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Oxidative phosphorylation is a key feature of neonatal monocyte immunometabolism promoting myeloid differentiation after birth.

Nature communications

Authors: Greta Ehlers, Annika Marie Tödtmann, Lisa Holsten, Maike Willers, Julia Heckmann, Jennifer Schöning, Maximilian Richter, Anna Sophie Heinemann, Sabine Pirr, Alexander Heinz, Christian Dopfer, Kristian Händler, Matthias Becker, Johanna Büchel, Achim Wöckel, Constantin von Kaisenberg, Gesine Hansen, Karsten Hiller, Joachim L Schultze, Christoph Härtel, Wolfgang Kastenmüller, Martin Vaeth, Thomas Ulas, Dorothee Viemann

Neonates primarily rely on innate immune defense, yet their inflammatory responses are usually restricted compared to adults. This is controversially interpreted as a sign of immaturity or essential programming, increasing or decreasing the risk of sepsis, respectively. Here, combined transcriptomic, metabolic, and immunological studies in monocytes of healthy individuals reveal an inverse ontogenetic shift in metabolic pathway activities with increasing age. Neonatal monocytes are characterized by enhanced oxidative phosphorylation supporting ongoing myeloid differentiation. This phenotype is gradually replaced during early childhood by increasing glycolytic activity fueling the inflammatory responsiveness. Microbial stimulation shifts neonatal monocytes to an adult-like metabolism, whereas ketogenic diet in adults mimicking neonatal ketosis cannot revive a neonate-like metabolism. Our findings disclose hallmarks of innate immunometabolism during healthy postnatal immune adaptation and suggest that premature activation of glycolysis in neonates might increase their risk of sepsis by impairing myeloid differentiation and promoting hyperinflammation.

© 2025. The Author(s).

PMID: 40050264

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