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

Gilbert Aaron Lee, Teng Nan Lin, Cheng Yu Chen, Shin Yi Mau, Wan Zhen Huang, Yu Chieh Kao, Ruo yu Ma, Nan Shih Liao

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)562-570
Number of pages9
JournalBrain, Behavior, and Immunity
Volume73
DOIs
Publication statusPublished - Oct 1 2018

Fingerprint

Interleukin-15
Reperfusion Injury
Brain Ischemia
Reperfusion
Ischemia
Brain
Stroke
Astrocytes
T-Lymphocytes
Neutralizing Antibodies
Brain Injuries
Microglia
Locomotion
Natural Killer Cells
Immune System

Keywords

  • Cerebral ischemia-reperfusion
  • IL-15
  • IL-15 antibody
  • Immune response

ASJC Scopus subject areas

  • Immunology
  • Endocrine and Autonomic Systems
  • Behavioral Neuroscience

Cite this

Interleukin 15 blockade protects the brain from cerebral ischemia-reperfusion injury. / Lee, Gilbert Aaron; Lin, Teng Nan; Chen, Cheng Yu; Mau, Shin Yi; Huang, Wan Zhen; Kao, Yu Chieh; Ma, Ruo yu; Liao, Nan Shih.

In: Brain, Behavior, and Immunity, Vol. 73, 01.10.2018, p. 562-570.

Research output: Contribution to journalArticle

Lee, Gilbert Aaron ; Lin, Teng Nan ; Chen, Cheng Yu ; Mau, Shin Yi ; Huang, Wan Zhen ; Kao, Yu Chieh ; Ma, Ruo yu ; Liao, Nan Shih. / Interleukin 15 blockade protects the brain from cerebral ischemia-reperfusion injury. In: Brain, Behavior, and Immunity. 2018 ; Vol. 73. pp. 562-570.
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AB - 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.

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