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

被引:132
作者
Thaxton, Jessica E. [1 ]
Romero, Roberto [2 ]
Sharma, Surendra [1 ]
机构
[1] Brown Univ, Women & Infants Hosp, Dept Pediat, Warren Alpert Med Sch, Providence, RI 02905 USA
[2] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Natl Inst Hlth, Dept Hlth & Human Serv, Detroit, MI 48201 USA
基金
美国国家卫生研究院;
关键词
TOLL-LIKE RECEPTORS; UTERINE NK CELLS; CPG-OLIGODEOXYNUCLEOTIDES; BACTERIAL-DNA; GENE POLYMORPHISMS; PRETERM BIRTH; EXPRESSION; INTERLEUKIN-10; MACROPHAGES; MOTIFS;
D O I
10.4049/jimmunol.0900788
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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 (similar to 25 mu g/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 (similar to 400 mu g/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-a rescued pregnancy to term. Our results have important implications for IL-10-mediated "uterine tolerance" against CpG-driven innate immune activation. The Journal of Immunology, 2009, 183: 1144-1154.
引用
收藏
页码:1144 / 1154
页数:11
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