Pregnancy-associated metabolic adaptations in circulating monocytes and macrophages favor clearance functions.

INTRODUCTION: Pregnancy requires coordinated immunometabolic adaptations that allow maternal immune tolerance while preserving tissue remodeling and host defense. Circulating monocytes contribute critically to these processes, yet how gestation shapes their metabolic state and functional specialization remains incompletely defined. METHODS: We investigated the metabolic and functional phenotype of maternal monocytes during earlymid pregnancy (1620 weeks of gestation) and explored the contribution of trophoblast-derived signals using an in vitro macrophage model and trophoblast-conditioned media. RESULTS: Maternal circulation was enriched in CD14(+)CD16(+) monocytes, accompanied by increased plasma lactate levels and elevated ex vivo lactate secretion by purified monocytes, without changes in mitochondrial mass or membrane potential. Monocytes from pregnant women displayed enhanced long-chain fatty acid uptake and increased expression of the fatty acid transporter CD36, while lipid droplet accumulation remained unchanged. Pregnancy-associated efferocytosis was dependent on fatty acid oxidation (FAO), as pharmacological FAO inhibition abrogated this response. Transcriptional profiling revealed differential regulation of TAM receptors, characterized by increased MERTK and reduced AXL expression, consistent with a homeostatic efferocytic program. Trophoblast-derived conditioned media recapitulated key features of this phenotype in macrophages, inducing fatty acid uptake, lipid dropletmitochondria colocalization, and upregulation of CPT1, DGAT1, LXRa and RARa. In this model, FAO was required to sustain ATP production and M2-like marker expression, while monocarboxylate transport was necessary for efficient efferocytosis and fatty acid uptake. DISCUSSION: Together, these findings identify a coordinated immunometabolic program in maternal monocytes integrating glycolysis, lactate signaling, and FAO, likely instructed by trophoblast-derived cues, to enhance efferocytic and pro-resolving functions during pregnancy. This metabolic adaptation may represent a systemic mechanism supporting immune tolerance and tissue remodeling in early gestation.