Inhibition of Interleukin-40 prevents multi-organ damage during sepsis by blocking NETosis

Despite intensive clinical and scientific efforts, the mortality rate of sepsis remains high due to the lack of precise biomarkers for patient stratification and therapeutic guidance. Interleukin 40 (IL-40), a novel cytokine with immune regulatory functions in human diseases, was elevated at admission in two independent cohorts of patients with sepsis. High levels of secreted IL-40 in septic patients were positively correlated with PCT, CRP, lactate (LDH), and Sequential Organ Failure Assessment (SOFA) scores, in which IL-40 levels were used to stratify the early death of critically ill patients with sepsis. Moreover, genetic knockout of IL-40 (IL-40^-/-) improved outcomes in mice with experimental sepsis, as evidenced by attenuated cytokine storm, multiple-organ failure, and early mortality, compared with those of wild-type (WT) mice. Mechanistically, single-cell RNA sequencing (scRNA-seq) and bulk RNA sequencing (RNA-seq) have revealed that S100A8/9^hi neutrophil influx into the peritoneal cavity along with neutrophil extracellular trap (NETs) formation accounts predominantly for the IL-40-mediated worsening of sepsis outcomes. Clinically, the IL-40 level was positively correlated with the NET-related MPO/dsDNA ratio in septic patients. Finally, with antibiotics (gentamycin), genetic knockout of IL-40 prevented polymicrobial sepsis fatalities more efficiently than without gentamycin treatment. In summary, these data reveal a novel prognostic strategy for sepsis and that IL-40 may serve as a novel therapeutic target for sepsis.