Integrated single cell analysis shows chronic alcohol drinking disrupts monocyte differentiation in the bone marrow

Chronic heavy alcohol drinking (CHD) rewires monocytes and macrophages toward heightened inflammatory states with compromised antimicrobial defenses that persist after 1-month abstinence. To determine whether these changes are mediated through alterations in the bone marrow niche, we profiled monocytes and hematopoietic stem cell progenitors (HSCPs) from CHD rhesus macaques using a combination of functional assays and single cell genomics. CHD resulted in transcriptional profiles consistent with increased activation and inflammation within bone marrow resident monocytes and macrophages. Furthermore, CHD resulted in transcriptional signatures associated with increased oxidative and cellular stress in HSCP. Differentiation of HSCP in vitro revealed skewing toward monocytes expressing "neutrophil-like" markers with greater inflammatory responses to bacterial agonists. Further analyses of HSCPs showed broad epigenetic changes that were in line with exacerbated inflammatory responses within monocytes and their progenitors. In summary, CHD alters HSCPs in the bone marrow leading to the production of monocytes poised to generate dysregulated hyper-inflammatory responses.