Work

Studying the role of natural killer cells mediating placental developmental defects in a humanized-TLR8 mouse model of spontaneous anti-phospholipid antibody induced pregnancy loss 4605

Year: 2025

Type: article

Abstract: Description TLR8 is implicated in anti-phospholipid antibody (aPL) mediated trophoblast injury, but its role in adverse pregnancy outcome is poorly understood due to lack of relevant mouse models; a 5aa deletion in TLR8 precludes ssRNA binding in mice. We generated a spontaneous model of aPL-induced pregnancy loss by crossing aPL+ Sle1 mice with human TLR8 transgenic mice (Sle1.huTLR8tg). Implantation was unaffected, but Sle1.huTLR8tg mice exhibited decreased feto-placental weight by day E8.5, followed by fetal resorptions, retarded growth and dystocia. Bulk RNASeq of Sle1.huTLR8tg E8.5 placentas showed suppressed natural killer cell (NK) genes; NK loss was confirmed by flow cytometry at E9.5 and E13.5. Uterine NK cells regulate spiral artery remodeling and comprise tissue-resident and circulating subsets. Both subsets were depleted suggesting lack of a crucial growth factor(s) to support NK expansion; a candidate is IL15 that was downregulated at Day E8.5. Myeloid cell genes were upregulated at E8.5, with increased CD11b+ cells by flow cytometry in E9.5 Sle1.huTLR8tg placentas. Sle1.huTLR8tg+ resident macrophages were preferentially recruited to placentas of bone marrow chimeras. Impaired placental vascularization and junctional zone formation at day E13.5 progressed to infarctions in mature placentas. These studies suggest a mechanism by which early aPL/TLR8-driven immune dysregulation compromises placental development, leading to hypoxic and inflammatory placental and fetal injury. Funding Sources Supported by NIAID, Lupus Research Alliance, 5T32AI155392-04 Topic Categories Basic Autoimmunity (BA)

Source: The Journal of Immunology

DOI: 10.1093/jimmun/vkaf283.2265

Authors: Yunwei Xia, Naomi I. Maria, Zhengzi Yi, Chirag Raparia, Weijia Zhang, Anne Davidson