Alcohol dependence promotes systemic IFN-γ and IL-17 responses in mice

AbstractAlcohol use disorder (AUD) is a chronic relapsing disorder characterized by an impaired ability to stop or control alcohol use despite adverse social, occupational, or health consequences. AUD is associated with a variety of physiological changes and is a substantial risk factor for numerous diseases. We aimed to characterize systemic alterations in immune responses using a mouse model of chronic intermittent alcohol exposure to induce alcohol dependence. We exposed mice to chronic intermittent ethanol vapor for 4 weeks and used multiparametric flow cytometry to analyze the expression of cytokines IFN-γ, IL-4, IL-10, IL-12 and IL-17 by different immune cells in the blood, spleen and liver of alcohol dependent and non-dependent control mice. We found increases in IFN-γ and IL-17 expression in a cell type- and organ-specific manner. Often, B cells and neutrophils are primary contributors to increased IFN-γ and IL-17 levels while other cell types play a secondary role. We conclude that chronic alcohol exposure promotes systemic pro-inflammatory IFN-γ and IL-17 responses in mice. These responses are likely important in the development of alcohol-related diseases, but further characterization is necessary to understand the initiation and effects of systemic inflammatory responses to chronic alcohol exposure.

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Alcohol dependence promotes systemic IFN-γ and IL-17 responses in mice

PLoS ONE ◽

10.1371/journal.pone.0239246 ◽

2020 ◽

Vol 15 (12) ◽

pp. e0239246

Author(s):

Kayla Frank ◽

Shawn Abeynaike ◽

Rana Nikzad ◽

Reesha R. Patel ◽

Amanda J. Roberts ◽

...

Keyword(s):

Alcohol Use ◽

Alcohol Dependence ◽

Inflammatory Responses ◽

Alcohol Exposure ◽

Cell Types ◽

Ethanol Vapor ◽

Chronic Alcohol ◽

Multiparametric Flow Cytometry ◽

Chronic Alcohol Exposure ◽

Ifn Γ

Alcohol use disorder (AUD) is a chronic relapsing disorder characterized by an impaired ability to stop or control alcohol use despite adverse social, occupational, or health consequences. AUD is associated with a variety of physiological changes and is a substantial risk factor for numerous diseases. We aimed to characterize systemic alterations in immune responses using a well-established mouse model of chronic intermittent alcohol exposure to induce alcohol dependence. We exposed mice to chronic intermittent ethanol vapor for 4 weeks and analyzed the expression of cytokines IFN-γ, IL-4, IL-10, IL-12 and IL-17 by different immune cells in the blood, spleen and liver of alcohol dependent and non-dependent control mice through multiparametric flow cytometry. We found increases in IFN-γ and IL-17 expression in a cell type- and organ-specific manner. Often, B cells and neutrophils were primary contributors to increased IFN-γ and IL-17 levels while other cell types played a secondary role. We conclude that chronic alcohol exposure promotes systemic pro-inflammatory IFN-γ and IL-17 responses in mice. These responses are likely important in the development of alcohol-related diseases, but further characterization is necessary to understand the initiation and effects of systemic inflammatory responses to chronic alcohol exposure.

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Alcohol Dependence in Rats Is Associated with Global Changes in Gene Expression in the Central Amygdala

Brain Sciences ◽

10.3390/brainsci11091149 ◽

2021 ◽

Vol 11 (9) ◽

pp. 1149

Author(s):

Brent R. Kisby ◽

Sean P. Farris ◽

Michelle M. McManus ◽

Florence P. Varodayan ◽

Marisa Roberto ◽

...

Keyword(s):

Gene Expression ◽

Endothelial Cells ◽

Alcohol Dependence ◽

Functional Groups ◽

Molecular Mechanisms ◽

Alcohol Exposure ◽

Cell Types ◽

Behavioral Changes ◽

Molecular Pathways ◽

Chronic Alcohol

Alcohol dependence is associated with adverse consequences of alcohol (ethanol) use and is evident in most severe cases of alcohol use disorder (AUD). The central nucleus of the amygdala (CeA) plays a critical role in the development of alcohol dependence and escalation of alcohol consumption in dependent subjects. Molecular mechanisms underlying the CeA-driven behavioral changes are not well understood. Here, we examined the effects of alcohol on global gene expression in the CeA using a chronic intermittent ethanol (CIE) vapor model in rats and RNA sequencing (RNA-Seq). The CIE procedure resulted in robust changes in CeA gene expression during intoxication, as the number of differentially expressed genes (DEGs) was significantly greater than those expected by chance. Over-representation analysis of cell types, functional groups and molecular pathways revealed biological categories potentially important for the development of alcohol dependence in our model. Genes specific for astrocytes, myelinating oligodendrocytes, and endothelial cells were over-represented in the DEG category, suggesting that these cell types were particularly affected by the CIE procedure. The majority of the over-represented functional groups and molecular pathways were directly related to the functions of glial and endothelial cells, including extracellular matrix (ECM) organization, myelination, and the regulation of innate immune response. A coordinated regulation of several ECM metalloproteinases (e.g., Mmp2; Mmp14), their substrates (e.g., multiple collagen genes and myelin basic protein; Mbp), and a metalloproteinase inhibitor, Reck, suggests a specific mechanism for ECM re-organization in response to chronic alcohol, which may modulate neuronal activity and result in behavioral changes, such as an escalation of alcohol drinking. Our results highlight the importance of glial and endothelial cells in the effects of chronic alcohol exposure on the CeA, and demonstrate further insight into the molecular mechanisms of alcohol dependence in rats. These molecular targets may be used in future studies to develop therapeutics to treat AUD.

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DNA Methylation of the Leptin Gene Promoter is Altered by Chronic Alcohol Exposure in an Animal Model for Alcohol Dependence

European Addiction Research ◽

10.1159/000496111 ◽

2019 ◽

Vol 25 (2) ◽

pp. 49-55 ◽

Cited By ~ 3

Author(s):

Jelte Wieting ◽

Mathias Rhein ◽

Thomas Hillemacher ◽

Ralf Lichtinghagen ◽

Viktoria Hoppe ◽

...

Keyword(s):

Dna Methylation ◽

Animal Model ◽

Alcohol Dependence ◽

Gene Promoter ◽

Alcohol Exposure ◽

Chronic Alcohol ◽

Chronic Alcohol Exposure

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P.5.029 P300 abnormality due to chronic alcohol exposure in patients with alcohol dependence

European Neuropsychopharmacology ◽

10.1016/s0924-977x(97)88862-1 ◽

1997 ◽

Vol 7 ◽

pp. S261

Author(s):

M. Fatih Karaaslan ◽

Seher Sofuoǧlu ◽

İbrahim Eren ◽

Mustafa Baştürk ◽

Ali Saffet Gönül ◽

...

Keyword(s):

Alcohol Dependence ◽

Alcohol Exposure ◽

Chronic Alcohol ◽

Chronic Alcohol Exposure

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Effects of Chronic Alcohol Exposure on Kainate Receptor-Mediated Neurotransmission in the Hippocampus

10.21236/ada412906 ◽

2002 ◽

Author(s):

C. F. Valenzuela ◽

Daniel D. Savage ◽

Jeff. L. Weiner

Keyword(s):

Alcohol Exposure ◽

Kainate Receptor ◽

Chronic Alcohol ◽

Chronic Alcohol Exposure

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Effects of Chronic Alcohol Exposure on Kainate Receptor-Mediated Neurotransmission in the Hippocampus

10.21236/ada434072 ◽

2004 ◽

Author(s):

C. F. Valenzuela

Keyword(s):

Alcohol Exposure ◽

Kainate Receptor ◽

Chronic Alcohol ◽

Chronic Alcohol Exposure

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CB1R Promotes Chronic Alcohol-Induced Neuronal Necroptosis in Mice Prefrontal Cortex

Alcohol and Alcoholism ◽

10.1093/alcalc/agaa135 ◽

2020 ◽

Author(s):

Lin Ye ◽

Shuhao Li ◽

Xiaochen Liu ◽

Dingang Zhang ◽

Liliang Li ◽

...

Keyword(s):

Prefrontal Cortex ◽

Protein Level ◽

Cannabinoid Receptors ◽

Alcohol Exposure ◽

Global Burden ◽

Dependent Manner ◽

Chronic Alcohol ◽

Inverse Agonists ◽

Alcohol Vapor ◽

Chronic Alcohol Exposure

Abstract Aims Alcohol abuse induces multiple neuropathology and causes global burden to human health. Prefrontal cortex (PFC) is one of the most susceptible regions to alcohol-induced neuropathology. However, precise mechanisms underlying these effects on PFC remain to be elucidated. Herein, we investigated whether RIP1/RIP3/MLKL-mediated necroptosis was involved in the alcohol-induced PFC injury, and explored the effect that cannabinoid receptors (CBRs) exerted on the neurotoxicity of alcohol. Methods In this study, dynamic development of neuronal necroptosis in the PFC region was monitored after 95% (v/v) alcohol vapor administration for 15 and 30 days, respectively. Selective CBRs agonists or inverse agonists were pretreated according to the experimental design. All the PFC tissues were isolated and further examined by biochemical and histopathological analyses. Results It was found that chronic alcohol exposure increased the protein level of MLKL and also the phosphorylated levels of RIP1, RIP3 and MLKL in a time-dependent manner, all of which indicated the activation of necroptosis signaling. Particularly, compared to astrocytes, neurons from the PFC showed more prototypical necrotic morphology in response to alcohol insults. In parallel, an increased protein level of CB1R was also found after 15 and 30 days alcohol exposure. Administration of specific inverse agonists of CB1R (AM251 and AM281), but not its agonists or CB2R modulators, significantly alleviated the RIP1/RIP3/MLKL-mediated neuronal necroptosis. Conclusion We reported the involvement of RIP1/RIP3/MLKL-mediated necroptosis in alcohol-induced PFC neurotoxicity, and identified CB1R as a critical regulator of neuronal necroptosis that enhanced our understanding of alcohol-induced neuropathology in the PFC.

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Chronic alcohol exposure inhibits biotin uptake by pancreatic acinar cells: possible involvement of epigenetic mechanisms

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00278.2014 ◽

2014 ◽

Vol 307 (9) ◽

pp. G941-G949 ◽

Cited By ~ 8

Author(s):

Padmanabhan Srinivasan ◽

Rubina Kapadia ◽

Arundhati Biswas ◽

Hamid M. Said

Keyword(s):

Transgenic Mice ◽

Chronic Exposure ◽

Methylation Status ◽

Acinar Cells ◽

Alcohol Exposure ◽

Significant Inhibition ◽

Pancreatic Acinar Cells ◽

Chronic Alcohol ◽

Wild Type ◽

Chronic Alcohol Exposure

Chronic exposure to alcohol affects different physiological aspects of pancreatic acinar cells (PAC), but its effect on the uptake process of biotin is not known. We addressed this issue using mouse-derived pancreatic acinar 266-6 cells chronically exposed to alcohol and wild-type and transgenic mice (carrying the human SLC5A6 5′-promoter) fed alcohol chronically. First we established that biotin uptake by PAC is Na+ dependent and carrier mediated and involves sodium-dependent multivitamin transporter (SMVT). Chronic exposure of 266-6 cells to alcohol led to a significant inhibition in biotin uptake, expression of SMVT protein, and mRNA as well as in the activity of the SLC5A6 promoter. Similarly, chronic alcohol feeding of wild-type and transgenic mice carrying the SLC5A6 promoter led to a significant inhibition in biotin uptake by PAC, as well as in the expression of SMVT protein and mRNA and the activity of the SLC5A6 promoters expressed in the transgenic mice. We also found that chronic alcohol feeding of mice is associated with a significant increase in the methylation status of CpG islands predicted to be in the mouse Slc5a6 promoters and a decrease in the level of expression of transcription factor KLF-4, which plays an important role in regulating SLC5A6 promoter activity. These results demonstrate, for the first time, that chronic alcohol exposure negatively impacts biotin uptake in PAC and that this effect is exerted (at least in part) at the level of transcription of the SLC5A6 gene and may involve epigenetic/molecular mechanisms.

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