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Updated: Oct 31, 2025

Assessment of Glutamine as a Fuel Source for Alveolar Macrophages Exposed to Chronic Ethanol Using an Extracellular Flux Bioanalyzer
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Assessment of Glutamine as a Fuel Source for Alveolar Macrophages Exposed to Chronic Ethanol Using an Extracellular Flux Bioanalyzer

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Pioglitazone Reverses Alcohol-Induced Alveolar Macrophage Phagocytic Dysfunction

Samantha M Yeligar1,2, Ashish J Mehta3,2, Frank L Harris4

  • 1Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine, Emory University, Atlanta, GA; syeliga@emory.edu.

Journal of Immunology (Baltimore, Md. : 1950)
|July 1, 2021
PubMed

Insights

Alcohol use disorders impair immune cells in the lungs, increasing infection risk. Researchers found a molecular pathway involving C/EBPβ and microRNAs that drives this dysfunction, offering a potential therapeutic target.

Area of Science:

  • Immunology
  • Molecular Biology
  • Pharmacology

Background:

  • Alcohol use disorders (AUD) significantly increase susceptibility to respiratory infections due to impaired alveolar macrophage (AM) immune function.
  • Alcohol induces oxidative stress in AMs, reducing their ability to clear microbes, partly by increasing NADPH oxidases (Noxes) and decreasing peroxisome proliferator-activated receptor γ (PPARγ).

Purpose of the Study:

  • To investigate the molecular mechanisms underlying alcohol-induced AM dysfunction.
  • To determine if CCAAT/enhancer-binding protein β (C/EBPβ) and Nox-related microRNAs (miRs) mediate alcohol's effects on AMs.
  • To assess the therapeutic potential of PPARγ activation in mitigating alcohol-induced AM dysfunction.

Main Methods:

  • Analysis of AMs isolated from human AUD subjects and control subjects.
  • Examination of C/EBPβ activation, Nox-related miR expression (miR-1264, miR-107), and Nox expression (Nox1, Nox2, Nox4) and activity.
  • Intervention studies involving C/EBPβ inhibition, miR overexpression, and pioglitazone (a PPARγ agonist) treatment.

Main Results:

  • Alcohol activated C/EBPβ in AMs, decreased miR-1264 and miR-107, and increased Nox1, Nox2, and Nox4 expression and activity.
  • These alcohol-induced changes were reversed by inhibiting C/EBPβ, overexpressing the miRs, or treating with pioglitazone.
  • Pharmacologic activation of PPARγ with pioglitazone attenuated alcohol-induced AM dysfunction.

Conclusions:

  • Alcohol-induced AM dysfunction is mediated by C/EBPβ-driven suppression of Nox-related miRs, leading to increased oxidative stress and impaired phagocytosis.
  • PPARγ ligands, such as pioglitazone, represent a promising therapeutic strategy to counteract alcohol-induced immune deficits and reduce respiratory infection risk in individuals with AUD.

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