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U.S.A."],"published-print":{"date-parts":[[2024,1,9]]},"abstract":"<jats:p>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\u03b1 (HIF1\u03b1)\u2013induced glycolysis. Using pharmacological inhibitors targeting HIF1\u03b1 activity or mice with the genetic ablation of gp130 in the endothelium, we found that inhibition of IL-6R (IL-6 receptor)\u2013HIF1\u03b1 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.<\/jats:p>","DOI":"10.1073\/pnas.2315898120","type":"journal-article","created":{"date-parts":[[2024,1,2]],"date-time":"2024-01-02T13:51:23Z","timestamp":1704203483000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":18,"title":["Gp130\u2013HIF1\u03b1 axis\u2013induced vascular damage is prevented by the short-term inhibition of IL-6 receptor signaling"],"prefix":"10.1073","volume":"121","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5086-1405","authenticated-orcid":false,"given":"Sujin","family":"Kang","sequence":"first","affiliation":[{"name":"Department of Immune Regulation, Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan"},{"name":"Department of Immune Regulation, Center for Infectious Disease Education and Research, Osaka 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