Obesity in Pregnancy Stimulates Macrophage Accumulation and Inflammation in the Placenta

Abstract

Obesity and pregnancy are associated with a combination of insulin resistance and inflammatory changes which exacerbate in combination. Based on the similarity between the inflammatory transcriptomes of adipose tissue and placenta, we hypothesized that the placenta develops exaggerated inflammation in response to obesity. The aim of this study was to characterize placental inflammatory mediators and macrophage accumulation in relation to peripheral inflammation in obesity.Placental macrophages and maternal peripheral mononuclear cells from 20 obese and 15 lean women were functionally and phenotypically characterized using immunohistochemistry, flow cytometry and expression for macrophage markers and inflammatory cytokines. The number of resident CD68+ and CD14+ cells was increased 2-3 fold in placenta of obese as compared to lean women. The enhanced macrophage population was characterized by a marked phenotypic heterogeneity with complex subsets of CD14+, CD68+ and CD11b+ cells and by an increased expression of the pro-inflammatory mediators IL-1, TNF-alpha, IL-6. Placental inflammation was associated with an activation of peripheral blood mononuclear cells with high amount of CD14, TNF-alpha, IL-6 and the chemokine receptors CCR2 and IL8-R in maternal but not fetal circulation. Additionally, plasma CRP and IL-6 concentrations were higher in obese compared to lean women.In conclusion, the chronic inflammation state of pre-gravid obesity is extending to in utero life with accumulation of an heterogeneous macrophage population and proinflammatory mediators in the placenta. The resulting inflammatory milieu in which the fetus develops may have critical consequences for short and long term programming of obesity. KeywordsObesity; pregnancy; placenta; inflammation; cytokines; fetus; programming The association between excess neonatal adiposity and high pre-gravid BMI and the alarming rise in the number of overweight women of reproductive age, call for elucidating the adverse consequences of obesity in pregnancy (1,2). In non gravid individuals, obesity is described as a low grade inflammatory condition associated with increased production of pro-inflammatory factors which originate from the macrophages infiltrating the adipose tissue (3,4). During pregnancy, however, the placenta becomes a significant source of a variety of cytokines and adipocytokines whose expression is dysregulated by maternal diabetes and obesity (5-7).Pregnancy is considered as a natural inflammatory state evident in activation of maternal leucocytes and increased systemic concentration of acute phase reactants and cytokines (8).The physiological inflammatory state of pregnancy becomes exaggerated when pregnancy is complicated by pre-eclampsia and gestational diabetes and returns to baseline levels after delivery (9-11). Products of inflammatory stress secreted by the placenta and microparticules shedding from the syncytial surface of the placenta into the systemic circulation have been proposed as mechanisms driving adaptive immunity (1...

A clinicopathological study of episomal papillomavirus infection of the human placenta and pregnancy complications

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“…HPV DNA was detected using the GenPoint HPV DNA Probe cocktail (identifies 13 high-risk HPV types: 16,18,31,33,35,39,45,51,52,56,58,59, and 68) and the GenPoint Tyramide Signal Amplification system according to the manufacturer's instructions with one modification (the biotinyl tyramide solution was added to each slide for five instead of 15 min) (Dako, Glostrup, Denmark). Cells were imaged using light microscopy.…”

The maternal and fetal impacts of obesity and gestational diabetes on pregnancy outcome

“…74 Placental tissue examined postpartum from obese mothers also has a higher macrophage population and greater concentrations of pro-inflammatory cytokines. 75 Therefore, the chronic inflammatory process associated with obesity extends to the placenta during pregnancy, with recently described direct, adverse fetal effects. 76 Many of the adverse pregnancy outcomes linked with maternal obesity have independent associations with chronic inflammation.…”

Impact de l’obésité et du diabète maternels sur la fonction placentaire

“…Obésité et inflammation L'index de masse corporelle maternel est corrélé positivement à l'inflammation systémique comme le montrent les taux élevés de MCP-1 (monocyte chemo-attractant protein-1), de TNF-, mais aussi d'IL-6 produits par le tissu adipeux [22]. L'inflammation peut également être locale.…”

“…Ainsi, dans les placentas de femmes obèses et ceux provenant de femelles babouins obèses, les macrophages s'accumulent dans le stroma des villosités placentaires [22]. Cette accumulation est associée à une augmentation de cytokines pro-inflammatoires [10,22,23]. [35].…”