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

摘要

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 beta-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 IKK beta and NF-kappa B were O-Glycosylated in AIEC LF82-treated cells. Mutations of IKK beta (S733A) and p65 (T352A) abrogated the O-GlcNAc in IKK beta and NF-kappa B and inhibited AIEC LF82-induced activation of NF-kappa B. Application of 6-diazO-5-oxO-L-norleucine, an agent that blocks the production of UDP-GlcNAc and inhibits O-GlcNAc, inactivated NF-kappa B 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-kappa B 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).

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