Laboratory of Animal Reproduction, Department of Agriculture, Tokyo University of Agriculture, Kanagawa 243-0034, Japan.
Division of Inflammation Research, Center for Molecular Medicine, Jichi Medical University, Tochigi 329-0498, Japan.
J Reprod Dev. 2020 Jun 12;66(3):241-248. doi: 10.1262/jrd.2020-007. Epub 2020 Feb 27.
Maternal obesity is one of the major risk factors for pregnancy complications and is associated with low-grade chronic systemic inflammation due to higher levels of pro-inflammatory cytokines such as interleukin (IL)-1β. Pregnant women with obesity have abnormal lipid profiles, characterized by higher levels of free fatty acids, especially palmitic acid (PA). Previously, we reported that PA stimulated IL-1β secretion via activation of NLRP3 inflammasome in human placental cells. These observations led us to hypothesize that higher levels of PA induce NLRP3 inflammasome activation and placental inflammation, resulting in pregnancy complications. However, the effects of PA on NLRP3 inflammasome during pregnancy in vivo remain unclear. Therefore, PA solutions were administered intravenously into pregnant mice on day 12 of gestation. Maternal body weight was significantly decreased and absorption rates were significantly higher in PA-injected mice. The administration of PA significantly increased IL-1β protein and the mRNA expression of NLRP3 inflammasome components (NLRP3, ASC, and caspase-1) within the placenta. In murine placental cell culture, PA significantly stimulated IL-1β secretion, and this secretion was suppressed by a specific NLRP3 inhibitor (MCC950). Simultaneously, the number of macrophages/monocytes and neutrophils, together with the mRNA expression of these chemokines increased significantly in the placentas of PA-treated mice. Treatment with PA induced ASC assembling and IL-1β secretion in macrophages, and this PA-induced IL-1β secretion was significantly suppressed in NLRP3-knockdown macrophages. These results indicate that transient higher levels of PA exposure in pregnant mice activates NLRP3 inflammasome and induces placental inflammation, resulting in the incidence of absorption.
母体肥胖是妊娠并发症的主要危险因素之一，由于促炎细胞因子（如白细胞介素-1β）水平升高，与低度慢性系统性炎症相关。肥胖孕妇的脂质谱异常，其特征是游离脂肪酸水平升高，尤其是棕榈酸（PA）。此前，我们报道 PA 通过激活人胎盘细胞中的 NLRP3 炎性小体刺激 IL-1β 分泌。这些观察结果使我们假设更高水平的 PA 诱导 NLRP3 炎性小体激活和胎盘炎症，从而导致妊娠并发症。然而，PA 对体内妊娠期间 NLRP3 炎性小体的影响尚不清楚。因此，在妊娠第 12 天，我们将 PA 溶液静脉注射到妊娠小鼠体内。PA 注射组小鼠的母体体重显著减轻，吸收率显著升高。PA 的给药显著增加了胎盘内 IL-1β 蛋白和 NLRP3 炎性小体成分（NLRP3、ASC 和 caspase-1）的 mRNA 表达。在鼠胎盘细胞培养中，PA 显著刺激 IL-1β 的分泌，而这种分泌被特异性 NLRP3 抑制剂（MCC950）抑制。同时，PA 处理小鼠的胎盘内巨噬细胞/单核细胞数量和这些趋化因子的 mRNA 表达显著增加。PA 诱导巨噬细胞 ASC 组装和 IL-1β 分泌，NLRP3 敲低的巨噬细胞中这种 PA 诱导的 IL-1β 分泌显著受到抑制。这些结果表明，妊娠小鼠中短暂的高水平 PA 暴露激活 NLRP3 炎性小体并诱导胎盘炎症，导致吸收率增加。
