NLRP3 inflammasome inhibition ameliorated placental ischemia‐induced hypertension

Abstract

Preeclampsia (PE), a pregnancy-specific syndrome characterized by de novo hypertension and vascular dysfunction, is widely accepted to be linked to placental ischemia-induced release of inflammatory cytokines and damage-associated molecular patterns. While placental damage and dysfunction caused by excessive inflammation can promote the occurrence of PE, the mechanisms whereby inflammation impacts placental ischemia-induced hypertension are not fully understood. Here we found that inflammation mediated by NLRP3 inflammasome occurs in the placenta predominantly from early onset PE, as evidenced by elevated levels of active caspase-1 and IL-1β(p<0.05). We further tested the hypothesis that inhibiting the activation of NLRP3 inflammasome can rescue the pregnancy outcome of PE. During pregnancy in rat, placental ischemia induced hypertension, proteinuria and excessive inflammatory cytokines production, whereas NLRP3 inflammasome inhibitor (MCC950, 10mg/kg/d) ameliorated the hypentension in RUPP model (117±2 vs. 101±1 mmHg, P<0.05), but exerts no beneficial effect on fetus (2.21±0.36 vs.2.09±0.49g) and placenta weights (0.40±0.06 vs.0.37±0.05g). Plasma levels of NLRP3 inflammasome associated cytokines, including IL-1β, were significantly elevated in RUPP rats compared to Sham rats, while inhibition of NLRP3 inflammasome activation attenuated the aberrant cytokines levels. Western blot also showed that MCC950 can inhibit the placental ischemia-induced expression levels of cleaved-CASP1 and mature IL-1β in the placenta. These findings suggest a promising role of NLRP3 in the development of PE and inhibiting NLRP3 inflammasome may provide a new target for the treatment of preeclampsia.