Impaired cellular energy metabolism in cord blood macrophages contributes to abortive response toward inflammatory threats

Neonatal sepsis is characterized by hyperinflammation causing enhanced morbidity and mortality compared to adults. This suggests differences in the response towards invading threats. Here we investigate activated cord blood macrophages (CBM Phi) in comparison to adult macrophages (PBM Phi), indicating incomplete interferon gamma (IFN-gamma) and interleukin 10 (IL-10)-induced activation of CBM Phi. CBM Phi show reduced expression of phagocytosis receptors and cytokine expression in addition to altered energy metabolism. In particular, IFN-gamma as well as IL-10-activated CBM Phi completely fail to increase glycolysis and furthermore show reduced activation of the mTOR pathway, which is important for survival in sepsis. MTOR inhibition by rapamycin equalizes cytokine production in CBM Phi and PBM Phi. Finally, incubation of PBM Phi with cord blood serum or S100A8/A9, which is highly expressed in neonates, suppresses mTOR activation, prevents glycolysis and the expression of an PBM Phi phenotype. Thus, a metabolic alteration is apparent in CBM Phi, which might be dependent on S100A8/A9 expression.