Placental thromboinflammation impairs embryonic survival by reducing placental thrombomodulin expression

Area of Science:

• Reproductive immunology
• Maternal-fetal medicine
• Thrombosis and hemostasis

Background:

• Preeclampsia (PE) is associated with excess platelet activation and trophoblast inflammasome activation.
• Embryonic thrombomodulin (TM) deficiency leads to embryonic lethality and is linked to maternal platelet activation.
• The mechanistic link between placental TM loss, platelet activation, and embryonic lethality via trophoblast inflammasome activation is unclear.

Purpose of the Study:

• To investigate the mechanistic link between placental TM expression, platelet activation, trophoblast inflammasome activation, and embryonic lethality in preeclampsia.
• To determine the role of extracellular vesicles (EVs) in placental inflammasome activation and its effect on trophoblast TM expression and function.
• To explore the therapeutic potential of soluble TM in mitigating PE-related complications.

Main Methods:

• Utilized mouse models with embryonic TM deficiency and induced PE-like phenotypes.
• Investigated the effects of EVs on trophoblast inflammasome activation, TM expression, and proliferation in vitro.
• Analyzed human PE placentae for correlations between TM expression, IL-1β, platelet counts, and trophoblast proliferation.
• Administered soluble TM treatment or restored placental TM expression in mouse models.

Main Results:

• Placental inflammasome activation and reduced placental TM expression exhibit a unidirectional interaction where IL-1β reduces trophoblast TM expression.
• EVs induce placental inflammasome activation, decrease trophoblast TM expression and proliferation, and contribute to PE-like phenotypes.
• Trophoblast TM expression negatively correlated with IL-1β and positively with platelet numbers and proliferation in human PE placentae.
• Soluble TM treatment or placental TM restoration ameliorated EV-induced PE-like phenotypes, preventing placental thromboinflammation and embryonic death.

Conclusions:

• EV-induced placental inflammasome activation reduces placental TM expression, promoting embryonic demise, and is a key mechanism in PE pathogenesis.
• Placental TM plays a critical role in regulating placental thromboinflammation and pregnancy outcomes.
• Soluble TM represents a potential therapeutic strategy for thromboinflammatory pregnancy complications like PE.