TLR9 activation coupled to IL-10 deficiency induces adverse pregnancy outcomes.
TLR9 activation coupled to IL-10 deficiency induces adverse pregnancy outcomes.
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DOI：
10.4049/jimmunol.0900788
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发表时间：
2009-07-15
期刊：
影响因子：
--
通讯作者：
Sharma S
中科院分区：
文献类型：
--
作者：
Thaxton JE;Romero R;Sharma S
宫内感染和炎症严重影响妊娠结局。尽管怀孕子宫微环境充满了先天免疫细胞和Toll样受体（TLR）表达，但促进其激活产生不良影响的机制在很大程度上尚不清楚。在这里，我们模拟TLR-9与其致病配体低甲基化CpG的激活，并证明IL-10的熟练程度防止CpG诱导的妊娠并发症。我们发现，当分别在妊娠第6天或第14天腹腔注射低剂量CpG（约25 μg/只小鼠）时，IL-10−/−小鼠中的胎儿吸收和早产迅速诱导。相比之下，野生型（WT）小鼠在相当剂量下未出现此类效应，但足月出生的幼仔在接受较高剂量（约400 µg/小鼠）后出现颅面/肢体缺陷。IL-10−/−小鼠的妊娠并发症与TLR-9触发的子宫中性粒细胞和巨噬细胞亚群的意外和强烈激活和扩增相关，随后它们迁移到胎盘区。此外，观察到小鼠KC（mKC）的血清水平和子宫F4/80+细胞产生的TNF-α显著增加，但子宫NK或GR 1 +/CD 11b+细胞未增加。耗尽F4/80+巨噬细胞或中和TNF-α可挽救妊娠至足月。我们的研究结果对IL-10介导的“子宫耐受”对CpG驱动的先天免疫激活具有重要意义。
Pregnancy outcome is severely compromised by intrauterine infections and inflammation. Although the pregnant uterine microenvironment is replete with innate immune cells and Toll-like receptor (TLR) expression, the mechanisms that facilitate adverse effects of their activation are largely unknown. Here we mimic the activation of TLR-9 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 (~25 µg/mouse) when injected i.p. on gestational day (gd)6 or gd14, respectively. In contrast, wild type (WT) mice failed to experience such effects at comparable doses, but pups born at term displayed craniofacial/limb defects in response to higher doses (~400 µg/mouse). Pregnancy complications in IL-10−/− mice were associated with unexpected and robust TLR-9-triggered activation and amplification of uterine neutrophil and macrophage subpopulations followed by their migration to the placental zone. Further, a dramatic increase in serum levels of mouse KC (mKC) and TNF-α production by uterine F4/80+ cells, but not uterine NK or GR1+/CD11b+ cells, was observed. Depletion of F4/80+ macrophages or neutralization of TNF-α 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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期刊：
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影响因子：
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作者：
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