Inhibition of interleukin-6 trans-signaling improves survival and prevents cognitive impairment in a mouse model of sepsis

•Soluble forms of gp130 (sgp130) bind to the IL-6-sIL-6R complex in the extracellular matrix and prevent it from activating membrane bound gp130 and function as natural IL-6 trans-signaling inhibitor.•Plasma levels of IL-6 increase in septic patients.•Sgp130 increased survival rate and mitigated sepsis-induced cognitive decline.•Sgp130 reduced inflammatory cytokines and preserved blood–brain barrier integrity after induction of sepsis.•Sgp130 affected monocytes/macrophages and lymphocytes trafficking and activation in septic mice.•Sgp130 inhibited sepsis-induced oxidative stress. Sepsis-associated encephalopathy (SAE) manifests clinically as acute and chronic cognitive impairments, which is associated with increased morbidity and mortality. Interleukin-6 (IL-6), a pro-inflammatory cytokine, is consistently up-regulated in sepsis. IL-6 initiates proinflammatory effects after binding to soluble IL-6 receptor (IL-6R) through trans-signalling, which requires the transducer gp130. In this study, we investigated whether inhibition of IL-6 trans-signalling is a putative therapeutic target for sepsis and SAE. Twenty-five patients (12 septic and 13 non-septic patients) were recruited for the study. A significant increase of IL-6, IL-1β, IL-10, and IL-8 was observed in the septic patients 24 h after ICU admission. In animal study, cecal ligation and puncture (CLP) was used to induce sepsis in male C57BL/6J mice. One hour before or after inducing sepsis, mice were treated with sgp130, a selective IL-6 trans-signaling inhibitor, respectively. Survival rate, cognition, levels of inflammatory cytokines, integrity of blood–brain barrier (BBB), and oxidative stress were assessed. In addition, immune cells activation and transmigration were evaluated in peripheral blood and brains. Sgp130 improved survival rate and cognitive functions, reduced levels of inflammatory cytokines, including IL-6, TNF-α, IL-10, and MCP-1, in plasma and hippocampus (hipp), mitigated BBB disruption, and ameliorated sepsis-induced oxidative stress. Sgp130 also affected monocytes/macrophages and lymphocytes transmigration and activation in septic mice. Our results indicate that selective inhibition of IL-6 trans-signaling by sgp130 exerts protective effects against SAE in a mouse model of sepsis, suggesting a potential therapeutic strategy.