# Role of macrophage evolution in hepatic adaptation to alcohol.

> **NIH VA I01** · KANSAS CITY VA MEDICAL CENTER · 2020 · —

## Abstract

PROJECT TITLE: Role of macrophage evolution in hepatic adaptation to alcohol
PROJECT SUMMARY / ABSTRACT
Acute alcoholic hepatitis (AH) is a severe inflammatory liver disease triggered by binge drinking. The disease
has a 30-day mortality of approximately 20%. One of the most striking features of AH is that it affects only a
small minority of heavy drinkers suggesting that most individuals are protected from developing alcoholic liver
disease by as yet unknown mechanisms. We have recently shown that alcohol exposure in mice causes early
changes in liver macrophage (MΦ) populations with a loss of up to 50% of Kupffer cells and entry of infiltrating
macrophages. By 10 days, Kupffer cell numbers are restored but their gene expression patterns have become
more like anti-inflammatory M2 macrophages. By 35 days of alcohol exposure, the hepatic MΦ gene expression
pattern changes further with a decrease in some of the classic M2 markers and the development of a gene
expression pattern associated with a restorative MΦ phenotype. The macrophage population changes correlate
with changes in the sensitivity of the liver to a challenge with LPS. We hypothesize that the “lost” Kupffer cells
are rapidly replaced by “adaptive” macrophages leading to a state in which liver inflammation is minimal. This
adaptive macrophage formation requires Kupffer cell-derived apoptotic bodies and Th2 cytokines such as IL4
and IL13. The balance of pro-and anti-inflammatory MΦs and the nature of the hepatic adaptive MΦ populations
change over time so that with prolonged alcohol exposure, adaptation can be lost and liver inflammation can
occur. Better understanding of the nature of the adaptive macrophages and the factors that lead to their
formation, maintenance and loss would provide new approaches for the therapy of alcoholic liver disease. We
will explore this hypothesis with the following specific aims: Aim 1: To determine the origins, gene expression
patterns and functional properties of the mouse liver MΦ subtypes that appear after alcohol exposure.
We will use lineage tracing techniques and single cell RNA sequencing to define the origin and diversity of the
macrophage populations present. We will then isolate the adaptive macrophage populations to determine their
functional properties both in vivo and in vitro. Aim 2: To define the signals responsible for production and
maintenance of alcohol adaptive MΦ populations. We will examine the role of specific apoptotic body
receptors, the impact of different sources of apoptotic bodies, timing of apoptotic body formation within the liver,
and the role of hepatocyte derived factors in the formation of adaptive macrophage populations. Aim 3: To
identify macrophage/monocyte populations that contribute to alcohol adaptation in humans. These
experiments will leverage the mouse findings made in the first two aims to identify alcohol adaptive macrophage
populations in humans. This will be done by immunohistochemical analysis of macropha...

## Key facts

- **NIH application ID:** 9782671
- **Project number:** 1I01BX004694-01
- **Recipient organization:** KANSAS CITY VA MEDICAL CENTER
- **Principal Investigator:** STEVEN A WEINMAN
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2019-10-01 → 2023-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9782671

## Citation

> US National Institutes of Health, RePORTER application 9782671, Role of macrophage evolution in hepatic adaptation to alcohol. (1I01BX004694-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9782671. Licensed CC0.

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