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Review
. 2011 Aug 30:8:110.
doi: 10.1186/1742-2094-8-110.

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

Andrew D Gaudet  1 , Phillip G Popovich, Matt S Ramer
Affiliations
Review

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

Andrew D Gaudet et al. J Neuroinflammation. .

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.

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Figures

Figure 1
Figure 1
Progression of Wallerian degeneration and axon regeneration after peripheral nerve injury (PNI). A single axon with associated myelinating Schwann cells is shown. Although myelin phagocytosis and degeneration occurs within the basal lamina (purple), the basal lamina is shown only in panel 1 for clarity. 1. The endoneurium of an uninjured nerve consists of axons, associated Schwann cells (myelinating and nonmyelinating), and resident, inactivated macrophages. 2. Soon after PNI, denervated myelinating Schwann cells release their myelin. These Schwann cells then proliferate within their basal lamina tubes, produce cytokines/trophic factors, and phagocytose detached debris. In addition, the reaction within the neuron cell body begins: this is characterized by cell soma hypertrophy, displacement of the nucleus to an eccentric position, and dissolution of Nissl bodies. 3. Wallerian degeneration is well underway within a week of injury. Soluble factors produced by Schwann cells and injured axons activate resident macrophages and lead to recruitment of hematogenous macrophages. The activated macrophages clear myelin and axon debris efficiently, and produce factors that facilitate Schwann cell migration and axon regeneration. 4. After a lag period, injured axons form a growth cone and begin to regenerate along bands of Büngner formed by Schwann cells. These tubes provide a permissive growth environment and guide extending axons towards potential peripheral targets. Schwann cells that have been chronically denervated (e.g., for a few months) are less supportive of regrowth and are more likely to undergo apoptosis. 5. If the axon is able to traverse the injury site, and its environment supports its growth along the entire distal stump, then the axon can connect with peripheral targets. Although myelinating Schwann cells do remyelinate the regenerated portion of axon, the myelin is thinner and the nodal length is shorter than in the uninjured portion of axon. See text for references.
Figure 2
Figure 2
Progression of axon degeneration (left panels) and macrophage accumulation (right panels) in mouse distal nerves after tight sciatic nerve ligation. Sciatic nerves from 129P3/J mice were harvested at the indicated timepoints post-injury. After sectioning nerves longitudinally, we used immunohistochemistry to visualize axons (PGP9.5) and macrophages (F4/80). Axons degenerate progressively, with early discontinuities visible within 1 day of injury, extensive degeneration at 3 days, and nearly complete degeneration within 7 days (axon regeneration is precluded by tight ligation of the sciatic nerve). Few macrophages reside within the uninjured (uninj.) nerve. Macrophage accumulation, which includes resident macrophage proliferation and hematogenous macrophage infiltration, begins by 1 day after injury and peaks between 3 and 7 days post-axotomy. Note the change in macrophage morphology and F4/80 immunoreactivity between 3 and 7 days: compact, elongated F4/80-positive cells predominate at 3 days, whereas most macrophages are large and amoeboid at 7 days post-axotomy. This switch reflects the phagocytosis of large amounts of debris by macrophages between those timepoints. Scale bar, 200 μm.
Figure 3
Figure 3
After injury and regeneration, proteins in newly-formed myelin contribute to resolution of the inflammatory response by facilitating macrophage exit from the basal lamina. A single axon (turquoise) with myelin (green) and basal lamina (purple) is shown in cross-section. 1. In the uninjured peripheral nerve, the myelinated axon is surrounded by many tight wraps of myelin; this unit is covered by the basal lamina. Resident macrophages (pink) perform a surveillance role and are present outside of the basal lamina. 2. After peripheral nerve injury, the axon degenerates and myelin break down begins. Activated resident and hematogenous macrophages accumulate and penetrate the basal lamina, where they phagocytose myelin and axon debris. Because the debris can physically prevent regeneration and also contains inhibitors to axon growth, this macrophage-mediated phagocytosis is a crucial step in nerve repair. 3. After debris phagocytosis, axon regeneration, and remyelination, macrophages are no longer useful within the basal lamina. Proteins on the surface of newly-formed myelin signal debris-laden macrophages to emigrate from the basal lamina. Inset (fourth panel): myelin-associated glycoprotein (MAG), present on myelin membranes, interacts with the receptor NgR and its signaling partner TROY on macrophage membranes. Engagement of this receptor complex in the trailing edge of macrophages leads to local activation of the small GTPase RhoA, which signals for local repulsion and movement away from the source of activation (myelin). Ultimately, this causes macrophage exit from the basal lamina once remyelination has occurred.
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