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

Themistoklis M. Tsarouchas, Daniel Wehner, Leonardo Cavone, Tahimina Munir, Marcus Keatinge, Marvin Lambertus, Anna Underhill, Thomas Barrett, Elias Kassapis, Nikolay Ogryzko, Yi Feng, Tjakko J. Ham, Thomas Becker () and Catherina G. Becker ()
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Themistoklis M. Tsarouchas: University of Edinburgh
Daniel Wehner: University of Edinburgh
Leonardo Cavone: University of Edinburgh
Tahimina Munir: University of Edinburgh
Marcus Keatinge: University of Edinburgh
Marvin Lambertus: University of Edinburgh
Anna Underhill: University of Edinburgh
Thomas Barrett: University of Edinburgh
Elias Kassapis: University of Edinburgh
Nikolay Ogryzko: Queen’s Medical Research Institute, University of Edinburgh
Yi Feng: Queen’s Medical Research Institute, University of Edinburgh
Tjakko J. Ham: Erasmus University Medical Center
Thomas Becker: University of Edinburgh
Catherina G. Becker: University of Edinburgh

Nature Communications, 2018, vol. 9, issue 1, 1-17

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-07036-w

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