Gp130-HIF1α axis-induced vascular damage is prevented by the short- term inhibition of IL-6 receptor signaling

• 成果类型: Article
• 署名作者: Kang, Sujin; Onishi, Shinya; Ling, Zhenzhen; Inoue, Hitomi; Zhang, Yingying; Chang, Hao; Zhao, Hui; Wang, Tong; Okuzaki, Daisuke; Matsuura, Hiroshi; Takamatsu, Hyota; Oda, Jun; Kishimoto, Tadamitsu
• 署名单位: University of Osaka; University of Osaka; University of Osaka; University of Osaka; University of Osaka
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-14476
• DOI: 10.1073/pnas.2315898120
• 发表日期: 2024-01-09
• 关键词: dendritic cell; hypoxia; interleukin-6; activation; hif-1-alpha; immune; genes; expression; cytokines; binding

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-1 alpha (HIF1 alpha)-induced glycolysis. Using pharmacological inhibitors targeting HIF1 alpha activity or mice with the genetic ablation of gp130 in the endothelium, we found that inhibition of IL 6R (IL 6 receptor)-HIF1 alpha 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.