Inhibition of sterile danger signals, uric acid and ATP, prevents inflammasome activation and protects from alcoholic steatohepatitis in mice

Iracheta-Vellve, Arvin; Petrášek, Jan; Satishchandran, Abhishek; Gyöngyösi, Benedek; Saha, Banishree; Kodys, Karen; Fitzgerald, Katherine A.; Kurt-Jones, Evelyn A.; Szabó, Gyöngyi

doi:10.1016/j.jhep.2015.06.013

Cited by 120 publications

(103 citation statements)

References 30 publications

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“…Immunoblotting was performed as described in Ref. 43. Antibodies specific for phospho-IRF3, phospho-TBK1, STING, Casp-8, Casp-3, cleaved Casp-8, cleaved Casp-3, and Bax were from Cell Signaling (Danvers, MA).…”

Section: Methodsmentioning

confidence: 99%

Endoplasmic Reticulum Stress-induced Hepatocellular Death Pathways Mediate Liver Injury and Fibrosis via Stimulator of Interferon Genes

Iracheta-Vellve

Petrášek

Gyöngyösi

et al. 2016

Journal of Biological Chemistry

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132

119

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Edited by Jeffrey PessinFibrosis, driven by inflammation, marks the transition from benign to progressive stages of chronic liver diseases. Although inflammation promotes fibrogenesis, it is not known whether other events, such as hepatocyte death, are required for the development of fibrosis. Interferon regulatory factor 3 (IRF3) regulates hepatocyte apoptosis and production of type I IFNs. In the liver, IRF3 is activated via Toll-like receptor 4 (TLR4) signaling or the endoplasmic reticulum (ER) adapter, stimulator of interferon genes (STING). We hypothesized that IRF3-mediated hepatocyte death is an independent determinant of chemically induced liver fibrogenesis. To test this, we performed acute or chronic CCl 4 administration to WT and IRF3-, Toll/ Interleukin-1R (TIR) domain-containing adapter-inducing interferon-␤ (TRIF)-, TRIF-related adaptor molecule (TRAM)-, and STING-deficient mice. We report that acute CCl 4 administration to WT mice resulted in early ER stress, activation of IRF3, and type I IFNs, followed by hepatocyte apoptosis and liver injury, accompanied by liver fibrosis upon repeated administration of CCl 4 . Deficiency of IRF3 or STING prevented hepatocyte death and fibrosis both in acute or chronic CCl 4 . In contrast, mice deficient in type I IFN receptors or in TLR4 signaling adaptors, TRAM or TRIF, upstream of IRF3, were not protected from hepatocyte death and/or fibrosis, suggesting that the proapoptotic role of IRF3 is independent of TLR signaling in fibrosis. Hepatocyte death is required for liver fibrosis with causal involvement of STING and IRF3. Thus, our results identify that IRF3, by its association with STING in the presence of ER stress, couples hepatocyte apoptosis with liver fibrosis and indicate that innate immune signaling regulates outcomes of liver fibrosis via modulation of hepatocyte death in the liver.

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Section: Methodsmentioning

confidence: 99%

Endoplasmic Reticulum Stress-induced Hepatocellular Death Pathways Mediate Liver Injury and Fibrosis via Stimulator of Interferon Genes

Iracheta-Vellve

Petrášek

Gyöngyösi

et al. 2016

Journal of Biological Chemistry

Self Cite

132

119

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“…The abundance of each DAMP is dependent on the type of injury and metabolic events [95]. For example, uric acid and ATP are required for activation of the inflammasome and IL-1β production for the development of inflammation in AH [96]. Moreover, exposure of hepatocytes and KCs to cholesterol crystals have been suggested in the NLRP3 activation during hepatic inflammation [97,98].…”

Section: Key Players In Aldmentioning

confidence: 99%

Key Events Participating in the Pathogenesis of Alcoholic Liver Disease

2017

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Alcoholic liver disease (ALD) is a leading cause of morbidity and mortality worldwide. It ranges from fatty liver to steatohepatitis, fibrosis, cirrhosis and hepatocellular carcinoma. The most prevalent forms of ALD are alcoholic fatty liver, alcoholic hepatitis (AH) and alcoholic cirrhosis, which frequently progress as people continue drinking. ALD refers to a number of symptoms/deficits that contribute to liver injury. These include steatosis, inflammation, fibrosis and cirrhosis, which, when taken together, sequentially or simultaneously lead to significant disease progression. The pathogenesis of ALD, influenced by host and environmental factors, is currently only partially understood. To date, lipopolysaccharide (LPS) translocation from the gut to the portal blood, aging, gender, increased infiltration and activation of neutrophils and bone marrow-derived macrophages along with alcohol plus iron metabolism, with its associated increase in reactive oxygen species (ROS), are all key events contributing to the pathogenesis of ALD. This review aims to introduce the reader to the concept of alcohol-mediated liver damage and the mechanisms driving injury.

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“…Pattern recognition receptors (PRR) or DAMP receptors are thought to increase expression of pro-IL-1ß transcripts when activated by their respective ligand [22,37]. One of the commonly studied PRR families is the Toll-Like receptor (TLR) family, ubiquitously expressed on macrophages and other immune cells present in the liver.…”

Section: Introductionmentioning

confidence: 99%

Role of the inflammasome in acetaminophen-induced liver injury and acute liver failure

Woolbright

Jaeschke

2017

Journal of Hepatology

317

257

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Drug-induced acute liver failure carries a high morbidity and mortality rate. Acetaminophen overdose is the number one cause of acute liver failure and remains a major problem in Western medicine. Administration of N-acetyl cysteine is an effective antidote when given before the initial rise in toxicity; however, many patients present to the hospital after this stage occurs. As such, treatments which can alleviate late-stage acetaminophen-induced acute liver failure are imperative. While the initial mechanisms of toxicity are well described, a debate has occurred recently in the literature over whether or not there exists a second phase of injury, mediated by inflammatory processes. Critical to this potential inflammatory process is the activation of caspase-1 and interleukin-1ß by a molecular complex known as the inflammasome. A number of different stimuli for formation of multiple different inflammasome complexes have been identified. Formation of the Nalp3 inflammasome in particular has directly been attributed to late-stage acetaminophen toxicity. In this review, we will discuss mechanisms of acetaminophen-induced liver injury in mice and man with a particular focus on the role of inflammation and the inflammasome.

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Inhibition of sterile danger signals, uric acid and ATP, prevents inflammasome activation and protects from alcoholic steatohepatitis in mice

Cited by 120 publications

References 30 publications

Endoplasmic Reticulum Stress-induced Hepatocellular Death Pathways Mediate Liver Injury and Fibrosis via Stimulator of Interferon Genes

Endoplasmic Reticulum Stress-induced Hepatocellular Death Pathways Mediate Liver Injury and Fibrosis via Stimulator of Interferon Genes

Key Events Participating in the Pathogenesis of Alcoholic Liver Disease

Role of the inflammasome in acetaminophen-induced liver injury and acute liver failure

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