The influence of interleukin-27 on metabolic fitness in a murine neonatal model of bacterial sepsis.

Human neonates are predisposed to an increased risk of mortality from infection due to fundamental differences in the framework of innate and adaptive immune responses relative to those in the adult population. As one key difference in neonates, an increase in the immunosuppressive cytokine, IL-27, is responsible for poor outcomes in a murine neonatal model of bacterial sepsis. In our model, the absence of IL-27 signaling during infection is associated with improved maintenance of body mass, increased bacterial clearance with reduced systemic inflammation, and decreased mortality rates that correlate to preservation of glucose homeostasis and insulin production. To further elucidate the mechanisms associated with IL-27 signaling and metabolic fitness, we analyzed global transcriptomes from spleen, liver, pancreas, and hindlimb muscle during Escherichia coli-induced sepsis in wild-type (WT) and IL-27Rα-deficient (KO) mice. Metabolically important tissues such as the liver, pancreas, and hindlimb muscle exhibit a shift in differential gene expression of pathways involved in oxidative phosphorylation, glycolysis, gluconeogenesis, lipid metabolism, and fatty acid β oxidation. The hindlimb muscle of KO pups demonstrated a significant reduction in all of these pathways during infection. The KO liver showed a significant down-regulation in gluconeogenesis and glycolytic pathways. Collectively, these findings suggest a negative influence of IL-27 on the metabolic profile during early-life infection. This is an important consideration for antagonization of IL-27 as a potential host-directed therapeutic opportunity as our findings point to an overall improvement in infectious disease parameters and metabolic fitness.NEW & NOTEWORTHY IL-27 has been linked with immune regulation during infection, but this is the first report of a combined influence of IL-27 on complete host response during systemic infection with metabolic fitness in a neonate. Novel findings demonstrate improved glucose homeostasis and insulin response supported by a reduced expression of genes involved in gluconeogenesis in the absence of IL-27 signaling. An increased expression of genes integral to cholesterol biosynthesis further supports a protective response during sepsis.