A prime time for trained immunity: innate immune memory in newborns and infants. High expression levels of macrophage migration inhibitory factor sustain the innate immune responses of neonates. Immaturity of infection control in preterm and term newborns is associated with impaired toll-like receptor signaling. Protecting the newborn and young infant from infectious diseases: lessons from immune ontogeny. Impact of sepsis on neurodevelopmental outcome in a Swiss national cohort of extremely premature infants. The global burden of paediatric and neonatal sepsis: a systematic review. We believe that these results may explain in part hepatic dysfunction with neonatal sepsis, and that there may be unrecognized developmental and long-term hepatic implications of early life exposure to systemic inflammatory stress.įleischmann-Struzek, C. We demonstrate that in contrast to adults, endotoxemic neonatal (P3) mice exhibit a significant increase in hepatic apoptosis associated with absent hepatic p65/NFκB signaling and c-Jun/AP1 activity. In adult models of inflammation and infection, innate immune signaling pathways such as p65/NFκB and c-Jun/AP1 are responsible for a protective, pro-inflammatory transcriptome and regulation of apoptosis. Various aspects of developmental immaturity of the innate immune system may help explain the increased risk of infection in the neonatal period. More work is needed to determine if this contributes to long-term hepatic dysfunction, and whether immunomodulatory approaches can prevent this injury. These results demonstrate that developmental absence of innate immune p65/NFκB and c-Jun/AP1 signaling, and target gene expression is associated with apoptotic injury in neonatal mice. Hepatic c-Jun/AP1 activity was attenuated in endotoxemic P3 mice, with resulting upregulation of pro-apoptotic factors. This is associated with absent hepatic p65/NFκB signaling and impaired expression of anti-apoptotic target genes. We demonstrate that in contrast to adults, endotoxemic neonatal (P3) mice exhibit a significant increase in hepatic apoptosis. Using a murine model of endotoxemia (LPS 5 mg/kg IP x 1) in neonatal (P3) and adult mice, we evaluated histologic evidence of hepatic injury and apoptosis, presence of p65/NFκB and c-Jun/AP1 activation and associated transcriptional regulation of apoptotic genes. Importantly, innate immune signaling pathways such as p65/NFκB and c-Jun/AP1 are responsible for the prevention of hepatocyte apoptosis in adult animals, yet whether developmental immaturity of these pathways increases the risk of hepatic injury in the neonatal period is unknown. The developmental immaturity of the innate immune system helps explains the increased risk of infection in the neonatal period.
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