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

Nature Communications, 2018 · DOI: 10.1038/s41467-018-07036-w · Published: November 6, 2018

Regenerative Medicine Immunology Neurology

Simple Explanation

Spinal cord injury in mammals often leads to a prolonged immune response that inhibits axonal regeneration. However, zebraﬁsh, which can regenerate their spinal cords, also exhibit an immune response after injury. This study investigates the role of the immune response, specifically macrophages, in successful spinal cord regeneration in zebraﬁsh larvae, showing that both inhibiting and promoting inflammation affect axonal regeneration. The study shows that macrophages dynamically control inflammation by producing pro-regenerative Tnf-α and reducing levels of Il-1β, which is crucial for functional spinal cord regeneration in zebraﬁsh.

Study Duration

Not specified

Participants

Approximately 11,000 zebraﬁsh larvae

Evidence Level

Not specified

Key Findings

1
Inhibiting inflammation reduces and promoting inflammation accelerates axonal regeneration in spinal-lesioned zebraﬁsh larvae.
2
Peripheral macrophages, but not neutrophils or microglia, are necessary for spinal cord repair in zebraﬁsh.
3
Macrophages control number of and cytokine expression by neutrophils, leading to prolonged presence of Il-1β+ neutrophils in the injury site of irf8 mutants.

Research Summary

The study demonstrates that spinal cord injury leads to an inflammatory response that promotes axonal regeneration. Inhibiting inflammation reduces the number of immune cells and impairs axonal bridging. Macrophages are crucial for successful spinal cord regeneration in zebraﬁsh. The absence of macrophages leads to increased levels of pro-inflammatory cytokines, which impair axonal regrowth and functional recovery. Tnf-α is essential for axonal regeneration, whereas excessive levels of Il-1β inhibit regeneration in irf8 mutants. Reducing Il-1β levels rescues axonal bridging and recovery of touch-evoked swimming distance.

Practical Implications

Therapeutic Potential

Understanding the dynamic role of immune cells and cytokines in spinal cord regeneration could lead to novel therapeutic strategies for promoting regeneration in non-regenerating systems, such as mammals.

Targeted Immunomodulation

Fine-tuning the immune response by promoting Tnf-α activity and controlling Il-1β levels may enhance axonal regeneration after spinal cord injury.

Macrophage-Based Therapies

Targeting macrophages to promote their pro-regenerative functions and suppress their pro-inflammatory activities could improve spinal cord repair.

Study Limitations

1
The study is conducted in zebraﬁsh larvae, which have different regenerative capabilities compared to mammals.
2
The specific mechanisms by which macrophages control Il-1β levels and promote Tnf-α-mediated regeneration are not fully elucidated.
3
The long-term effects of manipulating the immune response on spinal cord regeneration need further investigation.

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