Chronic heavy drinking drives distinct transcriptional and epigenetic changes in splenic macrophages

Sureshchandra, Suhas; Stull, Cara; Ligh, Brian Jin Kee; Nguyen, Selene Bich; Grant, Kathleen A.; Messaoudi, Ilhem

doi:10.1016/j.ebiom.2019.04.027

Cited by 21 publications

(44 citation statements)

References 77 publications

(85 reference statements)

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“…To understand functional consequences of CHD in relevant tissue-resident macrophages, we assessed alveolar macrophages (AM) isolated from bronchoalveolar lavage (BAL) samples taken from male and female macaques. Unlike our results from blood (Figure 2A) and the spleen (41) myeloid cells, no differences in relative frequency of AM were noted in the BAL with CHD (Figure 5C). Purified AM from control and CHD animals were stimulated with LPS (16 hours) and production of immune mediators was measured by Luminex (Supp.…”

contrasting

confidence: 99%

“…In contrast, prolonged exposure to alcohol results in increased production of pro-inflammatory mediators, notably TNF in response to LPS or PMA stimulation (22,25) potentially due to enhanced activation of NFB and ERK kinases (26). In line with these observations, monocytes as well as tissue resident macrophages, including Kupffer cells (27), microglia (28), alveolar macrophages (29), and splenic macrophages (17,30) taken from patients with alcoholic liver disease (ALD) produce higher levels of TNF- at resting state as well as in response to LPS (31).…”

Section: Introductionmentioning

confidence: 79%

“…Using this model, we reported that CHD disrupts the resting transcriptome and results in heightened inflammatory responses by peripheral blood mononuclear cells (PBMC) from male and female macaques (18,40). Additionally, splenic macrophages from CHD monkeys generate a hyper-inflammatory response following LPS stimulation that is accompanied by increased chromatin accessibility at promoters and intergenic regions that regulate genes important for inflammatory responses (41).…”

Section: Introductionmentioning

confidence: 99%

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Transcriptional, epigenetic, and functional reprogramming of blood monocytes in non-human primates following chronic alcohol drinking

Lewis

Sureshchandra

Doratt

et al. 2021

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Chronic heavy drinking (CHD) of alcohol is a known risk factor for increased susceptibility to bacterial and viral infection as well as impaired wound healing. Evidence suggests that these defects are mediated by a dysregulated inflammatory response originating from myeloid cells, notably monocytes and macrophages, but the mechanisms remain poorly understood. Our ability to study CHD is impacted by the complexities of human drinking patterns and behavior as well as comorbidities and confounding risk factors for patients with alcohol use disorders. To overcome these challenges, we utilize a translational rhesus macaque model of voluntary ethanol self-administration that closely recapitulates human drinking patterns and chronicity. In this study, we examined the effects of CHD on blood monocytes and alveolar macrophages in control and CHD female macaques after 12 months of daily ethanol consumption. While monocytes from CHD female macaques generated a hyper-inflammatory response to ex vivo LPS stimulation, their response to E.Coli was dampened. In depth scRNA-Seq analysis of purified monocytes revealed significant shifts in classical monocyte subsets with accumulation of cells expressing markers of hypoxia (HIF1A) and inflammation (NFkB signaling pathway) in CHD macaques. The increased presence of monocyte subsets poised to generate a hyperinflammatory response was confirmed by the epigenetic analysis which revealed higher accessibility of promoter regions that regulate genes involved in cytokine signaling pathways. Finally, alveolar macrophages (AM) from the same animals produced higher levels of inflammatory mediators in response to LPS stimulation, but reduced ability to phagocytose bacteria. Collectively, data presented in this manuscript demonstrate that CHD primes monocytes and tissue-resident macrophages towards a more hyper-inflammatory immune response with compromised functional abilities, which could be used in diagnostic purposes or preventative measures for patients with alcohol use disorders.

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confidence: 99%

Section: Introductionmentioning

confidence: 79%

Section: Introductionmentioning

confidence: 99%

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Transcriptional, epigenetic, and functional reprogramming of blood monocytes in non-human primates following chronic alcohol drinking

Lewis

Sureshchandra

Doratt

et al. 2021

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“…Chronic heavy alcohol drinking has been shown cause activation and hyper-inflammation in monocytes in the blood (31) and macrophages in the spleen (32). The alveolar space in the lung is home to a large population of tissue-resident macrophages and infiltrating monocytes that are the first responders to respiratory infections.…”

Section: Chronic Etoh Exposure Alters Surface Activation and Chemokine Receptor Expression On Monocyte And Macrophage Populations In The mentioning

confidence: 99%

Chronic ethanol drinking in non-human primates induces inflammatory cathepsin gene expression in alveolar macrophages accompanied by functional defects

Lewis

Doratt

Sureshchandra

et al. 2021

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Chronic alcohol drinking is associated with increased susceptibility to viral and bacterial respiratory pathogens. Investigating the effects of alcohol on the lung is challenging in humans because of the complexity of human drinking behavior and the challenge of obtaining samples. In this study, we utilize a rhesus macaque model of voluntary ethanol self-administration to study the effects of alcohol on the lung in a physiologically and genetically relevant model. We report a heightened activation and inflammatory state in alveolar macrophages (AM) obtained from ethanol drinking animals that is accompanied by increased chromatin accessibility in intergenic regions that regulate inflammatory genes and contain binding motifs for transcription factors AP-1, IRF8, and NFKB p-65. In line with these transcriptional and epigenetic changes at basal state, AM from ethanol drinking animals generate elevated inflammatory mediator responses to LPS and respiratory syncytial virus (RSV). Analysis using scRNA-Seq revealed heterogeneity in lung-resident macrophage and monocyte populations, including increased abundance of activated and cathepsin-expressing clusters and accelerated differentiation with ethanol. Finally, functional assays show increased mitochondrial content in AM from ethanol drinking animals, which is associated with observed increased ROS and decreased phagocytosis capacity. This comprehensive epigenomic, transcriptional and functional profiling of lung macrophages after ethanol drinking in macaques provides previously unidentified mechanisms of ethanol induced infection susceptibility in patients with alcohol use disorders.

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“…s c r i p t resident macrophages via epigenetic mechanisms(Sureshchandra et al 2019b). Recent studies have highlighted the NRLP3 inflammasome (a cytosolic complex of the innate immune system mainly expressed by myeloid cells like monocytes and macrophages) as an important inhibitory target of ethanol(Nurmi et al 2013).…”

mentioning

confidence: 99%

Ethanol and its metabolites: update on toxicity, benefits, and focus on immunomodulatory effects

Daré

Lagente

Gicquel

2019

Drug Metabolism Reviews

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This article summarizes recent experimental and epidemiological data on the toxic and beneficial effects of ethanol and its metabolites (acetaldehyde), and focuses on their immunomodulatory effects. The section dealing with the toxic effects of alcohol focuses on its chronic toxicity (liver disorders, carcinogenic effects, cardiovascular disorders, neuropsychic disorders, addiction and withdrawal syndrome, hematologic disorders, reprotoxicity, osteoporosis) although acute toxicity is considered. The role of oxidative metabolism of ethanol by alcohol dehydrogenase, cytochrome P450 2E1, and aldehyde dehydrogenase, as well as the impact of genetic polymorphism in its physiopathology are also highlighted. The section dealing with the beneficial effects of low to moderate alcohol consumption (on cardiovascular system, diabetes, the nervous system and sensory organs, autoimmune diseases, and rheumatology) highlights the importance of anti-inflammatory and immunomodulatory effects in these observations. This knowledge, enriched by a focus on the immunomodulatory effects of ethanol and its metabolites, in particular on the NLRP3 inflammasome pathway, might facilitate the development of treatments that can reduce ethanol's harmful effects or accentuate its beneficial effects.

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Chronic heavy drinking drives distinct transcriptional and epigenetic changes in splenic macrophages

Cited by 21 publications

References 77 publications

Transcriptional, epigenetic, and functional reprogramming of blood monocytes in non-human primates following chronic alcohol drinking

Transcriptional, epigenetic, and functional reprogramming of blood monocytes in non-human primates following chronic alcohol drinking

Chronic ethanol drinking in non-human primates induces inflammatory cathepsin gene expression in alveolar macrophages accompanied by functional defects

Ethanol and its metabolites: update on toxicity, benefits, and focus on immunomodulatory effects

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