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

Abstract

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.

Painful Terminal Neuroma Prevention by Capping PRGD/PDLLA Conduit in Rat Sciatic Nerves

“…These results were in accordance with the hallmarks of chronic inflammation, in which sustained macrophage influx hindered the resolution of inflammation and maintained the expression of genes of TNF‐α and IL‐1β 31. These cytokines in turn increased the blood–nerve barrier permeability and more inflammatory cells would accumulate at the lesion site to exacerbate or perpetuate the inflammatory process 32. In the rats with capping conduits, milder infiltration together with downregulation of related genes indicated that the inflammation was suppressed, which was mainly attributed to the presence of PRGD/PDLLA capping conduits.…”

Electrical Stimulation to Enhance Axon Regeneration After Peripheral Nerve Injuries in Animal Models and Humans

“…The axons that are separated from their neuronal cell bodies lose their myelin sheaths and undergo Wallerian degeneration [18][19][20][21][22][23][24]. The denervated Schwann cells, in turn, line the endoneurial tubes and cross the surgical gap as the Bands of Bungner that guide regenerating axons across the crush or transection site, through the tubes, and back to the denervated targets [24,25]. It is often said that, even without surgical repair, axons are emitted from the proximal nerve stump and frequently Bfind^their way back to the denervated nerve stump [26].…”

Effects of Renal Artery Denervation on Ventricular Arrhythmias in a Postinfarct Model

“…29,30 Complete degeneration of the axon varies from animal to animal and species to species. [31][32][33] In our study, we euthanized the animals 7 days after RDN, and thus, our histological analysis was limited to such a time period. This time factor could explain why we observed variable neurofilament scores outside the adventitia where large renal sympathetic nerves can be found.…”