ESA-SRB-AOTA 2019

Antiphospholipid antibodies induce endoplasmic reticulum stress in the syncytiotrophoblast and cause the extrusion of dangerous extracellular vesicles (#218)

Larry Chamley 1 , Qi Chen 1 , Tony Hickey 2 , Katie Groom 3 4
  1. Department of Obstetrics and Gynaecology, University of Auckland, Auckland, , New Zealand
  2. School of Biological Sciences, University of Auckland, Auckland, New Zealand
  3. Maternal-Fetal Medicine, National Women's Health, Auckland District Health Board, Auckland, New Zealand
  4. Liggins Institute, University of Auckland, Auckland, New Zealand

The human placenta is covered by the multinucleated syncytiotrophoblast, which extrudes large quantities of extracellular vesicles (EVs) into the maternal circulation. Antiphospholipid autoantibodies increase a woman’s risk of preeclampsia ten-fold. These antibodies are internalised by the syncytiotrophoblast where they bind intracellular vesicular structures1. Subsequently, EVs extruded from this cell are altered such that, they cause maternal endothelial cell activation. The mechanism driving this change in syncytiotrophoblast-derived EVs is unknown. We investigated whether endoplasmic reticulum stress was involved in the changes in EVs induced by antiphospholipid antibodies.

Normal first trimester placental explants were treated with two antiphospholipid antibodies, ID2 or IIC5 (25 ug/ml) overnight. Micro- and nano-EVs were harvested by differentiation ultracentrifugation. Misfolded proteins were quantified following staining with ThT. Specific proteins were quantified by western blot or ELISA. All experiments were repeated a minimum of three times.

Treating placental explants with antiphospholipid antibodies increased the amount of misfolded proteins in the syncytiotrophoblast and in both the micro-EVs (p=0.028) and nano-EVs (p=0.026) extruded from the explants. Levels of HSP70, a marker of endoplasmic reticulum stress, as well as secretion of TNFa, were also increased. The syncytiotrophoblast of a placenta from a pregnancy complicated by antiphospholipid antibodies also demonstrated increased misfolded proteins.

Excess misfolded proteins may cause cell death. To avoid death, cells can export the misfolded proteins. Micro- and nano-EVs are usually considered to have different biogenesis pathways and consequently to carry different cargos. However, to avoid accumulation of misfolded proteins induced by antiphospholipid antibodies, the syncytiotrophoblast exported these misfolded proteins in both micro- and nano-EVs. This may preserve the syncytiotrophoblast but it is possible the misfolded proteins then inflict damage on the maternal cells that clear the EVs. This is a potential mechanism by which antiphospholipid antibodies contribute to the dysfunction of maternal endothelial cells in preeclampsia.

  1. 1. Pantham, P. et al. Antiphospholipid antibodies bind syncytiotrophoblast mitochondria and alter the proteome of extruded syncytial nuclear aggregates. Placenta 36, 1463-1473 (2015).