Department of Pharmacology, University of Tennessee Health Science Center, 71 South Manassas Street, Memphis, TN, 38103, USA.
Department of Neurosurgery, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
J Neuroinflammation. 2018 Jan 8;15(1):8. doi: 10.1186/s12974-017-1038-8.
Neuroinflammation is implicated in the development and progression of many neurodegenerative diseases. Conditions that lead to a peripheral immune response are often associated with inflammation in the central nervous system (CNS), suggesting a communication between the peripheral immune system and the neuroimmune system. The underlying mechanism of this relationship remains largely unknown; however, experimental studies have demonstrated that exposure to infectious stimuli, such as lipopolysaccharide (LPS) or high-fat diet (HFD) feeding, result in profound peripheral- and neuro-inflammation.
Using the model of endotoxemia with LPS, we studied the role of serum-derived exosomes in mediating neuroinflammation. We purified circulating exosomes from the sera of LPS-challenged mice, which were then intravenously injected into normal adult mice.
We found that the recipient mice that received serum-derived exosomes from LPS-challenged mice exhibited elevated microglial activation. Moreover, we observed astrogliosis, increased systemic pro-inflammatory cytokine production, and elevated CNS expression of pro-inflammatory cytokine mRNA and the inflammation-associated microRNA (miR-155) in these recipient mice. Gene expression analysis confirmed that many inflammatory microRNAs were significantly upregulated in the purified exosomes under LPS-challenged conditions. We observed accumulated signaling within the microglia of mice that received tail-vein injections of fluorescently labeled exosomes though the percentage of those microglial cells was found low. Finally, purified LPS-stimulated exosomes from blood when infused directly into the cerebral ventricles provoked significant microgliosis and, to a lesser extent, astrogliosis.
The experimental results suggest that circulating exosomes may act as a neuroinflammatory mediator in systemic inflammation.
神经炎症与许多神经退行性疾病的发展和进展有关。导致外周免疫反应的情况通常与中枢神经系统（CNS）的炎症有关，这表明外周免疫系统和神经免疫系统之间存在通讯。这种关系的潜在机制在很大程度上尚不清楚；但是，实验研究表明，暴露于感染性刺激物（例如脂多糖（LPS）或高脂肪饮食（HFD）喂养）会导致明显的外周和神经炎症。
使用内毒素血症模型（LPS），我们研究了血清衍生的外泌体在介导神经炎症中的作用。我们从 LPS 挑战的小鼠血清中纯化了循环外泌体，然后将其静脉内注射到正常成年小鼠中。
我们发现，接受来自 LPS 挑战的小鼠血清衍生的外泌体的受体小鼠表现出小胶质细胞激活增加。此外，我们观察到星形胶质细胞增生，全身促炎细胞因子产生增加，以及这些受体小鼠中 CNS 表达促炎细胞因子 mRNA 和炎症相关 microRNA（miR-155）增加。基因表达分析证实，在 LPS 挑战条件下，许多炎症性 microRNA 在纯化的外泌体中显着上调。我们观察到接受尾静脉注射荧光标记的外泌体的小鼠的小胶质细胞内信号累积，尽管这些小胶质细胞的比例较低。最后，当将直接注入脑室的 LPS 刺激的外泌体从血液中纯化出来时，会引起明显的小胶质细胞增生，并且在较小程度上引起星形胶质细胞增生。
实验结果表明，循环外泌体可能在全身炎症中充当神经炎症的介质。
