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

Abstract

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 pre-gravid BMI (< 25 kg/m2 and > 30 kg/m2). 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 pre-gravid BMI, insulin resistance index, plasma insulin and C-reactive 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 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 pre-gravid condition as a significant contributor to metabolic inflammation in late pregnancy.

Effects of maternal obesity on placental function and fetal development

“…In normal pregnancy, TLR4 placental expression increases across gestation (Thaete et al 2013) and TLR4 has been shown to be present in cytotrophoblasts and syncytiotrophoblasts (Mitsunari et al 2006). Placental TLR4 expression has been reported to be elevated three to nine-fold in obese mothers and is positively correlated to maternal and placental IL-6 expression (Yang et al 2016). Similarly, in women with GDM, placental TLR4 expression is correlated with maternal hyperglycemia and insulin resistance (Feng et al 2016).…”

“…Moreover, studies in pregnant sheep have demonstrated that inflammation is associated with maternal obesity and up-regulates free fatty acid content in the cotyledon through TLR4 activation (Zhu et al 2010a; Zhu et al 2010b). Studies in human placenta likewise suggest that high maternal BMI promotes TLR4 signaling and propagation of inflammatory responses (Yang et al 2016). These studies suggest that up-regulated placental TLR4 expression may mediate placental inflammation and increased placental transfer of nutrients, including amino acids and fatty acids, thereby contributing to fetal overgrowth and/or increased fat deposition in pregnancies complicated by maternal obesity.…”

Fetal brain and placental programming in maternal obesity: A review of human and animal model studies

“…140 TLR-4 signaling has been implicated in obesity-associated neuroinflammation, [141][142][143] and trophoblastic TLR4 has been shown to be involved in the propagation of inflammation at the maternal-fetal interface. 144,145 Data on placental immune activation in obese pregnancy have been conflicting, and immune cell number and function may differ 146 Another study noted increased neutrophils in the maternal interstitial space and increased expression of chemotactic cytokines in the placenta but did not identify changes in the number of fetal placental immune cells. 147 This study assessed only the number of fetal placental immune cells, however, rather than differences in reactivity.…”

Impact of pregravid obesity on maternal and fetal immunity: Fertile grounds for reprogramming

“…121,144 In line with these observations, higher transcript levels of proinflammatory genes IL6, CCL2, IL8, and TLR4 are detected in a baboon model of HFD-induced obesity. 66,145 Similarly, chorionic villi macrophages obtained from placentas of diet-induced obese dams generate exacerbated responses to LPS (higher TNF , IL-6, and IL-1 ) both at the gene and protein levels, suggesting functional reprogramming of fetal macrophages as well. 100 A more recent study demonstrated reduced frequency of M1-like macrophages (HLA-DR+ CD163−) in the decidua with pregravid obesity, 146 potentially a compensatory mechanism against obesity-associated inflammation.…”