Adenosine accumulation in the blood of newborn mice weakens antimicrobial host defenses

Pediatric intensive care patients are particularly susceptible to severe bacterial infections because of ineffective neutrophil responses. The reasons why neutrophils of newborns are less responsive than those of adults are not clear. Because adenosine triphosphate and adenosine tightly regulate neutrophils, we studied whether the adenosine triphosphate and adenosine levels in the blood of newborn mice could impair the function of their neutrophils. We observed significant changes in plasma adenosine triphosphate and adenosine levels throughout the lifespan of mice. Adenosine levels in newborns were significantly higher than in older mice, while adenosine triphosphate levels were significantly lower. These changes were particularly striking in newborn and juvenile mice with adenosine triphosphate and adenosine levels of about 80 and 600 nM in newborns vs 130 and 190 nM in juveniles, respectively. The ratios of the adenosine triphosphate vs adenosine levels of newborns were (with 0.2) significantly lower than those of juveniles (1.4) and adults (0.5). These low adenosine triphosphate/adenosine ratios correlated with significantly weakened neutrophil activation responses following in vitro stimulation with a formyl peptide receptor agonist and a markedly higher morbidity and mortality rate of newborns following bacterial infection. We found that enhanced adenosine monophosphate hydrolysis via CD73, a lack of adenosine breakdown by adenosine deaminase, and reduced adenosine uptake by nucleoside transporters are responsible for the low adenosine triphosphate/adenosine ratios in blood of newborn mice. We conclude that the extracellular adenosine accumulation in newborn mice impairs inflammatory responses and reduces the ability of neutrophils to mount effective antimicrobial defenses against bacterial infections.