Sterile intra-amniotic inflammation is a clinical condition frequently observed in women with preterm labor and birth, the leading cause of neonatal morbidity and mortality worldwide. Growing evidence suggests that alarmins found in amniotic fluid, such as interleukin (IL)-1α, are central initiators of sterile intra-amniotic inflammation. However, no causal link between elevated intra-amniotic concentrations of IL-1α and preterm birth exists. Herein, using an animal model of ultrasound-guided intra-amniotic injection of IL-1α, we show that elevated concentrations of IL-1α cause preterm birth and neonatal mortality. Additionally, using immunoblotting techniques and a specific immunoassay, we report that the intra-amniotic administration of IL-1α induces activation of the NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome in the fetal membranes, but not in the decidua, as evidenced by a concomitant increase in the protein levels of NLRP3, active caspase-1, and IL-1β. Lastly, using Nlrp3^-/- mice, we demonstrate that the deficiency of this inflammasome sensor molecule reduces the rates of preterm birth and neonatal mortality caused by the intra-amniotic injection of IL-1α. Collectively, these results demonstrate a causal link between elevated IL-1α concentrations in the amniotic cavity and preterm birth as well as adverse neonatal outcomes, a pathological process that is mediated by the NLRP3 inflammasome. These findings shed light on the mechanisms underlying sterile intra-amniotic inflammation and provide further evidence that this clinical condition can potentially be treated by targeting the NLRP3 inflammasome.

中文翻译：

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警报蛋白白细胞介素 1α 通过 NLRP3 炎症小体导致早产。

无菌性羊膜腔内炎症是一种常见于早产和早产妇女的临床状况，是全球新生儿发病率和死亡率的主要原因。越来越多的证据表明，羊水中发现的警报素，如白细胞介素 (IL)-1α，是无菌羊膜腔内炎症的中心引发剂。然而，羊膜内 IL-1α 浓度升高与早产之间不存在因果关系。在此，我们使用超声引导下羊膜内注射 IL-1α 的动物模型，表明 IL-1α 浓度升高会导致早产和新生儿死亡。此外，使用免疫印迹技术和特定的免疫测定，我们报告了 IL-1α 的羊膜内给药诱导 NOD 样受体家族的激活，含有 3 的 pyrin 结构域（NLRP3）炎性体在胎膜中，但不在蜕膜中，这可以通过 NLRP3、活性 caspase-1 和 IL-1β 的蛋白质水平的同时增加来证明。最后，使用Nlrp3 ^-/-小鼠，我们证明这种炎性体传感器分子的缺乏降低了羊膜内注射 IL-1α 引起的早产率和新生儿死亡率。总的来说，这些结果表明羊膜腔中 IL-1α 浓度升高与早产以及不良新生儿结局（一种由 NLRP3 炎性体介导的病理过程）之间存在因果关系。这些发现阐明了无菌羊膜内炎症的潜在机制，并提供了进一步的证据，表明这种临床状况可以通过靶向 NLRP3 炎性体来治疗。