Fetal liver neutrophils are responsible for the postnatal neutrophil surge

Abstract

Mammalian neonates experience an abrupt surge of blood neutrophil count within the first day of life. The postnatal neutrophil surge is regarded as a defensive reaction against infection; however, the mechanisms underlying this surge remain unclear. The present study demonstrates that the postnatal neutrophil surge arises from the liver neutrophil pool. In rat neonates, the neutrophil surge was evident at 6 hours after birth. The proportion and immaturity of bone marrow neutrophils remained unaltered at 6 hours but increased only after the surge had peaked. In the rat fetal and neonatal livers, we observed prenatal neutrophil accumulation and acute loss of the neutrophils coinciding with the postnatal neutrophil surge. In Lys-EGFP mice, an acute loss of liver neutrophils was observed within 12 hours of birth. This loss was characterized by a decrease in mature neutrophils and by perivascular neutrophil localization in the livers. Additionally, mouse fetuses exhibited an accumulation of the liver neutrophil pool during the late gestational period (e15-18), which was attributable to neutrophil-biased myeloid differentiation mediated by granulocyte-colony stimulating factor (G-CSF). The liver neutrophils exhibited characteristic transcriptomic alterations within three hours of birth, exemplified by an increase in the Nos2 (iNOS) gene. The administration of a non-selective NOS inhibitor or an iNOS-selective inhibitor resulted in the inhibition of the postnatal neutrophil surge in rat neonates, accompanied by the retention of liver neutrophils. These findings shed light on the previously unidentified source of the postnatal neutrophil surge and the stimulus initiating it. Significance statementInfections in newborns, particularly those occurring within the first 72 hours of life, are leading cause of mortality and morbidity. Neutrophil, a type of leukocytes, acutely increases within 24 hours after birth in the newborns blood. This neutrophil surge is regarded as an innate defensive system against infection; however, the mechanisms of the surge have remained unknown. Here, we examined rats and mice and found that the neutrophils accumulated in the fetal livers during the late pregnancy and were released into blood after birth. We also found a specific factor causing the release of the liver neutrophils. These findings might explain why preterm or low-birth weight newborns often lack the postnatal neutrophil surge and are thus more susceptible to infections.