Macrophages (monocytes/microglia) could play a critical role in central nervous system repair. We have previously found a synchronism between the regression of spontaneous axonal regeneration and the deactivation of macrophages 34 wk after a compression-injury of rat spinal cord. To explore whether reactivation of endogenous macrophages might be beneficial for spinal cord repair, we have studied the effects of granulocyte-macrophage colony stimulating factor (GM-CSF) in the same paraplegia model and in cell cultures. There is significant, though transient, improvement of locomotor recovery after a single delayed intraperitoneal injection of 2g GM-CSF. This improvement is associated with an increased expression of 5HT at the level of the CPG (T13-L2). At longer survival delays, axonal regeneration is significantly enhanced in GM-CSF-treated rats. We then studied the effects of GM-CSF on brain-derived neurotrophic factor (BDNF)secretion by macrophages/microglia, inflammatory reaction and phagocytosis by macrophages/microglia. In vivo, at short post-treatment delays, we found that GM-CSF increases significantly the expression of Cr3 and BDNF by macrophages at the lesion site. In vitro, BV2 microglial cells expressed higher levels of BDNF in the presence of GM-CSF and neurons cocultured with microglial cells activated by GM-CSF generated more neurites, an effect blocked by a BDNF antibody. In vivo, we showed that GM-CSF treatment (either immediate or delayed) does not increase IL-6 expression by macrophages/microglia or astrocytes. We showed that a delayed GM-CSF treatment down regulates IL-1 expression by astrocytes. In vivo, we showed that a delayed GM-CSF treatment can decrease MAG expression at the lesion site. These experiments suggest that GM-CSF could be an interesting treatment option for spinal cord injury and that its beneficial effects might be mediated by BDNF.