Neonatal monocyte iron metabolism and immunometabolic responses in sepsis: a comparative ex vivo investigation

BACKGROUND: Neonatal sepsis is a leading cause of morbidity and mortality in neonates. The underdeveloped neonatal immune system, particularly innate immune cells such as monocytes, plays a critical role in susceptibility to infection. Monocyte-mediated regulation of iron metabolism, a key component of "nutritional immunity," is known to influence sepsis outcomes in adults. In this study, we investigated differences in iron sensing, iron-regulated gene expression, and intracellular iron content between neonatal and adult monocytes. METHODS: Monocytes were isolated from human umbilical cord blood and adult peripheral blood and stimulated in vitro with lipopolysaccharide (LPS), ferric nitrilotriacetate (FeNTA), or the iron chelator deferoxamine (DFO). Transferrin receptor 1 (TfR1) and differentiation markers were analyzed by flow cytometry, intracellular iron content by atomic absorption spectrometry, and metabolic and inflammatory responses via lactate and cytokine measurements. RESULTS: Neonatal monocytes exhibited lower basal TfR1 expression with a trend toward higher intracellular iron. LPS induced TfR1 upregulation exclusively in adult monocytes, while neonatal cells maintained consistently low expression. Although FeNTA increased intracellular iron in both groups, neonatal monocytes accumulated iron less efficiently. CONCLUSION: These findings indicate fundamental developmental differences in monocyte iron handling and immunometabolic adaptation, which may underlie the distinct immune profile observed in neonatal sepsis. IMPACT: Neonatal sepsis is a leading cause of morbidity and mortality in neonates. Particularly innate immune cells such as monocytes, play a critical role in susceptibility to infection. Monocyte-mediated regulation of iron metabolism, a key component of "nutritional immunity," is known to influence sepsis outcomes in adults. Our findings indicate fundamental developmental differences in monocyte iron handling and immunometabolic adaptation, which may play a role in both the distinct immune profile observed in neonatal sepsis and, consecutively, sepsis outcome. These findings imply that host-directed iron modulation could be a viable strategy to counteract immunoparalysis in neonatal sepsis without compromising cellular activation.