The Role of MERTK in Central Inflammatory Demyelination

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Author
Dwyer, Christopher MichaelDate
2020Affiliation
Florey Department of Neuroscience and Mental HealthMetadata
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PhD thesisAccess Status
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© 2020 Christopher Michael Dwyer
Abstract
Multiple sclerosis (MS) is, at least in part, an autoimmune demyelinating disease of the central nervous system. It is the most common cause of neurological dysfunction in young adults. In addition to demyelination, autoimmune destruction in MS results in oligodendrocyte loss, local inflammation and neurodegeneration. Later in the disease course, a pattern of neurodegeneration may emerge without obvious evidence of adaptive immune activation. Current evidence implicates dysregulation of the innate immune system as a major contributor to the neurodegeneration of progressive MS. It is well established that innate immunity influences central nervous system damage and modulates myelin repair.
The TAMs (TYRO3, AXL and MERTK) are a family of receptor tyrosine kinases expressed by discrete innate immune cell types, including macrophages, microglia and dendritic cells. They are involved the homeostatic regulation of adult, fully differentiated tissues that are subject to constant intrinsic and environmental challenge. The primary aim of this thesis was to provide additional insight into the biology of the MERTK receptor by examining its role in commonly employed mouse models of MS. In addition, I sought to identify whether serum levels of MERTK correlated with disease activity in MS patients experiencing relapse.
I established that heterozygote deletion of Mertk in CD11+ve cells worsens the clinical severity of EAE in male mice, demonstrating for the first time that changes in the expression of a TAM receptor can alter the outcomes of a model of MS. Conversely, homozygous deletion did not result in EAE exacerbation. Heterozygote deletion of Mertk in CD11+ve cells does not alter the outcomes of cuprizone-induced demyelination, suggesting that CNS-resident CD11c+ve cells (microglia) are not implicated in the clinical exacerbation observed in EAE cohorts. In human subjects, MERTK expression by monocytes and dendritic cells does not correlate with periods of increased inflammatory activity in MS. MERTK expression by circulating dendritic cells is very limited.
Taken together, the data in this thesis offer compelling evidence that MERTK is an important regulator of the outcomes of central inflammatory demyelination. They justify further research efforts in this area to better understand the mechanism of these disease states and to develop therapeutic targets for the treatment of MS.
Keywords
Multiple Sclerosis; Experimental Autoimmune Encephalomyelitis; Cuprizone Intoxication; TAM Receptors; MERTK; TYRO3; AXL; Sexual DimorphismExport Reference in RIS Format
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