糖蛋白130
细胞因子
信号转导
败血症
受体
内皮
缺氧(环境)
癌症研究
免疫学
生物
血管通透性
炎症
细胞生物学
白细胞介素6
医学
药理学
内科学
内分泌学
化学
有机化学
氧气
作者
Sujin Kang,Shinya Onishi,Ling Zhenzhen,Hiroshige Inoue,Mingchao Zhang,Haiyan Chang,Hui Zhao,Tong Wang,Daisuke Okuzaki,Hiroshi Matsuura,Hyota Takamatsu,Jun Oda,Tadamitsu Kishimoto
标识
DOI:10.1073/pnas.2315898120
摘要
Protection against endothelial damage is recognized as a frontline approach to preventing the progression of cytokine release syndrome (CRS). Accumulating evidence has demonstrated that interleukin-6 (IL-6) promotes vascular endothelial damage during CRS, although the molecular mechanisms remain to be fully elucidated. Targeting IL-6 receptor signaling delays CRS progression; however, current options are limited by persistent inhibition of the immune system. Here, we show that endothelial IL-6 trans-signaling promoted vascular damage and inflammatory responses via hypoxia-inducible factor-1α (HIF1α)-induced glycolysis. Using pharmacological inhibitors targeting HIF1α activity or mice with the genetic ablation of gp130 in the endothelium, we found that inhibition of IL-6R (IL-6 receptor)-HIF1α signaling in endothelial cells protected against vascular injury caused by septic damage and provided survival benefit in a mouse model of sepsis. In addition, we developed a short half-life anti-IL-6R antibody (silent anti-IL-6R antibody) and found that it was highly effective at augmenting survival for sepsis and severe burn by strengthening the endothelial glycocalyx and reducing cytokine storm, and vascular leakage. Together, our data advance the role of endothelial IL-6 trans-signaling in the progression of CRS and indicate a potential therapeutic approach for burns and sepsis.
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