Wallerian Degeneration

Wallerian degeneration (WD) is a process in which injury causes a strong reaction of peripheral nerves, especially non-neuronal cells in the distal nerve remnant.

Fig.1 Progression of WD and axon regeneration after peripheral nerve injury (PNI). (Gaudet, 2011)

The Molecular Trigger for WD

Two alternative models for how injury triggers WD are a pro degeneration signal generated at the lesion site and the absence of a prosurvival signal derived from the cell body. The disease studies clearly show that Wallerian-like processes can be triggered in the complete absence of physical injury. In contrast, there is a strong correlation with disorders of axonal transport. Non-lethal impairment of protein synthesis also triggers Wallerian-like degeneration.

The Cytokine Network of WD

PNS (peripheral nervous system) injury induces immune cells and non-immune cells to produce cytokines at the injury site and its distal end. Thus, a cytokine network is activated in wild-type mice during normal WD. Findings suggest that the timing and size of cytokine production depend on the identity and spatial distribution of non-neuronal cells producing cytokines in PNS tissues, as well as the timing of macrophage recruitment.

Fig.2 The cytokine network of WD. (Rotshenker, 2011)

Chemokines, Recruitment of Macrophages and WD

Chemokine MCP-1 (chemoattractant protein-1; known also as CCL2, C-C motif ligand 2) and MIP-1α (macrophage inflammatory protein-1α, known also as CCL3) promote the transmigration of monocytes across the endothelial cell wall of blood vessels. MCP-1/CCL2 produced by Schwann cells is upregulated within hours after the impact at injury sites, and after one day at the distal region during normal WD. In Wlds mice, MCP-1/CCL2 is produced at injury sites, but not further distal where slow WD develops. Therefore, the occurrence and timing of MCP-1/CCL2 production coincide with those of TNFα and IL-1β that induce them.

Immune Inhibitory Receptors and WD

Inhibition may be produced by a family of immune inhibitory receptors. SIRPα (signal-regulatory-protein-α, known also as CD172a and SHPS1) is a member of this family. SIRPα is expressed on myeloid cells (e.g., macrophages and microglia) and some neurons and is activated by its ligand CD47. CD47 is a cell membrane protein receptor that various cells express. Cells that express CD47 down-regulate their phagocytosis by macrophages after CD47 binds to SIRPα on phagocytes. CD47 functions, therefore, as a marker of “self” that protects cells from activated autologous macrophages by sending a “do not eat me” signal and protects intact myelin, Schwann cells, and oligoden drocytes from activated macrophages in PNS and activated microglia and macrophages in CNS. This mechanism may be useful under normal conditions and while combating invading pathogens since it protects bystander intact myelin and myelin-forming cells from macrophages and microglia that are activated to scavenge and kill pathogens.

Neurotrophic Factors and WD

Peripheral nerve injury induces the production of neurotrophic factors by Schwann cells and fibroblasts during normal WD. Among families of neurotrophic factors is the neurotrophin family. It consists of NGF, BDNF (brain-derived neurotrophic factor), NT (neurotrophin)-3, and NT-4/5. The production of NGF, BDNF, and NT-4 is upregulated during normal WD. Among these, NGF promotes neuronal survival and axon growth of sympathetic and subsets of sensory dorsal root neurons. 1L-1α, 1L-1β, and TNFα contribute to NGF mRNA upregulation in fibroblasts but not in Schwann cells.

The production of IL-6 and LIF is upregulated during normal WD. Apart from being modulators of innate-immune functions, IL-6 and LIF also display neurotrophic properties by promoting neuronal survival and axon growth. Further, LIF may also function as a Schwann cell growth factor.

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References

1. Gaudet, A.D.; et al. Wallerian degeneration: gaining perspective on inflammatory events after peripheral nerve injury. J Neuroinflammation. 2011 Aug 30; 8: 110.
2. Rotshenker, S. Wallerian degeneration: the innate-immune response to traumatic nerve injury. Journal of neuroinflammation. 2011, 8(1): 1-14.