Oxidative phosphorylation is a key feature of neonatal monocyte immunometabolism promoting myeloid differentiation after birth
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.
Authors
- Greg Ehlers
- Thomas Ulas (ORCID: https://orcid.org/0000-0002-9785-4197)
- Constantin von Kaisenberg (ORCID: https://orcid.org/0000-0001-5554-1937)
- Jennifer Schöning (ORCID: https://orcid.org/0000-0002-7541-7025)
- Lisa Holsten (ORCID: https://orcid.org/0000-0001-6238-1273)
- Maximilian Richter (ORCID: https://orcid.org/0000-0003-2583-3722)
- Christian Dopfer (ORCID: https://orcid.org/0000-0002-8932-513X)
- Dorothee Viemann (ORCID: https://orcid.org/0000-0002-9009-3559)
- Sabine Pirr (ORCID: https://orcid.org/0000-0002-3624-6251)
- Wolfgang Kastenmüller (ORCID: https://orcid.org/0000-0002-3835-1485)
- Anna S. Heinemann
- Kristian Händler (ORCID: https://orcid.org/0000-0001-5273-5277)
- Achim Wöckel (ORCID: https://orcid.org/0000-0002-6767-9666)
- Martin Vaeth (ORCID: https://orcid.org/0000-0001-8974-7052)
- Matthias Becker (ORCID: https://orcid.org/0000-0002-7120-4508)
- Maike Willers (ORCID: https://orcid.org/0000-0002-8190-273X)
- Gesine Hansen (ORCID: https://orcid.org/0000-0001-5185-9454)
- Christoph Härtel (ORCID: https://orcid.org/0000-0002-2181-7322)
- Joachim L. Schultze (ORCID: https://orcid.org/0000-0003-2812-9853)
- J. Heckmann
- Johanna Büchel
- Karsten Hiller (ORCID: https://orcid.org/0000-0001-9322-5820)
- Alexander Heinz
- Annika Marie Tödtmann
Institutions
- University of Bonn (DE)
- University of Würzburg (DE)
- German Center for Neurodegenerative Diseases (DE)
- Medizinische Hochschule Hannover (DE)
- Universitäts-Kinderklinik Würzburg (DE)
- Universitätsklinikum Würzburg (DE)
- University of Lübeck (DE)
- Technische Universität Braunschweig (DE)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-03-06
- DOI
- https://doi.org/10.1038/s41467-025-57357-w
- Citations
- 6
- Primary Topic
- Immune responses and vaccinations
- Type
- article
- Field-Weighted Citation Impact
- 3.99
Funders
- Deutsche Forschungsgemeinschaft
- Bundesministerium für Bildung und Forschung