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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.

SUBMITTER: Drieu A

PROVIDER: S-EPMC7101143 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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

Drieu Antoine A Lanquetin Anastasia A Levard Damien D Glavan Martina M Campos Francisco F Quenault Aurélien A Lemarchand Eloïse E Naveau Mikaël M Pitel Anne Lise AL Castillo José J Vivien Denis D Rubio Marina M

JCI insight 20200227 4

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 ...[more]

PMID: 31990687

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Project description:BackgroundEnlarged perivascular spaces (EPVS) are considered to be neuroimaging markers of cerebral small vessel disease (CSVD). It remains unknown whether EPVS are associated with hemorrhagic transformation (HT) after acute ischemic stroke (AIS). We performed this retrospective cohort study to explore the associations of EPVS with clinical risk factors and other CSVD imaging features, and to investigate the relationship between EPVS and HT in patients with AIS.MethodsAIS patients admitted within 24 hours of stroke onset between January 2016 and December 2017 were consecutively enrolled. EPVS, lacunes, and white matter hyperintensities (WMH) were rated with validated rating scales on magnetic resonance images after the stroke. HT was defined as hemorrhage determined by follow-up brain imaging during the patients' hospital stay. Logistic regression was used to determine the risk factors and associations with other CSVD markers of EPVS in the basal ganglia (BG) and centrum semiovale (CS) regions, and the impact of EPVS on HT was further explored.ResultsAmong 494 included patients (mean age 66.4 years, 58.1% male), 81 (16.4%) experienced HT. In the multivariate logistic analyses, increasing age [odd ratio (OR) 1.041, 95% confidence interval (CI), 1.017-1.066], hypertension (OR 2.174, 95% CI, 1.338-3.532), lacunar stroke (OR 1.968, 95% CI, 1.169-3.314), CS-EPVS (OR 2.474, 95% CI, 1.796-3.407), and periventricular WMH (OR 2.140, 95% CI, 1.441-3.176) were significantly associated with BG-EPVS; whereas only BG-EPVS (OR 4.349, 95% CI, 2.281-8.291) were independently related to CS-EPVS. After adjustment for potential variables, neither BG-EPVS (OR 0.674, 95% CI, 0.336-1.350) nor CS-EPVS (OR 0.792, 95% CI, 0.334-1.879) was significantly associated with the occurrence of HT.ConclusionsOur data showed that EPVS in the BG and CS regions were interrelated and had different risk factors in ischemic stroke patients. EPVS (particularly that in BG) were independently related to other CSVD markers. The presence or burden of EPVS was not significantly associated with HT after AIS.

Project description:BackgroundIn ischemic stroke, the function of the cerebral vasculature is impaired. This vascular structure is formed by the so-called neurovascular unit (NVU). A better understanding of the mechanisms involved in NVU dysfunction and recovery may lead to new insights for the development of highly sought therapeutic approaches. To date, there remains an unmet need for complex human in vitro models of the NVU to study ischemic events seen in the human brain.MethodsWe here describe the development of a human NVU on-a-chip model using a platform that allows culture of 40 chips in parallel. The model comprises a perfused vessel of primary human brain endothelial cells in co-culture with induced pluripotent stem cell derived astrocytes and neurons. Ischemic stroke was mimicked using a threefold approach that combines chemical hypoxia, hypoglycemia, and halted perfusion.ResultsImmunofluorescent staining confirmed expression of endothelial adherens and tight junction proteins, as well as astrocytic and neuronal markers. In addition, the model expresses relevant brain endothelial transporters and shows spontaneous neuronal firing. The NVU on-a-chip model demonstrates tight barrier function, evidenced by retention of small molecule sodium fluorescein in its lumen. Exposure to the toxic compound staurosporine disrupted the endothelial barrier, causing reduced transepithelial electrical resistance and increased permeability to sodium fluorescein. Under stroke mimicking conditions, brain endothelial cells showed strongly reduced barrier function (35-fold higher apparent permeability) and 7.3-fold decreased mitochondrial potential. Furthermore, levels of adenosine triphosphate were significantly reduced on both the blood- and the brain side of the model (4.8-fold and 11.7-fold reduction, respectively).ConclusionsThe NVU on-a-chip model presented here can be used for fundamental studies of NVU function in stroke and other neurological diseases and for investigation of potential restorative therapies to fight neurological disorders. Due to the platform's relatively high throughput and compatibility with automation, the model holds potential for drug compound screening.

Project description:Background: Innate immune response to neuronal death is one of the key events of the pathogenesis of ischemic brain injury. Interleukin-1 receptor-associated kinase (IRAK)-M, encoded by gene Irak3, negatively regulates toll-like receptor signaling by interacting with the MyD88-IRAK-4-IRAK-1 complex and blocking the phosphorylation and dissociation of IRAK-1. Its function in the ischemic stroke is unknown. Objective: This study aims to investigate whether IRAK-M deficiency could exacerbate neuroinflammation and neurovascular injuries during cerebral ischemia and reperfusion. Methods: Male C57BL/6 mice and Irak3 knockout mice were subjected to 45 min of middle cerebral artery occlusion and 4 or 24 h of reperfusion. Transcription of Irak3 gene was evaluated by quantitative real-time PCR (qRT-PCR). Then, infarct volume, neurological score, brain water content, and Evans blue leakage were compared between knock-out and wild-type mice after reperfusion. Through the observation of gross brain specimen after cerebral ischemia, the incidence of hemorrhage transformation was compared between KO and WT mice. To explore underlying signaling pathways involved in IRAK-M deficiency, major proinflammatory cytokines and NF-κB signaling were measured by qRT-PCR and Western blot. Results: The expression of IRAK-M peaked at 1 h after reperfusion, and then gradually decreased within the first 24 h, which was abolished by blocking the expression of hypoxia induced factor 1α. IRAK-M deficiency increased infarct volume, brain edema, the incidence of hemorrhage transformation, and the permeability of blood-brain barrier. In addition, the NF-κB-mediated expressions of proinflammatory cytokines and the activation of microglia in the ipsilateral brain from knock-out mice were much higher than those in wild-type littermates. Conclusion: IRAK-M deletion exacerbates neurovascular damages which are related to the pronounced activation of NF-κB signaling and neuroinflammatory responses during cerebral ischemia-reperfusion in mice. Our study indicates that IRAK-M has neuroprotective effect and has potential to facilitate the development of new pharmaceuticals that reduce neurovascular complications.

Dataset Information

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

Publications

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

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