Immunotolerant p50/NF?B Signaling and Attenuated Hepatic IFN? Expression Increases Neonatal Sensitivity to Endotoxemia.

ABSTRACT: Sepsis is a major cause of neonatal morbidity and mortality. The current paradigm suggests that neonatal susceptibility to infection is explained by an innate immune response that is functionally immature. Recent studies in adults have questioned a therapeutic role for IFN? in sepsis; however, the role of IFN? in mediating neonatal sensitivity to sepsis is unknown. We evaluated the transcriptional regulation and expression of IFN? in early neonatal (P0) and adult murine models of endotoxemia (IP LPS, 5 mg/kg). We found that hepatic, pulmonary, and serum IFN? expression was significantly attenuated in endotoxemic neonates when compared to similarly exposed adults. Furthermore, endotoxemia induced hepatic p65/NF?B and IRF3 activation exclusively in adults. In contrast, endotoxemia induced immunotolerant p50/NF?B signaling in neonatal mice without evidence of IRF3 activation. Consistent with impaired IFN? expression and attenuated circulating serum levels, neonatal pulmonary STAT1 signaling and target gene expression was significantly lower than adult levels. Using multiple in vivo approaches, the source of hepatic IFN? expression in endotoxemic adult mice was determined to be the hepatic macrophage, and experiments in RAW 264.7 cells confirmed that LPS-induced IFN? expression was NF?B dependent. Finally, treating neonatal mice with IFN? 2 h after endotoxemia stimulated pulmonary STAT1 signaling and STAT1 dependent gene expression. Furthermore, IFN? treatment of endotoxemic neonatal animals resulted in significantly improved survival following exposure to lethal endotoxemia. In conclusion, endotoxemia induced IFN? expression is attenuated in the early neonatal period, secondary to impaired NF?B-p65/IRF3 signaling. Pre-treatment with IFN? decreases neonatal sensitivity to endotoxemia. These results support further study of the role of impaired IFN? expression and neonatal sensitivity to sepsis.

SUBMITTER: McKenna S 

PROVIDER: S-EPMC6168645 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature