Wallerian degeneration: gaining perspective on inflammatory events after peripheral nerve injury

By Andrew D. Gaudet, P. Popovich, M. Ramer. Journal of Neuroinflammation, 2011

847 citations recorded by the source corpus.

In this review, we first provide a brief historical perspective, discussing how peripheral nerve injury (PNI) may have caused World War I. We then consider the initiation, progression, and resolution of the cellular inflammatory response after PNI, before comparing the PNI inflammatory response with that induced by spinal cord injury (SCI).In contrast with central nervous system (CNS) axons, those in the periphery have the remarkable ability to regenerate after injury. Nevertheless, peripheral nervous system (PNS) axon regrowth is hampered by nerve gaps created by injury. In addition, the growth-supportive milieu of PNS axons is not sustained over time, precluding long-distance regeneration. Therefore, studying PNI could be instructive for both improving PNS regeneration and recovery after CNS injury. In addition to requiring a robust regenerative response from the injured neuron itself, successful axon regeneration is dependent on the coordinated efforts of non-neuronal cells which release extracellular matrix molecules, cytokines, and growth factors that support axon regrowth. The inflammatory response is initiated by axonal disintegration in the distal nerve stump: this causes blood-nerve barrier permeabilization and activates nearby Schwann cells and resident macrophages via receptors sensitive to tissue damage. Denervated Schwann cells respond to injury by shedding myelin, proliferating, phagocytosing debris, and releasing cytokines that recruit blood-borne monocytes/macrophages. Macrophages take over the bulk of phagocytosis within days of PNI, before exiting the nerve by the circulation once remyelination has occurred. The efficacy of the PNS inflammatory response (although transient) stands in stark contrast with that of the CNS, where the response of nearby cells is associated with inhibitory scar formation, quiescence, and degeneration/apoptosis. Rather than efficiently removing debris before resolving the inflammatory response as in other tissues, macrophages infiltrating the CNS exacerbate cell death and damage by releasing toxic pro-inflammatory mediators over an extended period of time. Future research will help determine how to manipulate PNS and CNS inflammatory responses in order to improve tissue repair and functional recovery.

Subfields: Cellular and Molecular Neuroscience, Developmental Neuroscience, Pathology and Forensic Medicine

View Paper: https://www.semanticscholar.org/paper/ff952b4770bba13c5aee3da31f1e04b818d59542

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cellular and Molecular Neuroscience

1. R. Mirsky
2. K. Jessen
3. R. Baron
4. Christian A. von Hehn
5. Clifford J. Woolf
6. P. Yurchenco
7. R. Ji
8. Arne May

In Developmental Neuroscience

1. R. Mirsky
2. K. Jessen
3. Christian A. von Hehn
4. R. Baron
5. Clifford J. Woolf
6. P. Yurchenco

In Pathology and Forensic Medicine

1. Christian A. von Hehn
2. R. Baron
3. Clifford J. Woolf

Citations in the corpus

• Deconstructing the Neuropathic Pain Phenotype to Reveal Neural Mechanisms (2012, positive): “After nerve injury, increased levels of neurotrophins, particularly nerve growth factor (NGF), and cytokines are found at the site of and distal to the injury (Dogrul et al., 2011; Gaudet et al., 2011; Leung and Cahill, 2010).”
• The repair Schwann cell and its function in regenerating nerves (2016, background): “Second, denervated cells, unlike immature cells, are engaged in a local, innate immune response, involving expression of a number of cytokines, and the attraction and activation of macrophages (reviewed in Martini et al. 2008; Gaudet et al. 2011; Rotshenker, 2011).”