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, 3 (3), 1282-324

Myelin Recovery in Multiple Sclerosis: The Challenge of Remyelination

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Myelin Recovery in Multiple Sclerosis: The Challenge of Remyelination

Maria Podbielska et al. Brain Sci.

Abstract

Multiple sclerosis (MS) is the most common demyelinating and an autoimmune disease of the central nervous system characterized by immune-mediated myelin and axonal damage, and chronic axonal loss attributable to the absence of myelin sheaths. T cell subsets (Th1, Th2, Th17, CD8+, NKT, CD4+CD25+ T regulatory cells) and B cells are involved in this disorder, thus new MS therapies seek damage prevention by resetting multiple components of the immune system. The currently approved therapies are immunoregulatory and reduce the number and rate of lesion formation but are only partially effective. This review summarizes current understanding of the processes at issue: myelination, demyelination and remyelination-with emphasis upon myelin composition/ architecture and oligodendrocyte maturation and differentiation. The translational options target oligodendrocyte protection and myelin repair in animal models and assess their relevance in human. Remyelination may be enhanced by signals that promote myelin formation and repair. The crucial question of why remyelination fails is approached is several ways by examining the role in remyelination of available MS medications and avenues being actively pursued to promote remyelination including: (i) cytokine-based immune-intervention (targeting calpain inhibition), (ii) antigen-based immunomodulation (targeting glycolipid-reactive iNKT cells and sphingoid mediated inflammation) and (iii) recombinant monoclonal antibodies-induced remyelination.

Figures

Figure 1
Figure 1
A composite diagram summarizing features of CNS myelin: (A) architecture; (B) 3D-molecular composition and conformation-based assembly and (C) the unique sphingosine 3-O-acetylated-GalCer GL series. The diagram depicts arrangement of complex lipids (cholesterol, PLs and GLs) and most abundant proteins (PLP, MBP). The relative molar constancy of lipids: cholesterol (C):PLs:galactosylceramide (GalCer) is C:PLs:GalCer = 2:2:1. Proteins are marked in yellow and the comprising lipids are as follows: cholesterol in orange, PLs in pink and the glycosphingolipids (FMC, fast migrating cerebrosides; GalCer, galactosylceramide; GM1, mono-sialoganglioside; GM4, sialosyl-galactosylceramide; sGalCer, sulfatide) in blue. Structures of myelin acetyl-cerebrosides (FMCs) are shown. Adapted and modified from Podbielska et al. [20] with permission of Future Medicine Ltd. Additional abbreviations: CNP, 2′3′-cyclic-nucleotide 3′-phospodiesterase; MAG, myelin-associated glycoprotein; MBP, myelin basic protein; MOG, myelin oligodendrocyte glycoprotein; PLP, proteolipid protein.
Figure 2
Figure 2
Features of the myelination process. (A) Sequential stages of oligodendrocyte maturation. Specific markers for differentiation status of the oligodendrocyte lineage. Differentiation into mature oligodendrocytes is associated with acquisition of myelin-related proteins. (B) Myelin sheath organization in the CNS. Myelinating glial cells, oligodendrocytes in the CNS form the myelin sheath by enwrapping axons. Myelinated axon regions are interrupted by non-myelinated regions (nodes of Ranvier). Myelinated axons have four distinct domains: node (N), paranode (PN), juxtaparanode (JXP) and internode (INT). Nodes of Ranvier are regions of concentrated sodium channels that form between two internodes. Adjacent to the nodes of Ranvier are the paranode and the juxtaparanode. All four domains have characteristic proteins (see upper inset). At the nodes of Ranvier, Neurofascin 186 (Nf-186) supports the clustering of Na+ channels. The nodal Na+ channels are separated from the juxtaparanodal K+ channels via the paranode, where Neurofascin 155 (Nf-155) binds tightly to the axonal complex of Contactin and Contactin-associated protein (Caspr). CNP, an abundant cytoplasmic myelin protein, is predominantly found at the paranode. At the juxtaparanode, clustered K+ channels are associated to Caspr-2 and Contactin-2.
Figure 3
Figure 3
Characteristics of the demyelination process. Demyelination destroys the paranode and sodium channels migrate laterally. Following this is sodium channels (Nav) redistribution and re-expression of the immature isoform of sodium channels, Nav1.2. Persisting currents may cause conduction block and calcium overload, leading to axon injury and eventually loss.
Figure 4
Figure 4
Hypothetical outcomes for demyelinated axon.Denuded axon impermissive for myelination. (A,B): remyelination failure and axonal death. Oligodendrocyte ensheathing. (C,D): remyelination leading to long-term neuroregeneration and functional recovery. (A) Transforming growth factor-β 1 (TGF-β1), secreted by resident microglial and astroglial cells, stimulates astrocytes in MS lesions to re-express the Notch ligand Jagged1 [121]. Contact-mediated activation of canonical Notch signaling by ligand Jagged 1 inhibits oligodendrocyte progenitor cells (OPC) differentiation and impermissive for proliferation [120]. (B) The denuded axon impermissive for myelination through surface expression of inhibitory molecules, such as PSA-NCAM [109], and interactions between axonal LINGO-1 binding to oligodendroglial Nogo-A [133,134,135] prevent further myelination. (C) Activation of a non-canonical Notch signaling pathway triggered by axonal ligands including F3/contactin-1 in OPC [123,124]. (D) Axonal laminin and L1 bind oligodendroglial integrin (and then dystroglycan receptor) and contactin-2 promoting oligodendrocyte survival and myelination [136]. Additional abbreviations: L1, axonal cell adhesion molecule; MAG, myelin-associated glycoprotein; MOG, myelin oligodendrocyte glycoprotein; NgR1; Nogo-receptor 1; OPC, oligodendrocyte progenitor cell; PSA-NCAM, polysialic acid-neural cell adhesion molecule.
Figure 5
Figure 5
INKT cell-mediated immune responses (IR). Different antigenic GLs: microbial GLs; danger ligands; self antigens (Ags) compete for binding to iTCR; a pattern recognition receptor (PRR). Recognition is for different lipids—e.g., GLs, PLs and IR can be to microbial GLs (usually with high affinity) and overlap IR to self Ags (weaker affinity). The iNKT is (1) primed by the GL/iTCR/CD1d receptor complex and (2) responds according to environment, mainly cytokines-dependent with diverse outcomes: (i) pro-inflammatory (Th-1 type responses), (ii) regulatory (Th-2 type) or (iii) anti-pathogen (Th-17 type) as shown for IL-12 for iNKT pro-inflammatory functions; for an IL-10-driven response generating regulatory Tr1 Treg (e.g., CD4+CD25+Foxp3) and also anti-pathogen activity triggered by IL-17 and IL-23. From Hogan et al. [210] with permission of OMICS Publishing Group.

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