Abstract
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.
Highlights
During pregnancy, at the maternal-fetal interface, physiological inflammation is beneficial for the implantation and the preliminary stages of placentation
The time course of TANK-binding kinase 1 (TBK1) phosphorylation was further investigated by treating the cells with LPS (1 mg/mL), and the results showed that short- and long-term exposure to LPS significantly increased phosphorylated TBK1 levels in HTR-8/SVneo cells in a timedependent manner (Figures 1G–J)
We observed the phosphorylation of TBK1 during LPS-induced placental inflammation, as evident in mouse placental tissue and human trophoblasts
Summary
At the maternal-fetal interface, physiological inflammation is beneficial for the implantation and the preliminary stages of placentation. The NLR family pyrin domain-containing 3 (NLRP3) inflammasome is a large cytosolic multiprotein complex composed of an NLRP3 scaffold, an apoptosis-associated specklike protein (ASC) adaptor, and caspase-1 as an IL-1b-converting enzyme [10] They are activated by a wide range of pathogenassociated molecular patterns, such as a TLR4 ligand, lipopolysaccharide (LPS), or damage-associated molecular patterns such as ATP, and play a role in inflammation [11]. NLRP3 inflammasomes mediate the activation of caspase-1 and cleavage of inactive pro-IL-1b into its active form [12, 13] and are related to pregnancy dysfunction, including preterm birth, fetal growth restriction, and preeclampsia [14,15,16]. Aberrant IL-1b production in the placenta and human trophoblasts has been associated with NLRP3 inflammasome activation, contributing to placental inflammation [17]
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