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Published on: November 15, 2024
Peroxisome Proliferator-Activated Receptor γ Regulates Chronic Alcohol-Induced Alveolar Macrophage Dysfunction
Samantha M Yeligar1,2, Ashish J Mehta2, Frank L Harris1
11 Emory University, Department of Pediatrics, Division of Neonatal-Perinatal Medicine, Emory and Children's Healthcare of Atlanta Center for Developmental Lung Biology, Atlanta, Georgia.
Abstract:
Peroxisome proliferator-activated receptor (PPAR) γ is critical for alveolar macrophage (AM) function. Chronic alcohol abuse causes AM phagocytic dysfunction and susceptibility to respiratory infections by stimulating nicotinamide adenine dinucleotide oxidases (Nox), transforming growth factor-β1, and oxidative stress in the AM. Because PPARγ inhibits Nox expression, we hypothesized that alcohol reduces PPARγ, stimulating AM dysfunction. AMs were examined from: (1) patients with alcoholism or control patients; (2) a mouse model of chronic ethanol consumption; (3) PPARγ knockout mice; or (4) MH-S cells exposed to ethanol in vitro. Alcohol reduced AM PPARγ levels and increased Nox1, -2, and -4, transforming growth factor-β1, oxidative stress, and phagocytic dysfunction. Genetic loss of PPARγ recapitulated, whereas stimulating PPARγ activity attenuated alcohol-mediated alterations in gene expression and phagocytic function, supporting the importance of PPARγ in alcohol-induced AM derangements. Similarly, PPARγ activation in vivo reduced alcohol-mediated impairments in lung bacterial clearance. Alcohol increased levels of microRNA-130a/-301a, which bind to the PPARγ 3' untranslated region to reduce PPARγ expression. MicroRNA-130a/-301a inhibition attenuated alcohol-mediated PPARγ reductions and derangements in AM gene expression and function. Alcohol-induced Toll-like receptor 4 endocytosis was reversed by PPARγ activation. These findings demonstrate that targeting PPARγ provides a novel therapeutic approach for mitigating alcohol-induced AM derangements and susceptibility to lung infection.
Insights
Chronic alcohol abuse impairs alveolar macrophage function by reducing peroxisome proliferator-activated receptor gamma (PPARγ). Restoring PPARγ levels can mitigate alcohol-induced lung damage and susceptibility to infections.
Area of Science:
- Immunology
- Cell Biology
- Toxicology
Background:
- Alveolar macrophages (AMs) are crucial for lung immunity.
- Chronic alcohol abuse leads to AM phagocytic dysfunction and increased respiratory infection risk.
- Alcohol's effects are linked to nicotinamide adenine dinucleotide oxidases (Nox), transforming growth factor-β1, and oxidative stress.
Purpose of the Study:
- To investigate the role of peroxisome proliferator-activated receptor gamma (PPARγ) in alcohol-induced AM dysfunction.
- To determine if alcohol reduces PPARγ expression, leading to AM impairment.
- To explore therapeutic strategies targeting PPARγ for alcohol-related lung issues.
Main Methods:
- Examined AMs from human alcoholism patients and control groups.
- Utilized a mouse model of chronic ethanol consumption.
- Studied PPARγ knockout mice and in vitro cell models (MH-S cells) exposed to ethanol.
- Assessed gene expression, oxidative stress, phagocytic function, and microRNA levels.
Main Results:
- Alcohol consumption reduced PPARγ levels in AMs.
- Alcohol increased Nox1, Nox2, Nox4, transforming growth factor-β1, and oxidative stress, impairing phagocytosis.
- PPARγ loss mimicked alcohol-induced dysfunction; PPARγ activation reversed these effects.
- Alcohol increased microRNA-130a/-301a, which target PPARγ, and their inhibition restored PPARγ levels and function.
- PPARγ activation reversed alcohol-induced Toll-like receptor 4 endocytosis.
Conclusions:
- Alcohol abuse decreases PPARγ in AMs, causing phagocytic dysfunction and increased infection susceptibility.
- Targeting PPARγ is a potential therapeutic strategy to combat alcohol-induced lung derangements.
- MicroRNA-130a/-301a play a role in alcohol-mediated PPARγ suppression.
