Alcohol exposure–induced neurovascular inflammatory priming impacts ischemic stroke and is linked with brain perivascular macrophages
Antoine Drieu, … , Denis Vivien, Marina Rubio
Antoine Drieu, … , Denis Vivien, Marina Rubio
Published January 28, 2020
Citation Information: JCI Insight. 2020;5(4):e129226. https://doi.org/10.1172/jci.insight.129226.
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Research Article Inflammation Neuroscience

Alcohol exposure–induced neurovascular inflammatory priming impacts ischemic stroke and is linked with brain perivascular macrophages

Abstract

Alcohol abuse is a major public health problem worldwide, causing a wide range of preventable morbidity and mortality. In this translational study, we show that heavy drinking (HD) (≥6 standard drinks/day) is independently associated with a worse outcome for ischemic stroke patients. To study the underlying mechanisms of this deleterious effect of HD, we performed an extensive analysis of the brain inflammatory responses of mice chronically exposed or not to 10% alcohol before and after ischemic stroke. Inflammatory responses were analyzed at the parenchymal, perivascular, and vascular levels by using transcriptomic, immunohistochemical, in vivo 2-photon microscopy and molecular MRI analyses. Alcohol-exposed mice show, in the absence of any other insult, a neurovascular inflammatory priming (i.e., an abnormal inflammatory status including an increase in brain perivascular macrophages [PVM]) associated with exacerbated inflammatory responses after a secondary insult (ischemic stroke or LPS challenge). Similar to our clinical data, alcohol-exposed mice showed larger ischemic lesions. We show here that PVM are key players on this aggravating effect of alcohol, since their specific depletion blocks the alcohol-induced aggravation of ischemic lesions. This study opens potentially new therapeutic avenues aiming at blocking alcohol-induced exacerbation of the neurovascular inflammatory responses triggered after ischemic stroke.

Authors

Antoine Drieu, Anastasia Lanquetin, Damien Levard, Martina Glavan, Francisco Campos, Aurélien Quenault, Eloïse Lemarchand, Mikaël Naveau, Anne Lise Pitel, José Castillo, Denis Vivien, Marina Rubio

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Figure 2

Alcohol exposure provokes a microglial priming in mice.

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Alcohol exposure provokes a microglial priming in mice. (A) Experimental...
(A) Experimental design to study the effects of chronic alcohol exposure on microglia. (B) Representative photomicrographs of microglial cells stained with Iba1 and CD68. Scale bar: 100 μm. (C) High-magnification representative photomicrographs of microglial cells in control and alcohol-exposed mice. Scale bar: 10 μm. (D) Quantification of Iba1+CD68+ cells. (E) Quantification of CD68 area on Iba1+ microglial cells. (F) Quantification of Iba1+ cells. (G) Quantification of the number of processes starting from the soma. (H) Quantification of the area of microglial cells. n = 4 mice per group. (I) Experimental design to in vivo study the microglial phagocytic capacity: 1 μL of latex beads were injected in the cortex of control and alcohol-exposed mice. Eight hours later, phagocytosed latex beads were quantified by immunohistochemical analyses. (J) Representative photomicrographs of Iba1+ microglial cells and latex beads. Scale bar: 20 μm. (K) Detail of a latex bead phagocytosed by a microglial cell in an alcohol-exposed mouse. Note the lysosomal activation (CD68, red) at the apex of microglial process. Scale bar: 10 μm. (L) Quantification of phagocytosed latex beads/total number of beads. n = 4 mice per group; *P < 0.05 versus Control, Mann-Whitney U test. (M) Sequential confocal photomicrographs of a phagocytosed latex bead.