Down-regulation of interleukin 7 receptor (IL-7R) contributes to central nervous system demyelination

Oncotarget. 2017 Apr 25;8(17):28395-28407. doi: 10.18632/oncotarget.16081.

Abstract

Interleukin 7 receptor (IL-7R) has been associated with the pathogenesis of multiple sclerosis (MS), though the mechanisms are not clear. Because myelin expression is highly conserved between zebrafish and mammals, zebrafish have become an ideal model for studying demyelination. We used a transgenic (Tg; mbp:nfsB-egfp) zebrafish line in which oligodendrocytes expressed green fluorescent protein (GFP) from the larval stage to adulthood. Exposing adult transgenic zebrafish to metronidazole induced demyelination that resembled the morphological changes associated with the early stages of MS. The metronidazole-induced demyelination was confirmed by magnetic resonance imaging (MRI) for the first time. Microarray analysis revealed down-regulation of IL-7R during demyelination. Targeted knockdown of IL-7R demonstrated that IL-7R is essential for myelination in embryonic and larval zebrafish. Moreover, IL-7R down-regulation induced signaling via the JAK/STAT pathway leading to apoptosis in oligodendrocytes. These findings contribute to our understanding of the role of IL-7R in demyelination, and provide a rationale for the development of IL-7R-based therapies for MS and other demyelinating diseases.

Keywords: demyelination; interleukin 7 receptor (IL-7R); myelin basic protein; myelination; zebrafish.

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Central Nervous System Diseases / diagnostic imaging
  • Central Nervous System Diseases / genetics*
  • Central Nervous System Diseases / metabolism
  • Central Nervous System Diseases / pathology
  • Demyelinating Diseases / diagnostic imaging
  • Demyelinating Diseases / genetics*
  • Demyelinating Diseases / metabolism
  • Demyelinating Diseases / pathology
  • Disease Models, Animal
  • Down-Regulation
  • Gene Expression Profiling
  • Gene Expression Regulation*
  • Gene Knockdown Techniques
  • Genes, bcl-2
  • Janus Kinases / metabolism
  • Receptors, Interleukin-7 / genetics*
  • Receptors, Interleukin-7 / metabolism
  • STAT Transcription Factors / metabolism
  • Signal Transduction
  • Spinal Cord / metabolism
  • Spinal Cord / pathology
  • Zebrafish

Substances

  • Receptors, Interleukin-7
  • STAT Transcription Factors
  • Janus Kinases