Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, CT, United States.
Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, CT, United States.
J Reprod Immunol. 2022 Feb;149:103457. doi: 10.1016/j.jri.2021.103457. Epub 2021 Dec 2.
Inflammatory interleukin-1β (IL-1β) is an important mediator of preterm birth. IL-1β secretion is mediated by the inflammasome that processes pro-IL-1β into its active form. However the mechanisms involved at the level of the fetal membrane (FM) are not fully understood. This study sought to determine the FM compartment involved in IL-1β production in response to bacterial components and to evaluate the mechanism of inflammasome activation. Since IL-18 is also mediated by the inflammasome and IL-8 is a chemoattractant that contributes to neutrophil recruitment in chorioamnionitis, we also evaluated the production of these factors. A human explant system was used to evaluate the response of the chorion, amnion, and intact FMs to the bacterial components lipopolysaccharide (LPS), peptidoglycan (PGN), or muramyl dipeptide (MDP). The chorion was the major source of IL-1β and IL-8 production in response to LPS, PGN, and MDP. LPS, PGN, and MDP induced FM IL-1β and IL-18 secretion in a non-pyroptotic manner through activation of the NLRP3 inflammasome with contributions from ATP release through Pannexin-1, and ROS signaling. Since LPS, PGN, and MDP are not known to activate NLRP3 directly, the role of uric acid as a potential mediator was assessed. FMs produced elevated uric acid in response to LPS, PGN and MDP. FM IL-1β secretion was inhibited by allopurinol, which blocks uric acid production, for LPS and PGN, and to a lesser degree, MDP. These findings shed light on the mechanisms by which fetal membrane inflammation and subsequent preterm birth may arise.
炎症性白细胞介素-1β（IL-1β）是早产的重要介质。IL-1β 的分泌是由将前体 IL-1β 加工成其活性形式的炎症小体介导的。然而，在胎膜（FM）水平涉及的机制尚不完全清楚。本研究旨在确定 FM 隔室中与细菌成分引起的 IL-1β 产生有关的部分，并评估炎症小体激活的机制。由于 IL-18 也由炎症小体介导，IL-8 是一种趋化因子，有助于绒毛膜羊膜炎中的中性粒细胞募集，因此我们还评估了这些因子的产生。使用人离体系统评估了绒毛膜、羊膜和完整 FM 对细菌成分脂多糖（LPS）、肽聚糖（PGN）或 muramyl dipeptide（MDP）的反应。LPS、PGN 和 MDP 诱导 FM 中 IL-1β 和 IL-8 的产生，这是通过 NLRP3 炎症小体的非细胞焦亡激活，通过 Pannexin-1 释放 ATP 和 ROS 信号的贡献。由于 LPS、PGN 和 MDP 不被认为直接激活 NLRP3，因此评估了尿酸作为潜在介质的作用。FM 对 LPS、PGN 和 MDP 产生的尿酸升高。尿酸酶抑制剂别嘌呤醇可抑制 LPS 和 PGN 诱导的 FM IL-1β 分泌，但对 MDP 的抑制作用较小。这些发现揭示了胎儿膜炎症和随后早产可能发生的机制。
