Gp130-HIF1α axis-induced vascular damage is prevented by the short-term inhibition of IL-6 receptor signaling
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:121 |
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| Enthalten in: |
Proceedings of the National Academy of Sciences of the United States of America - 121(2024), 2 vom: 09. Jan., Seite e2315898120 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Kang, Sujin [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 04.01.2024 Date Revised 14.01.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1073/pnas.2315898120 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM366565656 |
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| 100 | 1 | |a Kang, Sujin |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Gp130-HIF1α axis-induced vascular damage is prevented by the short-term inhibition of IL-6 receptor signaling |
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| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a IL-6 | |
| 650 | 4 | |a anti-IL-6 receptor antibody | |
| 650 | 4 | |a burn injury | |
| 650 | 4 | |a cytokine release syndrome | |
| 650 | 4 | |a endothelial cell | |
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| 650 | 7 | |a Interleukin-6 |2 NLM | |
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| 700 | 1 | |a Onishi, Shinya |e verfasserin |4 aut | |
| 700 | 1 | |a Ling, Zhenzhen |e verfasserin |4 aut | |
| 700 | 1 | |a Inoue, Hitomi |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Yingying |e verfasserin |4 aut | |
| 700 | 1 | |a Chang, Hao |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Hui |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Tong |e verfasserin |4 aut | |
| 700 | 1 | |a Okuzaki, Daisuke |e verfasserin |4 aut | |
| 700 | 1 | |a Matsuura, Hiroshi |e verfasserin |4 aut | |
| 700 | 1 | |a Takamatsu, Hyota |e verfasserin |4 aut | |
| 700 | 1 | |a Oda, Jun |e verfasserin |4 aut | |
| 700 | 1 | |a Kishimoto, Tadamitsu |e verfasserin |4 aut | |
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