Alyssa Woltemath

 Introduction: Neonatal hypoxic-ischemic brain injury occurs in 1 to 6 births for every 1,000 live term births⁴. Researchers worked to understand the pathogenesis mechanism of HIE by upregulation and downregulation of IL-1b, IL-6 and IL-15. Interleukin-1b is produced by activated macrophages². IL-6 is a cytokine that induces maturation of B cells into antibody producing cells⁴. IL-15 is produced by astrocytes and enhances the adaptive and innate immune responses^1,2. Methods: To determine the role of molecular regulation of IL-1b and IL-6 in neonatal HIE, hypoxic-ischemic brain injury was induced in 3-day-old post-natal rats through right carotid artery ligation and were placed in an 8% O₂ environment³. Hypoxia was induced in primary rat astrocytes by exposing them to 2% O₂ and 98% N₂³. Morphological changes were observed in the astrocytes and IL-1b and IL-6 gene expression were monitored using PCR³. To downregulate IL-1b, researchers injected IL-1b siRNA lentivirus into the cerebral cortex motor area of neonatal mice³. To test the effects of increased production of IL-15, researchers generated a GFAP promoter-controlled IL-15 expressing transgenic mouse line². To assess the effect of blocking IL-15 on neonatal HIE, researchers used two methods. The first was using IL-15-/- mice that lack NK cells and CD8+ T cells to test the role of the innate immune system on reperfusion injury¹. The second was inducing HIE through middle cerebral artery occlusion in WT mice and subsequently treating them with IL-15 neutralizing antibody¹. Results: After HIE was induced, morphological analysis showed cellular swelling leading to increased stroma size and expression of IL-1b and reduced number of astrocytes³. It was found that knockdown of IL-1b counteracted cellular swelling, brain edema and neurological function deficits, as well as, IL-6 upregulation³. IL-15 upregulation resulted in enlarged brain infarcts and increased neurological deficits, as well as, increase in activated CD8+ T cells and NK cells^1,2. IL-15-/- mice showed smaller infarct volumes¹. Compared to IL-15-/- mice, WT mice had increased NK cells and CD8+ T cells¹. WT mice with the IL-15 blockade had reduced brain infarct volume¹. Conclusions: Knockdown of IL-1b and upregulation of IL-6 reduces HIE³. HIE in transgenic mice overexpressing IL-15 resulted in enlarged brain infarcts and increased neurological deficits, number of CD8+ T cells and NK cells^1,2. HIE in IL-15 knock-out mice resulted in reduced number of brain-infiltrating NK cells and CD8+ T cells¹. Administration of IL-15 neutralizing antibody after HIE in WT mice reduced infarct volume and neurological deficits¹.

1. Lee GA, Lin T-N, Chen C-Y, et al. Interleukin 15 blockade protects the brain from cerebral ischemia-reperfusion injury. Brain, Behavior, and Immunity. 2018;73:562-570. doi:10.1016/j.bbi.2018.06.021.
2. Li M, Li Z, Yao Y, et al. Astrocyte-derived interleukin-15 exacerbates ischemic brain injury via propagation of cellular immunity. Proceedings of the National Academy of Sciences. 2016;114(3). doi:10.1073/pnas.1612930114.
3. Liu S, Zhu S, Zou Y, Wang T, Fu X. Knockdown of IL-1β Improves Hypoxia–ischemia Brain Associated with IL-6 Up-regulation in Cell and Animal Models. Molecular Neurobiology. 2014;51(2):743-752. doi:10.1007/s12035-014-8764-z.
4. Gu Y, He M, Zhou X, et al. Endogenous IL-6 of mesenchymal stem cell improves behavioral outcome of hypoxic-ischemic brain damage neonatal rats by supressing apoptosis in astrocyte. Scientific Reports. 2016;6(1). doi:10.1038/srep18587.