# Innate immune signaling in alcoholic liver disease

> **NIH NIH R56** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2024 · $292,910

## Abstract

ABSTRACT
Alcohol-associated hepatitis (AH) is the most severe manifestation of alcohol-associated liver disease that is
characterized by hepatocyte dysfunction, systemic inflammation and poor clinical outcomes. We recently
reported heterogeneity in neutrophils in AH with over-activated, high-density (HDN), and functionally
exhausted, low density (LDN) neutrophil populations that contribute to liver damage. Here we hypothesize
that alcohol-induced extracellular traps (NETs) play a role in neutrophil heterogeneity and also contribute to
hepatocyte damage, inflammation and fibrosis in AH. Our preliminary results suggest that alcohol-induced
neutrophil activation and NET release are associated with increased activation and phosphorylation of the
Bruton tyrosine kinase (BTK), a non-receptor tyrosine kinase. We postulate that BTK is a master regulator in
AH by promoting both inflammation and hepatocyte dysfunction. Given that BTK can interact with the NLRP3
inflammasome as well as the STING/IRF3 pathways that play key roles in alcohol-induced inflammation,
hepatocyte damage and steatosis, we propose to explore the role of these interactions in AH. Finally, we
propose that therapeutic inhibition of NETs, BTK, or both will ameliorate neutrophil mediated inflammation
and liver damage. The aims of this proposal are #1: To characterize neutrophil phenotypes, populations
and the role alcohol-induced NETs in AH by: a) Characterizing neutrophil phenotypes and populations
from AH patients using single cell RNAseq; b) delineating mechanisms by which alcohol-induced NETs
activate monocytes/macrophages, hepatic stellate cells and hepatocytes; c) Defining the role of BTK
activation in alcohol-induced neutrophil NET induction and LDN generation. Aim 2 will evaluate the role of
cell-specific BTK phosphorylation in AH by assessing: a) Mechanisms of BTK activation by alcohol and
defining the impact of acute and chronic alcohol on BTK activation in the liver; b) A BTK phosphorylation on
the phenotypes and NLRP3 inflammasome activation in circulating monocytes of patients with AH; c) The
effect of myeloid- and neutrophil-specific deletion of BTK in a mouse model of AH. Aim 3 will evaluate
inhibition of NETs or BTK as potential therapeutic interventions in preclinical models of AH in mice.
Results from these experiments will unravel unique heterogeneity of neutrophils in AH that will lead to better
understanding of the controversial role of neutrophils in AH. Our results will characterize the functional
impact of NETs on inflammation and fibrosis in alcohol-induced liver damage. The proposed studies will
provide novel insights into the role of BTK at the molecular and cell-specific level and define its interactions
with other key signal transduction pathways and explore BTK and/or NETs as new therapeutic targets for
amelioration of AH.

## Key facts

- **NIH application ID:** 11144753
- **Project number:** 2R56AA017729-12A1
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** Gyongyi Szabo
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $292,910
- **Award type:** 2
- **Project period:** 2009-08-20 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11144753

## Citation

> US National Institutes of Health, RePORTER application 11144753, Innate immune signaling in alcoholic liver disease (2R56AA017729-12A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/11144753. Licensed CC0.

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