Causal relationship between obesity-related traits and TLR4-driven responses at the maternal-fetal interface

Aims/hypothesis Obesity triggers complex inflammatory networks within the innate immune system. During pregnancy, the placenta amplifies the low-grade inflammation through activation of Toll-like receptor 4 (TLR4) signalling pathways. The purpose of this study was to investigate the impact of obesity on placental TLR4 expression and inflammatory signals. The secondary aim was to analyse the placental cell type responsible for TLR4 activation. Methods Thirty-nine women recruited at term-scheduled Caesarean section were grouped according to their pregravid BMI (<25 kg/m(2) and >30 kg/m(2)). Placenta, venous maternal and cord blood were obtained at delivery for analysis. Data were analysed with linear regression and Spearman's rank correlation coefficient analysis. Results TLR4, IL6 and IL8 expression was increased three-to ninefold (p<0.001) in the placenta of obese vs lean women. There was a positive correlation between placental TLR4 and maternal systemic and placental IL6 and IL8 concentrations. Placental TLR4 expression was correlated with maternal pregravid BMI, insulin resistance index, plasma insulin and Creactive protein (r = 0.57, 0.31, 0.35, 0.53, respectively; p<0.001) but not with plasma glucose, maternal age, gestational age and gestational weight gain (r<0.2; p>0.1). TLR4 was located in both trophoblast and macrovascular endothelial cells lining fetal vasculature. Lipopolysaccharide-induced TLR4 activation was more robust in trophoblasts than in endothelial vascular cells (100-fold vs tenfold; p<0.001). Conclusions/interpretation Trophoblastic TLR4 is strongly implicated in the propagation of placental inflammation. Placental inflammation is related to maternal metabolic conditions such as pre-gravid BMI, whilst gestational weight gain or gestational age are not. These results implicate the pregravid condition as a significant contributor to metabolic inflammation in late pregnancy.