Oxidative phosphorylation is a key feature of neonatal monocyte immunometabolism promoting myeloid differentiation after birth PMID: 40050264

ADC Targets in Oncology

2026-04-10

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

Nat Commun. 2025 Mar 6;16(1):2239. doi: 10.1038/s41467-025-57357-w.

Greta Ehlers ^# ¹ , Annika Marie Tödtmann ^# ¹ , Lisa Holsten ^# ² ³ ⁴ ⁵ , Maike Willers ¹ , Julia Heckmann ² , Jennifer Schöning ² , Maximilian Richter ² , Anna Sophie Heinemann ¹ , Sabine Pirr ¹ , Alexander Heinz ⁶ , Christian Dopfer ¹ , Kristian Händler ⁴ ⁷ , Matthias Becker ⁴ ⁸ , Johanna Büchel ⁹ , Achim Wöckel ⁹ , Constantin von Kaisenberg ¹⁰ , Gesine Hansen ¹ ¹¹ , Karsten Hiller ⁶ , Joachim L Schultze ³ ⁴ ⁵ , Christoph Härtel ² , Wolfgang Kastenmüller ¹² , Martin Vaeth ¹² , Thomas Ulas ³ ⁴ ⁵ , Dorothee Viemann ¹³ ¹⁴ ¹⁵ ¹⁶

Affiliations

1. Department of Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Hannover, Germany.
2. Department of Pediatrics, University Hospital Würzburg, Würzburg, Germany.
3. Genomics and Immunoregulation, Life & Medical Sciences (LIMES) Institute, University of Bonn, Bonn, Germany.
4. Systems Medicine, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
5. PRECISE Platform for Single Cell Genomics and Epigenomics, DZNE and University of Bonn, Bonn, Germany.
6. Department for Bioinformatics and Biochemistry, BRICS, Technical University Braunschweig, Braunschweig, Germany.
7. Institute of Human Genetics, University of Lübeck, Lübeck, Germany.
8. Modular High Performance Computing and Artificial Intelligence, Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Bonn, Germany.
9. Department of Gynecology and Obstetrics, University Hospital Würzburg, Würzburg, Germany.
10. Department of Obstetrics and Gynecology, Hannover Medical School, Hannover, Germany.
11. Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany.
12. Würzburg Institute of Systems Immunology, Max Planck Research Group, Julius-Maximilians-University Würzburg, Würzburg, Germany.
13. Department of Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Hannover, Germany. [email protected].
14. Department of Pediatrics, University Hospital Würzburg, Würzburg, Germany. [email protected].
15. Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany. [email protected].
16. Center for Infection Research, University Würzburg, Würzburg, Germany. [email protected].
# Contributed equally.

Abstract

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.