Significance
Interleukin (IL)-6, an essential indicator of cytokine release syndromes (CRS), regulates vascular homeostasis and inflammation. Inhibition of IL-6 receptor (IL-6R) signaling is beneficial for various CRS; however, it is limited by adverse effects related to poor understanding of mechanisms involved. Here, we discovered that hypoxia-inducible factor (HIF1) α signaling is activated by IL-6R trans-signaling in endothelial cells, which promotes vascular inflammatory responses and endothelial permeability by glycolysis. Short-term inhibition of IL-6R–HIF1α signaling attenuated proinflammatory cytokines and coagulation cascade activation, and it prevented vascular damage by preserving endothelial glycocalyx during sepsis and burn injury-induced CRS. Endothelial IL-6R–HIF1α signaling has crucial roles in progression of CRS, suggesting novel therapeutic strategies for cytokine storm-related disease by relieving adverse effects of anti-IL-6R antibody treatment.
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.
