# Transcriptional and non-transcriptional function of IRF3 in ALD

> **NIH NIH R01** · CLEVELAND CLINIC LERNER COM-CWRU · 2024 · $567,648

## Abstract

ABSTRACT
Chronic alcohol abuse underlies the pathogenesis of alcohol-associated liver disease (ALD), encompassed by
a spectrum of pathologies, ranging from steatosis, to more severe forms of liver injury, including alcohol-
associated hepatitis (AH), fibrosis, and cirrhosis. Acute AH has a very high mortality rate, with no effective
therapeutic Patients with AH who exhibit stage 3-4 fibrosis have worse prognosis; however, treatment strategies do
not include therapy for the resolution of fibrosis, representing an important unmet clinical need. Recruitment of innate
immune cells to the liver and the regulation of their phenotype between pro-inflammatory/fibrogenic vs pro-resolution
activity, impacts both disease progression and resolution. Hepatic stellate cells (HSC), the primary producer of
extracellular matrix in the liver, are also regulated by innate immune pathways. During the previous granting cycle,
we discovered that IRF3-dependent pathways, a component of host anti-viral responses, contribute to injury in
murine models of ALD, NAFL/NASH and fibrosis. These data led us to ask the fundamental question: what is the
mechanism by which metabolic/sterile liver diseases activate anti-viral signaling and can this be leveraged to
develop novel therapeutics? We identified perturbations in homeostatic regulation of endogenous dsRNA in both
immune cells and HSCs suggesting that endogenous dsRNAs are novel host-derived DAMPs that activate IRF3
signaling and contribute to the pathogenesis of ALD. IRF3 is classically recognized as a transcription factor
essential for host anti-viral responses, but also has non-transcriptional activities. Using a novel knock-in mouse
expressing an IRF3 protein that only exhibits non-transcriptional functions of IRF3 (Irf3S1/S1), we discovered that
1) IRF3-mediated apoptosis of innate immune cells recruited to the liver in response to Gao-binge ethanol increases
inflammation and liver injury and 2) non-transcriptional functions of IRF3 restricted NFκB activity in a murine model
of NAFL/NASH. Here we propose to extend our studies into IRF3 functions in pathogenesis of hepatic fibrosis in
two specific aims: 1) Determine the contribution of the transcriptional and non-transcriptional IRF3 to murine
models of hepatic fibrosis: Using Irf3-/-, Irf3S1/S1 and cell-specific deletions of Irf3, we will test the hypothesis that
non-transcriptional activity of IRF3 contributes to recruitment of neutrophils to liver and enhances activation of
HSCs in mice exposed to CCl4+ethanol or CDAA models of fibrosis. 2) Discover the cell intrinsic functions of
IRF3 in the pathogenesis of fibrosis: Mechanistically, we will identify specific dsRNAs accumulating in cultured
HSCs and neutrophils, interrogate perturbations in expression of RNA chaperones and dsRNA recognition
molecules critical to IRF3 activation in fibrosis. Further, we will interrogate mechanisms for Irf3-dependent cell-
cell interactions in fibrosis using human-iPSC 3-dimensional l...

## Key facts

- **NIH application ID:** 10998989
- **Project number:** 2R01AA027456-04A1
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** LAURA E. NAGY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $567,648
- **Award type:** 2
- **Project period:** 2019-07-05 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10998989

## Citation

> US National Institutes of Health, RePORTER application 10998989, Transcriptional and non-transcriptional function of IRF3 in ALD (2R01AA027456-04A1). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/10998989. Licensed CC0.

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