The Role of IL-15, IL-1-beta, and IL-6 in Neonatal Hypoxic-Ischemic Encephalopathy

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 responses1,2. 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 cells1,2. 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 cells1,2. 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.