Intestinal epithelial cell-specific deletion of α-mannosidase II ameliorates experimental colitis

Koichiro Suzuki, Takahiro Yamada, Keiko Yamazaki, Masato Hirota, Narumi Ishihara, Mizuki Sakamoto, Daisuke Takahashi, Hideki Iijima, Kouji Hase

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Inflammatory bowel disease (IBD) is a refractory disease of the gastrointestinal tract that is believed to develop in genetically susceptible individuals. Glycosylation, a type of post-translational modification, is involved in the development of a wide range of diseases, including IBD, by modulating the function of various glycoproteins. To identify novel genes contributing to the development of IBD, we analyzed single nucleotide polymorphisms (SNPs) of glycosylation-related genes in IBD patients and identified MAN2A1, encoding alphamannosidase II (α-MII), as a candidate gene. α-MII plays a crucial, but not exclusive, role in the maturation of Nglycans. We also observed that intestinal epithelial cells (IECs), which establish the first-line barrier and regulate gut immunity, selectively expressed α-MII with minimal expression of its isozyme, alpha-mannosidase IIx (α-MIIx). This led us to hypothesize that IEC-intrinsic α-MII is implicated in the pathogenesis of IBD. To test this hypothesis, we generated IEC-specific α-MII-deficient (α-MIIΔIEC) mice. Although α-MII deficiency has been shown to have a minimal effect on N-glycan maturation in most cell types due to the compensation by α-MIIx, ablation of α-MII impaired the maturation of N-glycans in IECs. α-MIIΔIEC mice were less susceptible to dextran sulfate sodium-induced colitis compared with control littermates. In accordance with this, neutrophil infiltration in the colonic mucosa was attenuated in α-MIIΔIEC mice. Furthermore, gene expression levels of neutrophilattracting chemokines were downregulated in the colonic tissue. These results suggest that IEC-intrinsic α-MII promotes intestinal inflammation by facilitating chemokine expression. We propose SNPs in MAN2A1 as a novel genetic factor for IBD.

Original languageEnglish
Pages (from-to)25-39
Number of pages15
JournalCell Structure and Function
Volume43
Issue number1
DOIs
Publication statusPublished - 2018 Jan 1

Fingerprint

Colitis
Inflammatory Bowel Diseases
Epithelial Cells
Glycosylation
Chemokines
Single Nucleotide Polymorphism
Polysaccharides
Genes
alpha-Mannosidase
Dextran Sulfate
Neutrophil Infiltration
Post Translational Protein Processing
Isoenzymes
Gastrointestinal Tract
mannosyl-oligosaccharide 1,3 - 1,6-alpha-mannosidase
Immunity
Glycoproteins
Mucous Membrane
Down-Regulation
Inflammation

Keywords

  • Alpha-mannosidase II
  • Inflammatory bowel disease
  • Intestinal epithelial cell
  • N-glycosylation

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

Cite this

Intestinal epithelial cell-specific deletion of α-mannosidase II ameliorates experimental colitis. / Suzuki, Koichiro; Yamada, Takahiro; Yamazaki, Keiko; Hirota, Masato; Ishihara, Narumi; Sakamoto, Mizuki; Takahashi, Daisuke; Iijima, Hideki; Hase, Kouji.

In: Cell Structure and Function, Vol. 43, No. 1, 01.01.2018, p. 25-39.

Research output: Contribution to journalArticle

Suzuki, K, Yamada, T, Yamazaki, K, Hirota, M, Ishihara, N, Sakamoto, M, Takahashi, D, Iijima, H & Hase, K 2018, 'Intestinal epithelial cell-specific deletion of α-mannosidase II ameliorates experimental colitis', Cell Structure and Function, vol. 43, no. 1, pp. 25-39. https://doi.org/10.1247/csf.17022
Suzuki, Koichiro ; Yamada, Takahiro ; Yamazaki, Keiko ; Hirota, Masato ; Ishihara, Narumi ; Sakamoto, Mizuki ; Takahashi, Daisuke ; Iijima, Hideki ; Hase, Kouji. / Intestinal epithelial cell-specific deletion of α-mannosidase II ameliorates experimental colitis. In: Cell Structure and Function. 2018 ; Vol. 43, No. 1. pp. 25-39.
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