A Role for Uric Acid and the Nalp3 Inflammasome in Antiphospholipid Antibody-Induced IL-1β Production by Human First Trimester Trophoblast
A Role for Uric Acid and the Nalp3 Inflammasome in Antiphospholipid Antibody-Induced IL-1β Production by Human First Trimester Trophoblast
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DOI：
10.1371/journal.pone.0065237
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发表时间：
2013-06-06
期刊：
影响因子：
3.7
通讯作者：
Abrahams, Vikki M.
中科院分区：
文献类型：
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作者：
Mulla, Melissa J.;Salmon, Jane E.;Abrahams, Vikki M.
患有抗磷脂综合征 (APS) 的女性面临反复流产和产科疾病的风险，例如先兆子痫和宫内生长受限 (IUGR)。抗磷脂抗体 (aPL) 通过结合滋养层上表达的 β(2)-糖蛋白 I (β(2)GPI) 直接靶向胎盘。我们最近在人类妊娠早期滋养层细胞中证明，抗 β(2)GPI 抗体 (Abs) 以 Toll 样受体 4 (TLR4) 依赖性方式诱导 IL-1 β 的分泌。 IL-1 β 分泌需要 pro-IL-1 β 的加工，这是由炎症小体介导的，炎症小体是 Nalp3 的复合物，是含有 CARD (ASC) 和 caspase-1 的凋亡相关斑点样蛋白。本研究的目的是确定 aPL 是否通过炎症小体诱导滋养层中 IL-1 β 的产生。使用人类妊娠早期滋养层细胞系，我们证明了小鼠抗 β(2)GPI mAb 和人多克隆 aPL-IgG 诱导 IL-1 β 加工和分泌，而这种加工和分泌在 caspase-1 抑制后被部分阻断。 Nalp3 和 ASC 敲低也减弱了抗 β(2)GPI Ab 诱导的 IL-1 β 分泌。此外，aPL 以 TLR4 依赖性方式刺激尿酸的产生。抑制尿酸可阻止aPL诱导的滋养层产生IL-1β。这些发现表明，aPL 通过 TLR4 激活，诱导人滋养层中的尿酸反应，进而激活 Nalp3/ASC 炎性体，导致 IL-1 β 加工和分泌。这种新机制可能是母胎界面炎症的原因，炎症会导致胎盘功能障碍并增加 APS 患者不良妊娠结局的风险。
Women with antiphospholipid syndrome (APS) are at risk of recurrent pregnancy loss and obstetrical disorders, such as preeclampsia and intrauterine growth restriction (IUGR). Antiphospholipid antibodies (aPL) directly target the placenta by binding beta(2)-glycoprotein I (beta(2)GPI) expressed on the trophoblast. We recently demonstrated in human first trimester trophoblast cells that anti-beta(2)GPI antibodies (Abs) induce the secretion of IL-1 beta in a Toll-like receptor 4 (TLR4)-dependent manner. IL-1 beta secretion requires processing of pro-IL-1 beta and this is mediated by the inflammasome, a complex of Nalp3, apoptosis-associated speck-like protein containing a CARD (ASC) and caspase-1. The objective of this study was to determine if aPL induce IL-1 beta production in trophoblast via the inflammasome. Using a human first trimester trophoblast cell line, we demonstrated that a mouse anti-beta(2)GPI mAb and human polyclonal aPL-IgG induce IL-1 beta processing and secretion, which was partially blocked upon caspase-1 inhibition. Nalp3 and ASC knockdown also attenuated anti-beta(2)GPI Ab-induced IL-1 beta secretion. Furthermore, aPL stimulated the production of uric acid in a TLR4-dependent manner; and inhibition of uric acid prevented aPL-induced IL-1 beta production by the trophoblast. These findings demonstrate that aPL, via TLR4 activation, induce a uric acid response in human trophoblast, which in turn activates the Nalp3/ASC inflammasome leading to IL-1 beta processing and secretion. This novel mechanism may account for the inflammation at the maternal-fetal interface, which causes placental dysfunction and increases the risk of adverse pregnancy outcome in patients with APS.