Abstract
Structural perturbations of distinct extracellular matrix (ECM) molecules, such as those causing the aggregation of fibronectin, contribute to remyelination failure of axons in the chronic demyelinating disease multiple sclerosis. Accordingly, the development of means that prevent the inhibitory effect of fibronectin aggregates or that annihilate fibronectin aggregates, might be a promising therapeutic approach to reactivate myelin biogenesis in MS.
The work described in this thesis provides novel insight into the mechanism as to why fibronectin aggregates persist in MS lesions, and consequently led to the development of potential means to overcome remyelination failure, in spite of the presence of harmful fibronectin aggregates. It is demonstrated that matrix metalloproteinase 7 (MMP7), expressed by pro-regenerative microglia and macrophages, is capable of cleaving fibronectin aggregates into fragments. Furthermore, it was revealed that the expression of MMP7 is decreased in chronic MS lesions. Hence, although MMP7 has been hypothesized to induce demyelination, local application of this proteinase in MS lesions might serve as a useful tool in efforts to rescue remyelination in MS.
Interestingly, fibronectin aggregates can act as a scaffold for other molecules that can modulate the phenotype of microglia and macrophages, thereby inducing these cells to secrete molecular factors that prevent the generation of myelinating oligodendrocytes. However, upon co-treatment with IL-4, an inducer of pro-regenerative microglia and macrophages, the inhibition of oligodendrocyte maturation by microglia and macrophages in the presence of fibronectin, is reversed. Moreover, IL-4 exposure overcomes the impaired remyelination in demyelinated forebrain slice cultures in the presence of fibronectin-aggregrates. Hence, IL-4 may serve a novel and interesting tool to overcome inhibition of remyelination in MS lesions, due to the presence of fibronectin aggregates.
The work described in this thesis provides novel insight into the mechanism as to why fibronectin aggregates persist in MS lesions, and consequently led to the development of potential means to overcome remyelination failure, in spite of the presence of harmful fibronectin aggregates. It is demonstrated that matrix metalloproteinase 7 (MMP7), expressed by pro-regenerative microglia and macrophages, is capable of cleaving fibronectin aggregates into fragments. Furthermore, it was revealed that the expression of MMP7 is decreased in chronic MS lesions. Hence, although MMP7 has been hypothesized to induce demyelination, local application of this proteinase in MS lesions might serve as a useful tool in efforts to rescue remyelination in MS.
Interestingly, fibronectin aggregates can act as a scaffold for other molecules that can modulate the phenotype of microglia and macrophages, thereby inducing these cells to secrete molecular factors that prevent the generation of myelinating oligodendrocytes. However, upon co-treatment with IL-4, an inducer of pro-regenerative microglia and macrophages, the inhibition of oligodendrocyte maturation by microglia and macrophages in the presence of fibronectin, is reversed. Moreover, IL-4 exposure overcomes the impaired remyelination in demyelinated forebrain slice cultures in the presence of fibronectin-aggregrates. Hence, IL-4 may serve a novel and interesting tool to overcome inhibition of remyelination in MS lesions, due to the presence of fibronectin aggregates.
| Translated title of the contribution | Over de rol van macrofagen, microglia en de extracellulaire matrix bij remyelinisatie |
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| Original language | English |
| Qualification | Doctor of Philosophy |
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| Supervisors/Advisors |
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| Award date | 28-Mar-2018 |
| Place of Publication | [Groningen] |
| Publisher | |
| Print ISBNs | 978-94-034-0451-6 |
| Electronic ISBNs | 978-94-034-0450-9 |
| Publication status | Published - 2018 |