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Updated: Apr 26, 2026
Assessment of Glutamine as a Fuel Source for Alveolar Macrophages Exposed to Chronic Ethanol Using an Extracellular Flux Bioanalyzer
Published on: November 15, 2024
Chronic alcohol ingestion modulates hepatic macrophage populations and functions in mice
Meng Wang1, Qiang You2, Kenton Lor1
1Skaggs School of Pharmacy and Pharmaceutical Sciences and.
Insights
Chronic ethanol feeding recruits distinct liver macrophage subsets. Ly6C-high infiltrating macrophages (IMs) promote inflammation and liver injury, while Ly6C-low IMs are protective, highlighting therapeutic targets for alcoholic liver disease (ALD).
Area of Science:
- Hepatology
- Immunology
- Cell Biology
Background:
- Hepatic macrophages, including Kupffer cells (KCs) and infiltrating monocyte-derived cells (IMs), are crucial in alcoholic liver disease (ALD) pathogenesis.
- Previous research often treated hepatic macrophages as a single entity, limiting understanding of distinct cellular roles.
Purpose of the Study:
- To differentiate and compare the phenotypes and functions of IMs versus KCs in the liver.
- To investigate the roles of distinct IM subsets in ALD.
Main Methods:
- Utilized C57BL/6J mice subjected to chronic ethanol feeding.
- Distinguished KCs and IMs using F4/80 and CD11b markers.
- Subdivided IMs into Ly6C-high and Ly6C-low populations via FACS.
- Compared phagocytic capacity and gene expression profiles.
Main Results:
- Chronic ethanol feeding induced IM recruitment into the liver.
- Ly6C-low IMs displayed anti-inflammatory and tissue-protective functions.
- Ly6C-high IMs exhibited pro-inflammatory and tissue-damaging phenotypes.
- Ethanol bingeing increased the Ly6C-high/Ly6C-low ratio, exacerbating liver injury.
- Phagocytosis of apoptotic hepatocytes induced a phenotype switch in Ly6C-high IMs to Ly6C-low IMs.
Conclusions:
- Chronic ethanol exposure recruits two IM subsets with opposing roles in liver inflammation and repair.
- Understanding these distinct macrophage populations offers insights into ALD mechanisms.
- Identified potential therapeutic targets for ALD treatment based on IM subset functions.
Abstract:
Hepatic Macs, consisting of resident KCs and infiltrating monocytes/IMs, are thought to play an important role in the pathogenesis of ALD. Previous work has focused on KCs or studied hepatic Macs as one cell population. The aim of the current study is to distinguish IMs from KCs and to compare their phenotypes and functions. We show here that a 4-week ethanol feeding of C57BL/6J mice causes recruitment of IMs into the liver. KCs and IMs can be distinguished based on their differential expression of F4/80 and CD11b. IMs can be divided further into two subsets based on their differential expression of Ly6C. KCs and two subsets of IMs were separately purified by FACS. The phagocytosis abilities and the expression profiles of genes related to various functions were compared among different populations of hepatic Macs. Ly6C(low) IMs exhibit an anti-inflammatory and tissue-protective phenotype; in contrast, Ly6C(hi) IMs exhibit a proinflammatory, tissue-damaging phenotype. The ratio of Ly6C(hi)/Ly6C(low) increases when mice chronically fed ethanol were binged, which significantly enhanced liver injury. Moreover, upon phagocytosis of apoptotic hepatocytes, Ly6C(hi) IMs switch to Ly6C(low) IMs. Taken together, chronic ethanol feeding induces the recruitment of two subsets of hepatic IMs, which play different or even opposite roles in regulating liver inflammation and repair. These findings may not only increase our understanding of the complex functions of Macs in the pathogenesis of ALD but also help us to identify novel therapeutic targets for the treatment of this disease.
