation of DDX3X, resulting in lower type I IFN induction upon viral infection. These effects were dependent on the LRR domain of NLRP11 that we mapped as the interaction domain for DDX3X. In addition, NLRP11 also suppressed NLRP3-mediated caspase-1 activation in an LRR domain-dependent manner, suggesting that NLRP11 might sequester DDX3X and prevent it from promoting NLRP3-induced inflammasome activation. Taken together, our data revealed DDX3X as a central target of NLRP11, which can mediate the effects of NLRP11 on type I IFN induction as well as NLRP3 inflammasome activation. This expands our knowledge of the molecular mechanisms underlying NLRP11 function in innate immunity and suggests that both NLRP11 and DDX3X might be promising targets for modulation of innate immune responses.

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