Elsevier

Placenta

Volume 29, Issue 3, March 2008, Pages 274-281
Placenta

Obesity in Pregnancy Stimulates Macrophage Accumulation and Inflammation in the Placenta

https://doi.org/10.1016/j.placenta.2007.12.010Get rights and content

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 blood mononuclear cells (PBMC) 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 the placenta of obese as compared to lean women. The macrophage population was characterized by a marked phenotypic heterogeneity with complex subsets of CD14+, CD68+ and CD11b+ (mac-1) cells and by an increased expression of the pro-inflammatory cytokines IL-1, TNF-alpha, IL-6. Placental inflammation was associated with an activation of PBMC gene expression with an increase in the monocyte differentiation and maturation markers CD14 and CD68 in maternal but not fetal PBMC. The inflammatory changes were associated with higher plasma concentrations of C-reactive protein and IL-6 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 a heterogeneous macrophage population and pro-inflammatory 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.

Section snippets

Subjects and methods

The monoclonal antibody against human CD68, clone PGM-1 and the FITC-conjugated anti-CD68 were from DakoCytomation (Glostrup, Denmark). The monoclonal mouse antibody against human CD14, clone 7, was from Novocastra Laboratories Ltd (Newcastle, UK). The PE and FITC-conjugated CD14 and CD11b were from Abcam (Cambridge, MA). The FITC-conjugated CD133 was from Miltenyi-Biotech (Auburn, CA). The secondary antibodies anti-Rb biotin and streptavidin-HRP were from Vector (Burlingame, CA).

Obesity in pregnancy is associated with peripheral inflammation

Increased circulating concentrations of IL-6 (4.2 ± 0.3 vs 2.7 ± 0.2 ng/ml) and CRP (10,450 ± 602 vs 8162 ± 926 ng/ml) were detected in the plasma of obese women compared to lean women. By contrast there was no change in circulating TNF-alpha (Table 2). The doubling in insulin concentrations was associated with a 4 fold increase in insulin resistance measured by the HOMA index (Table 2). The higher adiposity of the obese women was supported by their higher circulating leptin concentration. Obese women

Discussion

Accumulation of macrophages with production of pro-inflammatory molecules, an immunological response of inflamed tissues, has emerged as a common feature of the chronic metabolic disturbances associated with insulin resistance. For example, macrophage infiltration in expanding adipose tissue is a mechanism contributing to the development of obesity and its stream of associated co-morbidities [27]. Pregnancy is another situation characterized by profound metabolic modifications i.e. increased

Acknowledgements

The authors wish to thank Patricia Mencin for recruitment of study participants and Larraine Presley for help with data analysis. The study was supported by grants of Diabetes Association of Greater Cleveland to SHM, National Institute of Health HD-22965 and GCRC MO-1, RR-00080 to PMC.

References (44)

  • M. Castellucci et al.

    Mitosis of the Hofbauer cell: possible implications for a fetal macrophage

    Placenta

    (1987)
  • D.M. Becroft et al.

    Placental villitis of unknown origin: epidemiologic associations

    Am J Obstet Gynecol

    (2005)
  • P.M. Catalano

    Increasing maternal obesity and weight gain during pregnancy: the obstetric problems of plentitude

    Obstet Gynecol

    (2007)
  • S.Y. Kim et al.

    Trends in pre-pregnancy obesity in nine states, 1993–2003

    Obesity

    (2007)
  • S.P. Weisberg et al.

    Obesity is associated with macrophage accumulation in adipose tissue

    J Clin Invest

    (2003)
  • H. Xu et al.

    Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance

    J Clin Invest

    (2003)
  • T. Radaelli et al.

    Gestational diabetes induces placental genes for chronic stress and inflammatory pathways

    Diabetes

    (2003)
  • J.E. Ramsay et al.

    Maternal obesity is associated with dysregulation of metabolic, vascular, and inflammatory pathways

    J Clin Endocrinol Metab

    (2002)
  • G.P. Sacks et al.

    Maternal C-reactive protein levels are raised at 4 weeks gestation

    Hum Reprod

    (2004)
  • J.P. Kirwan et al.

    Reversal of insulin resistance postpartum is linked to enhanced skeletal muscle insulin signaling

    J Clin Endocrinol Metab

    (2004)
  • C.A. Hubel

    Oxidative stress in the pathogenesis of preeclampsia

    Proc Soc Exp Biol Med

    (1999)
  • K. Takahashi et al.

    Development, differentiation, and maturation of macrophages in the chorionic villi of mouse placenta with special reference to the origin of Hofbauer cells

    J Leukoc Biol

    (1991)
  • Cited by (0)

    View full text