Enhanced O-linked Glcnacylation in Crohn's disease promotes intestinal inflammation.

Abstract

BACKGROUND:

Treatment of Crohn's disease (CD) remains to be a challenge due to limited insights for its pathogenesis. We aimed to determine the role of O-Linked β-N-acetylglucosamine (O-GlcNAc) in the development of CD and evaluate therapeutic effects of O-GlcNAc inhibitors on CD.

METHODS:

O-GlcNAc in intestinal epithelial tissues of CD, adherent-invasive Escherichia coli (AIEC) LF82-infected cells and mice was determined by immunoblot and immunohistochemistry. AIEC LF82 and dextran sulfate sodium were administrated into C57BL/6 mice for estabolishing inflammatory bowel disease model and for therapeutic study.

FINDINGS:

O-GlcNAc was increased in intestinal epithelial tissues of CD patients and AIEC LF82-infected mice. Infection of AIEC LF82 up-regulated the level of UDP-GlcNAc and increased O-GlcNAc in human colon epithelial HCT116 and HT-29 cells. We identified that IKKβ and NF-κB were O-Glycosylated in AIEC LF82-treated cells. Mutations of IKKβ (S733A) and p65 (T352A) abrogated the O-GlcNAc in IKKβ and NF-κB and inhibited AIEC LF82-induced activation of NF-κB. Application of 6-diazO-5-oxO-L-norleucine, an agent that blocks the production of UDP-GlcNAc and inhibits O-GlcNAc, inactivated NF-κB in AIEC LF82-infected cells, enhanced the formation of autophagy, promoted the removal of cell-associated AIEC LF82, alleviated intestinal epithelial inflammation, and improved the survival of the colitis mice.

INTERPRETATION:

Intestinal inflammation in CD is associated with increased O-GlcNAc modification, which is required for NF-κB activation and suppression of autophagy. Targeting O-GlcNAc could be an effective therapy for inflammatory bowel disease.

FUNDING:

National Natural Science Foundation of China (Nos. 81573087 and 81772924) and International Cooperation Foundation of Jilin Province (20190701006GH).

• Authors: Qian-Hui Sun, Yi-Shu Wang, Guolong Liu, Hong-Lan Zhou, Yong-Ping Jian, Ming-Di Liu, Dan Zhang, Qiang Ding, Rui-Xun Zhao, Jian-Feng Chen, Yi-Ning Li, Jiyong Liang, Yu-Lin Li, Cheng-Shi Quan, Zhi-Xiang Xu
• Journal: EBioMedicine (EBioMedicine) Vol. 53 Pg. 102693 (Mar 2020) ISSN: 2352-3964 [Electronic] Netherlands
• PMID: 32114385 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.

Chemical References

• NF-kappa B
• Acetylglucosamine

Topics

• Acetylation
• Acetylglucosamine (metabolism)
• Animals
• Autophagy
• Crohn Disease (metabolism)
• Female
• HCT116 Cells
• HT29 Cells
• Humans
• Intestinal Mucosa (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• NF-kappa B (metabolism)
• Protein Processing, Post-Translational