Uterine NK cells mediate inflammation-induced fetal demise in IL-10-null mice

Departments of Pediatrics and Pathology, Women and Infants' Hospital, Rhode Island Hospital-Brown University, Providence, RI 02905, USA.
The Journal of Immunology (Impact Factor: 4.92). 10/2005; 175(6):4084-90.
Source: PubMed


Specialized NK cells are recruited in high numbers to the mammalian embryo implantation sites, yet remain pregnancy compatible. It is not well understood whether uterine NK (uNK) cells become adversely activated and mediate fetal demise, a common complication of early pregnancy. In this study we show that mating of IL-10(-/-) mice resulted in fetal resorption or intrauterine growth restriction in response to very low doses of LPS. Pregnancy in congenic wild-type mice was normal even at 10-fold higher LPS doses. Fetal resorption in IL-10(-/-) mice was associated with a significant increase in uNK cell cytotoxic activation and invasion into the placenta. Depletion of uNK cells, TNF-alpha neutralization, or IL-10 administration rescued pregnancy in LPS-treated IL-10(-/-) animals. Our results identify an immune mechanism of fetal demise involving IL-10 deficiency, NK cells, and inflammation. These results may provide insight into adverse pregnancy outcomes in humans.

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    • "The uNK cells are proposed to play important roles in spiral arteriole remodelling and extravillous trophoblast invasion in early pregnancy (Erlebacher, 2013); however the role of uNKs in late pregnancy and parturition remains unclear. Depletion of uNK cells rescued LPS-induced fetal resorption and preterm birth in IL-10 KO mice (Murphy et al., 2005, 2009), but not CpG ODN-induced fetal resorption or preterm birth in IL-10 KO mice (Thaxton et al., 2009), suggesting that the role of uNK cells may depend on the nature of the inflammatory insult. "

    Molecular Human Reproduction 01/2015; 21(4). DOI:10.1093/molehr/gav002 · 3.75 Impact Factor
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    • "However, White et al. [60] have shown that IL-10 is not essential for maternal immune tolerance or a successful pregnancy. In order to uncover the role of IL-10, Murphy et al. [61] showed that IL-10 plays an important protective role during pregnancy following a stress challenge such as the injection of low doses of LPS. In the absence of IL-10, fetal resorptions were observed in association with cytotoxic uNK cell activation and TNFα production. "
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    ABSTRACT: Despite much interest in the mechanisms regulating fetal-maternal interactions, information on leukocyte populations and major cytokines present in uterus and placenta remains fragmentary. This report presents a detailed and quantitative study of leukocyte populations at the mouse fetal-maternal interface, including a comparison between pregnancies from syngeneic and allogeneic crosses. Our results provide evidence for drastic differences not only in the composition of leukocyte populations in the uterus during pregnancy, but also between uterine and placental tissues. Interestingly, we have observed a significant decrease in the number of myeloid Gr1+ cells including monocytes, and myeloid CD11c+ cells including DCs in placenta from an allogeneic pregnancy. In addition, we have compared the expression levels of a panel of cytokines in non-pregnant (NP) or pregnant mouse uterus, in placenta, or in their isolated resident leukocytes. Qualitative and quantitative differences have emerged between NP, pregnant uterus and placenta. Unexpectedly, IL-9 was the major cytokine in NP uterus, and was maintained at high levels during pregnancy both in uterus and placenta. Moreover, we have found that pregnancy is associated with an increase in uterine IL-1a and a significant decrease in uterine G-CSF and GM-CSF. Comparing allogeneic versus syngeneic pregnancy, less allogeneic placental pro-inflammatory cytokines CCL2 (MCP-1), CXCL10 (IP-10) and more IL1-α in whole uterus was reproducibly observed. To our knowledge, this is the first report showing a detailed overview of the leukocyte and cytokine repertoire in the uterus of virgin females and at the fetal-maternal interface, including a comparison between syngeneic and allogeneic pregnancy. This is also the first evidence for the presence of IL-9 in NP uterus and at the maternal-fetal interface, suggesting a major role in the regulation of local inflammatory or immune responses potentially detrimental to the conceptus.
    PLoS ONE 09/2014; 9(9):e107267. DOI:10.1371/journal.pone.0107267 · 3.23 Impact Factor
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    • "Pregnancies in LPS-treated IL-10 deficient mice could be rescued through depleting uNK cells, IL-10 administration, or TNF-alpha reversal. These results suggested an immune mechanism of fetal destruction by which uNK cells mediate inflammation in the absence of IL-10 whereas a regulatory cross-talk between IL-10 and uNK cells contributes toward a positive pregnancy outcome (122). "
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    ABSTRACT: Reproductive immunology research has long focused on T cell responses to paternal antigens and tolerance mechanisms supporting fetal well-being. The participation of B cells herein was not widely studied. Because of the fascinating immunological uniqueness of pregnancy it is however to be expected that such pleiotropic cells play a considerable role. In fact, on the one hand B cells contribute towards pregnancy tolerance by secreting the immunomodulatory cytokine IL-10 but on the other hand can seriously harm pregnancy because of their capacity of producing autoantibodies. As for protective B cells, new evidences in mouse models arise suggesting that IL-10 producing B cells, the so called B10 cells, help in maintaining tolerance towards semiallogenic fetal antigens. They may be also important to fight danger signals at the fetal- maternal as e.g. in the case of infections with the aim to restore the disrupted fetal tolerance. In human pregnancies, IL-10 producing B cells increase with pregnancy onset but not in the case of spontaneous abortions. In vitro, they are able to suppress TNF-α production by T cells from pregnant individuals. Their generation and functionality will be discussed throughout this review article. B cells can be deleterious to pregnancy as well. Aberrant B cell compartment is associated with obstetric pathologies. In particular the capacity of B2 cells to produce specific autoantibodies or of B1aB cells to secrete natural autoantibodies that can turn autoreactive will be discussed herein.
    Frontiers in Immunology 06/2014; 5:285. DOI:10.3389/fimmu.2014.00285
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