Deciphering the Role and Mechanism of Decidual Monocyte-Derived Macrophage Infiltration in Obstetric Antiphospholipid Syndrome at Single-Cell Resolution.

Abstract

Obstetric antiphospholipid syndrome (OAPS) is an autoimmune disorder characterized by pathologic pregnancies and the presence of antiphospholipid antibodies (aPLs). Despite significant infiltration of decidual macrophages observed in OAPS patients, the underlying connections between decidual and peripheral immune cells remain unclear. In this study, an integrated single-cell atlas is constructed of the decidua and peripheral blood mononuclear cells (PBMCs) from OAPS patients and HCs. Using this atlas, substantial disparities are identified in immune cells between the decidua and PBMCs. The functional changes in immune cells of OAPS patients are also different in decidua and PBMCs. Moreover, increased infiltration of monocyte-derived macrophages (MDMs) into the decidua is found to contribute to inflammation and trophoblast dysfunction in OAPS. The role of CCL2 is further discovered in recruiting MDMs, driven by excess CCL2 secreted from decidual macrophages stimulated by the aPLs and β₂-glycoprotein I complex via the TLR4-NF-κB pathway. Decidual vascular endothelial cells express higher levels of ACKR1, which aggregates CCL2 on their surface. Targeting CCR2 and TLR4 improved pregnancy outcomes in OAPS mouse models induced by aPLs, suggesting that these pathways may serve as potential therapeutic targets for OAPS. This study provides new insights into the pathogenesis of OAPS, particularly regarding decidual MDMs infiltration.