Studying the role of humanized-TLR8 on immune cell dynamics in the placental microenvironment in a spontaneous mouse model of aPL-induced pregnancy loss

Antiphospholipid antibodies (aPL) confer a high risk for adverse pregnancy outcomes, especially in women with SLE. aPLs can induce pro-inflammatory signaling via TLR8 receptors, but mouse models to study the role of TLR8 are limited due to the attenuated ssRNA-binding capacity of mouse TLR8. We generated a spontaneous model of aPL-induced pregnancy loss by crossing Sle1 mice with mice expressing a human TLR8 transgene (Sle1.huTLR8tg). Sle1.huTLR8tg mice, but not Sle1 or C57BL6.huTLR8tg mice, have a high frequency of pregnancy loss, demonstrating the requirement for both autoantibodies and TLR8 in fetal-placental injury. Term placentas from Sle1.huTLR8tg mice displayed multiple abnormalities, including attenuation of vessels in the labyrinth, thinning of the junctional zone, thickened arterial walls, placental infarcts and inflammation. Resorptions were observed in Sle1.huTLR8tg mice at embryonic day (E)13.5, and Sle1.huTLR8tg feto-placental units were decreased in size as early as E8.5, suggesting early developmental defects. The goal of this study was to investigate transcriptional changes in early placental development that could be playing a role in the subsequent adverse pregnancy outcomes. Overall design: Bulk RNA-sequencing was conducted on feto-placental units from Sle1 and Sle1.huTLR8tg mice at Day E8.5 (day of peak decidualization and spiral artery remodeling) and on formed placentas from Day E13.5 (at which time the placenta has been fully formed). Sle1 feto-placental units and placentas acted as the control group for both timepoints, while feto-placental units and placentas from Sle1.huTLR8tg mice were further divided into 2 categories: resorbed and non-resorbed.