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

Sloan A. Lewis; Brianna M. Doratt; Qi Qiao; Madison Blanton; Kathleen A. Grant; Ilhem Messaoudi

doi:10.1016/j.stemcr.2023.08.001

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

Sloan A. Lewis
, Brianna M. Doratt
, Qi Qiao
, Madison Blanton
, Kathleen A. Grant
, Ilhem Messaoudi

Research output: Contribution to journal › Article › peer-review

13 Scopus citations

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.

Original language	English
Pages (from-to)	1884-1897
Number of pages	14
Journal	Stem Cell Reports
Volume	18
Issue number	9
DOIs	https://doi.org/10.1016/j.stemcr.2023.08.001
State	Published - Sep 12 2023

Bibliographical note

Publisher Copyright:
© 2023 The Author(s)

Funding

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.

Funders	Funder number
National Institutes of Health (NIH)	5U01AA013510-20, 1R01AA028735-01, P-51OD011092, 2R24AA019431-11
Oregon National Primate Research Center	1F31A028704-01

Keywords

alcohol
bone marrow
monocytes
monopoiesis
myelopoiesis
non-human primates
progenitors

ASJC Scopus subject areas

Biochemistry
Genetics
Developmental Biology
Cell Biology

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10.1016/j.stemcr.2023.08.001

Cite this

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title = "Integrated single cell analysis shows chronic alcohol drinking disrupts monocyte differentiation in the bone marrow",

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.",

keywords = "alcohol, bone marrow, monocytes, monopoiesis, myelopoiesis, non-human primates, progenitors",

author = "Lewis, \{Sloan A.\} and Doratt, \{Brianna M.\} and Qi Qiao and Madison Blanton and Grant, \{Kathleen A.\} and Ilhem Messaoudi",

note = "Publisher Copyright: {\textcopyright} 2023 The Author(s)",

year = "2023",

month = sep,

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doi = "10.1016/j.stemcr.2023.08.001",

language = "English",

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AU - Lewis, Sloan A.

AU - Doratt, Brianna M.

AU - Qiao, Qi

AU - Blanton, Madison

AU - Grant, Kathleen A.

AU - Messaoudi, Ilhem

PY - 2023/9/12

Y1 - 2023/9/12

N2 - 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.

AB - 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.

KW - alcohol

KW - bone marrow

KW - monocytes

KW - monopoiesis

KW - myelopoiesis

KW - non-human primates

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

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

Access to Document

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