1,25-Dihydroxyvitamin D3 protects against placental inflammation by suppressing NLRP3-mediated IL-1β production via Nrf2 signaling pathway in preeclampsia

Background: Maternal vitamin D deficiency is associated with an increased risk of preeclampsia, a potentially life-threatening multi-system disorder specific to human pregnancy. Placental trophoblast dysfunction is a key factor in the development of preeclampsia, and the activation of NOD-like Receptor protein 3 (NLRP3) inflammasome may play a crucial role in this process. Previous studies have suggested that vitamin D can exert beneficial effects by suppressing inflammasome activation, but the underlying mechanism has not been fully elucidated. This study aims to explore the protective effects of 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃] on the placenta and to investigate the mechanisms by which 1,25(OH)₂D₃ attenuates NLRP3 inflammasome activation in a rat model of preeclampsia and hypoxia-cultured placental trophoblast cells.

Results: Our findings demonstrated that supplementation of rats with 1,25(OH)₂D₃ mitigated placental inflammation and prevented multi-organ dysfunction associated with preeclampsia. Treatment with 1,25(OH)₂D₃ inhibited inflammasome-mediated inflammation in trophoblast cells via its receptor VDR by reducing the expression of NLRP3, Caspase-1, and apoptosis-associated speck-like protein containing a Caspase recruitment domain (ASC), decreasing IL-1β production, reducing mitochondrial Reactive Oxygen Species generation, and enhancing the expression and enzymatic activity of Cu/Zn-superoxide dismutase (SOD). Mechanistically, 1,25(OH)₂D₃ upregulated nuclear factor erythroid 2-related factor 2 (Nrf2) signaling, subsequently suppressing NLRP3-mediated IL-1β overproduction in trophoblast cells.

Conclusions: Our study indicates that 1,25(OH)₂D₃ inhibits NLRP3-mediated inflammation in trophoblast cells during preeclampsia by stimulating the Nrf2 signaling pathway and inhibiting oxidative stress.