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Problem: Intrauterine infection is one of the most jeopardizing conditions associated with adverse outcomes, including preterm birth; however, multiple tolerance mechanisms operate at the maternal–fetal interface to avoid the rejection of the fetus. Among the factors that maintain the uterus as an immunoprivileged site, Galectin‐1 (Gal‐1), an immunomodulatory glycan‐binding protein secreted by the maternal‐fetal unit, is pivotal in promoting immune cell homeostasis. This work aimed to evaluate the role of Gal‐1 during a lipopolysaccharide (LPS)‐induced‐inflammatory milieu. Method of Study: Using an ex vivo culture with two independent compartments, human fetal membranes at term were pretreated with 40 and 80 ng/mL of Gal‐1, then to reproduce an intraamniotic inflammation, the fetal side of membranes was stimulated with 500 ng/mL of LPS for 24 h. The concentrations of tumor necrosis factor (TNF)‐α, interleukin (IL)‐1β, IL‐6, monocyte chemoattractant protein (MCP1), macrophage inflammatory protein (MIP1) α, regulated upon activation normal T cell expressed and secreted (RANTES), and matrix metalloproteinase (MMP)‐9 were measured in both amnion and choriodecidua compartments. Results: In a tissue‐specific fashion profile, pretreatment with the physiologic concentration of Gal‐1 significantly diminished the LPS‐dependent secretion of TNF‐α, IL‐1β, Il‐6, MCP1, MIP1α, RANTES, and MMP‐9. Conclusion: Gal‐1 elicits an anti‐inflammatory effect on the human fetal membranes stimulated with LPS, which supports the hypothesis that Gal‐1 is part of the immunomodulatory mechanisms intended to stop the harmful effect of inflammation of the maternal–fetal interface. [ABSTRACT FROM AUTHOR]

Placentas from gestational diabetes mellitus (GDM) patients undergo significant metabolic and immunologic adaptations due to hyperglycemia, which results in an exacerbated synthesis of proinflammatory cytokines and an increased risk for infections. Insulin or metformin are clinically indicated for the treatment of GDM; however, there is limited information about the immunomodulatory activity of these drugs in the human placenta, especially in the context of maternal infections. Our objective was to study the role of insulin and metformin in the placental inflammatory response and innate defense against common etiopathological agents of pregnancy bacterial infections, such as E. coli and S. agalactiae, in a hyperglycemic environment. Term placental explants were cultivated with glucose (10 and 50 mM), insulin (50–500 nM) or metformin (125–500 µM) for 48 h, and then they were challenged with live bacteria (1 × 105 CFU/mL). We evaluated the inflammatory cytokine secretion, beta defensins production, bacterial count and bacterial tissue invasiveness after 4–8 h of infection. Our results showed that a GDM-associated hyperglycemic environment induced an inflammatory response and a decreased beta defensins synthesis unable to restrain bacterial infection. Notably, both insulin and metformin exerted anti-inflammatory effects under hyperglycemic infectious and non-infectious scenarios. Moreover, both drugs fortified placental barrier defenses, resulting in reduced E. coli counts, as well as decreased S. agalactiae and E. coli invasiveness of placental villous trees. Remarkably, the double challenge of high glucose and infection provoked a pathogen-specific attenuated placental inflammatory response in the hyperglycemic condition, mainly denoted by reduced TNF-α and IL-6 secretion after S. agalactiae infection and by IL-1β after E. coli infection. Altogether, these results suggest that metabolically uncontrolled GDM mothers develop diverse immune placental alterations, which may help to explain their increased vulnerability to bacterial pathogens. [ABSTRACT FROM AUTHOR]