Human TLR8 Adversely Affects Placental Development and Induces Spontaneous Pregnancy Loss in a model of Systemic Lupus Erythematosus

Abstract

Abstract SLE is associated with adverse pregnancy outcomes, particularly in the presence of antiphospholipid antibodies (aPL). Pathogenic mechanisms damaging the fetal-maternal unit, however, remain poorly understood. A role for endosomal TLR8 was recently hypothesized in aPL induced placental damage. The role of TLR8 in systemic autoimmunity has remained elusive as TLR8 function differs from mouse to man. We investigated the effect of human (hu)TLR8 expression on pregnancy outcomes in Sle1 mice that develop aPL antibodies. huTLR8 transgenic(tg) Sle1 mice were generated and huTLR8 DNA copy number and mRNA expression was confirmed by qDigital- and qRT-PCR. Pregnancies were closely followed and terminal C-sections performed at signs of dystocia/prolonged labor. Pup and placental weight was assessed. Placental tissues were characterized by H&E and Myeloperoxidase (MPO) staining and inflammatory cytokine expression was assessed in placental tissue. Splenic and bone marrow immune populations were analyzed using flow cytometry. Female Sle1.huTLR8tg mice developed aPL and sm/RNP autoantibodies earlier than Sle1 controls and ±50% loss of litters was observed, compared to 0% in controls. IL-6, TNFa and MPO mRNA expression was significantly increased in placentas of affected litters and negatively correlated with placental weight. Abnormal placental morphology included placental infarcts, loss of placental lakes, arterial wall thickening and increased netting neutrophils. Here we identify a new model to study adverse pregnancy complications in SLE. In the presence of both Sle1 and huTLR8, we observed early onset of aPS autoantibodies and pregnancy loss attributed to placental developmental abnormalities, infarcts and inflammation.