Chronic alcohol-induced neuroinflammation involves CCR2/5-dependent peripheral macrophage infiltration and microglia alterations

Abstract Background Chronic alcohol consumption is associated with neuroinflammation, neuronal damage, and behavioral alterations including addiction. Alcohol-induced neuroinflammation is characterized by increased expression of proinflammatory cytokines (including TNFα, IL-1β, and CCL2) and microglial activation. We hypothesized chronic alcohol consumption results in peripheral immune cell infiltration to the CNS. Since chemotaxis through the CCL2-CCR2 signaling axis is critical for macrophage recruitment peripherally and centrally, we further hypothesized that blockade of CCL2 signaling using the dual CCR2/5 inhibitor cenicriviroc (CVC) would prevent alcohol-induced CNS infiltration of peripheral macrophages and alter the neuroinflammatory state in the brain after chronic alcohol consumption. Methods C57BL/6J female mice were fed an isocaloric or 5% (v/v) ethanol Lieber DeCarli diet for 6 weeks. Some mice received daily injections of CVC. Microglia and infiltrating macrophages were characterized and quantified by flow cytometry and visualized using CX3CR1eGFP/+ CCR2RFP/+ reporter mice. The effect of ethanol and CVC treatment on the expression of inflammatory genes was evaluated in various regions of the brain, using a Nanostring nCounter inflammation panel. Microglia activation was analyzed by immunofluorescence. CVC-treated and untreated mice were presented with the two-bottle choice test. Results Chronic alcohol consumption induced microglia activation and peripheral macrophage infiltration in the CNS, particularly in the hippocampus. Treatment with CVC abrogated ethanol-induced recruitment of peripheral macrophages and partially reversed microglia activation. Furthermore, the expression of proinflammatory markers was upregulated by chronic alcohol consumption in various regions of the brain, including the cortex, hippocampus, and cerebellum. Inhibition of CCR2/5 decreased alcohol-mediated expression of inflammatory markers. Finally, microglia function was impaired by chronic alcohol consumption and restored by CVC treatment. CVC treatment did not change the ethanol consumption or preference of mice in the two-bottle choice test. Conclusions Together, our data establish that chronic alcohol consumption promotes the recruitment of peripheral macrophages into the CNS and microglia alterations through the CCR2/5 axis. Therefore, further exploration of the CCR2/5 axis as a modulator of neuroinflammation may offer a potential therapeutic approach for the treatment of alcohol-associated neuroinflammation.

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The Loss of α- and β-Tubulin Proteins Are a Pathological Hallmark of Chronic Alcohol Consumption and Natural Brain Ageing

Brain Sciences ◽

10.3390/brainsci8090175 ◽

2018 ◽

Vol 8 (9) ◽

pp. 175 ◽

Cited By ~ 3

Author(s):

Wajana Labisso ◽

Ana-Caroline Raulin ◽

Lucky Nwidu ◽

Artur Kocon ◽

Declan Wayne ◽

...

Keyword(s):

Alcohol Consumption ◽

Protein Expression ◽

Neuronal Damage ◽

Alcohol Intoxication ◽

Post Mortem ◽

Chronic Alcohol ◽

Chronic Alcohol Consumption ◽

Protein Levels ◽

Brain Ageing ◽

Tubulin Protein

Repetitive excessive alcohol intoxication leads to neuronal damage and brain shrinkage. We examined cytoskeletal protein expression in human post-mortem tissue from Brodmann’s area 9 of the prefrontal cortex (PFC). Brain samples from 44 individuals were divided into equal groups of 11 control, 11 alcoholic, 11 non-alcoholic suicides, and 11 suicide alcoholics matched for age, sex, and post-mortem delay. Tissue from alcoholic cohorts displayed significantly reduced expression of α- and β-tubulins, and increased levels of acetylated α-tubulin. Protein levels of histone deacetylase-6 (HDAC6), and the microtubule-associated proteins MAP-2 and MAP-tau were reduced in alcoholic cohorts, although for MAPs this was not significant. Tubulin gene expressions increased in alcoholic cohorts but not significantly. Brains from rats administered alcohol for 4 weeks also displayed significantly reduced tubulin protein levels and increased α-tubulin acetylation. PFC tissue from control subjects had reduced tubulin protein expression that was most notable from the sixth to the eighth decade of life. Collectively, loss of neuronal tubulin proteins are a hallmark of both chronic alcohol consumption and natural brain ageing. The reduction of cytosolic tubulin proteins could contribute to the brain volumetric losses reported for alcoholic patients and the elderly.

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Chronic Alcohol Consumption Increases the Expression of Uncoupling Protein-2 and -4 in the Brain

Alcoholism Clinical and Experimental Research ◽

10.1111/acer.12144 ◽

2013 ◽

pp. n/a-n/a ◽

Cited By ~ 1

Author(s):

Jan A. Graw ◽

Clarissa von Haefen ◽

Deniz Poyraz ◽

Nadine Möbius ◽

Marco Sifringer ◽

...

Keyword(s):

Alcohol Consumption ◽

Uncoupling Protein ◽

Uncoupling Protein 2 ◽

Chronic Alcohol ◽

Chronic Alcohol Consumption ◽

The Brain

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Chronic Alcohol Exposure Alters Gene Expression and Neurodegeneration Pathways in the Brain of Adult Mice

Journal of Alzheimer s Disease ◽

10.3233/jad-215508 ◽

2022 ◽

pp. 1-17

Author(s):

Mingjing Liu ◽

Shipeng Guo ◽

Daochao Huang ◽

Dongjie Hu ◽

Yili Wu ◽

...

Keyword(s):

Energy Metabolism ◽

Alcohol Consumption ◽

Alcohol Exposure ◽

Chronic Alcohol ◽

Rna Seq ◽

Chronic Alcohol Consumption ◽

Mitochondrial Energy Metabolism ◽

Brain Transcriptome ◽

Chronic Alcohol Exposure ◽

The Brain

Background: Chronic alcohol consumption can alter the structure of the central nervous system and disrupt cognitive function. Alcoholics are more likely to develop neurodegenerative disorders such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). However, the role of alcohol in promoting neurotoxicity and neurodegeneration remains unclear. Objective: In this study, we aimed at estimating the effects of chronic binge alcohol exposure on brain transcriptome and behavior changes in a chronic “Drinking in the Dark” (DID) mouse model. Methods: The adult C57BL/6J male mice were exposed to alcohol for 4 weeks. RNA-seq was applied to assess the effects of chronic alcohol exposure on transcriptome in brain. The open field test and novel object recognition test were used to assess the changes of anxiety level, locomotive function, and short-term memory induced by alcohol. RNA-seq analysis revealed that chronic alcohol exposure caused significant change in the brain transcriptome, especially in prefrontal cortex. Results: The gene dysregulation caused by chronic alcohol exposure includes pathways related to mitochondrial energy metabolism (such as oxidative phosphorylation) and multiple neurodegenerative diseases (such as AD and PD). Furthermore, the pathway and network analyses suggest that the genes involved in mitochondrial energy metabolism, ubiquitin-proteasome system, Wnt signaling pathway, and microtubules may attribute to the neurotoxicity and neurodegeneration caused by chronic alcohol consumption. Additionally, locomotive function was also significantly impaired. Conclusion: This work provides gene transcriptional profile data for future research on alcohol-induced neurodegenerative diseases, especially AD and PD.

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Effects of chronic alcohol consumption on the expression of different NR1 splice variants in the brain of AA and ANA lines of rats

Molecular Brain Research ◽

10.1016/s0169-328x(99)00218-1 ◽

1999 ◽

Vol 72 (2) ◽

pp. 166-175 ◽

Cited By ~ 38

Author(s):

Anett Winkler ◽

Beatrice Mahal ◽

Kalervo Kiianmaa ◽

Walter Zieglgänsberger ◽

Rainer Spanagel

Keyword(s):

Alcohol Consumption ◽

Splice Variants ◽

Chronic Alcohol ◽

Chronic Alcohol Consumption ◽

The Brain

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Alcohol-Induced Mesenteric Lymphatic Permeability: Link to Immunometabolic Modulation of Perilymphatic Adipose Tissue

International Journal of Molecular Sciences ◽

10.3390/ijms20174097 ◽

2019 ◽

Vol 20 (17) ◽

pp. 4097 ◽

Cited By ~ 2

Author(s):

Flavia M. Souza-Smith ◽

Liz Simon ◽

Robert Siggins ◽

Patricia E. Molina

Keyword(s):

Adipose Tissue ◽

Alcohol Consumption ◽

Glucose Uptake ◽

Immune Cell ◽

Lymphatic Vessels ◽

Male Rats ◽

Chronic Alcohol ◽

Mesenteric Lymph Nodes ◽

Blood Leukocytes ◽

Chronic Alcohol Consumption

Alcohol exerts significant immunomodulatory effects on innate and adaptive immune responses, impairing host defense against infections. Gut-mucosa-derived dendritic cells (DCs) traffic to mesenteric lymph nodes (MLNs) through mesenteric lymphatic vessels (MLVs), contributing to intestinal antigen homeostasis. Previously, we demonstrated that acute alcohol administration to male rats induces MLV hyperpermeability resulting in perilymphatic adipose tissue (PLAT) inflammation and insulin signaling dysregulation. We hypothesized that alcohol-induced MLV hyperpermeability can lead to DC leakage to PLAT. DCs promote adipose tissue regulatory T cell (Treg) expansion, and this has been proposed as a mechanism underlying age-associated insulin resistance (IR). The aim of this study was to determine whether chronic alcohol consumption promotes DC leakage to PLAT and results in metabolic dysregulation. Male rats received a Lieber–DeCarli liquid diet containing 36% of calories from alcohol for 10 weeks. Time-matched control animals were pair-fed. PLAT, MLNs, and peripheral blood leukocytes (PBLs) were isolated for flow cytometry analyses. PLAT explants were used for determinations of insulin-induced glucose uptake. Chronic alcohol consumption decreased MLN CD4/CD8 ratio and Treg frequency in PBLs. Alcohol increased the frequency of DCs, CD4 T cells, and Tregs in PLAT. Lastly, alcohol decreased insulin-stimulated glucose uptake in PLAT. Collectively, these findings suggest that alcohol-induced immune cell deviation from the gut–MLN pathway is associated with PLAT immunometabolic dysregulation. Whether this immune cell deviation impacts induction of mucosal immunity warrants further investigation.

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