2. Academic Validation
  3. Gp130-HIF1α axis-induced vascular damage is prevented by the short-term inhibition of IL-6 receptor signaling

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

  • Proc Natl Acad Sci U S A. 2024 Jan 9;121(2):e2315898120. doi: 10.1073/pnas.2315898120.
Sujin Kang # 1 2,  Shinya Onishi # 3,  Zhenzhen Ling 1,  Hitomi Inoue 1,  Yingying Zhang 1,  Hao Chang 1,  Hui Zhao 1,  Tong Wang 1,  Daisuke Okuzaki 4,  Hiroshi Matsuura 3,  Hyota Takamatsu 5 6,  Jun Oda 3,  Tadamitsu Kishimoto 1 2
Affiliations

Affiliations

  • 1 Department of Immune Regulation, Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.
  • 2 Department of Immune Regulation, Center for Infectious Disease Education and Research, Osaka University, Suita, Osaka 565-0871, Japan.
  • 3 Department of Traumatology and Acute Critical Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
  • 4 Next Generation-Sequencing Core Facility, Bioinformatics Center, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan.
  • 5 Department of Clinical Research Center for Autoimmune Disease, Osaka Minami Medical Center, National Hospital Organization, Kawachinagano, Osaka 586-8521, Japan.
  • 6 Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
  • # Contributed equally.
PMID: 38165930 DOI: 10.1073/pnas.2315898120
Abstract

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.

Keywords

IL-6; anti-IL-6 receptor antibody; burn injury; cytokine release syndrome; endothelial cell.

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