A reparative neutrophil subpopulation promotes spinal cord regeneration in zebrafish by controlling macrophage inflammation via Il-4

In mammals, a dysregulated immune response is detrimental to spinal cord repair. In zebrafish, which are capable of spinal cord regeneration, the immune response promotes regeneration. Neutrophils are the first immune cells to arrive at a spinal cord injury site, but their role in successful regeneration is not fully understood. Here we show that ablating neutrophils, including a subpopulation that expresses the cytokine il4, increases expression of il1b (coding for Il-1{beta}) in macrophages/microglia and impairs anatomical and functional recovery after a spinal cord injury in larval zebrafish. Regeneration is fully rescued by over-expression of il4 alone or experimentally reducing Il-1{beta} levels. Disruption of il4 mimics the detrimental effect of neutrophil ablation for axonal regeneration and is also rescued by reducing Il-1{beta} levels. Hence, after spinal cord injury, a pro-regenerative neutrophil subpopulation promotes spinal cord regeneration in larval zebrafish by controlling expression of il1b in macrophages/microglia. For this neutrophil action, il4 expression is necessary and sufficient. HIGHLIGHTS- Neutrophil ablation impairs spinal cord repair in zebrafish - The neutrophil response can be replaced by reducing Il-1{beta} levels - A pro-regenerative subpopulation of neutrophils expresses il4 - il4 overexpression fully rescues effects of neutrophil ablation