Maternal obesity drives functional alterations in uterine NK cells
Sofie Perdu, … , Lauren DeLuca, Alexander G. Beristain
Sofie Perdu, … , Lauren DeLuca, Alexander G. Beristain
Published July 21, 2016
Citation Information: JCI Insight. 2016;1(11):e85560. https://doi.org/10.1172/jci.insight.85560.
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Research Article Immunology Reproductive biology

Maternal obesity drives functional alterations in uterine NK cells

Abstract

Over one-fifth of North American women of childbearing age are obese, putting these women at risk for a variety of detrimental chronic diseases. In addition, obesity increases the risk for developing major complications during pregnancy. The mechanisms by which obesity contributes to pregnancy complications and loss remain unknown. Increasing evidence indicates that obesity results in major changes to adipose tissue immune cell composition and function; whether or not obesity also affects immune function in the uterus has not been explored. Here we investigated the effect of obesity on uterine natural killer (uNK) cells, which are essential for uterine artery remodeling and placental development. Using a cohort of obese or lean women, we found that obesity led to a significant reduction in uNK cell numbers accompanied with impaired uterine artery remodeling. uNK cells isolated from obese women had altered expression of genes and pathways associated with extracellular matrix remodeling and growth factor signaling. Specifically, uNK cells were hyper-responsive to PDGF, resulting in overexpression of decorin. Functionally, decorin strongly inhibited placental development by limiting trophoblast survival. Together, these findings establish a potentially new link between obesity and poor pregnancy outcomes, and indicate that obesity-driven changes to uterine-resident immune cells critically impair placental development.

Authors

Sofie Perdu, Barbara Castellana, Yoona Kim, Kathy Chan, Lauren DeLuca, Alexander G. Beristain

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Figure 5

PDGFR induces survival signals in uterine NK (uNK) cells but does not alter cytokine expression, cytotoxicity, or migration.

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PDGFR induces survival signals in uterine NK (uNK) cells but does not al...
(A) Representative images of decidual tissues at 11–13 weeks of gestation from control (n = 10) and obese (n = 10) women immunostained for CD56 (red) and PDGFR-α (green). Nuclei are labeled with DAPI (blue). Scale bars: 50 μm. (B) Representative flow cytometry histogram showing PDGFR-β cell-surface intensity on uNK cells from control or obese women. The median fluorescence intensity (MFI) ± SEM between control (n = 6) and obese (n = 6) uNK cells is shown above plot: solid color indicates the fluorescence minus one baseline signal. Immunoblots (C) and densitometric quantification (D) depicting activation of PDGFR-α, Erk1/2, and Akt after 10 minutes of stimulation with 100 ng/ml PDGF-BB (BB; a PDGFR ligand capable of activating both α- and β-type PDGFRs) in control (n = 3) and obese (n = 3) uNK cells. Molecular weights (kDa) are shown to the left and β-actin indicates loading control. (E) Representative flow cytometry plots of intracellular IFN-γ and TNF-α, as well as surface expression of CD107a in 1 × 106 CD56+ uNK cells either untreated (–) or treated with 30 ng/ml PDGF-BB for 5 hours in the presence or absence of K562 target cells (effector/target ratio 2:1). UC = untreated control. Proportion (%) of CD56+ uNK cells showing positivity for these makers is indicated within plots. Scatter plots show proportional levels of CD56+ uNK cell (n = 6) (F) IFN-γ, (G) TNF-α, and (H) CD107a. (I) Line graphs indicate fold-change (FC) differences in migration of 2 × 105 uNK cells treated or untreated with PDGF-BB over 3 hours. uNK cells were purified from control (black, n = 3) or obese (green, n = 3) subjects. FBS treatment served as a positive control. Results are presented as scatter plots with indicated median and interquartile range. Statistical analyses between groups were performed using a nonparametric 2-tailed Mann-Whitney t test. NS, not significant; PMA, phorbol 12-myristate 13-acetate.