Investigating microRNA-mediated glial cell contributions in the pathophysiology of MS and its animal models

Galloway, Dylan A. (2021) Investigating microRNA-mediated glial cell contributions in the pathophysiology of MS and its animal models. Doctoral (PhD) thesis, Memorial University of Newfoundland.

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Abstract

Multiple sclerosis (MS) is a chronic neurological disease characterized by the immune-mediated destruction of myelin within the central nervous system (CNS). During the course of MS, diverse cell populations including microglia, monocyte-derived macrophages and astrocytes contribute towards neuroinflammation and demyelination; however, these cells can also facilitate remyelination and brain repair. Consequently, defining the molecular mechanisms that balance inflammation and regeneration within the CNS is essential for understanding the pathophysiology of MS and investigating novel disease-modifying therapies. microRNAs (miRNAs) are small RNA molecules that posttranscriptionally regulate gene expression and are of significant interest in many diseases since they can repress several functionally related genes and robustly alter cell phenotype and function. The overall goal of this thesis was to investigate miRNAs that control glial cell activation and myelin repair in MS and its animal models. Dimethyl fumarate (DMF) is a commonly prescribed MS disease-modifying therapy. While studying the effects DMF on human astrocytes, it was observed that this molecule, and not its metabolite, suppressed pro-inflammatory astrocyte activation and miRNA expression. In MS patient monocytes, miR-223-3p was identified as a differentially regulated miRNA that is essential for pro-regenerative myeloid cell phenotypes. Specifically, miR-223-3p promoted anti-inflammatory polarization and myelin phagocytosis by macrophages and microglia, and miR-223-3p deficiency impaired myelin debris clearance and remyelination following experimental demyelination in vivo. Gene expression profiling of demyelinated lesions revealed that genes associated with the inflammasome, a complex that induces pro-inflammatory cytokine secretion and cell death, were highly upregulated in acutely demyelinated lesions and subsided during remyelination. In MS lesions and experimental demyelination, it was confirmed that the NLRP3 inflammasome was highly expressed in macrophages and microglia. NLRP3 was identified as a miR-223-3p target gene, and both miR-223-3p and a small-molecule NLRP3 inhibitor suppressed inflammasome activation in vitro. In vivo, NLRP3 inhibition reduced axonal injury following demyelination. Overall, this thesis has established a role for miRNAs as regulators of glial cell responses and are functionally relevant during CNS repair following demyelination. Moving forward, modifying the expression of miRNAs, such as miR-223-3p, may represent a novel therapeutic approach in the treatment of MS and other inflammatorymediated demyelinating conditions.

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