Deficiency of α1,6-fucosyltransferase promotes neuroinflammation by increasing the sensitivity of glial cells to inflammatory mediators.

α1,6-Fucosyltransferase-deficient (Fut8-/-) mice displayed increased locomotion and schizophrenia-like behaviors. Since neuroinflammation is a common pathological change in most brain diseases, this study was focused on investigating the effects of Fut8 in microglia and astrocytes. Brain tissues were analyzed using immunohistochemical staining. Core fucosylation and protein expression were analyzed using lectin blot and western blot, respectively. Fut8-knockout (KO) cells were established by the CRISPR/Cas9 system. The number of Iba-1 positive cells and GFAP positive cells were significantly increased in both untreated and lipopolysaccharide stimulated inflammatory conditional Fut8-/- mice by comparison with both wild-type (Fut8+/+) and hetero (Fut8+/-) mice. Stimulation with pro-inflammatory factors, such as IFN-γ and IL-6, induced expression levels of fucosylation in primary microglia and astrocytes, as well as in glial cell lines. Cell motility and iNOS expression were easily induced by IFN-γ in Fut8-KO BV-2 cells compared with wild-type (WT) cells. In a similar manner, both Fut8-KO C6 cells and primary astrocytes treated with 2-fluoro-L-fucose, a specific inhibitor for fucosylation, showed a higher response to IL-6-stimulated phospho-STAT3 signaling, compared with WT cells. Core fucosylation negatively regulates the states of neuroinflammation by modulating the sensitivity of microglia and astrocytes to inflammatory mediators. The disorders of Fut8-/- mice are caused not only by neurons but also by glial cell dysfunction. Core fucose is a novel regulator for neuroinflammation in the central nervous system.