Ethanol Consumption Induces Nonspecific Inflammation and Functional Defects in Alveolar Macrophages

Sloan A. Lewis, Brianna M. Doratt, Suhas Sureshchandra, Allen Jankeel, Natali Newman, Weining Shen, Kathleen A. Grant, Ilhem Messaoudi

    Research output: Contribution to journalArticlepeer-review

    2 Scopus citations

    Abstract

    Chronic alcohol drinking is associated with increased susceptibility to viral and bacterial respiratory pathogens. In this study, we use a rhesus macaque model of voluntary ethanol self-administration to study the effects of long-term alcohol drinking on the immunological landscape of the lung. We report a heightened inflammatory state in alveolar macrophages (AMs) obtained from ethanol (EtOH)-drinking animals that is accompanied by increased chromatin accessibility in intergenic regions that regulate inflammatory genes and contain binding motifs for transcription factors AP-1, IRF8, and NFKB p-65. In line with these transcriptional and epigenetic changes at the basal state, AMs from EtOH-drinking animals generate elevated inflammatory mediator responses to lipopolysaccharides and respiratory syncytial virus. However, the transcriptional analysis revealed an inefficient induction of interferon-stimulated genes with EtOH in response to the respiratory syncytial virus, suggesting disruption of antimicrobial defenses. Correspondingly, AMs from EtOHdrinking animals exhibited transcriptional shifts indicative of increased oxidative stress and oxidative phosphorylation, which was coupled with higher cytosolic reactive oxygen species and mitochondrial potential. This heightened oxidative stress state was accompanied by decreased ability to phagocytose bacteria. Bulk RNA and assay for transposase-accessible chromatin sequencing data further revealed reduced expression and chromatin accessibility of loci associated with tissue repair and maintenance with chronic EtOH drinking. Similarly, analysis of single-cell RNA sequencing data revealed shifts in cell states from tissue maintenance to inflammatory responses with EtOH. Collectively, these data provide novel insight into mechanisms by which chronic EtOH drinking increases susceptibility to infection in patients with alcohol use disorders.

    Original languageEnglish (US)
    Pages (from-to)112-124
    Number of pages13
    JournalAmerican journal of respiratory cell and molecular biology
    Volume67
    Issue number1
    DOIs
    StatePublished - Jul 2022

    Keywords

    • alcohol
    • ATAC-Seq
    • lung
    • macrophages
    • scRNA-Seq

    ASJC Scopus subject areas

    • Molecular Biology
    • Pulmonary and Respiratory Medicine
    • Clinical Biochemistry
    • Cell Biology

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