# Alcohol and Monocyte Signaling

> **NIH NIH R01** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2024 · $597,407

## Abstract

ABSTRACT
Alcohol use is associated with both pro-inflammatory and immunosuppressive effects; however, cellular and
molecular mechanisms or therapeutic interventions to normalize immune disturbances caused by alcohol are
yet to be explored. Increased pro-inflammatory responses in the monocyte/macrophage and neutrophil
populations are complicated by immune exhaustion leading to poor clinical outcomes in alcohol-associated
hepatitis (AH). Recent studies described “trained immunity” that is characterized by long-term epigenetic
reprogramming of innate immune cells by an infection or host factors such as, potentially, alcohol use. Our
preliminary data suggest that alcohol induces features of “trained immunity” that is characterized by enhanced
pro-inflammatory responses to subsequent insults. Thus, we hypothesize that chronic and/or binge alcohol use
result in trained immunity in monocytes/macrophages and neutrophils and this contributes to exacerbated
inflammatory responses in AH. Emerging evidence suggests that trained immunity is a result of
immunometabolic and epigenetic programming of innate immune cells including bone marrow precursors.
Consistent with this, we found increased utilization of glycolysis as opposed to OXPHOX in PBMCs of patients
with AH. Thus, we hypothesize that alcohol-induced trained immunity is mediated by immunometabolic
reprogramming. Our preliminary results also show altered metabolic profile in mice, specifically when challenged
with LPS. We postulate that by identifying key alcohol-induced immunometabolic and epigenetic events, we can
design targets for reversal of dysregulated innate immunity in AH. Our Aims are #1: To investigate the effects of
alcohol use on features of trained immunity in mouse models and in human alcohol-associated hepatitis (AH) by
a) Evaluating “trained immunity” in bone marrow granulocyte-monocyte progenitors (BM-GMP) and in liver
neutrophils and monocyte/macrophages (Mo/Mφ) in alcohol “trained mice” after an LPS challenge; b) Identifying
epigenetic features of trained immunity in liver neutrophil and Mo/Mφ populations and BM-GMP by
snRNA+scATAC seq, and determine specific gene activation/repression marks by ChIP-qPCR; c) Characterizing
the phenotypic and epigenetic signature of “trained immunity” in circulating neutrophil and Mo/Mφ populations in
AH patients. #2: To identify the immunometabolic signature in “alcohol trained” mice after an LPS challenge and
in humans with AH; and #3: To evaluate underlying mechanisms by which alcohol induces metabolic
reprogramming and trained immunity by a) Assessing the role of the cellular energy sensor “PAS Kinase” in in
vivo models of alcohol-induced trained immunity in mice; b) Restoring immune cell functionality by modulating
specific immunometabolic receptors (SUCNR1, OXGR1), and immune checkpoint receptors (PD-1); c) Targeting
key epigenetic regulators (HDAC9) in restoration of alcohol-induced trained immunity. Results from this proposal
will provide nove...

## Key facts

- **NIH application ID:** 10905941
- **Project number:** 2R01AA011576-21
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** Gyongyi Szabo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $597,407
- **Award type:** 2
- **Project period:** 1998-04-01 → 2029-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10905941

## Citation

> US National Institutes of Health, RePORTER application 10905941, Alcohol and Monocyte Signaling (2R01AA011576-21). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10905941. Licensed CC0.

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