# Innate immune signaling in alcoholic liver disease

> **NIH NIH R01** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2021 · $393,750

## Abstract

Abstract
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.

## Key facts

- **NIH application ID:** 10092047
- **Project number:** 5R01AA017729-11
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** Gyongyi Szabo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $393,750
- **Award type:** 5
- **Project period:** 2019-09-23 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10092047

## Citation

> US National Institutes of Health, RePORTER application 10092047, Innate immune signaling in alcoholic liver disease (5R01AA017729-11). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10092047. Licensed CC0.

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