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©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.
O-linked β-N-acetylglucosamine transferase regulates macrophage polarization in diabetic periodontitis: In vivo and in vitro study
Ye-Ke Wu, Min Liu, Hong-Ling Zhou, Xiang He, Jing Wei, Wei-Han Hua, Hui-Jing Li, Qiang-Hua Yuan, Yun-Fei Xie
Ye-Ke Wu, Xiang He, Jing Wei, Hui-Jing Li, Department of Stomatology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, Sichuan Province, China
Min Liu, Department of Gynaecology, Chengdu University of Traditional Chinese Medicine, Chengdu 610072, Sichuan Province, China
Hong-Ling Zhou, Center of Stomatology, West China Xiamen Hospital of Sichuan University, Xiamen 361021, Fujian Province, China
Wei-Han Hua, Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan Province, China
Qiang-Hua Yuan, Department of Pharmacy, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, Sichuan Province, China
Yun-Fei Xie, Department of Nuclear Medicine, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu 610072, Sichuan Province, China
Author contributions: Wu YK and Liu M conceived the study, and they were a major contributor in writing the manuscript; Wu YK, Zhou HL, He X and Wei J conducted the experiments; Hua WH, Li HJ, Yuan QH and Xie YF analyzed the data; All authors read and approved the final manuscript.
Supported by the National Natural Science Foundation of China, No. 81973684; Natural Science Foundation of Sichuan Province, No. 2023NSFSC1760; and Youth Talent Fund of Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, No. 2021QN09.
Institutional review board statement: The study does not involve human experiments.
Institutional animal care and use committee statement: All animal experimental procedures were approved by the Ethics Committee of the Hospital of Chengdu University of Traditional Chinese Medicine and conducted in accordance with the Guide for the Care and Use of Laboratory Animals (No. 2022-126).
Conflict-of-interest statement: The authors declare that they have no conflict of interest.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Data sharing statement: The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
https://creativecommons.org/Licenses/by-nc/4.0/ Corresponding author: Yun-Fei Xie, MD, Doctor, Department of Nuclear Medicine, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, No. 32 West Section 2, 1
st Ring Road, Chengdu 610072, Sichuan Province, China.
xyfsub@126.com
Received: April 1, 2024
Revised: September 30, 2024
Accepted: December 23, 2024
Published online: March 15, 2025
Processing time: 295 Days and 1.3 Hours
BACKGROUND
Periodontitis, when exacerbated by diabetes, is characterized by increased M1 macrophage polarization and decreased M2 polarization. O-linked β-N-acetylglucosamine (O-GlcNAcylation), catalyzed by O-GlcNAc transferase (OGT), promotes inflammatory responses in diabetic periodontitis (DP). Additionally, p38 mitogen-activated protein kinase regulates macrophage polarization. However, the interplay between OGT, macrophage polarization, and p38 signaling in the progression of DP remains unexplored.
AIM
To investigate the effect of OGT on macrophage polarization in DP and its role in mediating O-GlcNAcylation of p38.
METHODS
For in vivo experiments, mice were divided into four groups: Control, DP model, model + short hairpin (sh) RNA-negative control, and model + sh-OGT. Diabetes was induced by streptozotocin, followed by ligation and lipopolysaccharide (LPS) administration to induce periodontitis. The impact of OGT was assessed by injecting sh-OGT lentivirus. Maxillary bone destruction was evaluated using micro-computed tomography analysis and tartrate-resistant acid phosphatase staining, while macrophage polarization was determined through quantitative real-time polymerase chain reaction (qPCR) and immunohistochemistry. For in vitro experiments, RAW264.7 cells were treated with LPS and high glucose (HG) (25 mmol/L D-glucose) to establish a cell model of DP. OGT was inhibited by OGT inhibitor (OSMI4) treatment and knocked down by sh-OGT transfection. M1/M2 polarization was analyzed using qPCR, immunofluorescence, and flow cytometry. Levels of O-GlcNAcylation were measured using immunoprecipitation and western blotting.
RESULTS
Our results demonstrated that M1 macrophage polarization led to maxillary bone loss in DP mice, associated with elevated O-GlcNAcylation and OGT levels. Knockdown of OGT promoted the shift from M1 to M2 macrophage polarization in both mouse periodontal tissues and LPS + HG-induced RAW264.7 cells. Furthermore, LPS + HG enhanced the O-GlcNAcylation of p38 in RAW264.7 cells. OGT interacted with p38 to promote its O-GlcNAcylation at residues A28, T241, and T347, as well as its phosphorylation at residue Y221.
CONCLUSION
Inhibition of OGT-mediated p38 O-GlcNAcylation deactivates the p38 pathway by suppressing its self-phosphorylation, thereby promoting M1 to M2 macrophage polarization and mitigating DP. These findings suggested that modulating macrophage polarization through regulation of O-GlcNAcylation may represent a novel therapeutic strategy for treating DP.
Core Tip: O-linked β-N-acetylglucosamine (O-GlcNAcylation) transferase (OGT) promotes the O-GlcNAcylation of p38 at S28, T241, and T347 sites and further activates the p38/mitogen-activated protein kinase pathway by phosphorylation itself at Y221. Inhibition of O-GlcNAcylation promotes M2-type polarization and inhibits M1-type polarization of macrophages, accelerating alveolar bone rebuild to decelerate diabetic periodontitis progression.
