# Targeting mononuclear phagocytes development in alcohol induced liver damage: pathological and immunological pathways

> **NIH NIH R01** · RUSH UNIVERSITY MEDICAL CENTER · 2020 · $353,250

## Abstract

ABSTRACT
Alcohol consumption causes a spectrum of clinical illness and morphological changes that range from fatty
liver to hepatic inflammation (alcoholic hepatitis) and progressive fibrosis (alcoholic cirrhosis). Alcoholic liver
disease has an incompletely known pathogenesis and specific treatments are lacking. It is an extremely
common disease with significant mortality and morbidity. T cellular immune responses were shown to be
affected and involved in these outcomes. Decreased resistance to infections and an abnormal systemic
inflammatory response to infections are common events associated with alcohol consumption. Alcohol
exposure has complex effects on gut permeability and the immune system, resulting in activation of
mononuclear phagocytes, steatosis, neutrophil recruitment and altered cellular immune responses. Dendritic
cells (DC), professional antigen presenting cells, are emerging as an important regulator of tissue
microenvironment. After four decades of research, we now know that DC arise from a hematopoietic lineage
distinct from other leukocytes (including monocytes and macrophages), establishing the DC lineage as a
unique hematopoietic branch. Several DC populations coexist in mice and humans with similar developmental
pathways: (1) conventional DC (cDC) involved in antigen presentation; (2) plasmacytoid DC (pDC),
characterized by a high capacity of cytokine production. pDC development and maintenance is under control of
a transcription factor: E2-2. pDC release from marrow is dependent of CCR2. These data, combined with our
central preliminary observation showing increased hepatic pDC in a well-established model of chronic alcohol
consumption, sparked the idea of a potential effect of alcohol on pDC development with accumulation of
hepatic pDC that reshapes the hepatic pro-inflammatory cytokine milieu and results in abnormal T helper 1 and
Th17 cellular immune responses known to be present after chronic alcohol consumption.
 Our long-term goal is to investigate the effects of alcohol on DC homeostasis and their effect on
immune and pathological characteristics seen in alcoholic liver disease. Our central hypothesis is that alcohol
induces abnormal DC development and hepatic pDC accumulation. The high cytokine production capacity of
pDC stimulated by bacterial products reaching the liver may contribute to hepatic and blood TNFα production,
a well-known central mediator of alcoholic liver injury. Further, pDC participate in increased generation of Th17
(well-known to be directly involved in promoting neutrophilic inflammation) and down-regulation of Th1 immune
responses. We will test our central hypothesis through the following interrelated Specific Aims: (1) We will test
whether alcohol consumption increases pDC release from bone marrow by increasing E2-2 dependent pDC
development and their CCR2 dependent egress. (2) We will test if alcohol primes hepatic pDC for NFκB-
mediated cytokine production, contributing to Th17 induction,...

## Key facts

- **NIH application ID:** 9996313
- **Project number:** 5R01AA024762-04
- **Recipient organization:** RUSH UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Costica Aloman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $353,250
- **Award type:** 5
- **Project period:** 2017-09-15 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9996313

## Citation

> US National Institutes of Health, RePORTER application 9996313, Targeting mononuclear phagocytes development in alcohol induced liver damage: pathological and immunological pathways (5R01AA024762-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9996313. Licensed CC0.

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