Alcoholic liver disease (ALD) and its clinically most devastating presentation, alcoholic hepatitis, is a result of cumulative biological events such as leaky gut, hepatocyte damage and inflammation that collectively contribute to the severity of liver damage. Our studies delineated a unique role for interferon regulatory factor 3 (IRF3) in alcohol-related inflammation and hepatocyte damage. We reported that the endoplasmic reticulum (ER) adapter, stimulator of interferon genes (STING), is required for IRF3 phosphorylation and that IRF3 induces mitochondrial apoptosis in hepatocytes. Preliminary data shows that both alcohol binge or chronic alcohol increase circulating bacterial 16S DNA and mitochondrial DNA levels in mice and humans. These double stranded DNAs are ligands for the cyclic GMP-AMP kinase (cGAS) that produces 2?3?-cGAMP (cGAMP) that can activate STING to trigger IRF3 activation and Type I IFN production. We postulate that STING activation is at the crossroads of alcohol-induced liver pathology and in addition to ER stress, STING is also activated via cGAS-cGAMP in ALD. We further hypothesize that cGAS-mediated signals and STING activation represent a trigger for an acute-on-chronic alcohol-induced liver injury often seen in acute alcoholic hepatitis. We proposee that the cGAS-cGAMP-STING activation axis plays a role both in hepatocytes and immune cells in alcoholic hepatitis. We also discovered that sterile danger signals released by damaged hepatocytes activate the NLRP3 inflammasome in immune cells and that disruption of inflammasome activation pathways can ameliorate ALD in mice. We propose that inflammasome activation and ER stress are bi-directionally regulated in ALD.
Our Aims are: 1. To investigate the role of the DNA sensor, cGAS, and dsDNA in STING-IRF3 activation in ALD; 2. To delineate the cell-specificity of cGAS and STING activation in ALD in hepatocytes and innate immune cells; 3. To investigate interactions between ER stress, inflammasome activation and STING-IRF3 activation in ALD; 4. To investigate the biological effect and therapeutic benefit of cGAS and STING inhibition on liver damage, steatosis and inflammation in ALD. These experiments will test novel roles of the cGAS-STING innate immune signaling pathways in ALD and identify key signaling molecules, for designing new therapies for ALD.

Public Health Relevance

Alcoholic liver disease (ALD) and its clinically most devastating presentation, alcoholic hepatitis, represent the most common cause of chronic liver disease across all continents. Yet, there is no effective therapy for this disease. This research will test new mechanisms in alcoholic liver disease that contribute to liver cell damage and inflammation that are two major characteristics of the disease. Our research will identify candidate molecules that trigger acute alcoholic hepatitis. We propose to test novel interventions in the mouse model of ALD that will provide basis for future studies in patients with alcoholic hepatitis.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA017729-10
Application #
9856392
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Wang, Joe
Project Start
2019-09-23
Project End
2022-01-31
Budget Start
2020-02-01
Budget End
2021-01-31
Support Year
10
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Lowe, Patrick P; Gyongyosi, Benedek; Satishchandran, Abhishek et al. (2018) Reduced gut microbiome protects from alcohol-induced neuroinflammation and alters intestinal and brain inflammasome expression. J Neuroinflammation 15:298
Tilg, Herbert; Moschen, Alexander R; Szabo, Gyongyi (2016) Interleukin-1 and inflammasomes in alcoholic liver disease/acute alcoholic hepatitis and nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Hepatology 64:955-65
Bukong, Terence N; Iracheta-Vellve, Arvin; Saha, Banishree et al. (2016) Inhibition of spleen tyrosine kinase activation ameliorates inflammation, cell death, and steatosis in alcoholic liver disease. Hepatology 64:1057-71
Iracheta-Vellve, Arvin; Petrasek, Jan; Gyongyosi, Benedek et al. (2016) Endoplasmic Reticulum Stress-induced Hepatocellular Death Pathways Mediate Liver Injury and Fibrosis via Stimulator of Interferon Genes. J Biol Chem 291:26794-26805
Ganz, Michal; Bukong, Terence N; Csak, Timea et al. (2015) Progression of non-alcoholic steatosis to steatohepatitis and fibrosis parallels cumulative accumulation of danger signals that promote inflammation and liver tumors in a high fat-cholesterol-sugar diet model in mice. J Transl Med 13:193
Szabo, Gyongyi; Iracheta-Vellve, Arvin (2015) Inflammasome activation in the liver: Focus on alcoholic and non-alcoholic steatohepatitis. Clin Res Hepatol Gastroenterol 39 Suppl 1:S18-23
Szabo, Gyongyi; Petrasek, Jan (2015) Inflammasome activation and function in liver disease. Nat Rev Gastroenterol Hepatol 12:387-400
Sanyal, Arun J; Gao, Bin; Szabo, Gyongyi (2015) Gaps in Knowledge and Research Priorities for Alcoholic Hepatitis. Gastroenterology 149:4-9
Petrasek, Jan; Iracheta-Vellve, Arvin; Saha, Banishree et al. (2015) Metabolic danger signals, uric acid and ATP, mediate inflammatory cross-talk between hepatocytes and immune cells in alcoholic liver disease. J Leukoc Biol 98:249-56
Iracheta-Vellve, Arvin; Petrasek, Jan; Satishchandran, Abhishek et al. (2015) Inhibition of sterile danger signals, uric acid and ATP, prevents inflammasome activation and protects from alcoholic steatohepatitis in mice. J Hepatol 63:1147-55

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