title: Causal relationship between obesity-related traits and TLR4-driven responses at the maternal-fetal interface.
abstract: 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.
  
  
  
  Thirty-nine women recruited at term-scheduled Caesarean section were grouped according to their pre-gravid 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.
  
  
  
  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).
  
  
  
  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 pre-gravid condition as a significant contributor to metabolic inflammation in late pregnancy.
authors.affiliation: Center for Reproductive Health, MetroHealth Medical Center, Case Western Reserve University School of Medicine, 2500 MetroHealth Dr., Cleveland, OH, 44109-1998, USA.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Yang
authors.affiliation: Epidemiology and Biostatistics Department, School of Medicine, Case Western Reserve University, Cleveland, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Li
authors.affiliation: Center for Reproductive Health, MetroHealth Medical Center, Case Western Reserve University School of Medicine, 2500 MetroHealth Dr., Cleveland, OH, 44109-1998, USA.
authors.forename: Maricela
authors.initials: M
authors.lastname: Haghiac
authors.affiliation: Center for Reproductive Health, MetroHealth Medical Center, Case Western Reserve University School of Medicine, 2500 MetroHealth Dr., Cleveland, OH, 44109-1998, USA.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Catalano
authors.affiliation: Center for Reproductive Health, MetroHealth Medical Center, Case Western Reserve University School of Medicine, 2500 MetroHealth Dr., Cleveland, OH, 44109-1998, USA.
authors.forename: Perrie
authors.initials: P
authors.lastname: O'Tierney-Ginn
authors.affiliation: Center for Reproductive Health, MetroHealth Medical Center, Case Western Reserve University School of Medicine, 2500 MetroHealth Dr., Cleveland, OH, 44109-1998, USA. shdemouzon@metrohealth.org.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Hauguel-de Mouzon
mesh_terms: D002097:C-Reactive Protein / Q000378:metabolism; D005260:Female; D005865:Gestational Age; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000378:metabolism; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D009765:Obesity; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D015398:Signal Transduction / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
chemical_list: D007328:Insulin; D015850:Interleukin-6; D016209:Interleukin-8; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D002097:C-Reactive Protein
keywords: Gestational weight gain; Inflammation; LPS; Macrovascular endothelial cells; Obesity; Placenta; Pregnancy; Toll-like receptor 4; Trophoblast