Excess platelet-activation by extracellular vesicles (EVs) results in trophoblast inflammasome activation, IL-1β activation, preeclampsia (PE) and partial embryonic lethality. Furthermore, embryonic thrombomodulin (TM) deficiency, which causes embryonic lethality hallmarked by impaired trophoblast proliferation, has been linked with maternal platelet-activation. Hence, we hypothesized that placental TM loss, platelet-activation, and embryonic lethality are mechanistically linked to trophoblast inflammasome activation. Here, we uncover a unidirectional interaction of placental inflammasome activation and reduced placental TM-expression: while inflammasome inhibition did not rescue TM-null embryos from lethality, the inflammasome-dependent cytokine IL-1β reduced trophoblast TM expression and impaired pregnancy outcome. Likewise, 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 thrombo-inflammation and embryonic death. Collectively, 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, which promotes placental and embryonic demise. These data identify a new function of placental TM in PE and suggest that soluble TM limits thrombo-inflammatory pregnancy complications.
Maternal extracellular vesicles and platelets promote preeclampsia via inflammasome activation in trophoblasts