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Maternal extracellular vesicles and platelets promote preeclampsia through inflammasome activation in embryonic trophoblast

Shrey Kohli, Satish Ranjan, Juliane Hoffmann, Muhammed Kashif, Evelyn A. Daniel, Moh'd Mohanad Al-Dabet, Fabian Bock, Sumra Nazir, Hanna Huebner, Peter R. Mertens, Klaus-Dieter Fischer, Ana C. Zenclussen, Stefan Offermanns, Anat Aharon, Benjamin Brenner, Khurrum Shahzad, Matthias Ruebner and Berend Isermann

Key points

  • EV cause accumulation of activated maternal platelets within the placenta, resulting in a thrombo-inflammatory response and PE.

  • Activated maternal platelets cause NLRP3-inflammasome activation in trophoblast cells via ATP release and purinergic signaling.

Abstract

Preeclampsia (PE) is a placenta-induced inflammatory disease associated with maternal and fetal morbidity and mortality. The mechanisms underlying PE remain enigmatic and delivery of the placenta is the only known remedy. PE is associated with coagulation and platelet-activation and increased extracellular vesicles (EV) formation. However, thrombotic occlusion of the placental vascular bed is rarely observed and the mechanistic relevance of EV and platelet-activation remains unknown. Here we show that EV induce a thrombo-inflammatory response specifically in the placenta. Following EV-injection activated platelets accumulate particularly within the placental vascular bed. EV cause ATP release from platelets and inflammasome activation within trophoblast cells through purinergic signaling. Inflammasome activation in trophoblast cells triggers a PE-like phenotype, characterized by pregnancy failure, elevated blood pressure, increased plasma sFlt-1, and renal dysfunction. Intriguingly, genetic inhibition of inflammasome activation specifically in the placenta, pharmacological inhibition of inflammasome or purinergic signaling, or genetic inhibition of maternal platelet-activation abolishes the PE-like phenotype. Inflammasome activation in trophoblast cells of women with preeclampsia corroborates the translational relevance of these findings. These results strongly suggest that EV cause placental sterile inflammation and PE through activation of maternal platelets and purinergic inflammasome activation in trophoblast cells, uncovering a novel thrombo-inflammatory mechanism at the maternal-embryonic interface.

  • Submitted March 14, 2016.
  • Accepted August 23, 2016.