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Abstract
BackgroundInjury to the peripheral branch of dorsal root ganglia (DRG) neurons prior to injury to the central nervous system (CNS) DRG branch results in the regeneration of the central branch. The exact mechanism mediating this regenerative trigger is not fully understood. It has been proposed that following peripheral injury, the intraganglionic inflammatory response by macrophage cells plays an important role in the pre-conditioning of injured CNS neurons to regenerate. In this study, we investigated whether the presence of macrophage cells is crucial for this type of regeneration to occur. We used a clodronate liposome technique to selectively and temporarily deplete these cells during the conditioning phase of DRG neurons.ResultsRetrograde and anterograde tracing results indicated that in macrophage-depleted animals, the regenerative trigger characteristic of pre-conditioned DRG neurons was abolished as compared to injury matched-control animals. In addition, depletion of macrophage cells led to: (i) a reduction in macrophage infiltration into the CNS compartment even after cellular repopulation, (ii) astrocyte up-regulation at rostral regions and down-regulation in brain derived neurotrophic factor (BDNF) concentration in the serum.ConclusionActivation of macrophage cells in response to the peripheral nerve injury is essential for the enhanced regeneration of ascending sensory neurons.
Highlights
Injury to the peripheral branch of dorsal root ganglia (DRG) neurons prior to injury to the central nervous system (CNS) DRG branch results in the regeneration of the central branch
We found that the temporal depletion of these cells completely abolished the regenerative trigger characteristic of this model and we propose a beneficial role of macrophage cells in the regeneration of pre-conditioned DRG neurons
Our results revealed a significant difference in macrophage numbers during liposome treatment (1 week after first injection), indicative of successful cellular depletion (P < 0.0001; Figure 1A-B &1I)
Summary
Injury to the peripheral branch of dorsal root ganglia (DRG) neurons prior to injury to the central nervous system (CNS) DRG branch results in the regeneration of the central branch. In dorsal root ganglion (DRG) neurons, injury to the peripheral branch in the form of a sciatic nerve injury (SNI) prior to injury to the CNS branch (spinal cord - dorsal column cut), has been previously shown to result in axonal regeneration of centrally projecting ascending fibres [7]. This is referred to as conditioning of DRG neurons and it demonstrates the regenerative capacity of injured fibres in the matured CNS. It has been proposed that activation of macrophage cells, together with satellite cell activation and proliferation within the DRG, as part of the normal PNS response to injury, might be playing a crucial role [8]
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