Linking TLR-7 Signaling to Downregulation of Placental P-Glycoprotein: Implications for Fetal Drug Exposure
<b>Background/Objectives:</b> 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...
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2025-06-01
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| author | Mario Riera-Romo Eliza R McColl Micheline Piquette-Miller |
| author_facet | Mario Riera-Romo Eliza R McColl Micheline Piquette-Miller |
| author_sort | Mario Riera-Romo |
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| description | <b>Background/Objectives:</b> 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. <b>Methods:</b> 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. <b>Results:</b> IMQ administration resulted in <i>Irf7</i> 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. <b>Conclusions:</b> 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. |
| format | Article |
| id | doaj-art-46df6d52b4a84722b0d8c3929f01cd9f |
| institution | Kabale University |
| issn | 1999-4923 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | MDPI AG |
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| series | Pharmaceutics |
| spelling | doaj-art-46df6d52b4a84722b0d8c3929f01cd9f2025-08-20T03:27:22ZengMDPI AGPharmaceutics1999-49232025-06-0117674110.3390/pharmaceutics17060741Linking TLR-7 Signaling to Downregulation of Placental P-Glycoprotein: Implications for Fetal Drug ExposureMario Riera-Romo0Eliza R McColl1Micheline Piquette-Miller2Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON M5S 3M2, CanadaSection of Infectious Diseases, Baylor College of Medicine, Houston, TX 77030, USALeslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON M5S 3M2, Canada<b>Background/Objectives:</b> 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. <b>Methods:</b> 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. <b>Results:</b> IMQ administration resulted in <i>Irf7</i> 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. <b>Conclusions:</b> 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.https://www.mdpi.com/1999-4923/17/6/741viral infectionsautoimmune diseasesTLR-7inflammationtransportersP-glycoprotein |
| spellingShingle | Mario Riera-Romo Eliza R McColl Micheline Piquette-Miller Linking TLR-7 Signaling to Downregulation of Placental P-Glycoprotein: Implications for Fetal Drug Exposure Pharmaceutics viral infections autoimmune diseases TLR-7 inflammation transporters P-glycoprotein |
| title | Linking TLR-7 Signaling to Downregulation of Placental P-Glycoprotein: Implications for Fetal Drug Exposure |
| title_full | Linking TLR-7 Signaling to Downregulation of Placental P-Glycoprotein: Implications for Fetal Drug Exposure |
| title_fullStr | Linking TLR-7 Signaling to Downregulation of Placental P-Glycoprotein: Implications for Fetal Drug Exposure |
| title_full_unstemmed | Linking TLR-7 Signaling to Downregulation of Placental P-Glycoprotein: Implications for Fetal Drug Exposure |
| title_short | Linking TLR-7 Signaling to Downregulation of Placental P-Glycoprotein: Implications for Fetal Drug Exposure |
| title_sort | linking tlr 7 signaling to downregulation of placental p glycoprotein implications for fetal drug exposure |
| topic | viral infections autoimmune diseases TLR-7 inflammation transporters P-glycoprotein |
| url | https://www.mdpi.com/1999-4923/17/6/741 |
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