Chronic heavy drinking drives distinct transcriptional and epigenetic changes in splenic macrophages.
Alcohol Drinking
/ adverse effects
Alcoholism
/ genetics
Animals
Biomarkers
Epigenesis, Genetic
Female
Gene Expression Profiling
Immunophenotyping
Lipopolysaccharides
/ immunology
Macaca mulatta
Macrophages
/ drug effects
Male
Spleen
/ cytology
Stress, Physiological
/ genetics
Transcription, Genetic
Transcriptome
Chromatin accessibility
Chronic heavy drinking
Ethanol
LPS
Rhesus macaques
Splenic macrophages
Journal
EBioMedicine
ISSN: 2352-3964
Titre abrégé: EBioMedicine
Pays: Netherlands
ID NLM: 101647039
Informations de publication
Date de publication:
May 2019
May 2019
Historique:
received:
25
01
2019
revised:
08
04
2019
accepted:
12
04
2019
pubmed:
22
4
2019
medline:
26
11
2019
entrez:
22
4
2019
Statut:
ppublish
Résumé
Chronic heavy alcohol drinking (CHD) leads to significant organ damage, increased susceptibility to infections, and delayed wound healing. These adverse outcomes are believed to be mediated by alterations in the function of myeloid cells; however, the mechanisms underlying these changes are poorly understood. We determined the impact of CHD on the phenotype of splenic macrophages using flow cytometry. Changes in functional responses to LPS were measured using luminex and RNA-Seq. Finally, alterations in chromatin accessibility were uncovered using ATAC-Seq. A history of CHD led to increased frequency of splenic macrophages that exhibited a heightened activation state at resting. Additionally, splenic macrophages from CHD animals generated a larger inflammatory response to LPS, both at protein and gene expression levels. Finally, CHD resulted in increased levels of H3K4me3, a histone mark of active promoters, as well as chromatin accessibility at promoters and intergenic regions that regulate inflammatory responses. These findings suggest that a history of CHD alters the immune fitness of tissue-resident macrophages via epigenetic mechanisms. FUND: National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health (NIH) - R24AA019431, U01 AA13641, U01 AA13510, R21AA021947, and R21AA025839.
Sections du résumé
BACKGROUND
BACKGROUND
Chronic heavy alcohol drinking (CHD) leads to significant organ damage, increased susceptibility to infections, and delayed wound healing. These adverse outcomes are believed to be mediated by alterations in the function of myeloid cells; however, the mechanisms underlying these changes are poorly understood.
METHODS
METHODS
We determined the impact of CHD on the phenotype of splenic macrophages using flow cytometry. Changes in functional responses to LPS were measured using luminex and RNA-Seq. Finally, alterations in chromatin accessibility were uncovered using ATAC-Seq.
FINDINGS
RESULTS
A history of CHD led to increased frequency of splenic macrophages that exhibited a heightened activation state at resting. Additionally, splenic macrophages from CHD animals generated a larger inflammatory response to LPS, both at protein and gene expression levels. Finally, CHD resulted in increased levels of H3K4me3, a histone mark of active promoters, as well as chromatin accessibility at promoters and intergenic regions that regulate inflammatory responses.
INTERPRETATION
CONCLUSIONS
These findings suggest that a history of CHD alters the immune fitness of tissue-resident macrophages via epigenetic mechanisms. FUND: National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health (NIH) - R24AA019431, U01 AA13641, U01 AA13510, R21AA021947, and R21AA025839.
Identifiants
pubmed: 31005514
pii: S2352-3964(19)30266-X
doi: 10.1016/j.ebiom.2019.04.027
pmc: PMC6557917
pii:
doi:
Substances chimiques
Biomarkers
0
Lipopolysaccharides
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
594-606Subventions
Organisme : NIAAA NIH HHS
ID : U01 AA013510
Pays : United States
Organisme : NIH HHS
ID : P51 OD011092
Pays : United States
Organisme : NIAAA NIH HHS
ID : U01 AA013641
Pays : United States
Organisme : NIAAA NIH HHS
ID : R21 AA021947
Pays : United States
Organisme : NIAAA NIH HHS
ID : R24 AA019431
Pays : United States
Organisme : NIAAA NIH HHS
ID : R21 AA025839
Pays : United States
Informations de copyright
Copyright © 2019. Published by Elsevier B.V.
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