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

• DOI: 10.1073/pnas.2315898120
• Publication Date: 2024-01-02T18:51:23Z
• Authors: Sujin Kang; Shinya Onishi; Zhenzhen Ling; Hitomi Inoue; Yingying Zhang; Hao Chang; Hui Zhao; Tong Wang; Daisuke Okuzaki; Hiroshi Matsuura; Hyota Takamatsu; Jun Oda; Tadamitsu Kishimoto
• Keywords: Glycoprotein 130; Hypoxia; Vascular permeability

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 during CRS, although molecular mechanisms remain be fully elucidated. Targeting IL-6 receptor signaling delays CRS progression; however, current options are limited by persistent inhibition immune system. Here, we show trans-signaling promoted and inflammatory responses via hypoxia-inducible factor-1α (HIF1α)–induced glycolysis. Using pharmacological inhibitors targeting HIF1α activity or mice with genetic ablation gp130 in endothelium, found IL-6R (IL-6 receptor)–HIF1α cells protected injury caused septic provided survival benefit mouse model sepsis. In addition, developed short half-life anti-IL-6R antibody (silent antibody) it was highly effective at augmenting for sepsis severe burn strengthening glycocalyx reducing storm, leakage. Together, our data advance role indicate potential therapeutic burns