A reparative neutrophil subpopulation accelerates 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-1β) mainly in macrophages/microglia and delays anatomical and functional recovery after a spinal cord injury in larval zebrafish. Experimentally reducing Il-1β levels rescues axonal regeneration. Disruption of il4 mimics the detrimental effect of neutrophil ablation for axonal regeneration and this is also rescued by reducing Il-1β levels. Moreover, after ablation of neutrophils, axonal regeneration and il1b expression levels are both rescued by over-expression of il4. Hence, after spinal cord injury, a pro-regenerative neutrophil subpopulation accelerates spinal cord regeneration in larval zebrafish by controlling expression of il1b mainly in macrophages/microglia. For this neutrophil action, il4 expression is necessary and sufficient.