Abstract

Multiple sclerosis is a complex neurological disorder, involving both the adaptive and innate immune system as well as the CNS. The interaction between these systems is complex, and as such there is the potential for MS therapies to have conflicting effects in different tissues. It is therefore critical that in addition to tissue-specific studies, system-wide effects of potential therapeutic pathways are explored. The circulating protein Gas6 is a promising therapy to promote remyelination in people with multiple sclerosis. Gas6 is a ligand for the TAM family of receptor protein tyrosine kinases, that are widely expressed in the immune system and in the CNS, highlighting the potential for multi-system effects as a result of Gas6 treatment. In this study we demonstrate that global genetic deletion of either Gas6 or the Gas6 receptor Tyro3 results in reduced disease severity following induction of experimental immune encephalomyelitis in mice. The reduction in severity was accompanied by increased expression of IL-4 in Tyro3 KO mice, a cytokine known to be protective in inflammatory demyelination in mice. Conversely, loss of Tyro3 was associated with an increase in the expression of the pathological cytokine IL-17a. These data highlight the multi-faceted role of TAM receptor signalling in inflammatory demyelination.