Following spinal cord injury, central nervous system neurons show extremely limited regenerative response and fail to reconnect with their targets resulting in permanent disabilities. However, a conditioning lesion, which triggers a regenerative response, shows that the ability of adult neurons to regenerate could be reactivated. The conditioning lesion is displayed by dorsal root ganglia (DRG) neurons, where an injury to their peripheral branches induces regeneration of their central branches, which would otherwise fail to occur. The first part of the thesis investigated novel signalling mechanisms required for the conditioning lesion paradigm. After a peripheral injury, an inflammatory response occurs with the rapid recruitment of macrophages at the lesion site, which have been shown to be required for the conditioning lesion effect. These cells produce high levels of reactive oxygen species (ROS) and create an oxidative environment around the axons, which led us to hypothesize that ROS may play an important role in the conditioning effect. We discovered that exosomal NOX2, a ROS-producing complex, is released by macrophages, internalized by the axons and retrogradely transported in signalling endosomes to the somas promoting regeneration of DRG axons via oxidative inhibition of PTEN. In the second part, we have explored a novel paradigm where we combined the conditioning lesion with environmental enrichment, establishing a new “enriched” conditioning (EE+SNA) model. We found that EE+SNA induced an additive effect on axonal regeneration after SCI. Gene expression analysis of DRG after EE+SNA showed a striking upregulation of NOX2 pathway with upregulation of all the components of NOX2 complex. Mechanistically, we showed that PKC-dependent STAT3 phosphorylation induces binding of STAT3 on hyper-acetylated NOX2 promoter regions and triggers neuronal intrinsic NOX2 expression. This, in turn, is required for EE+SNA-dependent redox signalling and for the regeneration of DRG sensory fibres after SCI.