Mast cells as mediators of astrocyte morphology associated with neuroinflammatory disease states

Abstract

Abstract Morphological deficits observed in astrocytes, the most abundant glial cell type in the central nervous system, are associated with various neuroinflammatory diseases. The morphological and molecular astrocyte changes associated with multiple sclerosis are well-characterized and concentrated in the white matter of the brain. While the exact mechanisms behind this autoimmune disease are not fully understood, mast cells play a key role in the progression of white matter demyelination. We hypothesize mast cells orchestrate morphological astrocyte changes that are associated with neuroinflammatory disease states. To test this hypothesis, we used GFAP as a marker to visualize astrocyte morphology in white matter tracts of wild type (WT) and mast cell deficient KitW–sh/W–sh (sash) mice. Using skeleton analysis, we quantified astrocyte characteristics such as number of endpoints, branches, and branch length. Compared with WT mice, sash mice exhibited fewer branches (77 vs. 54 branches/cell) and endpoints per cell (49.5 vs. 24.5 P<0.001). These findings suggest that mast cells may drive altered astrocyte morphology and function in white matter. In order to determine whether this effect is due to altered development, studies using sash mice at time points across the lifespan are in progress. In addition, we are using diphtheria toxin in combination with novel genetic lines to ablate mast cells acutely in adult mice. Along with new molecular techniques, this will allow us to better characterize the interaction between mast cells and astrocytes in the adult and developing brain. Unraveling this interplay will be critical to understanding the role of mast cells in neurodevelopment and neuroinflammatory diseases such as multiple sclerosis.