AbstractNeuroinflammation is a key feature of neurodegenerative disorders, including multiple sclerosis (MS). Glial cells, particularly microglia and astrocytes, are key players in the CNS pro-inflammatory response, capable of secreting inflammatory mediators and altering their phenotypes in response to external cues. The TAM (Tyro3, Axl, Mer) family of receptor tyrosine kinases are important negative regulators of the inflammatory response and have also been implicated in MS. The main aims of this thesis were to investigate the roles of TAM receptors and their ligands Gas6 and ProS1 in suppressing pro-inflammatory mediator production in glial cells, in regulating pro-resolving functions such as astrocyte migration, and to investigate TAM dysregulation in post-mortem MS brain lesions.
Experiments utilised cultures of primary brain glial cells, as well as organotypic brain slices, from mice of wild-type, Tyro3-/-, Axl-/-, and Mertk-/- genetic backgrounds. Experiments revealed that Mer and Axl were key receptors in modulating the pro-inflammatory response to lipopolysaccharide. In microglia, Axl signalling proved essential for Tnf upregulation and regulated the expression of Mertk. Furthermore, Gas6 suppressed induction of both TNF-α and GM-CSF, acting through Mer and Axl receptors. The Gas6 suppressive effect occurred through blocking NF-κB signalling and was able to alter the morphology and reactivity of glial cells. Furthermore, Gas6 reduced astrocyte migration under inflammatory conditions, with a dependence on microglial interactions. To correlate in vitro findings with human lesion pathology, clinical samples from MS brains were analysed by immunohistochemistry. Analysis revealed an increase in Mer, Axl and Gas6 within MS lesions, irrespective of the stage of lesion development.
Overall, this PhD study presents novel information on the role of TAM signalling in the modulation of the inflammatory response in microglia and astrocytes. Future investigations that translate these findings into clinically relevant models could lead to development of novel therapies for neurodegenerative disorders such as MS
|Date of Award||Dec 2021|
|Supervisor||Sassan Hafizi (Supervisor) & Jerome Swinny (Supervisor)|