Abstract

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.

Document Type

Article

Publication Date

2023

Notes/Citation Information

© 2023 The Author(s). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Digital Object Identifier (DOI)

https://doi.org/10.1016/j.stemcr.2023.08.001

Funding Information

We thank the members of the Grant laboratory for expert animal care and sample procurement; Dr. Jennifer Atwood for assistance with sorting in the flow cytometry core at the Institute for Immunology, UCI; Dr. Melanie Oakes from the UCI Genomics and High- Throughput Facility for assistance with sequencing; and Dr. Helen Goodridge for assistance with CFU assay protocols and analysis. This study was supported by NIH 1R01AA028735-01 (I.M.), 5U01AA013510-20 (K.A.G.), 2R24AA019431-11 (K.A.G.), and P- 51OD011092 (ONPRC core grant support). S.A.L. was supported by NIH 1F31A028704-01. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

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