title: Maternal extracellular vesicles and platelets promote preeclampsia via inflammasome activation in trophoblasts.
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 vesicle (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 EVs induce a thromboinflammatory response specifically in the placenta. Following EV injection, activated platelets accumulate particularly within the placental vascular bed. EVs cause adenosine triphosphate (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 soluble fms-like tyrosine kinase 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 EVs cause placental sterile inflammation and PE through activation of maternal platelets and purinergic inflammasome activation in trophoblast cells, uncovering a novel thromboinflammatory mechanism at the maternal-embryonic interface.
authors: Institute of Clinical Chemistry and Pathobiochemistry, Otto von Guericke University, Magdeburg, Germany.
authors: Shrey
authors: S
authors: Kohli
authors: Institute of Clinical Chemistry and Pathobiochemistry, Otto von Guericke University, Magdeburg, Germany.
authors: Satish
authors: S
authors: Ranjan
authors: Institute of Clinical Chemistry and Pathobiochemistry, Otto von Guericke University, Magdeburg, Germany.
authors: Juliane
authors: J
authors: Hoffmann
authors: Centre for Thrombosis and Hemostasis, University Medical Center Mainz, Mainz, Germany.
authors: Muhammed
authors: M
authors: Kashif
authors: Institute of Clinical Chemistry and Pathobiochemistry, Otto von Guericke University, Magdeburg, Germany; Institute of Neuropathology, Otto von Guericke University, Magdeburg, Germany.
authors: Evelyn A
authors: EA
authors: Daniel
authors: Institute of Clinical Chemistry and Pathobiochemistry, Otto von Guericke University, Magdeburg, Germany.
authors: Moh'd Mohanad
authors: MM
authors: Al-Dabet
authors: Institute of Clinical Chemistry and Pathobiochemistry, Otto von Guericke University, Magdeburg, Germany.
authors: Fabian
authors: F
authors: Bock
authors: Institute of Clinical Chemistry and Pathobiochemistry, Otto von Guericke University, Magdeburg, Germany.
authors: Sumra
authors: S
authors: Nazir
authors: Department of Gynaecology and Obstetrics, Laboratory for Molecular Medicine, University-Clinic Erlangen, Erlangen, Germany.
authors: Hanna
authors: H
authors: Huebner
authors: Department of Nephrology and Hypertension, Diabetes and Endocrinology.
authors: Peter R
authors: PR
authors: Mertens
authors: Institute of Biochemistry and Cell Biology and Department of Functional Genomics and Medical Toponomics, and.
authors: Klaus-Dieter
authors: KD
authors: Fischer
authors: Experimental Obstetrics and Gynecology, Medical Faculty, Otto von Guericke University, Magdeburg, Germany.
authors: Ana C
authors: AC
authors: Zenclussen
authors: Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
authors: Stefan
authors: S
authors: Offermanns
authors: Department of Hematology, Rambam Health Care Campus, Haifa, Israel; and.
authors: Anat
authors: A
authors: Aharon
authors: Department of Hematology, Rambam Health Care Campus, Haifa, Israel; and.
authors: Benjamin
authors: B
authors: Brenner
authors: Institute of Clinical Chemistry and Pathobiochemistry, Otto von Guericke University, Magdeburg, Germany; Department of Molecular Genetics, University of Health Sciences, Khayaban-e-Jamia Punjab, Lahore, Pakistan.
authors: Khurrum
authors: K
authors: Shahzad
authors: Department of Gynaecology and Obstetrics, Laboratory for Molecular Medicine, University-Clinic Erlangen, Erlangen, Germany.
authors: Matthias
authors: M
authors: Ruebner
authors: Institute of Clinical Chemistry and Pathobiochemistry, Otto von Guericke University, Magdeburg, Germany.
authors: Berend
authors: B
authors: Isermann
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000276:immunology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D000067128:Extracellular Vesicles / Q000276:immunology / Q000473:pathology*; D005260:Female; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D058847:Inflammasomes / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission; D015539:Platelet Activation / Q000502:physiology*; D011225:Pre-Eclampsia / Q000276:immunology / Q000473:pathology / Q000503:physiopathology*; D011247:Pregnancy; D014327:Trophoblasts / Q000276:immunology / Q000473:pathology*
chemical_list: D058847:Inflammasomes