NETs exacerbate placental inflammation and injury through high mobility group protein B1 during preeclampsia

Inflammatory stress at the maternal-fetal interface plays an important role in the occurrence and development of preeclampsia(PE) caused by different etiologies. Many pathological neutrophil extracellular traps (NETs) at the maternal-fetal interface are believed to be among the main pathogenic factors leading to preeclampsia and the worsening of its symptoms. However, the underlying mechanism is largely unclear. This study aimed to elucidate the role of high mobility group box 1 (HMGB1) in NETs involved in the pathogenesis of PE.

The concentration of NETs was detected in the plasma of patients with PE using enzyme-linked immunosorbent assay (ELISA). Placental samples were collected from patients with PE to detect the expression of HMGB1 through Western Blot and PCR. For in vitro experiments, human trophoblast HTR-8/SVneo cells were treated with NETs, and their proliferation, invasion, migration, and apoptosis ability; degree of oxidative stress; and secretion of inflammatory factors were detected.

Compared with that in normal pregnant women, an increase in the release of NETs was observed in the peripheral blood of patients with PE. HMGB1 was increased in the placenta of PE patients and colocalized with NETs. The treatment of human trophoblast HTR-8/SVneo cells with NETs resulted in the inhibition of HTR-8/SVneo cell invasion and migration and increases in the release of reactive oxygen species (ROS), and several inflammatory factors (IL-1β, IL-6, IL-8, and TNF-α). These damaging effects can be reversed by the HMGB1 scavenger glycyrrhizin, which indicates that NETs can mediate trophoblast damage and the expression of several inflammatory factors through HMGB1.

NETs can cause trophoblast inflammation-related functional damage through HMGB1 during the occurrence and development of preeclampsia. HMGB1 produces a marked effect in the PE cascade of oxidative stress involving NETs. Inhibiting HMGB1 to suppress NETs damage is a possible approach for the future treatment of PE.