Pregnancy Entails a Metabolic Rewiring of Maternal Circulating Neutrophils

Abstract

Immunometabolism is an emerging growing field that focuses on the role of cellular metabolism in the regulation of immune cell function and fate. Thus, proliferation, differentiation, activation, and function of immune cell populations are modulated by reprogramming their fueling and metabolic pathways. Pregnancy entails a fine immune and metabolic regulation of the maternal−fetal interaction to assist the energetic demands of the fetus where trophoblast cells have a central role. Maternal neutrophil functional shaping by trophoblast cells has been proposed though their metabolic conditioning during pregnancy has not been studied yet. Here, we explored the effects of trophoblast-derived factors on the metabolic rewiring of neutrophils from nonpregnant women and its impact on central functions like reactive oxygen species (ROS) production, neutrophil extracellular trap (NET) release, and migration. In parallel, the immunometabolic status and function of neutrophils isolated from pregnant women (16−20 weeks) was compared with nonpregnant age-matched control samples. Trophoblast-derived factors induced glucose uptake and lipid droplet accumulation without activating ROS production or NET release. Conditioned media from trophoblast cells also inhibited PMA-induced NETosis partly by impairing glucose uptake in neutrophils. In turn, neutrophils from pregnant women had increased basal ROS production, lipid accumulation, and glucose uptake compared to neutrophils from nonpregnant women, accompanied by a higher release of PMA-induced NETs. Interestingly, PMA-induced NETs was blocked by a fatty acid oxidation inhibitor in neutrophils from pregnant women indicating the contribution of fatty acid metabolism to neutrophil activity during pregnancy. Results are consistent with immunometabolic mechanisms underlying the functional shaping of neutrophils during pregnancy and point out the contribution of trophoblast-derived factors to their metabolic profiling. These findings provide novel immunometabolic clues to understand immune homeostasis maintenance during pregnancy and raise the clinical potential of monitoring neutrophil metabolism during normal and complicated pregnancies.