Purinergic and extracellular vesicle signaling in alcohol-induced blood–brain barrier breakdown and neuroimmune activation

IF 7.6 2区 医学 Q1 IMMUNOLOGY
Namdev S. Togre , Priyanka S. Bhoj , Naveen Mekala, Rebecca Hancock, Jayshil Trivedi, Yuri Persidsky
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Abstract

Chronic alcohol consumption is a major risk factor for neuroinflammation and cognitive decline, yet the molecular underpinnings connecting peripheral alcohol-induced injury to central nervous system (CNS) dysfunction remain poorly defined. Emerging evidence implicates purinergic P2X7 receptor (P2X7R) signaling and extracellular vesicles (EVs) as key mediators in peripheral–central communication. Ethanol exposure promotes oxidative stress, mitochondrial dysfunction, and blood–brain barrier (BBB) disruption, leading to sustained microglial activation and neuronal injury. Concurrently, alcohol-induced damage in the gut, liver, and lung, triggers systemic inflammation and EV release. These EVs, enriched in proinflammatory cytokines, miRNAs, mitochondrial DNA, and other DAMPs, can cross the compromised BBB and engage innate immune receptors, such as TLR4 and P2X7R, on glial cells, amplifying neuroimmune responses.
In this review, we integrated recent findings on EV biogenesis, P2X7R signaling, and neurovascular dysfunction in the context of alcohol use disorder. We proposed a mechanistic model in which ethanol-triggered P2X7R activation drives EV release, turning these vesicles into inflammatory couriers that carry peripheral injury signals to the brain. We emphasize EV cargo as promising biomarkers of alcohol-related neurodegeneration and explore emerging therapies that target EV pathways or P2X7R to curb alcohol-induced CNS damage.
酒精诱导的血脑屏障破坏和神经免疫激活中的嘌呤能和细胞外囊泡信号。
慢性饮酒是神经炎症和认知能力下降的主要危险因素,然而外周酒精诱导损伤与中枢神经系统(CNS)功能障碍之间的分子基础仍不明确。新出现的证据表明嘌呤能P2X7受体(P2X7R)信号和细胞外囊泡(ev)是外周-中枢通讯的关键介质。乙醇暴露促进氧化应激、线粒体功能障碍和血脑屏障(BBB)破坏,导致持续的小胶质细胞激活和神经元损伤。同时,酒精引起的肠道、肝脏和肺部损伤会引发全身炎症和EV释放。这些富含促炎细胞因子、mirna、线粒体DNA和其他DAMPs的EVs可以穿过受损的血脑屏障,并与神经胶质细胞上的TLR4和P2X7R等先天免疫受体结合,放大神经免疫反应。在这篇综述中,我们整合了酒精使用障碍背景下EV生物发生、P2X7R信号和神经血管功能障碍的最新发现。我们提出了一种机制模型,其中乙醇触发的P2X7R激活驱动EV释放,将这些囊泡转化为炎症信使,将外周损伤信号传递到大脑。我们强调EV货物是酒精相关神经变性的有希望的生物标志物,并探索针对EV通路或P2X7R的新兴疗法来抑制酒精诱导的中枢神经系统损伤。
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来源期刊
CiteScore
29.60
自引率
2.00%
发文量
290
审稿时长
28 days
期刊介绍: Established in 1987, Brain, Behavior, and Immunity proudly serves as the official journal of the Psychoneuroimmunology Research Society (PNIRS). This pioneering journal is dedicated to publishing peer-reviewed basic, experimental, and clinical studies that explore the intricate interactions among behavioral, neural, endocrine, and immune systems in both humans and animals. As an international and interdisciplinary platform, Brain, Behavior, and Immunity focuses on original research spanning neuroscience, immunology, integrative physiology, behavioral biology, psychiatry, psychology, and clinical medicine. The journal is inclusive of research conducted at various levels, including molecular, cellular, social, and whole organism perspectives. With a commitment to efficiency, the journal facilitates online submission and review, ensuring timely publication of experimental results. Manuscripts typically undergo peer review and are returned to authors within 30 days of submission. It's worth noting that Brain, Behavior, and Immunity, published eight times a year, does not impose submission fees or page charges, fostering an open and accessible platform for scientific discourse.
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