Department of Cell Biology, Konyang University College of Medicine, Daejeon 35365, Korea.
Myunggok Medical Research Institute, Konyang University College of Medicine, Daejeon 35365, Korea.
Cells. 2020 Mar 16;9(3):728. doi: 10.3390/cells9030728.
Emerging evidence indicates that aberrant maternal inflammation is associated with several pregnancy-related disorders such as preeclampsia, preterm birth, and intrauterine growth restriction. Sirtuin1 (SIRT1), a class III histone deacetylase, is involved in the regulation of various physiopathological processes including cellular inflammation and metabolism. However, the effect of SIRT1 on the placental proinflammatory environment remains to be elucidated. In this study, we investigated the effect of SIRT1 on lipopolysaccharide (LPS)-induced NLRP3 inflammasome activation and its underlying mechanisms in human first-trimester trophoblasts (Sw.71 and HTR-8/SVneo cells). Treatment with LPS elevated SIRT1 expression and induced NLRP3 inflammasome activation in mouse placental tissues and human trophoblasts. Knockdown of SIRT1 enhanced LPS-induced NLRP3 inflammasome activation, inflammatory signaling, and subsequent interleukin (IL)-1β secretion. Furthermore, knockdown of NLRP3 considerably attenuated the increase of IL-1β secretion in SIRT1-knockdown cells treated with LPS. Moreover, SIRT1 inhibited LPS-induced NLRP3 inflammasome activation by reducing oxidative stress. This study revealed a novel mechanism via which SIRT1 exerts anti-inflammatory effects, suggesting that SIRT1 is a potential therapeutic target for the prevention of inflammation-associated pregnancy-related complications.
新出现的证据表明，母体炎症异常与子痫前期、早产和宫内生长受限等几种与妊娠相关的疾病有关。Sirtuin1（SIRT1）是一种 III 类组蛋白去乙酰化酶，参与包括细胞炎症和代谢在内的多种生理病理过程的调节。然而，SIRT1 对胎盘促炎环境的影响仍有待阐明。在这项研究中，我们研究了 SIRT1 对脂多糖（LPS）诱导的 NLRP3 炎性小体激活及其在人早孕滋养层（Sw.71 和 HTR-8/SVneo 细胞）中的潜在机制。LPS 处理可提高小鼠胎盘组织和人滋养层细胞中 SIRT1 的表达并诱导 NLRP3 炎性小体激活。SIRT1 的敲低增强了 LPS 诱导的 NLRP3 炎性小体激活、炎症信号和随后的白细胞介素（IL）-1β分泌。此外，在 LPS 处理的 SIRT1 敲低细胞中，敲低 NLRP3 可显著减弱 IL-1β 分泌的增加。此外，SIRT1 通过减少氧化应激来抑制 LPS 诱导的 NLRP3 炎性小体激活。这项研究揭示了 SIRT1 发挥抗炎作用的新机制，表明 SIRT1 是预防与炎症相关的妊娠相关并发症的潜在治疗靶点。
