Inflammatory astrocyte and T cell interactions are supported by hyaluronan in a murine model of Multiple Sclerosis

Multiple Sclerosis (MS) is an autoimmune disorder characterized by demyelination, neurodegeneration, and immune cell infiltration into the central nervous system (CNS). Inflammatory astrocytes, one of the first described subtypes of reactive astrocytes, are thought to play a role in the development of demyelinating lesions. In this thesis, I characterized the distribution of inflammatory astrocytes and their interactions in the experimental autoimmune encephalomyelitis (EAE) model of MS. Using this model and in vitro cultures of astrocytes, I identified a novel cell surface marker to identify inflammatory astrocytes. By flow cytometry and confocal microscopy, I determined that the frequency of inflammatory astrocytes is significantly increased in the acute and chronic stages of EAE. I determined that CD4+ T cells are spatially closer to inflammatory astrocytes in EAE tissue, compared to control tissue, and maintain this close distance throughout disease. I further observed that inflammatory astrocytes extend their processes and physically envelop T cells in EAE. In addition, when inflammatory astrocytes and activated T cells are cultured together, the viability of T cells is increased. Moreover, I found that in vitro generated inflammatory astrocytes have increased expression of hyaluronan synthases. Hyaluronan is an extracellular matrix component that is primarily released by astrocytes in the CNS. It has been shown to accumulate in MS and EAE lesions and is thought to support encephalitogenic properties of T cells. However, if astrocyte were treated with the drug 4-methylumbelliferone, which reduces hyaluronan synthesis, this effect on T cell viability is abrogated. Together, my findings suggest that inflammatory astrocytes play a pathogenic role in the progression of EAE through their interactions with T cells, which may be supported by their release of hyaluronan.

Name thesis:degree_name

Doctor of Philosophy (PhD)

Discipline thesis:degree_discipline

Medicine – Neuroscience

Grantor dc:publisher.institution

Graduate Studies

Year dc:date.issued

2025

Author dc:creator

• Reid, Jacqueline Kelsey

Advisors dc:contributor.advisor

• Kuipers, Hedwich
• Yong, Wee V.

Committee members dc:contributor.committeemember

• Gordon, Grant
• Jirik, Frank

Statement dc:rights

• University of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.

Language dc:language.iso

en

DOI

https://dx.doi.org/10.11575/PRISM/48600

OAI identifier oai:identifier

oai:ucalgary.scholaris.ca:1880/121010