Review: Myelin clearance is critical for regeneration after peripheral nerve injury

Abstract

Traumatic peripheral nerve injury occurs frequently and is a major clinical and public health problem that can lead to functional impairment and permanent disability. Despite the availability of modern diagnostic procedures and advanced microsurgical techniques, active recovery after peripheral nerve repair is often unsatisfactory. Peripheral nerve regeneration involves several critical events, including the recreation of the microenvironment and remyelination. Results from previous studies suggest that the peripheral nervous system (PNS) has a greater capacity for repair than the central nervous system. Thus, it will be important to understand myelin and myelination specifically in the PNS. This review provides an update on myelin biology and myelination in the PNS and discusses the mechanisms that promote myelin clearance after injury. The roles of Schwann cells and macrophages are considered at length, together with the possibility of exogenous intervention.

Keywords: Schwann cell; autophagy; demyelination; macrophages; myelin clearance; peripheral nerve injury.

Figure 1

Immediately after injury, SCs and macrophages (including resident and early-stage infiltrating macrophages) begin to remove myelin debris (34). SC-mediated phagocytosis reaches a peak at approximately 5 days post-injury (dpi; green line). Most of the engulfment results from macrophage activity that increases from 5 to 7 dpi (red line). Macrophage-mediated phagocytosis reaches a peak at approximately 14 dpi and remains detectable at day 56 (35). Fibroblasts and neutrophils also contribute to myelin clearance at this stage (35, 36). The myelin fragments are ultimately cleared by localized apoptosis followed by transport by the lymphatics to the spleen.

Figure 2

Immediately after injury, ErbB2, MAPK, PI3K, Notch, and EphA4 signals respond in SCs, their crosstalk, and the downstream signaling pathways that regulate factors that mediate myelination. This results in the downregulation of pro-myelinating genes, including Zeb2, Oct6, and Krox20, and the upregulation of negative regulatory factors, including Sox-2, Pax-3, and c-Jun. In addition, activated Rac promotes F-actin polymerization to generate myelin ovoids. Myelin is also cleared during this stage.

Figure 3

Myelin fragments at the site of injury form phagophores which develop into autophagosomes. The autophagosomes then fuse with lysosomes that contain enzymes capable of digesting myelin fragments. The decomposed fragments are then released into circulation. Autophagy in SCs is mTOR independent.

Figure 4

Myelin debris that accumulates after PNI is cleared by macrophages, including resident cells and those recruited locally from the neurovasculature. The infiltrating macrophages are recruited in response to chemokines and cytokines that are expressed by dedifferentiated SCs and resident macrophages.