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 4

Differential gene expression (DE) between uterine NK (uNK) cell control- and obese-enriched groups.

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Differential gene expression (DE) between uterine NK (uNK) cell control-...
(A) Volcano plot of differential mRNA levels averaged between G1/G2 and G3/G4 sample groups. x axis: coefficients from linear model in log2 scale; y axis: P values adjusted for multiple testing. Black circles indicate probes with an FDR ≥ 0.001; orange and red circles indicate probes with an FDR < 0.001; red circles indicate probe overlap with high coefficient of variation (high-CV) probes. (B) Hierarchical clustering of uNK cell samples from obese and control subjects informed by the DE signature (FDR < 0.001) comparing G1/G2 and G3/G4 groups. For each sample, patient BMI and C-reactive protein (CRP) status is indicated above the heatmap (control = black; obese = green; low CRP = white; high CRP = red). (C) Venn diagram showing the number of genes shared between the 200 high-CV list and DE upregulated and downregulated genes (FDR < 0.001). (D) Dotmap depiction of significant pathways enriched in the 885 DE gene signature determined by ToppGene. FDR values (q value, Bonferroni) are represented by box color, and percentage of genes in the GO annotated list are indicated by circle size. ECM, extracellular matrix. (E) qPCR analysis of PDGFRA, PDGFRB, COL1A1, and DCN in G1/G2 and G3/G4 groups. GAPDH was used for normalization. Individual sample values are indicated by color: black = control/low CRP; red with black = control/high CRP; green = obese/high CRP. Statistical analyses for DE were performed in the R statistical environment; qPCR statistical analyses were performed using a nonparametric 2-tailed Mann-Whitney t test.