Regeneration-associated macrophages： a novel approach to boost intrinsic regenerative capacity for axon regeneration

Axons in central nervous system （CNS） do not regenerate spontaneously after injuries such as stroke and traumatic spinal cord iniury. Both intrinsic and extrinsic factors are responsible for the regeneration fail- ure, Although intensive research efforts have been invested on extrinsic regeneration inhibitors, the extent to which glial inhibitors contribute to the regeneration failure in viva still remains elusive. Recent exper- imental evidence has rekindled interests in intrinsic factors for the regulation of regeneration capacity in adult mammals. In this review, we propose that activating macrophages with pro-regenerative molecular signatures could be a novel approach for boosting intrinsic regenerative capacity of CNS neurons. Using a conditioning injury model in which regeneration of central branches of dorsal root ganglia sensory neu- rons is enhanced by a preceding injury to the peripheral branches, we have demonstrated that perineuronal macrophages surrounding dorsal root ganglia neurons are critically involved in the maintenance of en- hanced regeneration capacity. Neuron-derived chemokine （C-C motif） ligand 2 （CCL2） seems to mediate neuron-macrophage interactions conveying injury signals to perineuronal macrophages taking on a soley pro-regenerative phenotype, which we designate as regeneration-associated macrophages （RAMs）. Ma- nipulation of the CCL2 signaling could boost regeneration potential mimicking the conditioning injury, suggesting that the chemokine-mediated RAM activation could be utilized as a regenerative therapeutic strategy for CNS injuries.