Acute Stroke Programme, RDM-Investigative Medicine, University of Oxford, Oxford, UK.
Division of Cardiovascular Medicine, RDM, University of Oxford, Oxford, UK.
Sci Rep. 2017 Aug 29;7(1):9574. doi: 10.1038/s41598-017-09710-3.
Brain injury elicits a systemic acute-phase response (APR), which is responsible for co-ordinating the peripheral immunological response to injury. To date, the mechanisms responsible for signalling the presence of injury or disease to selectively activate responses in distant organs were unclear. Circulating endogenous extracellular vesicles (EVs) are increased after brain injury and have the potential to carry targeted injury signals around the body. Here, we examined the potential of EVs, isolated from rats after focal inflammatory brain lesions using IL-1β, to activate a systemic APR in recipient naïve rats, as well as the behavioural consequences of EV transfer. Focal brain lesions increased EV release, and, following isolation and transfer, the EVs were sequestered by the liver where they initiated an APR. Transfer of blood-borne EVs from brain-injured animals was also enough to suppress exploratory behaviours in recipient naïve animals. EVs derived from brain endothelial cell cultures treated with IL-1β also activated an APR and altered behaviour in recipient animals. These experiments reveal that inflammation-induced circulating EVs derived from endothelial cells are able to initiate the APR to brain injury and are sufficient to generate the associated sickness behaviours, and are the first demonstration that EVs are capable of modifying behavioural responses.
脑损伤会引发全身性急性期反应 (APR)，该反应负责协调损伤部位的外周免疫反应。迄今为止，对于负责向远处器官发出信号以选择性激活反应的损伤或疾病的信号机制仍不清楚。脑损伤后循环中的内源性细胞外囊泡 (EV) 会增加，并且有可能在全身范围内传递靶向损伤信号。在这里，我们研究了使用 IL-1β 从大鼠局灶性炎症性脑损伤中分离出的 EV 激活受体未致敏大鼠全身性 APR 的潜力，以及 EV 转移的行为后果。局灶性脑损伤会增加 EV 的释放，并且在分离和转移后，EV 被肝脏隔离，在肝脏中引发 APR。来自脑损伤动物的血液源性 EV 的转移也足以抑制受体未致敏动物的探索行为。用 IL-1β 处理的脑内皮细胞培养物衍生的 EV 也能激活 APR 并改变受体动物的行为。这些实验表明，由内皮细胞产生的炎症诱导的循环 EV 能够引发脑损伤的 APR，并足以产生相关的疾病行为，这也是 EV 能够改变行为反应的首次证明。
