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 microgl...
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doaj-f2e228b87454444f855fb0cf94714fab2020-11-25T04:09:18ZengBMCJournal of Neuroinflammation1742-20942020-10-0117111810.1186/s12974-020-01972-5Chronic alcohol-induced neuroinflammation involves CCR2/5-dependent peripheral macrophage infiltration and microglia alterationsPatrick P. Lowe0Caroline Morel1Aditya Ambade2Arvin Iracheta-Vellve3Erica Kwiatkowski4Abhishek Satishchandran5Istvan Furi6Yeonhee Cho7Benedek Gyongyosi8Donna Catalano9Eric Lefebvre10Laurent Fischer11Star Seyedkazemi12Dorothy P. Schafer13Gyongyi Szabo14Department of Medicine, University of Massachusetts Medical SchoolDepartment of Medicine, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical SchoolDepartment of Medicine, University of Massachusetts Medical SchoolDepartment of Medicine, University of Massachusetts Medical SchoolDepartment of Medicine, University of Massachusetts Medical SchoolDepartment of Medicine, University of Massachusetts Medical SchoolDepartment of Medicine, University of Massachusetts Medical SchoolDepartment of Medicine, University of Massachusetts Medical SchoolDepartment of Medicine, University of Massachusetts Medical SchoolDepartment of Medicine, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical SchoolAllerganAllerganAllerganDepartment of Neurobiology, University of Massachusetts Medical SchoolDepartment of Medicine, University of Massachusetts Medical SchoolAbstract 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.http://link.springer.com/article/10.1186/s12974-020-01972-5MacrophageMicrogliaAlcoholNeuroinflammationCytokines |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Patrick P. Lowe Caroline Morel Aditya Ambade Arvin Iracheta-Vellve Erica Kwiatkowski Abhishek Satishchandran Istvan Furi Yeonhee Cho Benedek Gyongyosi Donna Catalano Eric Lefebvre Laurent Fischer Star Seyedkazemi Dorothy P. Schafer Gyongyi Szabo |
spellingShingle |
Patrick P. Lowe Caroline Morel Aditya Ambade Arvin Iracheta-Vellve Erica Kwiatkowski Abhishek Satishchandran Istvan Furi Yeonhee Cho Benedek Gyongyosi Donna Catalano Eric Lefebvre Laurent Fischer Star Seyedkazemi Dorothy P. Schafer Gyongyi Szabo Chronic alcohol-induced neuroinflammation involves CCR2/5-dependent peripheral macrophage infiltration and microglia alterations Journal of Neuroinflammation Macrophage Microglia Alcohol Neuroinflammation Cytokines |
author_facet |
Patrick P. Lowe Caroline Morel Aditya Ambade Arvin Iracheta-Vellve Erica Kwiatkowski Abhishek Satishchandran Istvan Furi Yeonhee Cho Benedek Gyongyosi Donna Catalano Eric Lefebvre Laurent Fischer Star Seyedkazemi Dorothy P. Schafer Gyongyi Szabo |
author_sort |
Patrick P. Lowe |
title |
Chronic alcohol-induced neuroinflammation involves CCR2/5-dependent peripheral macrophage infiltration and microglia alterations |
title_short |
Chronic alcohol-induced neuroinflammation involves CCR2/5-dependent peripheral macrophage infiltration and microglia alterations |
title_full |
Chronic alcohol-induced neuroinflammation involves CCR2/5-dependent peripheral macrophage infiltration and microglia alterations |
title_fullStr |
Chronic alcohol-induced neuroinflammation involves CCR2/5-dependent peripheral macrophage infiltration and microglia alterations |
title_full_unstemmed |
Chronic alcohol-induced neuroinflammation involves CCR2/5-dependent peripheral macrophage infiltration and microglia alterations |
title_sort |
chronic alcohol-induced neuroinflammation involves ccr2/5-dependent peripheral macrophage infiltration and microglia alterations |
publisher |
BMC |
series |
Journal of Neuroinflammation |
issn |
1742-2094 |
publishDate |
2020-10-01 |
description |
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. |
topic |
Macrophage Microglia Alcohol Neuroinflammation Cytokines |
url |
http://link.springer.com/article/10.1186/s12974-020-01972-5 |
work_keys_str_mv |
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