Riera-Romo Mario, McColl Eliza R, Piquette-Miller Micheline
Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON M5S 3M2, Canada.
Section of Infectious Diseases, Baylor College of Medicine, Houston, TX 77030, USA.
Pharmaceutics. 2025 Jun 5;17(6):741. doi: 10.3390/pharmaceutics17060741.
Activation of the Toll-like receptor 7 (TLR-7) plays an important role in the pathogenesis of many autoimmune diseases and viral infections. Although we have previously observed inflammation-mediated dysregulation of placental transporters, the role of TLR-7 has not been examined. Using the TLR-7 agonist, imiquimod (IMQ), we evaluated transporter expression in IMQ-treated pregnant rats and ex vivo in cultured rat placental explants. We administered 5 mg/kg (IP) of IMQ to pregnant Sprague Dawley rats on gestational day (GD) 14. The expression levels of inflammatory biomarkers and transporters were measured in maternal and fetal tissues by qRT-PCR and immunodetection methods, and effects on the placental proteome were assessed using LC/MS/MS. The involvement of TLR-7 was confirmed in rat placental explants. IMQ administration resulted in induction and increased levels of IL-6, Tnf-α, and type-I/II interferon pathways in maternal liver and placenta, which is consistent with TLR-7 activation. Proteomic profiling revealed IMQ-mediated activation of pathways involved in immune response, vesicle trafficking, and oxidative stress. Significantly decreased placental, hepatic, and renal protein expression of P-glycoprotein (PGP) was seen in the IMQ group. Likewise, TLR-7 activation using single-stranded RNA resulted in an induction of inflammatory biomarkers and downregulation of PGP in rat placental explants. We demonstrated that the activation of TLR-7 signaling during pregnancy reduces the expression of PGP in placenta and maternal tissues. Further studies are warranted, as decreased protein expression could result in decreased activity and altered fetal exposure to its substrates.
Toll样受体7（TLR-7）的激活在许多自身免疫性疾病和病毒感染的发病机制中起重要作用。虽然我们之前观察到炎症介导的胎盘转运蛋白失调，但尚未研究TLR-7的作用。我们使用TLR-7激动剂咪喹莫特（IMQ），评估了IMQ处理的妊娠大鼠以及离体培养的大鼠胎盘外植体中的转运蛋白表达。在妊娠第14天，对妊娠的Sprague Dawley大鼠腹腔注射5 mg/kg的IMQ。通过qRT-PCR和免疫检测方法测量母胎组织中炎症生物标志物和转运蛋白的表达水平，并使用LC/MS/MS评估对胎盘蛋白质组的影响。在大鼠胎盘外植体中证实了TLR-7的参与。给予IMQ导致母体肝脏和胎盘中IL-6、Tnf-α以及I/II型干扰素途径的诱导和水平升高，这与TLR-7激活一致。蛋白质组学分析揭示了IMQ介导的免疫反应、囊泡运输和氧化应激相关途径的激活。在IMQ组中，胎盘、肝脏和肾脏中P-糖蛋白（PGP）的蛋白表达显著降低。同样，使用单链RNA激活TLR-7导致大鼠胎盘外植体中炎症生物标志物的诱导和PGP的下调。我们证明，妊娠期间TLR-7信号的激活会降低胎盘和母体组织中PGP的表达。由于蛋白表达降低可能导致活性降低以及胎儿对其底物的暴露改变，因此有必要进行进一步研究。
