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.
Highlights
Nerve injury may have caused World War I In 1914, Austria’s Archduke Ferdinand was assassinated in Sarajevo
We found that injury-induced macrophage accumulation is delayed and diminished in galectin-1 null mutant mice [122]
Whereas Schwann cells mediate myelin clearance in early stages of Wallerian degeneration, resident endoneurial and hematogenous macrophages play a crucial role in debris removal and nerve repair beginning within a week of peripheral nerve injury (PNI)
Summary
Nerve injury may have caused World War I In 1914, Austria’s Archduke Ferdinand was assassinated in Sarajevo. In addition to proliferating and phagocytosing debris after PNI, Schwann cells in the distal nerve stump secrete trophic factors that promote axon growth along with cytokines and chemokines that recruit immune cells into the injured nerve. Schwann cells in the distal nerve initially mount an effective response that promotes axon regeneration, their ability to survive and support axon growth declines within eight weeks of denervation [102,103]. Whereas Schwann cells mediate myelin clearance in early stages of Wallerian degeneration, resident endoneurial and hematogenous macrophages play a crucial role in debris removal and nerve repair beginning within a week of PNI. Endogenous CNS cells contribute to the hostile environment: astrocytes proliferate and release inhibitory factors, oligodendrocytes atrophy and release myelinassociated inhibitors, and microglia operate as sub-optimal phagocytes and possibly as neurotoxic effector cells
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