Division of Reproductive Sciences, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45299, USA; College of Medicine, University of Cincinnati, Cincinnati, OH 45221, USA.
Division of Diabetes, Endocrinology, and Metabolism, Department of Internal Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Cell Rep. 2019 May 7;27(6):1755-1768.e4. doi: 10.1016/j.celrep.2019.04.049.
Preterm birth (PTB) is a syndrome with many origins. Among them, infection or inflammation are major risk factors for PTB; however, local defense mechanisms to mount anti-inflammatory responses against inflammation-induced PTB are poorly understood. Here, we show that endothelial TLR4 in the decidual bed is critical for sensing inflammation during pregnancy because mice with endothelial Tlr4 deletion are resistant to lipopolysaccharide (LPS)-induced PTB. Under inflammatory conditions, IL-6 is readily expressed in decidual endothelial cells with signal transducer and activator of transcription 3 (Stat3) phosphorylation in perivascular stromal cells, which then regulates expression of anti-inflammatory IL-10. Our observation that administration of an IL-10 neutralizing antibody predisposing mice to PTB shows IL-10's anti-inflammatory role to prevent PTB. We show that the integration of endothelial and perivascular stromal signaling can determine pregnancy outcomes. These findings highlight a role for endothelial TLR4 in inflammation-induced PTB and may offer a potential therapeutic target to prevent PTB.
早产（PTB）是一种多病因综合征。其中，感染或炎症是 PTB 的主要危险因素；然而，针对炎症诱导的 PTB 产生抗炎反应的局部防御机制仍知之甚少。在这里，我们表明，胎盘床中的内皮 TLR4 对于在怀孕期间感知炎症至关重要，因为内皮 Tlr4 缺失的小鼠对脂多糖（LPS）诱导的 PTB 具有抗性。在炎症条件下，白细胞介素 6（IL-6）在胎盘血管周围基质细胞中很容易表达信号转导和转录激活因子 3（Stat3）磷酸化，然后调节抗炎白细胞介素 10（IL-10）的表达。我们观察到，给予抗白细胞介素 10 中和抗体会使小鼠易患 PTB，这表明白细胞介素 10 发挥抗炎作用以预防 PTB。我们表明，内皮细胞和胎盘血管周围基质细胞信号的整合可以决定妊娠结局。这些发现强调了内皮 TLR4 在炎症诱导的 PTB 中的作用，并可能为预防 PTB 提供一个潜在的治疗靶点。
