Exogenous l-fucose attenuates neuroinflammation induced by lipopolysaccharide

Abstract

α1,6-Fucosyltransferase (Fut8) catalyzes the transfer of fucose to the innermost N-acetylglucosamine residue of N-glycan to form core fucosylation. Our previous studies showed that lipopolysaccharide (LPS) treatment highly induced neuroinflammation in Fut8 homozygous knockout (Fut8−/−) or heterozygous knockout (Fut8+/−) mice, compared with the wide-type (Fut8+/+) mice. To understand the underlying mechanism, we utilized a sensitive inflammation-monitoring mouse system that contains the human interleukin-6 (hIL6) bacterial artificial chromosome (BAC) transgene modified with luciferase (Luc) reporter cassette. We successfully detected LPS-induced neuroinflammation in the central nervous system by exploiting this BAC transgenic monitoring system. Then we examined the effects of L-fucose on neuroinflammation in the Fut8+/− mice. The lectin blot and mass spectrometry analysis showed that L-fucose pre-administration increased the core fucosylation levels in the Fut8+/− mice. Notably, exogenous L-fucose attenuated the LPS-induced IL-6 mRNA and Luc mRNA expression in the cerebral tissues induced by LPS, confirmed using the hIL6-Luc bioluminescence imaging system. The activation of microglial cells, which provoke neuroinflammatory responses upon LPS stimulation, was inhibited by L-fucose pre-administration. L-Fucose also suppressed the downstream intracellular signaling of IL-6, such as the phosphorylation levels of JAK2, Akt, and STAT3. L-Fucose administration increased gp130 core fucosylation levels and decreased the association of gp130 with the IL-6 receptor in Fut8+/− mice, which was further confirmed in BV-2 cells. These results indicate that L-fucose administration ameliorates the LPS-induced neuroinflammation in the Fut8+/− mice, suggesting that core fucosylation plays a vital role in anti-inflammation and that L-fucose is a potential prophylactic compound against neuroinflammation.