Critical role of astrocytic interleukin-17 A in post-stroke survival and neuronal differentiation of neural precursor cells in adult mice

Cell Death Dis. 2016 Jun 23;7(6):e2273. doi: 10.1038/cddis.2015.284.

Abstract

The brain and the immune system interact in complex ways after ischemic stroke, and the long-term effects of immune response associated with stroke remain controversial. As a linkage between innate and adaptive immunity, interleukin-17 A (IL-17 A) secreted from gamma delta (γδ) T cells has detrimental roles in the pathogenesis of acute ischemic stroke. However, to date, the long-term actions of IL-17 A after stroke have not been investigated. Here, we found that IL-17 A showed two distinct peaks of expression in the ischemic hemisphere: the first occurring within 3 days and the second on day 28 after stroke. Our data also showed that astrocyte was the major cellular source of IL-17 A that maintained and augmented subventricular zone (SVZ) neural precursor cells (NPCs) survival, neuronal differentiation, and subsequent synaptogenesis and functional recovery after stroke. IL-17 A also promoted neuronal differentiation in cultured NPCs from the ischemic SVZ. Furthermore, our in vitro data revealed that in primary astrocyte cultures activated astrocytes released IL-17 A via p38 mitogen-activated protein kinase (MAPK). Culture media from reactive astrocytes increased neuronal differentiation of NSCs in vitro. Blockade of IL-17 A with neutralizing antibody prevented this effect. In addition, after screening for multiple signaling pathways, we revealed that the p38 MAPK/calpain 1 signaling pathway was involved in IL-17 A-mediated neurogenesis in vivo and in vitro. Thus, our results reveal a previously uncharacterized property of astrocytic IL-17 A in the maintenance and augment of survival and neuronal differentiation of NPCs, and subsequent synaptogenesis and spontaneous recovery after ischemic stroke.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / pathology*
  • Animals
  • Astrocytes / drug effects
  • Astrocytes / metabolism*
  • Axons / drug effects
  • Axons / metabolism
  • Calpain / metabolism
  • Cell Differentiation* / drug effects
  • Cell Movement / drug effects
  • Cell Survival / drug effects
  • Interleukin-17 / metabolism*
  • Interleukin-17 / pharmacology
  • Male
  • Mice, Inbred C57BL
  • Nerve Regeneration / drug effects
  • Neural Stem Cells / drug effects
  • Neural Stem Cells / metabolism
  • Neural Stem Cells / pathology*
  • Neurogenesis / drug effects
  • Neurons / drug effects
  • Neurons / metabolism
  • Neurons / pathology*
  • Recombinant Proteins / pharmacology
  • Recovery of Function / drug effects
  • Stroke / metabolism
  • Stroke / pathology*
  • Stroke / physiopathology
  • Synapses / drug effects
  • Synapses / metabolism
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Interleukin-17
  • Recombinant Proteins
  • p38 Mitogen-Activated Protein Kinases
  • Calpain