Exogenous l-fucose attenuates neuroinflammation induced by lipopolysaccharide

Xing Xu; Tomohiko Fukuda; Jun Takai; Sayaka Morii; Yuhan Sun; Jianwei Liu; Shiho Ohno; Tomoya Isaji; Yoshiki Yamaguchi; Miyako Nakano; Takashi Moriguchi; Jianguo Gu

doi:10.1016/j.jbc.2023.105513

Exogenous l-fucose attenuates neuroinflammation induced by lipopolysaccharide

J Biol Chem. 2024 Jan;300(1):105513. doi: 10.1016/j.jbc.2023.105513. Epub 2023 Dec 1.

Authors

Affiliations

¹ Division of Regulatory Glycobiology, Institute of Molecular Biomembrane and Glycobiology, Tohoku Medical and Pharmaceutical University, Sendai, Miyagi, Japan.
² Division of Medical Biochemistry, Tohoku Medical and Pharmaceutical University, Sendai, Miyagi, Japan.
³ Graduate School of Integrated Sciences for Life, Hiroshima University, Higashi-Hiroshima, Japan.
⁴ Division of Structural Glycobiology, Institute of Molecular Biomembrane and Glycobiology, Tohoku Medical and Pharmaceutical University, Sendai, Miyagi, Japan.
⁵ Division of Regulatory Glycobiology, Institute of Molecular Biomembrane and Glycobiology, Tohoku Medical and Pharmaceutical University, Sendai, Miyagi, Japan. Electronic address: jgu@tohoku-mpu.ac.jp.

Abstract

α1,6-Fucosyltransferase (Fut8) catalyzes the transfer of fucose to the innermost GlcNAc residue of N-glycan to form core fucosylation. Our previous studies showed that lipopolysaccharide (LPS) treatment highly induced neuroinflammation in Fut8 homozygous KO (Fut8^-/-) or heterozygous KO (Fut8^+/-) mice, compared with the WT (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 transgene modified with luciferase (Luc) reporter cassette. We successfully detected LPS-induced neuroinflammation in the central nervous system by exploiting this bacterial artificial chromosome 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 preadministration 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, 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 preadministration. l-Fucose also suppressed the downstream intracellular signaling of IL-6, such as the phosphorylation levels of JAK2 (Janus kinase 2), Akt (protein kinase B), and STAT3 (signal transducer and activator of transcription 3). 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.

Keywords: N-glycosylation; core fucosylation; interleukin-6; microglia; neuroinflammation.

MeSH terms

Animals
Cytokine Receptor gp130
Fucose* / metabolism
Fucose* / pharmacology
Fucosyltransferases / genetics
Fucosyltransferases / metabolism
Humans
Inflammation* / drug therapy
Inflammation* / metabolism
Interleukin-6 / genetics
Lipopolysaccharides* / toxicity
Mice
Neuroinflammatory Diseases
RNA, Messenger

Substances

Cytokine Receptor gp130
Fucose
Fucosyltransferases
Interleukin-6
Lipopolysaccharides
RNA, Messenger