TY - JOUR
T1 - Intestinal epithelial cell-specific deletion of α-mannosidase II ameliorates experimental colitis
AU - Suzuki, Koichiro
AU - Yamada, Takahiro
AU - Yamazaki, Keiko
AU - Hirota, Masato
AU - Ishihara, Narumi
AU - Sakamoto, Mizuki
AU - Takahashi, Daisuke
AU - Iijima, Hideki
AU - Hase, Koji
N1 - Funding Information:
We would like to thank Yumiko Fujimura and Kei Takizawa (Keio University) for technical support. This work was supported by JSPS KAKENHI (Grant number: 15J02654 to KS; 17H04089 to KH; 26293180 to KY), MEXT KAKENHI (Grant number: 16H01369 and 26116709 to KH). Health Labour Sciences Research Grant (KH), AMED-Crest (KH). Yakult Foundation (KH), Takeda Science Foundation (KH), and the BioBank Japan Project (KY).
Funding Information:
Acknowledgments. We would like to thank Yumiko Fujimura and Kei Takizawa (Keio University) for technical support. This work was supported by JSPS KAKENHI (Grant number: 15J02654 to KS; 17H04089 to KH; 26293180 to KY), MEXT KAKENHI (Grant number: 16H01369 and 26116709 to KH), Health Labour Sciences Research Grant (KH), AMED-Crest (KH), Yakult Foundation (KH), Takeda Science Foundation (KH), and the BioBank Japan Project (KY).
Publisher Copyright:
© 2018 The Author(s).
PY - 2018
Y1 - 2018
N2 - 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.
AB - 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.
KW - Alpha-mannosidase II
KW - Inflammatory bowel disease
KW - Intestinal epithelial cell
KW - N-glycosylation
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UR - http://www.scopus.com/inward/citedby.url?scp=85047205659&partnerID=8YFLogxK
U2 - 10.1247/csf.17022
DO - 10.1247/csf.17022
M3 - Article
C2 - 29343654
AN - SCOPUS:85047205659
VL - 43
SP - 25
EP - 39
JO - Cell Structure and Function
JF - Cell Structure and Function
SN - 0386-7196
IS - 1
ER -