Glucose and Metformin Modulate Human First Trimester Trophoblast Function: a Model and Potential Therapy for Diabetes‐Associated Uteroplacental Insufficiency

Abstract

Problem Diabetes confers an increased risk of preeclampsia, but its pathogenic role in preeclampsia is poorly understood. The objective of this study was to elucidate the effects of excess glucose on trophoblast function and whether any changes could be reversed by metformin. Method of Study The human first trimester trophoblast cell line (Sw.71) was treated with glucose at 5mM, 10mM, 25mM and 50mM, in the presence and absence of metformin. Trophoblast migration was quantified and supernatant cytokine, chemokine, and angiogenic factors measured. Results Increasing concentrations of glucose significantly increased trophoblast secretion of the inflammatory cytokines/chemokines: IL-1β, IL-6, IL-8, GRO-α, RANTES and G-CSF; significantly increased trophoblast secretion of the anti-angiogenic factors sFlt-1 and sEndoglin; and significantly decreased trophoblast migration. Excess glucose-induced trophoblast IL-1β production was inhibited by disabling the Nalp3/ASC inflammasome. Metformin partially reduced the glucose-induced inflammatory response, but had no effect on the anti-angiogenic or anti-migratory response. Conclusion Excess glucose induced a pro-inflammatory, anti-angiogenic, and anti-migratory state in first trimester trophoblast cells. Glucose-induced trophoblast IL-1β secretion was mediated by the inflammasome. Glucose-induced inflammation was partially reversed by metformin. These findings demonstrate the pleiotropic effects of hyperglycemia on the trophoblast, providing potential explanations for the strong link between diabetes and preeclampsia.

Uric Acid Crystals Induce Placental Inflammation and Alter Trophoblast Function via an IL-1–Dependent Pathway: Implications for Fetal Growth Restriction

“…Basal activation of caspase-1 was observed in term placental explants (Fig 2G-H) due to the constant release of alarmins (i.e. fetal DNA, trophoblast debris) in such a culture setting and to the trophoblast own production of uric acid as previously reported27,28.…”

“…The inflammatory actions of MSU crystals have been described in immune cells, as an activator of the NALP3 inflammasome, upstream of caspase-1, leading to the production of interleukin IL-1β25,35,36. Information on the action of MSU crystals at the maternal-fetal interface is scarce but it has been published that it does induce IL-1β secretion in a first trimester trophoblast cell line through activation of caspase-1 and of the NLRP3 inflammasome26–28. NLRP3 activation by MSU crystals was also observed in monocytes from PE patients37.…”

“…MSU crystals can exert pro-inflammatory effects in humans and animals24,25; however, the effects of MSU crystals at the maternal-fetal interface are still mostly unknown. Studies using human first trimester trophoblast cell lines showed that interleukin (IL)-1β was produced in response to MSU crystals via the activation of the Nlrp3 inflammasome26,27,28. Furthermore, it has been reported that uric acid decreased system A amino acid transporter activity in third trimester placental explants29; a decrease in the activity of this transporter in the placenta has previously been associated with FGR30.…”

Placental origins of adverse pregnancy outcomes: potential molecular targets: an Executive Workshop Summary of the Eunice Kennedy Shriver National Institute of Child Health and Human Development

“…Moreover, the IL-1β response is associated with elevated uric acid and is dependent upon activation of the Nalp3 inflammasome. 96 Indeed elevated serum uric acid has been associated with high-risk pregnancies, such as those complicated by preeclampsia, gestational hypertension, cases of reduced fetal movements, or obstetric aPL syndrome. 92,97,98,99 Thus, rather than simply correlating levels with disease, uric acid can act as a direct mediator of trophoblast inflammasome activation and placental inflammation, 93 suggesting it may play a pathological role.…”

“…Since uric acid mediates placental inflammasome function 92,93,96 currently available drugs that inhibit xanthine oxidase, such as allopurinol or febuxostat, may provide potential avenues to explore. However, this is only one mechanism by which IL-1β production can arise; there are a number of other inflammasomes that uric acid may not activate, 112 as well as non-inflammasome-mediated pathways, 113 all of which could be possible targets.…”