2. Academic Validation
  3. 1,25-Dihydroxyvitamin D3 protects against placental inflammation by suppressing NLRP3-mediated IL-1β production via Nrf2 signaling pathway in preeclampsia

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

  • Metabolism. 2025 Jan:162:156058. doi: 10.1016/j.metabol.2024.156058.
Xueqing Liu 1,  Xinyu Zhang 1,  Linlin Ma 1,  Na Qiang 1,  Jiao Wang 1,  Yujia Huang 1,  Xiaolei Yuan 2,  Chunmei Lu 1,  Yang Cao 3,  Jie Xu 4
Affiliations

Affiliations

  • 1 Department of Physiology, Harbin Medical University, Harbin 150081, P.R. China.
  • 2 Department of Obstetrics and Gynecology, The Second Affiliated Hospital, Harbin Medical University, Harbin 150081, P.R. China.
  • 3 Department of Physiology, Harbin Medical University, Harbin 150081, P.R. China. Electronic address: cao_yang@hrbmu.edu.cn.
  • 4 Department of Physiology, Harbin Medical University, Harbin 150081, P.R. China. Electronic address: xujie@ems.hrbmu.edu.cn.
PMID: 39488297 DOI: 10.1016/j.metabol.2024.156058
Abstract

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.

Keywords

NLRP3 inflammasome; Nrf2 signaling pathway; Placenta; Preeclampsia; Vitamin D.

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