Department of Cell Biology, Konyang University College of Medicine, Daejeon, South Korea.
Myunggok Medical Research Institute, Konyang University College of Medicine, Daejeon, South Korea.
Front Immunol. 2021 Nov 9;12:743700. doi: 10.3389/fimmu.2021.743700. eCollection 2021.
Pathological maternal inflammation and abnormal placentation contribute to several pregnancy-related disorders, including preterm birth, intrauterine growth restriction, and preeclampsia. TANK-binding kinase 1 (TBK1), a serine/threonine kinase, has been implicated in the regulation of various physiological processes, including innate immune response, autophagy, and cell growth. However, the relevance of TBK1 in the placental pro-inflammatory environment has not been investigated. In this study, we assessed the effect of TBK1 inhibition on lipopolysaccharide (LPS)-induced NLRP3 inflammasome activation and its underlying mechanisms in human trophoblast cell lines and mouse placenta. TBK1 phosphorylation was upregulated in the trophoblasts and placenta in response to LPS. Pharmacological and genetic inhibition of TBK1 in trophoblasts ameliorated LPS-induced NLRP3 inflammasome activation, placental inflammation, and subsequent interleukin (IL)-1 production. Moreover, maternal administration of amlexanox, a TBK1 inhibitor, reversed LPS-induced adverse pregnancy outcomes. Notably, TBK1 inhibition prevented LPS-induced NLRP3 inflammasome activation by targeting the mammalian target of rapamycin complex 1 (mTORC1). Thus, this study provides evidence for the biological significance of TBK1 in placental inflammation, suggesting that amlexanox may be a potential therapeutic candidate for treating inflammation-associated pregnancy-related complications.
病理性母体炎症和异常胎盘形成与几种妊娠相关疾病有关，包括早产、宫内生长受限和子痫前期。TANK 结合激酶 1（TBK1）是一种丝氨酸/苏氨酸激酶，它参与调节多种生理过程，包括先天免疫反应、自噬和细胞生长。然而，TBK1 在胎盘促炎环境中的相关性尚未得到研究。在这项研究中，我们评估了 TBK1 抑制对人滋养层细胞系和小鼠胎盘中脂多糖（LPS）诱导的 NLRP3 炎性体激活及其潜在机制的影响。TBK1 磷酸化在 LPS 刺激的滋养层细胞和胎盘中上调。在滋养层细胞中，用药理学和遗传学方法抑制 TBK1 可改善 LPS 诱导的 NLRP3 炎性体激活、胎盘炎症和随后的白细胞介素（IL）-1 产生。此外，TBK1 抑制剂 amlexanox 对母体的给药可逆转 LPS 诱导的不良妊娠结局。值得注意的是，TBK1 抑制通过靶向哺乳动物雷帕霉素复合物 1（mTORC1）来阻止 LPS 诱导的 NLRP3 炎性体激活。因此，这项研究为 TBK1 在胎盘炎症中的生物学意义提供了证据，表明 amlexanox 可能是治疗与炎症相关的妊娠相关并发症的潜在治疗候选药物。
