TAM signalling in CNS demyelination and multiple sclerosis

© 2015 Dr. Zhi-Ming Gerry MaMultiple sclerosis (MS) is an immune-mediated demyelinating disease of the central nervous system (CNS). Involvement of the immune system in the pathogenesis of MS is a key feature of the disease, and an understanding of the mechanisms underlying how immune responses are shaped during CNS demyelination will provide insight into the development of new therapeutic strategies. The TAM (Tyro3, Axl, Mertk) family of receptor tyrosine kinases and their ligands Growth Arrest-Specific 6 (Gas6) and Protein S (ProS) have been shown to modulate many immunological processes important during central demyelination. The major aim of this thesis is to provide further insight into TAM biology in the context of both an animal model of inflammatory demyelination and human MS. By conducting a study examining MS patients and common genetic variations within TAM genes, I identified the MERTK gene as a novel MS susceptibility gene. Examination of plasma from MS patients revealed that levels of the TAM ligand PROS are decreased in MS and that low PROS levels are associated with increased MS disease severity. To interrogate the role of TAM signalling in modulating disease severity during inflammatory demyelination, I used the experimental autoimmune encephalomyelitis (EAE) animal model and observed major changes in TAM gene expression within the CNS and peripheral immune cells during EAE. Examination of Gas6-/- mice during EAE showed that absence of the TAM receptor ligand Gas6 results in both attenuated microglial/macrophage responses and disease severity during the effector phase of EAE. Conditional deletion of Mertk from dendritic cells (DC) resulted in worse disease during the effector phase of EAE. Stratification by sex revealed sexual dimorphism in TAM gene expression and also in the outcome of EAE in both Gas6-/- mice and mice with DC-specific deletion of Mertk. In summary, the data presented in this thesis suggest that the TAM family plays key roles in MS susceptibility and modulating innate immune responses during inflammatory demyelination, providing evidence for members of the TAM family as either markers of disease severity and/or therapeutic targets for the treatment of MS