Cell Death Discovery ( IF 6.1 ) Pub Date : 2023-08-25 , DOI: 10.1038/s41420-023-01614-8 Shuainan Zhu 1, 2 , Ying Yu 1, 2 , Mengdi Qu 1, 2 , Zhiyun Qiu 1, 2 , Hao Zhang 1, 2 , Changhong Miao 1, 2 , Kefang Guo 1, 2
Neutrophil extracellular traps (NETs) are involved in the activation and dysfunction of multiple overlapping and interacting pathways, including the immune response to injury, inflammation, and coagulation, which contribute to the pathogenesis of sepsis-induced acute lung injury (SI-ALI). However, how NETs mediate the relationship between inflammation and coagulation has not been fully clarified. Here, we found that NETs, through stimulator of interferon genes (STING) activation, induced endothelial cell damage with abundant production of tissue factor (TF), which magnified the dysregulation between inflammatory and coagulant responses and resulted in poor prognosis of SI-ALI model mice. Disruption of NETs and inhibition of STING improved the outcomes of septic mice and reduced the inflammatory response and coagulation. Furthermore, Toll-like receptor 2 (TLR2) on the surface of endothelial cells was involved in the interaction between NETs and the STING pathway. Collectively, these findings demonstrate that NETs activate the coagulant cascade in endothelial cells in a STING-dependent manner in the development of SI-ALI.
中文翻译:
中性粒细胞胞外陷阱通过脓毒症相关肺损伤中的 STING 途径促进免疫血栓形成
中性粒细胞胞外陷阱 (NET) 参与多个重叠和相互作用途径的激活和功能障碍,包括对损伤、炎症和凝血的免疫反应,这导致脓毒症引起的急性肺损伤 (SI-ALI) 的发病机制。然而,NETs如何介导炎症和凝血之间的关系尚未完全阐明。在这里,我们发现NETs通过干扰素基因刺激剂(STING)激活,诱导内皮细胞损伤并大量产生组织因子(TF),从而放大炎症反应和凝血反应之间的失调,导致SI-ALI模型预后不良老鼠。破坏 NET 和抑制 STING 可改善脓毒症小鼠的预后,并减少炎症反应和凝血。此外,内皮细胞表面的Toll样受体2(TLR2)参与NETs和STING通路之间的相互作用。总的来说,这些发现表明,在 SI-ALI 的发展过程中,NET 以 STING 依赖性方式激活内皮细胞中的凝血级联。