In the PNS, even before the arrival of phagocytotic cells at the site of nerve injury, Schwann cells initiate removal of myelin debris. Recent studies demonstrate that resident macrophages (normally present in small numbers in the peripheral nerves) become activated after nerve injury. They migrate to the site of nerve injury, proliferate, and then phagocytize myelin debris.
The efficient clearance of myelin debris in the PNS is attributed to the massive recruitment of monocyte-derived macrophages that migrate from blood vessels and infiltrate the vicinity of the nerve injury (Fig 12. 34). When an axon is injured, the blood–nerve barrier (see page 376) is disrupted along the entire length of the injured axon, which allows for the influx of these cells into the site of injury. The presence of large numbers of monocyte-derived macrophages speeds up the process of myelin removal, which in peripheral nerves is usually completed within 2 weeks.
In the CNS, inefficient clearance of myelin debris due to limited access of monocyte-derived macrophages, the inefficient phagocytic activity of microglia, and the formation of an astrocyte-derived scar severely restrict nerve regeneration.
A key difference in the CNS response to axonal injury relates to the fact that the blood–brain barrier (see page 385) is disrupted only at the site of injury and not along entire length of the injured axon (see Fig 12.34). This limits infiltration of monocyte-derived macrophages to the CNS and dramatically slows the process of myelin removal, which can take months or even years. Although the number of microglial cells increases at sites of CNS injury, these reactive microglia cells do not possess the full phagocytotic capabilities of migrating macrophages. The inefficient clearance of myelin debris is a major factor in the failure of nerve regeneration in the CNS. Another factor that affects nerve regeneration is the formation of a glial (astrocyte-derived) scar that fills the empty space left by degenerated axons. Scar formation is discussed in Folder 12.3.
Traumatic degeneration occurs in the proximal part of the injured nerve.
FIGURE 12.33 • Response of a nerve fber to injury. a. A normal nerve fiber at the time of injury, with its nerve cell body and the effector cell (striated skeletal muscle). Note the position of the neuron nucleus and the number and distribution of Nissl bodies.
b. When the fiber is injured, the neuronal nucleus moves to the cell periphery, and the number of Nissl bodies is greatly reduced. The nerve fiber distal to the injury degenerates along with its myelin sheath. Schwann cells dedifferentiate and proliferate; myelin debris are phagocytosed by macrophages. c. Proliferated Schwann cells form cellular cords of Bunger that are penetrated by the growing axonal sprout. The axon grows at a rate of 0.5 to 3 mm/day. Note that the muscle fiber show a pronounced atrophy. d. A confocal immunofluorescent image showing reinnervated skeletal muscle of the mouse. Regenerating motor axons are stained green for neurofilaments reestablished connections with two neuromuscular junctions visualized in pink color, which reflects specific staining for postsynaptic acetylcholine receptors; Schwann cells are stained blue for S100, which represents a Schwann cell–specific calcium-binding protein. Regenerating axons extended along Schwann cells, which led them to the original synaptic sites of the muscle fibers. 640. (Courtesy of Dr. Young-Jin Son.)