Placental thromboinflammation impairs embryonic survival by reducing placental thrombomodulin expression
| Autor: | Matthias Ruebner, Rajiv Rana, Berend Isermann, Dheerendra Gupta, Kunal Kumar Singh, Ahmed Elwakiel, Paulina Markmeyer, Franziska Lochmann, Shrey Kohli, Hanna Huebner, Anubhuti Gupta |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Inflammasomes Placenta Thrombomodulin medicine.medical_treatment Interleukin-1beta Immunology Down-Regulation 030204 cardiovascular system & hematology Biochemistry Extracellular Vesicles 03 medical and health sciences 0302 clinical medicine Pre-Eclampsia Pregnancy NLR Family Pyrin Domain-Containing 3 Protein medicine Animals Humans Platelet activation Fetal Death reproductive and urinary physiology Platelet-Rich Plasma Chemistry Pregnancy Outcome Interleukin Trophoblast Inflammasome Cell Biology Hematology Platelet Activation Embryonic stem cell Recombinant Proteins Trophoblasts Cell biology Mice Inbred C57BL Interleukin 1 Receptor Antagonist Protein 030104 developmental biology medicine.anatomical_structure Cytokine embryonic structures Female Genes Lethal Receptors Thrombin BLOOD Commentary Cell Division medicine.drug |
| Zdroj: | Blood |
| ISSN: | 1528-0020 0006-4971 |
| Popis: | Excess platelet activation by extracellular vesicles (EVs) results in trophoblast inflammasome activation, interleukin 1β (IL-1β) activation, preeclampsia (PE), and partial embryonic lethality. Embryonic thrombomodulin (TM) deficiency, which causes embryonic lethality hallmarked by impaired trophoblast proliferation, has been linked with maternal platelet activation. We hypothesized that placental TM loss, platelet activation, and embryonic lethality are mechanistically linked to trophoblast inflammasome activation. Here, we uncover unidirectional interaction of placental inflammasome activation and reduced placental TM expression: although inflammasome inhibition did not rescue TM-null embryos from lethality, the inflammasome-dependent cytokine IL-1β reduced trophoblast TM expression and impaired pregnancy outcome. EVs, known to induce placental inflammasome activation, reduced trophoblast TM expression and proliferation. Trophoblast TM expression correlated negatively with IL-1β expression and positively with platelet numbers and trophoblast proliferation in human PE placentae, implying translational relevance. Soluble TM treatment or placental TM restoration ameliorated the EV-induced PE-like phenotype in mice, preventing placental thromboinflammation and embryonic death. The lethality of TM-null embryos is not a consequence of placental NLRP3 inflammasome activation. Conversely, EV-induced placental inflammasome activation reduces placental TM expression, promoting placental and embryonic demise. These data identify a new function of placental TM in PE and suggest that soluble TM limits thromboinflammatory pregnancy complications. |
| Databáze: | OpenAIRE |
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