Neutrophil extracellular traps aggravate placental injury in OAPS by facilitating activation of BNIP3 mediated mitophagy.

Obstetric antiphospholipid syndrome (OAPS) is an autoimmune disease mediated by antiphospholipid antibodies (aPL), characterized by miscarriage, pre-mature birth caused by pre-eclampsia, intrauterine growth restriction, and other pregnancy complications. Neutrophil extracellular traps (NETs) consist of chromatin scaffolds coated with histones, proteases, granules, and cytosolic proteins. Here, we have observed increased levels of NETs in both human OAPS placental tissues and animal models, accompanied by apoptosis increases. In vitro, NETs induce a decrease in trophoblasts proliferation and an increase in apoptosis. In addition, NETs induce oxidative stress and mitochondrial reactive oxygen species (mtROS) production, upregulation of fission-associated mitochondrial proteins coupled with reduced fusion-associated protein levels. It also led to a rise in BNIP3 and autophagy-related protein expressions, along with an increase in autophagosomal numbers. Moreover, mtROS scavenging or knockdown strategies targeting BNIP3 effectively attenuated mitophagic activation alongside trophoblast apoptosis induction. Furthermore, upregulation of BNIP3 expression was evident in placentas from both APS murine models and human OAPS cases. These results suggest that aPL-induced NETs trigger BNIP3-mediated mitophagy, elevate ROS production, induce apoptosis in trophoblasts, and thereby exacerbate placental damage, with implications for our understanding of the pathogenesis of OAPS and devising novel treatment strategies.