Chronic alcohol-induced neuroinflammation involves CCR2/5-dependent peripheral macrophage infiltration and microglia alt
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RESEARCH
Open Access
Chronic alcohol-induced neuroinflammation involves CCR2/5dependent peripheral macrophage infiltration and microglia alterations Patrick P. Lowe1, Caroline Morel2, Aditya Ambade1, Arvin Iracheta-Vellve1, Erica Kwiatkowski1, Abhishek Satishchandran1, Istvan Furi1, Yeonhee Cho1,2, Benedek Gyongyosi1, Donna Catalano2, Eric Lefebvre3, Laurent Fischer3, Star Seyedkazemi3, Dorothy P. Schafer4 and Gyongyi Szabo1,2*
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. (Continued on next page)
* Correspondence: [email protected] 1 Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA 2 Department of Medicine, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, ST-214B, Boston, MA 02215, USA Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this lic
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