Am J Respir Cell Mol Biol. 2022 Apr 5. doi: 10.1165/rcmb.2021-0346OC. Online ahead of print.
ABSTRACT
Chronic alcohol drinking is associated with increased susceptibility to viral and bacterial respiratory pathogens. In this study, we utilize 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 heightened inflammatory state in alveolar macrophages (AM) 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 basal state, AM from EtOH drinking animals generate elevated inflammatory mediator responses to LPS and respiratory syncytial virus (RSV). However, transcriptional analysis revealed an inefficient induction of interferon stimulated genes with EtOH in response to RSV, suggesting disruption of anti-microbial defenses. Correspondingly, AM from EtOH drinking animals exhibited transcriptional shifts indicative of increased oxidative stress and oxidative phosphorylation which was coupled with higher cytosolic reactive oxygen species (ROS) and mitochondrial potential. This heightened oxidative stress state was accompanied by decreased ability to phagocytose bacteria. Bulk RNA and ATAC sequencing data further revealed reduced expression and chromatin accessibility of loci associated with tissue repair and maintenance with chronic EtOH drinking. Similarly, analysis of scRNA-Seq 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.
PMID:35380939 | DOI:10.1165/rcmb.2021-0346OC
