Investigating The Role Of Extracellular Vesicles And MicroRNA-155 In Cerebrovascular Function In Inflammation

Roig-Carles, David (2021). Investigating The Role Of Extracellular Vesicles And MicroRNA-155 In Cerebrovascular Function In Inflammation. PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.00012a28

Abstract

Blood-brain barrier (BBB) dysfunction is an early feature of several central nervous system (CNS) pathologies and is characterised by increased leukocyte migration to the CNS and increased paracellular permeability of brain endothelial cells (BECs). The mechanisms by which the BBB actively participates in the inflammatory events that contribute to the progression of many CNS diseases is still poorly understood. Extracellular vesicles (EVs) are a novel mechanism of cell-to-cell communication. Endothelial cell-derived EVs are upregulated in circulating blood in different pathologies (e.g. multiple sclerosis) and systemic inflammation. TNFα-stimulated BECs secrete a higher number of EVs, which carry a pro-inflammatory cargo. However, the role of cerebrovascular EVs modulating inflammation at the BBB is still unclear.

In this project, EVs secreted from BECs were characterised based on number, size and RNA cargo. Indeed, BECs secreted higher number of EVs in inflammation that carried pro-inflammatory modulators (e.g. miRNA-155). Uptake of EVs by NVU cells and their role in BEC function was investigated. Interestingly, EVs decreased transendothelial resistance and increased T cell adhesion to BECs via up-regulation of adhesion molecules.

TNFα/IFNγ–mediated BECs dysfunction is partially modulated by miRNA-155. However, the mechanism by which miRNA-155 modulates T cell adhesion remains to be elucidated. WNK1 was identified as possible target of miRNA-155 and shown to modulate T cell adhesion.

Finally, unexpected increased polydipsia in female aged miRNA-155 knock-out mice was investigated but this unexpected phenotype was attributed to a miRNA-155-independent pathway.

Results from this work constitute the first evidence that BEC-derived EVs modulate BBB function in inflammation, which is likely to be a mechanism of the cells to amplify pro-inflammatory cytokine signalling in the vasculature. Additionally, this work has demonstrated endothelial WNK1 as a modulator of T cell adhesion. Genotyping tissue from miRNA-155 KO mice will serve for future identification of novel modulators of water balance.

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