Immune Perturbations of Macrophages, Monocytes, and Myeloid Progenitors with Chronic Alcohol Drinking
Chronic alcohol drinking adversely affects human health and is a significant risk factor for numerous conditions including cardiac and liver disease, cancer, and sepsis. Furthermore, patients who consume alcohol chronically have increased susceptibility to viral and bacterial infections, suggesting...
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| Format: | Dissertation |
| Language: | English |
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ProQuest Dissertations & Theses
01-01-2021
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| Online Access: | Get full text |
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| Summary: | Chronic alcohol drinking adversely affects human health and is a significant risk factor for numerous conditions including cardiac and liver disease, cancer, and sepsis. Furthermore, patients who consume alcohol chronically have increased susceptibility to viral and bacterial infections, suggesting compromised immune function. Studies to date have shown a disproportionate effect of alcohol on innate immune cells, notably monocytes and tissue resident macrophages, but the mechanisms by which chronic alcohol consumption leads to immune cell dysfunction remains poorly understood. Moreover, whether alcohol and its metabolic products are acting on immune cells in the periphery or on their progenitor cells in the bone marrow has yet to be investigated. This work aims to address the broad hypothesis that chronic alcohol drinking perturbs the epigenetic, transcriptomic, and functional landscapes of macrophages, monocytes, and their progenitor cells in the bone marrow. To that end, we utilized a non-human primate model of chronic alcohol self-administration, which is both physiologically relevant and accurately recapitulates human drinking behavior. After 12 months of daily alcohol drinking, we profiled three major cell populations from these animals: tissue-resident macrophages from the alveolar space, monocytes from the blood, and progenitor cells from the bone marrow. For each of these populations, we integrated large scale epigenomic and transcriptional data with cell-type relevant functional assays to explore alcohol-induced perturbations of immune function and the mechanisms behind them. In alveolar macrophages, we show increased baseline activation transcriptionally and epigenetically with alcohol, poising the cells towards heightened inflammatory responses to lipopolysaccharide (LPS) and respiratory syncytial virus (RSV). This was accompanied by increased ROS production but decreased ability to phagocytose bacteria. scRNA-Seq revealed oxidative stress and oxidative phosphorylation signatures, which was coupled with increased mitochondrial activation. These findings show reprogramming of the alveolar macrophages towards heightened inflammation and stress coupled with reduced functional capabilities with alcohol, which could lead to reduced ability of these cells to identify and clear infections. This may explain the increased susceptibility of patients who chronically consume alcohol to respiratory pathogens. Frequency of blood monocytes were increased in circulation with alcohol and showed a similar phenotype of hyper-inflammatory protein response to LPS. This was also complemented epigenetically with increased chromatin accessibility of loci encoding cytokine response genes at baseline state, suggesting alcohol is priming these cells for the inflammatory response. Moreover, similarly to alveolar macrophages, scRNA-Seq of monocytes revealed shifts towards oxidative stress and HIF1A induction indicating a broad impact of alcohol and its metabolites on circulating and tissue resident cells. As monocytes are short-lived cells in the blood, we determined that this hyper-inflammatory phenotype persisted after a one-month abstinence period from alcohol suggesting bone marrow progenitor involvement. Indeed, CD14+ cells in the bone marrow broadly expressed markers of stress and inflammation with alcohol. Assessment of the function of CD34+ progenitors suggested skewing of colony differentiation towards granulocyte/monocyte colonies and increased production of hyper-inflammatory monocytes in culture. scRNA-Seq of the CD34+ cells showed increased inflammatory markers in myeloid lineage subsets and broad signatures of oxidative stress with alcohol. Taken together, these data suggest an impact of alcohol on myeloid cell production and function at multiple levels: in the bone marrow, in circulation, and in the lung. |
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| ISBN: | 9798790630576 |