# Role of neutrophil-specific NOX2 in alcohol-induced liver injury

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · 2024 · $500,583

## Abstract

PROJECT SUMMARY
The goal of this proposal is to define the role of neutrophil-specific NADPH oxidase 2 (NOX2) in alcoholic
liver
disease(ALD) and to evaluate its potential as a therapeutic target. ALD affectsmore than 10 million people in
the U.S. and accounts for nearly half of liver cirrhosis-associated deaths. Understanding the pathogenesis of
ALD is imperative for the development of effective therapies. Neutrophil accumulation in the liver is a hallmark
for ALD. Evidence suggests that neutrophils are a key contributor to ALD. However, better understanding of
molecular pathways important in regulating neutrophil functions is required to target these cells for ALD
treatment. It is recently revealed that the activity and expression levels of NADPH oxidase (NOX)2, a major
source of reactive oxygen species (ROS), were dramatically reduced in neutrophils from patients with
advanced alcoholic cirrhosis or alcoholic hepatitis. Although ROS has been associated with inflammation,
mounting evidence also suggests that NOX2-derived ROS actually plays a critical role in limiting, rather than
promoting, inflammatory responses. Given the paradoxical role of NOX2, this proposal aims to fill the
knowledge gaps regarding whether and how NOX2 regulates neutrophil functions.
Our preliminary data demonstrate that mice with neutrophil-specific deletion of NOX2 develop exacerbated
liver injury and prolonged inflammation after chronic plus binge ethanol treatment. NOX2-deficient neutrophils
release much higher levels of IL-1 than WT-neutrophils. Together these findings led to our hypothesis that
neutrophil-specific NOX2 plays a critical role in limiting inflammation and promoting resolution of
inflammation during ALD. We propose three Specific Aims to (1) elucidate the mechanism accounting for
increased IL-1 production by NOX2-deficient neutrophils during ALD, (2) investigate the role of neutrophil-
specific NOX2 in the resolution of inflammation during ALD, (3) evaluate the potential of targeting neutrophil-
specific NOX2 to treat ALD.

## Key facts

- **NIH application ID:** 10849683
- **Project number:** 5R01AA030735-02
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
- **Principal Investigator:** Cynthia Ju
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $500,583
- **Award type:** 5
- **Project period:** 2023-06-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10849683

## Citation

> US National Institutes of Health, RePORTER application 10849683, Role of neutrophil-specific NOX2 in alcohol-induced liver injury (5R01AA030735-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10849683. Licensed CC0.

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