Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut, USA.
J Cell Mol Med. 2022 May;26(9):2566-2578. doi: 10.1111/jcmm.17252. Epub 2022 Mar 23.
Preterm birth is a major contributor to neonatal mortality and morbidity. Infection results in elevation of inflammation-related cytokines followed by infiltration of immune cells into gestational tissue. CXCL12 levels are elevated in preterm birth indicating it may have a role in preterm labour (PTL); however, the pathophysiological correlations between CXCL12/CXCR4 signalling and premature labour are poorly understood. In this study, PTL was induced using lipopolysaccharide (LPS) in a murine model. LPS induced CXCL12 RNA and protein levels significantly and specifically in myometrium compared with controls (3-fold and 3.5-fold respectively). Highest levels were found just before the start of labour. LPS also enhanced the infiltration of neutrophils, macrophages and T cells, and induced macrophage M1 polarization. In vitro studies showed that condition medium from LPS-treated primary smooth muscle cells (SMC) induced macrophage migration, M1 polarization and upregulated inflammation-related cytokines such as interleukin (IL)-1, IL-6 and tumor necrosis factor alpha (TNF-α). AMD3100 treatment in pregnant mice led to a significant decrease in the rate of PTL (70%), prolonged pregnancy duration and suppressed macrophage infiltration into gestation tissue by 2.5-fold. Further, in-vitro treatment of SMC by AMD3100 suppressed the macrophage migration, decreased polarization and downregulated IL-1, IL-6 and TNF-α expression. LPS treatment in pregnant mice induced PTL by increasing myometrial CXCL12, which recruits immune cells that in turn produce inflammation-related cytokines. These effects stimulated by LPS were completely reversed by AMD3100 through blocking of CXCL12/CXCR4 signalling. Thus, the CXCL12/CXCR4 axis presents an excellent target for preventing infection and inflammation-related PTL.
早产是新生儿死亡和发病的主要原因。感染会导致炎症相关细胞因子的升高，随后免疫细胞浸润到妊娠组织中。在早产中，CXCL12 水平升高，表明其可能在早产（PTL）中发挥作用；然而，CXCL12/CXCR4 信号与早产之间的病理生理相关性还知之甚少。在这项研究中，通过脂多糖（LPS）在小鼠模型中诱导 PTL。与对照组相比，LPS 显著且特异性地诱导子宫肌层中 CXCL12 RNA 和蛋白水平升高（分别为 3 倍和 3.5 倍）。最高水平出现在分娩开始前。LPS 还增强了中性粒细胞、巨噬细胞和 T 细胞的浸润，并诱导了巨噬细胞 M1 极化。体外研究表明，LPS 处理的原代平滑肌细胞（SMC）的条件培养基诱导巨噬细胞迁移、M1 极化，并上调炎症相关细胞因子，如白细胞介素（IL）-1、IL-6 和肿瘤坏死因子-α（TNF-α）。AMD3100 治疗妊娠小鼠可显著降低 PTL 发生率（70%），延长妊娠时间，并使巨噬细胞浸润妊娠组织减少 2.5 倍。此外，AMD3100 体外处理 SMC 可抑制巨噬细胞迁移，减少极化，并下调 IL-1、IL-6 和 TNF-α 的表达。LPS 处理妊娠小鼠通过增加子宫肌层中的 CXCL12 诱导 PTL，招募免疫细胞，进而产生炎症相关细胞因子。LPS 刺激的这些作用通过阻断 CXCL12/CXCR4 信号完全被 AMD3100 逆转。因此，CXCL12/CXCR4 轴是预防感染和炎症相关 PTL 的一个极好靶点。
