Aryl hydrocarbon receptor impairs HK2-controlled flux of the hexosamine biosynthesis pathway to suppress NETosis in an N-glycosylation-dependent manner

作者：Shijia Li, Jingchao Zhu, Jie Song, Yang Li, Y.-H. Gong, Yue Dai, Zhifeng Wei · 发表于：Journal of Advanced Research · 年份：2025 · DOI：10.1016/j.jare.2025.06.078 · 被引用次数：3 · 研究领域：Neutrophil, Myeloperoxidase and Oxidative Mechanisms、Immune cells in cancer、Infant Nutrition and Health

INTRODUCTION: The aryl hydrocarbon receptor (AhR) is a promising therapeutic target for ulcerative colitis (UC) and plays a role in regulating neutrophil function. OBJECTIVE: We aimed to investigate the effects and mechanisms of AhR on NETosis, a neutrophil-driven process that disrupts intestinal epithelial homeostasis, to support the development of anti-UC therapies. METHODS: A dextran sulphate sodium (DSS)-induced colitis mouse model was established, and bioinformatics analyses combined with multiple molecular biology techniques were used to assess changes in NETosis and signalling pathway activation. RESULTS: Data from the Gene Expression Omnibus database and DSS-induced colitis mice confirmed an inverse correlation between AhR activation and NETosis in UC. In vitro experiments, including assays for double-stranded DNA release, co-localisation of myeloperoxidase with DNA and neutrophil elastase (NE)/citrullinated histone H3, histone H4 degradation, and chromatin decondensation, demonstrated that AhR activation directly inhibits NETosis. Further investigations using gene knockdown plasmids, enzyme substrate assays, and flow cytometry revealed that AhR activation reduced the NE activity-independent of pcDNA-peptidyl arginine deiminase 4-through an N-glycosylation-dependent mechanism involving the physiological NE inhibitors alpha-1 antitrypsin (AAT) and alpha-2-macroglobulin (A2M). Mechanistically, AhR functioned as an E3 ligase that bound to hexokinase 2 (HK2), promoting it...