Neuroinflammation and Depression: Microglia Activation, Extracellular Microvesicles and microRNA Dysregulation.
Neuroinflammation and Depression: Microglia Activation, Extracellular Microvesicles and microRNA Dysregulation.
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DOI：
10.3389/fncel.2015.00476
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发表时间：
2015
影响因子：
5.3
通讯作者：
Fernandes A
中科院分区：
文献类型：
--
作者：
Brites D;Fernandes A
慢性炎症患者通常与抑郁症状的出现有关，而确诊的抑郁症患者循环细胞因子水平升高。进一步的研究揭示了抑郁症患者大脑免疫细胞小胶质细胞的激活，自杀个体的激活幅度更大，表明神经炎症在抑郁症脑发病机制中起着至关重要的作用。在过去的15-20年里，对小胶质细胞和星形胶质细胞神经生物学的了解取得了迅速的进展。事实上，最近的数据显示，除了参与免疫反应产生的细胞因子外，小胶质细胞在管理神经细胞死亡、神经发生和突触相互作用方面发挥着重要作用。小胶质细胞和神经元之间的通讯对于使这些不同的功能与大脑活动同步是必不可少的。越来越多的证据表明，分泌性胞外囊泡(EVS)是细胞间信号转导的关键分子，它由大小为0.1-1μm的胞外体和胞外体组成。这些EV可能携带特定的蛋白质、mRNAs和microRNAs(MiRNAs)。外切体向神经元的转移被证明是由少突胶质细胞、小胶质细胞和星形胶质细胞介导的，这些细胞可能支持神经元，也可能传播疾病。有趣的是，最近的几篇报道发现抑郁症患者的miRNAs发生了变化，这些变化不仅针对与突触可塑性、学习和记忆相关的关键途径，还针对神经营养因子的产生和免疫细胞的调节。在这篇文章中，我们讨论了神经炎症在抑郁症发生中的作用，即小胶质细胞对刺激反应状态的动态变化，以及它们的激活表型如何在神经退行性变，特别是在抑郁样行为中起病因学作用。我们将概述miRNAs、外切体、胞外体和小胶质细胞参与调节与抑郁相关的关键通路，以及它们如何参与其他大脑疾病，包括肌萎缩侧索硬化症(ALS)、阿尔茨海默病(AD)和帕金森病(PD)，这些疾病具有几个与神经炎症相关的过程。将特别提到EVS作为潜在的生物标记物和疾病监测方法，重点放在它们作为药物输送载体的潜力，以及使用基于自体外体的输送系统治疗神经退行性疾病和精神疾病的假定治疗策略。
Patients with chronic inflammation are often associated with the emergence of depression symptoms, while diagnosed depressed patients show increased levels of circulating cytokines. Further studies revealed the activation of the brain immune cell microglia in depressed patients with a greater magnitude in individuals that committed suicide, indicating a crucial role for neuroinflammation in depression brain pathogenesis. Rapid advances in the understanding of microglial and astrocytic neurobiology were obtained in the past 15–20 years. Indeed, recent data reveal that microglia play an important role in managing neuronal cell death, neurogenesis, and synaptic interactions, besides their involvement in immune-response generating cytokines. The communication between microglia and neurons is essential to synchronize these diverse functions with brain activity. Evidence is accumulating that secreted extracellular vesicles (EVs), comprising ectosomes and exosomes with a size ranging from 0.1–1 μm, are key players in intercellular signaling. These EVs may carry specific proteins, mRNAs and microRNAs (miRNAs). Transfer of exosomes to neurons was shown to be mediated by oligodendrocytes, microglia and astrocytes that may either be supportive to neurons, or instead disseminate the disease. Interestingly, several recent reports have identified changes in miRNAs in depressed patients, which target not only crucial pathways associated with synaptic plasticity, learning and memory but also the production of neurotrophic factors and immune cell modulation. In this article, we discuss the role of neuroinflammation in the emergence of depression, namely dynamic alterations in the status of microglia response to stimulation, and how their activation phenotypes may have an etiological role in neurodegeneneration, in particular in depressive-like behavior. We will overview the involvement of miRNAs, exosomes, ectosomes and microglia in regulating critical pathways associated with depression and how they may contribute to other brain disorders including amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD) and Parkinson’s disease (PD), which share several neuroinflammatory-associated processes. Specific reference will be made to EVs as potential biomarkers and disease monitoring approaches, focusing on their potentialities as drug delivery vehicles, and on putative therapeutic strategies using autologous exosome-based delivery systems to treat neurodegenerative and psychiatric disorders.