Cellular and Molecular Mechanisms Underpinning Macrophage Activation during Remyelination

Abstract

Remyelination is an example of central nervous system (CNS) regeneration, whereby myelin is restored around demyelinated axons, re-establishing saltatory conduction and trophic/metabolic support. In progressive multiple sclerosis, remyelination is limited or fails altogether which is considered to contribute to axonal damage/loss and consequent disability. Macrophages have critical roles in both CNS damage and regeneration, such as remyelination. This diverse range in functions reflects the ability of macrophages to acquire tissue microenvironment-specific activation states. This activation is dynamically regulated during efficient regeneration, with a switch from pro-inflammatory to inflammation-resolution/pro-regenerative phenotypes. Although, some molecules and pathways have been implicated in the dynamic activation of macrophages, such as NFκB, the cellular and molecular mechanisms underpinning plasticity of macrophage activation are unclear. Identifying mechanisms regulating macrophage activation to pro-regenerative phenotypes may lead to novel therapeutic strategies to promote remyelination in multiple sclerosis.

Distinct patterns of glia repair and remyelination in antibody‐mediated demyelination models of multiple sclerosis and neuromyelitis optica

“…Scale bars: 50 μm models, increasing evidence has suggested that microglia play an important role in remyelination. Minocycline-induced inhibition of microglia activation significantly impairs remyelination following ethidium bromide injection in rat cerebellum (Li, Setzu, Zhao, & Franklin, 2005), and activation of microglia or adoptive transfer of cytokine- Microglia function in remyelination likely involves phagocytosis of myelin debris and the secretion of factors to recruit OPCs and promote oligodendrocyte regeneration (Lloyd & Miron, 2016;McMurran, Jones, Fitzgerald, & Franklin, 2016;Olah et al, 2012). However, without any characterization of the regenerated oligodendrocytes in these studies, it is not clear whether microglia promote OPC differentiation or oligodendrocyte maturation from the early myelinating to mature myelinating stage.…”

Differential expression of alarmins—S100A9, IL-33, HMGB1 and HIF-1α in supraspinatus tendinopathy before and after treatment

“…3 More recently, the identification of key immune cell populations and signalling molecules as important regulators in the initiation and propagation of other musculoskeletal diseases, including rheumatoid arthritis (RA) and spondyloarthropathy, has led to a re-emergence of interest in the role of inflammation in tendon disease. [4][5][6][7] The term 'tendinopathy' has been popularised to reinforce the notion that the Key points " We found differential protein expression of alarmins in healthy and diseased human supraspinatus tendons, before and after treatment. " The cell types expressing S100A9, interleukin-33 (IL-33) and hypoxia-inducible factor 1a (HIF-1a) included macrophages and tendon stromal cells. "…”

Drug discovery for remyelination and treatment of MS

“…In addition to direct manipulation of the oligodendrocyte lineage, it is clear that axons, neural stem cells, microglia/macrophages, Schwann cells, astrocytes, cells of the vasculature, as well as additional innate and adaptive immune cells, are also likely to represent possible therapeutic targets for the treatment of the progressive stages of MS. Consideration of the diverse pathologies of MS and potential strategies and entry‐points for its treatment are beyond the scope of this review, but have been extensively described and reviewed elsewhere (Barnett & Linington, ; Correale & Farez, ; Dombrowski et al, ; Domingues, Portugal, Socodato, & Relvas, ; Franklin & Goldman, ; Liddelow et al, ; Lloyd & Miron, ; Nait Oumesmar et al, ; Ransohoff, Hafler, & Lucchinetti, ; Ransohoff, Schafer, Vincent, Blachère, & Bar‐Or, ; Waxman, ; Yuen et al, ; Zawadzka et al, ). In the final section of this review we focus on emerging technologies that will play important roles in dissecting the basic biology of disease and in providing platforms that allow screening for drug discovery.…”