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<p>Diabetic retinopathy (DR) is a major cause of blindness globally. Neutrophils and neutrophil extracellular traps (NETs) are believed to play a role in the development of DR. However, the specific contribution of NETs to hyperglycemia-induced vascular endothelial cell dysfunction remains unclear. In this study, we cocultured high glucose-activated neutrophils (HGNs) with human umbilical vein endothelial cells (HUVECs) to investigate the role of NETs in high glucose-induced HUVEC dysfunction. Our findings indicate that high glucose levels promote NETs formation, which can be inhibited by a toll-like receptor (TLR) 2 antagonist and a TLR4 antagonist. It was observed that reactive oxygen species production plays a role in TLR2- but not TLR4-mediated NETs formation. Additionally, HGNs were found to promote HUVEC proliferation through phagocytosis rather than NETs. We also discovered that NETs contribute to high glucose-induced HUVEC dysfunction by enhancing neutrophil-HUVEC adhesion, inhibiting HUVEC migration, and compromising the barrier function of the cells by reducing zonula occludens-1 expression. This dysfunction could be partially mitigated by TLR2 and TLR4 antagonists. In conclusion, high glucose stimulates NETs formation, leading to vascular endothelial cell damage, and TLRs may facilitate high glucose-induced endothelial dysfunction by modulating NETs formation.</p>

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Toll Like Receptors Promote High Glucose-Induced Vascular Endothelial Cell Dysfunction by Regulating Neutrophil Extracellular Traps Formation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月15日

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  • Shirou Wu,
  • Yahui Chen,
  • Xiuming Jin,
  • Jiayun Yu,
  • Xueping Chen,
  • Ting Wan

摘要

Diabetic retinopathy (DR) is a major cause of blindness globally. Neutrophils and neutrophil extracellular traps (NETs) are believed to play a role in the development of DR. However, the specific contribution of NETs to hyperglycemia-induced vascular endothelial cell dysfunction remains unclear. In this study, we cocultured high glucose-activated neutrophils (HGNs) with human umbilical vein endothelial cells (HUVECs) to investigate the role of NETs in high glucose-induced HUVEC dysfunction. Our findings indicate that high glucose levels promote NETs formation, which can be inhibited by a toll-like receptor (TLR) 2 antagonist and a TLR4 antagonist. It was observed that reactive oxygen species production plays a role in TLR2- but not TLR4-mediated NETs formation. Additionally, HGNs were found to promote HUVEC proliferation through phagocytosis rather than NETs. We also discovered that NETs contribute to high glucose-induced HUVEC dysfunction by enhancing neutrophil-HUVEC adhesion, inhibiting HUVEC migration, and compromising the barrier function of the cells by reducing zonula occludens-1 expression. This dysfunction could be partially mitigated by TLR2 and TLR4 antagonists. In conclusion, high glucose stimulates NETs formation, leading to vascular endothelial cell damage, and TLRs may facilitate high glucose-induced endothelial dysfunction by modulating NETs formation.