Remyelination in a mouse model of multiple sclerosis resulting from microbial metabolite sensor disruption

University Of Virginia, Charlottesville VA

Investigators

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Abstract

ABSTRACT: Multiple sclerosis (MS) is a debilitating and complex autoimmune disorder in which the myelin within the central nervous system is attacked. The frequency and severity of relapses are highly variable and are linked to both environmental and genetic etiologies. Compelling data obtained from patients and animal models of MS show that the gut microbiome is a critical mediator of pathogenesis. While the relationship between the commensal microbiota and the immune system is well established, the precise mechanisms underlying microbiota-immune crosstalk seen in MS remain unclear. In this proposed study, I suggest a mechanistic link between microbiome and myelin recovery in a mouse model of MS, experimental autoimmune encephalomyelitis (EAE). A sensor of microbial metabolites called the aryl hydrocarbon receptor (AHR) is a transcription factor that modulates immune and metabolic homeostasis at barrier tissues including the skin, lungs, and, importantly, the gastrointestinal tract. AHR activity in T cells has the capacity to modify the gut microbiome as well as modify immune cell fitness. Previous work has focused on germ-line AHR knockouts or cell specific knock out in the nervous system; however, I have produced a CD4 T cell specific AHR knockout mouseline, and these animals exhibit a microbiome-dependent recovery from EAE. These mice have increased myelin coverage after initial paralysis and decreased IL-12 in the spinal cord at peak of disease. Additionally, I have found that IL-12 reduces oligodendrocyte progenitor cell (OPC) differentiation into myelinating oligodendrocytes in vitro. Under this proposal, I aim to use my previously described model of recovery, T cell Ahr knockout mice, to 1) characterize the myelin dynamics in a remyelinating lesions and 2) determine the role of IL-12 as an intermediary between the immune system and myelinating oligodendrocyte progenitor cells. I will determine whether myelin recovery is the result of OPC differentiation or of mature oligodendrocyte recovery using transmission electron microscopy and lineage tracing. I will attempt to understand the source of the IL-12 in this model and the cell intrinsic signaling cascades in OPCs and oligodendrocytes affected by IL-12. Finally, I will utilize an IL-12 receptor knockout to understand the role of IL-12 during myelination in vivo. Understanding this mechanistic link between the microbiome and the central nervous system will have implications for early stage MS patients recovering from relapsing symptoms. By establishing the direct and indirect effects of an environmental sensor (AHR) on the spinal cord microenvironment, we can better understand the underlying basis of recovery in MS and identify more targeted therapeutics, thus avoiding the current approach of systemic immunosuppression.