Antiphospholipid Antibodies Increase Endometrial Stromal Cell Decidualization, Senescence, and Inflammation via Toll‐like Receptor 4, Reactive Oxygen Species, and p38 MAPK Signaling

Abstract

Objective Miscarriage affects 1 in 7 pregnancies, and antiphospholipid autoantibodies (aPLs) are one of the biggest risk factors for recurrent pregnancy loss. While aPLs target the endometrial stroma, little is known about their impact. Endometrial stromal cells (EnSCs) undergo decidualization each menstrual cycle, priming the uterus to receive implanting embryos. Thus, appropriate decidualization and EnSC function is key for establishment of a successful pregnancy. This study was undertaken to explore the effects of aPL on EnSC decidualization, senescence, and inflammation. Methods EnSCs under decidualizing conditions were exposed to aPL or control IgG alone or in the presence of either a Toll‐like receptor 4 (TLR‐4) antagonist, a p38 MAPK inhibitor, a reactive oxygen species (ROS) inhibitor, low molecular weight heparin (LMWH), or acetyl salicylic acid. Secretion of decidualization markers and inflammatory interleukin‐8 were quantified by enzyme‐linked immunosorbent assay, and senescence‐associated β‐galactosidase activity was evaluated. In a mouse model of decidualization, aPL or control IgG was administered, and uterine expression levels of decidualization and inflammatory markers were quantified by real‐time quantitative polymerase chain reaction. Results Antiphospholipid antibodies increased human EnSC decidualization, senescence, and inflammation. This phenotype was recapitulated in the mouse model. The decidualization and inflammatory responses were partially mediated by TLR‐4 and p38 MAPK, while the decidualization and senescence responses were ROS‐dependent. LMWH, commonly used to treat aPL‐positive women at risk of obstetric complications, reduced the ability of aPL to increase EnSC decidualization and inflammation. Conclusion These findings shed new light on the pathogenesis of pregnancy complications in women with aPLs and underscore the benefit of heparin in preventing pregnancy loss in this high‐risk population.

Single-cell transcriptome analyses reveal disturbed decidual homoeostasis in obstetric antiphospholipid syndrome

“…We found a decreased proportion of STCs in OAPS decidua, indicating a relatively deficiency of STCs. Moreover, aPLs induce senescence and inflammation of endometrial STCs 41. Activated STCs would secrete many chemokines including CCL2/3/4/8 and IFN-γ, promoting chemotaxis and activation of inflammatory cells 41.…”

“…Moreover, aPLs induce senescence and inflammation of endometrial STCs 41. Activated STCs would secrete many chemokines including CCL2/3/4/8 and IFN-γ, promoting chemotaxis and activation of inflammatory cells 41. Lower SCARA5 and higher DIO2 in STCs indicated a prosenescent response 26.…”

The mTOR pathway in the antiphospholipid syndrome

“…To be noted that several other signaling pathways (e.g. NFκb, p38 MAPK) besides mTOR have also been reported to be involved in the pathogenesis of APS, as well as other systemic autoimmune diseases [ 16 ], [ 17 ], [ 18 ], which deserves more attention.…”

TLR8-Activating miR-146a-3p is an Intermediate Signal Contributing to Fetal Membrane Inflammation in Response to Bacterial LPS

“…Mouse FM expression of IL1B and KC was measured by RT-qPCR using the SuperScript II kit (Invitrogen; Waltham, MA) and the Kapa SYBR Fast qPCR kit (Sigma-Aldrich; St. Louis, MO) and normalized to GAPDH . Primer sequences have been previously reported (17, 25). RT-qPCR data was analyzed using the 2 −ΔΔCT method and reported as either fold change or relative abundance (RA).…”