Cytokine release syndrome (CRS) is a life-threatening acute systemic inflammation caused by the over-reacted network of cytokines including interleukin (IL) -1, IL-6, IL18, etc. Among these, IL-6 regulating vascular homeostasis and inflammation is one of the essential indicators of CRS. Although inhibition of IL-6 receptor signalling is beneficial in treating patients with CRS, such treatment also causes severe adverse effects since the underlying mechanism of IL-6 signalling was poorly understood. However, a group of researchers from Osaka University have solved part of the mystery. Researchers first discovered that interleukin 6 receptor (IL-6R) triggers inflammatory responses in endothelial cells through activating hypoxia-inducible factor-1α (HIF1α). The enhanced HIF1α activity leads to an increased level of glycolysis promoting endothelial inflammatory response. Further experiments showed that inhibition of gp130-HIF1α signalling can ameliorate cytokine storm and enhance the survival rate of the mouse sepsis model via strengthening vascular endothelial cells and improving vessel integrity. The research group then generated an altered anti-IL-6R antibody with H435A inhibiting IL-6R signalling. The newly synthesized anti-IL-6R antibody has a shorter half-life compared to conventional antibodies and does not bind to the neonatal Fc receptor (FcRn), yet it still showed comparable inhibitory activity and has proven to improve septic shock survival in the mouse model. In addition to the mouse sepsis model, the anti-IL-6R antibody treatment can also protect against burn injury-induced cytokine storm as demonstrated in the murine dorsal thermal injury model with a significant reduction of serum PAI-1 level post-thermal injury. Overall, this study has uncovered the mechanism underlying IL-6-related inflammation and proposed a potential therapeutic approach for CRS induced by burns and sepsis.