Division of Experimental Medicine, McGill University, Quebec, Canada.
Department of Obstetrics and Gyneocology, McGill University, Quebec, Canada.
Biol Reprod. 2020 May 26;102(6):1340-1350. doi: 10.1093/biolre/ioaa037.
Preterm birth remains the major cause of perinatal mortality and morbidity worldwide, affecting up to 12% of pregnancies and accounting for ~75% of neonatal deaths. However, the mechanisms and causes that underlie it are still largely unknown. One of the major causes of preterm birth is infection or inflammation within the maternal-fetal interface. Our lab has previously shown that a uterine specific deletion of Nodal results in mutant females delivering 2 days prior to term demonstrating an important role for this factor in the maintenance of pregnancy. Here, we have addressed the function of Nodal in the uterus during pregnancy. We demonstrate that Nodal heterozygous mice have an increase in basal levels of pro-inflammatory cytokines IL-1β, IL-6, IL-12p, TNF-α, and IFN-γ as well as an increase in the number of macrophages in response to the inflammatory agent, lipopolysaccharide (LPS). Using bone marrow-derived macrophages, we demonstrated that pretreatment with recombinant Nodal reduces pro-inflammatory gene expression when these cells are challenged with LPS. Our results demonstrate that Nodal is required to maintain the uterine environment in an anti-inflammatory state by preventing proinflammatory cytokine expression.
早产仍然是全球围产期死亡和发病的主要原因，影响多达 12%的妊娠，占新生儿死亡人数的~75%。然而，其背后的机制和原因在很大程度上仍不清楚。早产的一个主要原因是母体-胎儿界面的感染或炎症。我们的实验室之前已经表明，在子宫特异性敲除 Nodal 的情况下，突变型雌性会在足月前提前 2 天分娩，这表明该因子在维持妊娠中起着重要作用。在这里，我们研究了 Nodal 在怀孕期间子宫中的功能。我们证明，Nodal 杂合子小鼠在基础状态下促炎细胞因子 IL-1β、IL-6、IL-12p、TNF-α 和 IFN-γ 的水平升高，并且对炎症剂脂多糖（LPS）的反应中巨噬细胞数量增加。使用骨髓来源的巨噬细胞，我们证明当这些细胞受到 LPS 挑战时，预处理重组 Nodal 可降低促炎基因的表达。我们的结果表明，Nodal 通过防止促炎细胞因子的表达，需要维持子宫环境处于抗炎状态。
