Abstract

Obesity is prevalent among women of reproductive age and is associated with increased risk of developing multiple pregnancy disorders. Pregnancy must induce immune tolerance to avoid fetal rejection, while obesity can cause chronic inflammation through activating the immune system. Impaired maternal immuno-tolerance leads to pregnancy failure, such as recurrent spontaneous abortion (RSA), one of the most common complications during early pregnancy. How does maternal immune response change under obesity stress in normal pregnancy and RSA? In turn, is obesity affected by different gestational statuses? Limited information is presently available now. Our study investigated pregnancy outcomes and maternal immune responses in two murine models (normal pregnancy and spontaneous abortion models) after obesity challenge with a high-fat diet (HFD). Abortion-prone mice fed HFD had significantly higher weight gains during pregnancy than normal pregnant mice with HFD feeding. Nonetheless, the embryo implantation and resorption rates were comparable between HFD and normal chow diet (NCD)-fed mice in each model. Evaluation of immune cell subsets showed HFD-induced obesity drove the upregulation of activated NK cell-activating receptor (NKp46)+ NK cells and pro-inflammatory macrophages (MHCIIhigh Mφ) as well as CD4+ and CD8+ T cells in the normal pregnancy group. However, in the abortion-prone group, relative more immature NK cells with decreased activity phenotypes were found in obese mice. Moreover, there were increased DCreg (CD11bhigh DC) cells and decreased CD4+ and CD8+ T cells detected in the HFD abortion-prone mice relative to those fed the NCD diet. Our findings reveal how pregnancy obesity and maternal immune regulation are mutually influenced. It is worth noting that the abortion-prone model where active maternal immune status was intensified by obesity, in turn stimulated an overcompensation response, leading to an over-tolerized immune status, and predisposing to potential risks of perinatal complications.

Highlights

  • Obesity is recognized as a public health concern due to imbalanced energy metabolism and immune homeostasis attributable to overfeeding and sedentary lifestyles in modern society

  • Jennet et al reported that the overall activity as well as the natural cytotoxicity receptor 1 (NCR1) expression level in uterine NK cells was increased in obese women, and these changes were tightly linked with dampened artery remodeling [20]

  • Using murine models of normal and abortion-prone pregnancy, our study investigated the relationships among maternal obesity, pregnancy outcomes, and maternal immune responses by examining the frequencies along with phenotypes of innate and adaptive immune cells both locally within the uterus and systemically

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Summary

Introduction

Obesity is recognized as a public health concern due to imbalanced energy metabolism and immune homeostasis attributable to overfeeding and sedentary lifestyles in modern society. Immune cells infiltrate into adipose tissue, potentiating pro-inflammatory polarization and promoting the secretion of pro-inflammatory cytokines by leukocytes [12, 13]. Supporting this notion, the peripheral blood of obese pregnant women contains elevated levels of tumor necrosis factor alpha (TNF-a), C-reactive protein (CRP), and interleukin 6 (IL-6) [14,15,16]. Jennet et al reported that the overall activity as well as the natural cytotoxicity receptor 1 (NCR1) expression level in uterine NK cells was increased in obese women, and these changes were tightly linked with dampened artery remodeling [20]. Maternal obesity influences the biology of diverse subsets of uterine immune cells, altering the immune cell landscape of the decidua

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