Abstract 144: Astrocyte-Derived Interleukin-15 Accelarates Ischemic Brain Injury
Background and Purpose: Astrocytes play a pivotal role in post-ischemic brain inflammation, but the relevant astrocyte-derived mediators of ischemic brain injury remain to be defined. This study aims to investigate the impact of astrocyte-derived factors such as IL-15 on ischemic brain injury.
Methods and Results: We show that IL-15 is a prominent factor relased by astrocytes after brain ischemia in a mouse model of transient focal brain ischemia. To further eluciate the biological functions of astrcoyte-derived IL-15 in ischemic stroke, we generated a glial fibrillary acidic protein (GFAP) promoter-controlled IL-15-expressing transgenic mouse line (GFAP-IL-15tg). We demonstrate that astrocyte-specific overproduction of IL-15 leads to larger brain infarcts, worse neurodeficits and enhanced lymphocyte infiltration. In GFAP-IL-15tg mice, we found increased accumulation and activation of CD8+ T and natural killer (NK) cells after cerebral ischemia. Importantly, depletion of either CD8+ T or NK cells in GFAP-IL-15tg mice prior to cerebral ischemia attenuates the accelerated brain infarction and neurodeficits. Of note, CD8+ T and NK cells are within the proximity of astrocytes in the post-ischemic brain and either knockdown of IL-15 receptor α or blockade of cell-to-cell contact diminishes the activation and effector function of CD8+ T and NK cells caused by astrocytic overproduction of IL-15, suggesting that astrocytic IL-15 is delivered in trans to target cells. Additionally, CD8+ T and NK cells are seen closely adjacent to IL-15-producing astrocytes in acute ischemic lesions of postmortem human brain tissues, implying that astrocytic IL-15-mediated brain injury may be relevant to human stroke.
Conclusion: These findings indicate that astrocytic IL-15 contributes to post-ischemic brain damage.
Author Disclosures: M. Li: None. Z. Li: None. K. Wood: None. W. Jin: None. F. Shi: None. Q. Liu: None.
This research has received full or partial funding support from the American Heart Association, Western States - Alaska, Arizona, California, Hawaii, Idaho, Montana, Nevada, Oregon, Utah, Washington.
- © 2016 by American Heart Association, Inc.