Abstract Text: Astrocytes contribute to the maintenance of the health of the central nervous system (CNS) and have also been implicated in the onset and progression of neurodegenerative diseases. Recently, it has become evident that metabolism regulates the pathological responses of microglia and astrocytes. Glucose uptake by astrocytes provides substrates that can be processed by the hexosamine pathway (HBP). UDP-GlcNAc is the end product of HBP, which is used as a substrate for O-GlcNAcylation, a post-translational modification controlled by the enzymes O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). O-GlcNAcylation is associated with the triggering inflammatory responses by immune cells, and the development of neurodegenerative diseases. Here, we report that culture-purified astrocytes responded to the inflammatory stimulus by TNF and LPS through the production of IL-6, CCL2, CXCL1 and CXCL10. The production of these mediators correlates with an increase in the expression of enzymes in the HBP. Additionally, we noticed that increased O-GlcNAcylation by the suppression of OGA activity using Thiamet-G reduced the production of IL-6 and CXCL1. However, in vivo we observed a reduction in the expression of OGT and OGA in the spinal cord of animals submitted to the experimental model of autoimmune encephalomyelitis (EAE). We also generated and validated astrocyte-specific OGT conditional knockout mice. Aldh1creER/OGTfl/fl mice were immunized with MOG35–55 peptide. Notably, the loss of OGT in astrocytes significantly reduced the clinical severity. These data, although preliminary, demonstrate that the hexosamine pathway regulates the inflammatory response of astrocytes and may be a future target for the treatment of neurodegenerative diseases.
