The impact of IL-1β on glial cells and myelin regeneration in models of Multiple Sclerosis

Abstract

Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system (CNS) targeting the myelin sheath and oligodendrocytes (OL). Destruction of both can lead to the loss of underlying neurons and functional decline in patients. Myelin regeneration (remyelination) can occur in early stages of the disease but often fails with disease progression, in part due to impaired oligodendrocyte progenitor (OPC) differentiation. However, to date there are no treatments available that can therapeutically enhance remyelination.

Intriguingly, remyelination is boosted in areas of inflammation. IL-1β, a potent pro-inflammatory mediator, was found in MS lesions but conversely, was also shown to enhance CNS repair in an animal model of MS. However, its function in OPC biology, myelination and remyelination remains incompletely understood.

This project aims to determine the function of pro-inflammatory IL-1β signalling on glial cells in non-injury context and after damage.

Mixed and pure glial cultures were used to investigate the impact of IL-1 signalling on OPC biology in context of other CNS glial cells and in isolation. IL-1β exposure enhanced differentiation of OPC and increased myelin basic protein (MBP) production indicating OPC differentiation into mature OL but did not affect OPC proliferation.
In order to investigate the role of IL-1 signalling on glial cells after myelin damage mice deficient of IL1 signalling were subjected to focal demyelination and oligodendrocyte lineage cells investigated. Absence of IL-1 signalling did not affect OPC differentiation or OL numbers in the damaged area but enhanced the number of proliferating OPC early after demyelination.

We here show OPC response to IL-1β varies depending on the context. As IL-1β was found in MS lesions, this could be important for the outcome of the response after myelin damage. Further analysis will uncover the underlying mechanisms, which might prove valuable for the development of novel MS therapies targeting IL-1 signalling.

Thesis is embargoed until 31 July 2028.

Date of Award	Jul 2023
Original language	English
Awarding Institution	Queen's University Belfast
Sponsors	MS Society
Supervisor	Denise Fitzgerald (Supervisor), Yvonne Dombrowski (Supervisor) & Andriana Margariti (Supervisor)