GLUT1-mediated HMGB1 O-GlcNAcylation drives hyperglycemia-Induced neutrophil extracellular trap networks formation via TLR4 signaling and exacerbates fibroblast inflammation.

ABSTRACT: Neutrophil extracellular traps (NETs) exacerbate fibroblast inflammatory injury in hyperglycemic conditions, yet the role of glucose metabolism and O-linked N-acetylglucosamine (O-GlcNAc) glycosylation in this process remains unclear. Here, we investigate how glucose transporter protein 1 (GLUT1)-dependent glucose uptake regulates O-GlcNAcylation of high-mobility group box 1 (HMGB1) to drive NET formation and fibroblast inflammation. Mouse peripheral blood neutrophils (MPBN) were treated with high glucose (25 mM) and phorbol ester (PMA) to induce NETs. Co-culture of NETs with mouse fibroblasts (L929) reduced fibroblast viability by 1.1 fold and migration by 1.2 fold within 24 h, while upregulating pro-inflammatory cytokines (Tumor Necrosis Factor-α (TNF-α): +1.3-fold; Interleukin-1β (IL-1β

SUBMITTER: Sun W 

PROVIDER: S-EPMC12122836 | biostudies-literature | 2025 May

REPOSITORIES: biostudies-literature