Journal
BLOOD
Volume 137, Issue 7, Pages 977-982Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood.2020005225
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Funding
- Deutsche Forschungsgemeinschaft [KO-5736/1-1, 361210922/GRK2408, IS-67/4-3, IS-67/16-1]
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The study revealed a unidirectional interaction between placental inflammasome activation and reduced placental TM expression, and demonstrated that soluble TM treatment or placental TM restoration can alleviate PE-like symptoms.
Excess platelet activation by extracellular vesicles (EVs) results in trophoblast inflammasome activation, interleukin 1 beta (IL-1 beta) 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-1 beta 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-1 beta 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.
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