Oxidative phosphorylation is a key feature of neonatal monocyte immunometabolism promoting myeloid differentiation
Greta Ehlers1, Annika Marie Tödtmann1, Lisa Holsten2,3,4,5
1Department of Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Hannover, Germany.
Insights
Neonatal monocytes use oxidative phosphorylation for myeloid differentiation, unlike older children who use glycolysis for inflammation. This metabolic shift is crucial for immune adaptation after birth.
Area of Science:
- Immunology
- Metabolism
- Neonatal Development
Background:
- Neonates exhibit restricted inflammatory responses, debated as immaturity or protective programming.
- Understanding neonatal innate immunity is critical for sepsis risk assessment.
Purpose of the Study:
- To investigate the ontogenetic shift in monocyte metabolism during postnatal immune adaptation.
- To determine the metabolic drivers of neonatal versus adult immune responses.
Main Methods:
- Combined transcriptomic, metabolic, and immunological analyses of monocytes from healthy individuals across age groups.
- Comparative studies involving microbial stimulation and ketogenic diets.
Main Results:
- Neonatal monocytes exhibit enhanced oxidative phosphorylation, supporting myeloid differentiation.
- A metabolic shift towards glycolysis occurs during childhood, enhancing inflammatory responses.
- Microbial stimulation induces an adult-like metabolic profile in neonatal monocytes.
- Ketogenic diets in adults do not replicate neonatal metabolic phenotypes.
Conclusions:
- Identified key immunometabolic adaptations during healthy postnatal immune development.
- Premature glycolytic activation in neonates may elevate sepsis risk by hindering myeloid differentiation and promoting hyperinflammation.
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.
