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

Fátima Isabel Merech^1,2Daiana Rios^1,2Ana Schafir^2,3Ignacio Ezequiel Rojas Campión^1,2Melisa Bentivegna⁴Juan Beauquis⁴María Catalina Lava^5,6Eugenio Antonio Carrera Silva⁵Andrea Emilse Errasti⁶Melisa Fariz⁷Daniel Paparini^3,7Aldo Fabian Squassi⁸Luciana D´Eramo⁸Rosanna Ramhorst^3,7Claudia Pérez Leirós^2,3Soledad Gori^2,3Vanesa Hauk^1,2DAIANA M. VOTA^1,2*

• ¹UBA. CONICET. IQUIBICEN-CONICET. Laboratory of Immunomodulation, Metabolism and Cell communication. FCEN-UBA, Buenos Aires, Argentina
• ²Universidad de Buenos Aires, Facultad de Ciencias Exactas y Naturales (FCEN-UBA). Departamento de Química Biológica., Buenos Aires, Argentina
• ³UBA. CONICET. IQUIBICEN-CONICET. Laboratory of Immunopharmacology. FCEN-UBA, Buenos Aires, Argentina
• ⁴Laboratory of Neurobiology of Aging, Instituto de Biología y Medicina Experimental (IBYME), CONICET y Fundación IBYME, Buenos Aires, Argentina
• ⁵Instituto de Medicina Experimental (IMEX), Academia Nacional de Medicina-CONICET, Buenos Aires, Argentina
• ⁶Instituto de Farmacología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
• ⁷Universidad de Buenos Aires, Facultad de Ciencias Exactas y Naturales (FCEN-UBA). Departamento de Química Biológica, Buenos Aires, Argentina
• ⁸Universidad de Buenos Aires, Facultad de Odontología, Instituto de Investigaciones en Salud Pública, Cátedra de Odontología Preventiva y Comunitaria, Buenos Aires, Argentina

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. Here, we investigated the metabolic and functional phenotype of maternal monocytes during early– mid pregnancy and explored the contribution of trophoblast-derived signals using an in vitro macrophage model. We show that at 16–20 weeks of gestation, maternal circulation is 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. Functionally, pregnancy-associated efferocytosis was dependent on fatty acid oxidation (FAO), as pharmacological FAO inhibition abrogated this response. Transcriptional profiling further revealed differential regulation of TAM receptors, characterized by increased MERTK and reduced AXL expression, consistent with a homeostatic efferocytic program. Using trophoblast-derived cell conditioned media, we demonstrate that trophoblast-derived soluble factors recapitulate key features of this phenotype in macrophages, inducing fatty acid uptake, lipid droplet–mitochondria colocalization, and upregulation of CPT1, DGAT1, LXRα and RARα. 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. Together, these findings identify a coordinated immunometabolic program in maternal monocytes that integrate 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.