Department of Medical Research, Taipei Medical University Hospital, Taipei, Taiwan.
Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
Brain Behav Immun. 2018 Oct;73:562-570. doi: 10.1016/j.bbi.2018.06.021. Epub 2018 Jun 27.
Acute ischemic stroke is followed by a complex interplay between the brain and the immune system in which ischemia-reperfusion leads to a detrimental inflammatory response that causes brain injury. In the brain, IL-15 is expressed by astrocytes, neurons and microglia. Previous study showed that ischemia-reperfusion induces expression of IL-15 by astrocytes. Transgenic over-expression of IL-15 in astrocytes aggravates ischemia-reperfusion brain damage by increasing the levels and promoting the effector functions of CD8 T and NK cells. Treatment of neonatal rats with IL-15 neutralizing antibody before hypoxia-ischemia induction reduces the infarct volume. However, as stroke-induced inflammatory responses differ between neonate and adult brain, the effects of IL-15 blockade on the injury and immune response arising from stroke in adult animals has remained unclear. In this study, we examined the effect of post-ischemia/reperfusion IL-15 blockade on the pathophysiology of cerebral ischemia-reperfusion in adult mice. Using a cerebral ischemia-reperfusion model, we compared infarct size and the infiltrating immune cells in the brain of wild type (WT) mice and Il15 mice lacking NK and memory CD8 T cells. We also evaluated the effects of IL-15 neutralizing antibody treatment on brain infarct volume, motor function, and the status of brain-infiltrating immune cells in WT mice. Il15 mice show a smaller infarct volume and lower numbers of activated brain-infiltrating NK, CD8 T, and CD4 T cells compared to WT mice after cerebral ischemia-reperfusion. Post-ischemia/reperfusion IL-15 blockade reduces infarct size and improves motor and locomotor activity. Furthermore, IL-15 blockade reduces the effector function of NK, CD8 T, and CD4 T cells in the ischemia-reperfusion brain of WT mice. Ablation of IL-15 responses after cerebral ischemia-reperfusion ameliorates brain injury in adult mice. Therefore, targeting IL-15 is a potential effective therapy for ischemic stroke.
急性缺血性中风后，大脑和免疫系统之间会发生复杂的相互作用，其中缺血再灌注导致有害的炎症反应，从而导致脑损伤。在大脑中，IL-15 由星形胶质细胞、神经元和小胶质细胞表达。先前的研究表明，缺血再灌注诱导星形胶质细胞表达 IL-15。在星形胶质细胞中转基因过表达 IL-15 通过增加 CD8 T 和 NK 细胞的水平并促进其效应功能，加重缺血再灌注脑损伤。在缺氧缺血诱导前用 IL-15 中和抗体治疗新生大鼠可减少梗死体积。然而，由于中风引起的炎症反应在新生儿和成人大脑之间存在差异，IL-15 阻断对成年动物中风引起的损伤和免疫反应的影响仍不清楚。在这项研究中，我们研究了缺血再灌注后 IL-15 阻断对成年小鼠脑缺血再灌注病理生理学的影响。使用脑缺血再灌注模型，我们比较了野生型 (WT) 小鼠和缺乏 NK 和记忆 CD8 T 细胞的 Il15 小鼠的脑梗死面积和脑内浸润免疫细胞。我们还评估了 IL-15 中和抗体治疗对 WT 小鼠脑梗死体积、运动功能和脑浸润免疫细胞状态的影响。与 WT 小鼠相比，Il15 小鼠在脑缺血再灌注后表现出较小的梗死体积和较低数量的激活脑浸润 NK、CD8 T 和 CD4 T 细胞。缺血再灌注后 IL-15 阻断减少梗死体积并改善运动和运动活动。此外，IL-15 阻断降低了 WT 小鼠缺血再灌注脑中 NK、CD8 T 和 CD4 T 细胞的效应功能。脑缺血再灌注后 IL-15 反应的消融可改善成年小鼠的脑损伤。因此，靶向 IL-15 可能是缺血性中风的一种有效治疗方法。
