Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 114, Issue 3, Pages E396-E405Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1612930114
Keywords
astrocyte; interleukin-15; lymphocytes; inflammation; ischemic brain injury
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Funding
- National Basic Research Program of China [2013CB966900]
- National Science Foundation of China [81230028, 81301044, 81471535, 81322018]
- Youth Top-Notch Talent Support Program
- National Institutes of Health [R01NS092713]
- American Heart Association [16SDG27250236]
- National Multiple Sclerosis Society Research Grant [RG-1507-05318]
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Astrocytes are believed to bridge interactions between infiltrating lymphocytes and neurons during brain ischemia, but the mechanisms for this action are poorly understood. Here we found that interleukin-15 (IL-15) is dramatically up-regulated in astrocytes of postmortem brain tissues from patients with ischemic stroke and in a mouse model of transient focal brain ischemia. We generated a glial fibrillary acidic protein (GFAP) promoter-controlled IL-15-expressing transgenic mouse (GFAP-IL-15(tg)) line and found enlarged brain infarcts, exacerbated neurodeficits after the induction of brain ischemia. In addition, knockdown of IL-15 in astrocytes attenuated ischemic brain injury. Interestingly, the accumulation of CD8(+) T and natural killer (NK) cells was augmented in these GFAP-IL-15(tg) mice after brain ischemia. Of note, depletion of CD8(+) T or NK cells attenuated ischemic brain injury in GFAP-IL-15(tg) mice. Furthermore, knockdown of the IL-15 receptor a or blockade of cell-to-cell contact diminished the activation and effector function of CD8(+) T and NK cells in GFAP-IL-15(tg) mice, suggesting that astrocytic IL-15 is delivered in trans to target cells. Collectively, these findings indicate that astrocytic IL-15 could aggravate postischemic brain damage via propagation of CD8(+) T and NK cell-mediated immunity.
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