Dynamic control of proinflammatory cytokines Il-1β and Tnf-α by macrophages in zebrafish spinal cord regeneration

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Themistoklis M. Tsarouchas - , University of Edinburgh (Author)
  • Daniel Wehner - , University of Edinburgh, TUD Dresden University of Technology (Author)
  • Leonardo Cavone - , University of Edinburgh (Author)
  • Tahimina Munir - , University of Edinburgh (Author)
  • Marcus Keatinge - , University of Edinburgh (Author)
  • Marvin Lambertus - , University of Edinburgh, University of Oslo (Author)
  • Anna Underhill - , University of Edinburgh (Author)
  • Thomas Barrett - , University of Edinburgh (Author)
  • Elias Kassapis - , University of Edinburgh (Author)
  • Nikolay Ogryzko - , University of Edinburgh (Author)
  • Yi Feng - , University of Edinburgh (Author)
  • Tjakko J. van Ham - , Erasmus University Rotterdam (Author)
  • Thomas Becker - , University of Edinburgh (Author)
  • Catherina G. Becker - , University of Edinburgh (Author)

Abstract

Spinal cord injury leads to a massive response of innate immune cells in non-regenerating mammals, but also in successfully regenerating zebrafish. However, the role of the immune response in successful regeneration is poorly defined. Here we show that inhibiting inflammation reduces and promoting it accelerates axonal regeneration in spinal-lesioned zebrafish larvae. Mutant analyses show that peripheral macrophages, but not neutrophils or microglia, are necessary for repair. Macrophage-less irf8 mutants show prolonged inflammation with elevated levels of Tnf-α and Il-1β. Inhibiting Tnf-α does not rescue axonal growth in irf8 mutants, but impairs it in wildtype animals, indicating a pro-regenerative role of Tnf-α. In contrast, decreasing Il-1β levels or number of Il-1β + neutrophils rescue functional regeneration in irf8 mutants. However, during early regeneration, interference with Il-1β function impairs regeneration in irf8 and wildtype animals. Hence, inflammation is dynamically controlled by macrophages to promote functional spinal cord regeneration in zebrafish.

Details

Original languageEnglish
Article number4670
JournalNature communications
Volume9
Issue number1
Publication statusPublished - 7 Nov 2018
Peer-reviewedYes
Externally publishedYes

External IDs

PubMed 30405119