Interleukin 15 blockade protects the brain from cerebral ischemia-reperfusion injury

• Published in: Brain, behavior, and immunity Vol. 73; pp. 562 - 570
• Main Authors: Lee, Gilbert Aaron, Lin, Teng-Nan, Chen, Cheng-Yu, Mau, Shin-Yi, Huang, Wan-Zhen, Kao, Yu-Chieh, Ma, Ruo-yu, Liao, Nan-Shih
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01.10.2018
• Subjects: Animals; Astrocytes - metabolism; Brain - metabolism; Brain Injuries - metabolism; Brain Ischemia - metabolism; CD4-Positive T-Lymphocytes - metabolism; CD8-Positive T-Lymphocytes - metabolism; Cerebral ischemia-reperfusion; Disease Models, Animal; IL-15; IL-15 antibody; Immune response; Interleukin-15 - antagonists & inhibitors; Interleukin-15 - metabolism; Killer Cells, Natural - metabolism; Male; Mice, Inbred C57BL; Mice, Knockout; Neurons - metabolism; Rats; Reperfusion Injury - metabolism; Reperfusion Injury - prevention & control; Stroke - metabolism; Stroke - physiopathology; PMN; HI; Immune response; Cerebral ischemia-reperfusion; NK cell; IL-15 antibody; IL-15; Th1; WT
• ISSN: 0889-1591; 1090-2139
• DOI: 10.1016/j.bbi.2018.06.021

•IL-15 system aggravates the brain injury after cerebral ischemia-reperfusion.•Post-ischemia IL-15 blockade reduces brain injury and improves motor function.•Post-ischemia IL-15 blockade reduces NK, CD8+ and CD4+ T cell effector function. 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.