TLR9 Activation Coupled to IL-10 Deficiency Induces Adverse Pregnancy Outcomes

Department of Pediatrics, Women and Infants Hospital of Rhode Island, Warren Alpert Medical School of Brown University, Providence, RI 02905 USA.
The Journal of Immunology (Impact Factor: 4.92). 07/2009; 183(2):1144-54. DOI: 10.4049/jimmunol.0900788
Source: PubMed


Pregnancy outcome is severely compromised by intrauterine infections and inflammation. Although the pregnant uterine microenvironment is replete with innate immune cells and TLR expression, the mechanisms that facilitate adverse effects of their activation are largely unknown. In this study, we mimic the activation of TLR9 with its pathogenic ligand hypomethylated CpG and demonstrate that IL-10 proficiency protects against CpG-induced pregnancy complications. We show that fetal resorption and preterm birth are rapidly induced in IL-10(-/-) mice by low doses of CpG (approximately 25 microg/mouse) when injected i.p. on gestational day 6 or gestational day 14, respectively. In contrast, wild-type mice failed to experience such effects at comparable doses, but pups born at term displayed craniofacial/limb defects in response to higher doses (approximately 400 microg/mouse). Pregnancy complications in IL-10(-/-) mice were associated with unexpected and robust TLR9-triggered activation and amplification of uterine neutrophil and macrophage subpopulations followed by their migration to the placental zone. Furthermore, a dramatic increase in serum levels of mouse KC and TNF-alpha production by uterine F4/80(+) cells, but not uterine NK or Gr-1(+)CD11b(+) cells, was observed. Depletion of F4/80(+) macrophages or neutralization of TNF-alpha rescued pregnancy to term. Our results have important implications for IL-10-mediated "uterine tolerance" against CpG-driven innate immune activation.

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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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    • "Our own in vitro studies have shown that LPS directly induces contractions of isolated human myometrial cells (Hutchinson et al., 2013). Influx of immune cells likely also contributes to the process, although further work is required to define their precise roles (Timmons and Mahendroo, 2006; Murphy et al., 2009; Thaxton et al., 2009; Gonzalez et al., 2011; Rinaldi et al., 2014). Given the link between inflammation and spontaneous labour onset, and the association between intrauterine infection and PTL, there has been a growing interest in examining whether anti-inflammatory agents could be effective novel therapeutic options for PTL (Rinaldi et al., 2011). "
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    ABSTRACT: Preterm birth remains the leading cause of neonatal mortality and morbidity worldwide. There are currently few effective therapies and therefore an urgent need for novel treatments. Although there is much focus on trying to alter gestation of delivery, the primary aim of preterm birth prevention therapies should be to reduce prematurity related mortality and morbidity. Given the link between intrauterine infection and inflammation and preterm labour (PTL), we hypothesised that administration of lipoxins, key anti-inflammatory and pro-resolution mediators, could be a useful novel treatment for PTL. Using a mouse model of infection-induced PTL we investigated whether 15-epi-lipoxin A4 could delay lipopolysaccharide (LPS)-induced PTL and reduce pup mortality. On D17 of gestation mice (n=9-12) were pre-treated with vehicle or 15-epi-lipoxin A4 prior to intrauterine administration of LPS or PBS. Although pre-treatment with 15-epi-lipoxin A4 did not delay LPS-induced PTL, there was a significant reduction in the mortality amongst prematurely delivered pups (defined as delivery within 36 hours of surgery) in mice treated with 15-epi-lipoxin A4 prior to LPS treatment, compared to those receiving LPS alone (p<0.05). Quantitative real time (QRT)-PCR analysis of utero-placental tissues harvested 6 hours post-treatment demonstrated that 15-epi-lipoxin A4 treatment increased Ptgs2 expression in the uterus, placenta and fetal membranes (p<0.05) and decreased 15-Hpgd expression (p<0.05) in the placenta and uterus, suggesting that 15-epi-lipoxin A4 may regulate the local production and activity of prostaglandins. These data suggest that augmenting lipoxin levels could be a useful novel therapeutic option in the treatment of PTL, protecting the fetus from the adverse effects of infection-induced preterm birth. © The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.
    Molecular Human Reproduction 01/2015; 21(4). DOI:10.1093/molehr/gau117 · 3.75 Impact Factor
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    • "IL-10 is not essential for the growth and development of the fetus in mice but rather it plays an important role to inhibit excessive inflammation. Pregnant IL-10−/− mice are susceptible to low doses of LPS and CpG (a TLR 9 agonist) compared to WT mice (44, 45). These results suggest that IL-10 acts as a protective agent during infection and deficiency of IL-10 exacerbates inflammation in mice. "
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    ABSTRACT: Inflammation mediated by both innate and adaptive immune cells is necessary for several important processes during pregnancy. Pro-inflammatory immune cell activation plays a critical role in embryo implantation, placentation, and parturition; however dysregulation of these cells can lead to detrimental pregnancy outcomes including spontaneous abortion, fetal growth restriction, maternal pathology including hypertensive disorders, or fetal and maternal death. The resolution of inflammation plays an important role throughout pregnancy and is largely mediated by immune cells that produce interleukin (IL)-4 and IL-10. The temporal and spatial aspects of reducing inflammation during pregnancy represent a complex process that if not functioning optimally can lead to persistent inflammation and pregnancy complications. In this review, we examine how immune cells that produce IL-4 and IL-10 are regulated throughout pregnancy as well as the effects that reduced IL-4 and IL-10 signaling has on fetal and maternal physiology.
    Frontiers in Immunology 05/2014; 5:253. DOI:10.3389/fimmu.2014.00253
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