Generation and clearance of myelin debris after spinal cord injury

Abstract

Traumatic spinal cord injury often leads to the disintegration of nerve cells and axons, resulting in a substantial accumulation of myelin debris that can persist for years. The abnormal buildup of myelin debris at sites of injury greatly impedes nerve regeneration, making the clearance of debris within these microenvironments crucial for effective post-spinal cord injury repair. In this review, we comprehensively outline the mechanisms that promote the clearance of myelin debris and myelin metabolism and summarize their roles in spinal cord injury. First, we describe the composition and characteristics of myelin debris and explain its effects on the injury site. Next, we introduce the phagocytic cells involved in myelin debris clearance, including professional phagocytes (macrophages and microglia) and non-professional phagocytes (astrocytes and microvascular endothelial cells), as well as other cells that are also proposed to participate in phagocytosis. Finally, we focus on the pathways and associated targets that enhance myelin debris clearance by phagocytes and promote lipid metabolism following spinal cord injury. Our analysis indicates that myelin debris phagocytosis is not limited to monocyte-derived macrophages, but also involves microglia, astrocytes, and microvascular endothelial cells. By modulating the expression of genes related to phagocytosis and lipid metabolism, it is possible to modulate lipid metabolism disorders and influence inflammatory phenotypes, ultimately affecting the recovery of motor function following spinal cord injury. Additionally, therapies such as targeted mitochondrial transplantation in phagocytic cells, exosome therapy, and repeated trans-spinal magnetic stimulation can effectively enhance the removal of myelin debris, presenting promising potential for future applications.

Keywords: foam cells; lipid droplets; lipid metabolism; macrophages; microglia; myelin debris; myelin proteins; myelin sheath; nerve regeneration; phagocytosis; spinal cord injury.

Figure 1

Timeline of typical studies reported in the literature to promote myelin debris clearance and lipid metabolism. BMSC-Exos: Bone marrow-derived mesenchymal stem cell-derived exosomes; BRO: bromocriptine; CD36: CD36 molecule (thrombospondin receptor); CD47: cluster of differentiation 47; LPS: lipopolysaccharide; TREM2: triggering receptor expressed on myeloid cells 2.

Figure 2

Schematic diagram of the production and phagocytosis of myelin debris after SCI. (A) Four major phagocytes, including professional phagocytes (macrophages and microglia) and amateur phagocytes (microvascular endothelial cells and astrocytes). (B) Myelin debris is phagocytosed by phagocytes. (C) Excessive phagocytosis of myelin debris leads to foam cell formation (upper part), and by targeting relevant targets, phagocytosis can be promoted and lipid metabolism can be regulated (lower part). ABCA1/ABCG1: aTP-binding cassette transporter A1/ATP-binding cassette transporter G1; AMPK: aMP-activated protein kinase; APOE: apolipoprotein E; CD36:CD36 molecule (thrombospondin receptor); CD47: cluster of differentiation 47; ERK1/2: extracellular signal-regulated kinase 1/2; GIT1: G protein-coupled receptor kinase 2 interacting protein-1; HDAC 6: histone deacetylase 6; MSR1: macrophage scavenger receptor 1; SCI: spinal cord injury; TLR4: Toll-like receptor 4; TREM2: triggering receptor expressed on myeloid cells 2.

Figure 3

Dual effects of macrophage phagocytosis of myelin debris in SCI. (1) After SCI, axons disintegrate and produce large amounts of myelin sheath and cell debris, which are subsequently swallowed by macrophages. These cells will then initiate myelin degradation of myelin-derived lipid droplets, creating a microenvironment that promotes regeneration. (2) Large absorption of myelin debris will lead to the formation of foam cells, thereby stimulating NF-kB signaling, promoting inflammation, and inducing neuronal cell death. (3) Absorption of axon remnants by phagocytes triggers secondary axon contraction. Reprinted with permission from Van Broeckhoven et al., 2021. Copyright 2021 The Authors. NF-κB: Nuclear factor kappa B; SCI: spinal cord injury.

Figure 4

Pathways for the processing and degradation of myelin debris by phagocytes. (A) After spinal cord injury, a large number of myelin debris are produced; (B) myelin debris is processed by various receptors on phagocytes; (C) the endosomal–lysosomal pathway degrades myelin debris; (D) the autophagy–lysosomal pathway degrades myelin debris. ABCA1/ABCG1: ATP-binding cassette transporter A1/ATP-binding cassette transporter G1; CD36: CD36 molecule (thrombospondin receptor); CD47: cluster of differentiation 47; MSR1: macrophage scavenger receptor 1; TLR4: Toll-like receptor 4; TREM2: triggering receptor expressed on myeloid cells 2.

Figure 5

Schematic diagram of mechanisms in alternative approaches to promote myelin debris clearance. (A) rTSMS treatment may enhance functional recovery in rats with SCI by promoting the clearance of myelin debris, potentially mediated by LRP-1 in microglia (adapted with permission from Zhai et al., 2024). (B) BMSC-exosomes mixed with hydrogel and transplanted onto the surface of the injured spinal cord can restore normal macrophage function, facilitating myelin debris clearance through the upregulation of macrophage receptor with collagen structure (MARCO) in macrophages (adapted from Sheng et al., 2021). (C, D) The construction process and therapeutic mechanism of the mitochondria-triphenylphosphonium-cation-cysteine-alanine-glutamine-lysine (Mito-Tpp-CAQK) compound (adapted from Xu et al., 2024). ADAM17: Adisintegrin and metalloproteinase 17; BMDM: bone marrow-derived macrophages; BMSC-Exos: bone marrow-derived mesenchymal stem cell-derived exosomes; LRP1: low-density lipoprotein receptor-related protein 1; rTSMS: repeated trans-spinal magnetic stimulation; SCI: spinal cord injury.